PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (1601143)

Clipboard (0)
None

Related Articles

1.  Single Nucleotide Variant rs2232710 in the Protein Z-Dependent Protease Inhibitor (ZPI, SERPINA10) Gene Is Not Associated with Deep Vein Thrombosis 
PLoS ONE  2016;11(3):e0151347.
Rare mutations in PROC, PROS1 or SERPINC1 as well as common variants in F5, F2, F11 and SERPINC1 have been identified as risk factors for deep vein thrombosis (DVT). To identify novel genetic risk factors for DVT, we have developed and applied next-generation DNA sequencing (NGS) of the coding area of hemostatic and proinflammatory genes. Using this strategy, we previously identified a single nucleotide variant (SNV) rs6050 in the FGA gene and novel, rare SNVs in the ADAMTS13 gene associated with DVT. To identify novel coding variants in the genetic predisposition to DVT, we applied NGS analysis of the coding area of 186 hemostatic and proinflammatory genes in 94 DVT cases and 98 controls and we identified 18 variants with putative role in DVT. A group of 585 Italian idiopathic DVT patients and 550 healthy controls was used to genotype all the 18 risk-associated variants identified by NGS. Replication study in the Italian population identified the rs2232710 variant in the protein Z-dependent protease inhibitor (ZPI) gene to be associated with an increased risk of DVT (OR 2.74; 95% CI 1.33–5.65; P = 0.0045; Bonferroni P = 0.081). However, the rs2232710 SNV showed no association with DVT in two Dutch replication cohorts the LETS study (454 patients and 451 controls) and the MEGA study (3799 patients and 4399 controls), indicating that the rs2232710 variant is not a risk factor for DVT.
doi:10.1371/journal.pone.0151347
PMCID: PMC4794167  PMID: 26982741
2.  Synergistic Effects of Hypofibrinolysis and Genetic and Acquired Risk Factors on the Risk of a First Venous Thrombosis 
PLoS Medicine  2008;5(5):e97.
Background
Previously, we demonstrated that hypofibrinolysis, a decreased capacity to dissolve a blood clot as measured with an overall clot lysis assay, increases the risk of venous thrombosis. Here, we investigated the combined effect of hypofibrinolysis with established risk factors associated with hypercoagulability.
Methods and Findings
Fibrinolytic potential was determined with a plasma-based clot lysis assay in 2,090 patients with venous thrombosis and 2,564 control participants between 18 and 70 y of age enrolled in the Multiple Environmental and Genetic Assessment (MEGA) of risk factors for venous thrombosis study, a population-based case-control study on venous thrombosis. Participants completed a standardized questionnaire on acquired risk factors.
Hypofibrinolysis alone, i.e., clot lysis time (CLT) in the fourth quartile (longest CLT) (in absence of the other risk factor of interest) increased thrombosis risk about 2-fold relative to individuals with CLT in the first quartile (shortest CLT). Oral contraceptive use in women with CLT in the first quartile gave an odds ratio (OR) of 2.6 (95% confidence interval [CI] 1.6 to 4.0), while women with hypofibrinolysis who used oral contraceptives had an over 20-fold increased risk of venous thrombosis (OR 21.8, 95% CI 10.2 to 46.7). For immobilization alone the OR was 4.3 (95% CI 3.2 to 5.8) and immobilization with hypofibrinolysis increased the risk 10.3-fold (95% CI 7.7 to 13.8). Factor V Leiden alone increased the risk 3.5-fold (95% CI 2.3 to 5.5), and hypofibrinolysis in factor V Leiden carriers gave an OR of 8.1 (95% CI 5.3 to 12.3). The combination of hypofibrinolysis and the prothrombin 20210A mutation did not synergistically increase the risk. All ORs and 95% CIs presented are relative to individuals with CLT in the first quartile and without the other risk factor of interest.
Conclusions
The combination of hypofibrinolysis with oral contraceptive use, immobilization, or factor V Leiden results in a risk of venous thrombosis that exceeds the sum of the individual risks.
Frits Rosendaal and colleagues show that the combination of hypofibrinolysis with oral contraceptive use, immobilization, or factor V Leiden results in a risk of venous thrombosis that exceeds the sum of the individual risks.
Editors' Summary
Background.
When a blood vessel is injured, proteins in the blood called clotting factors “coagulate” (solidify) the blood at the injury site. The resultant clot (thrombus) plugs the wound and prevents blood loss. When the injury has healed, other proteins dissolve the clot, a process called “fibrinolysis.” Sometimes, however, a thrombus develops inside an undamaged blood vessel and partly or completely blocks the blood flow. A clot that occurs in one of the veins (vessels that take the blood to the heart) deep within the body (usually in the leg) is a deep vein thrombosis (DVT). Some DVTs have no symptoms; others cause pain, swelling, and tenderness in one leg. They are usually treated with heparin and warfarin, anticoagulant drugs that stop the clot growing. If left untreated, part of the clot (an embolus) can break off and travel to the lungs, where it can cause a life-threatening condition called a pulmonary embolism (PE).
Why Was This Study Done?
Most people are very unlikely to develop venous thrombosis (the collective term for DVT and PE), but anything that makes blood “hypercoagulable” (prone to clotting) increases this risk. Genetic risk factors can be inherited changes in blood clotting proteins (for example, a mutation in a gene coding for one protein, factor V, which is involved in clotting, is known as factor V Leiden—Leiden, The Netherlands, was where it was first described). There are also acquired risk factors such as taking oral contraceptives or being immobilized (for example, during bed rest). These risk factors often act in such a way that the risk of developing venous thrombosis for a person with multiple risk factors is greater than the sum of the individual risks. Another recently identified but little studied risk factor for venous thrombosis is “hypofibrinolysis,” a decreased capacity to dissolve blood clots. In this study (part of the “MEGA” study on risk factors for venous thrombosis), the researchers investigate the combined effect of hypofibrinolysis and established risk factors associated with hypercoagulability on the risk of developing venous thrombosis.
What Did the Researchers Do and Find?
The researchers collected blood from more than 2,000 individuals after their first DVT or PE and from a similar number of persons without venous thrombosis (controls). For each blood sample, they measured the time it took to dissolve a clot generated from that blood in a test tube (the clot lysis time or CLT) and determined which participants had the factor V Leiden mutation or a genetic change in the clotting factor prothrombin that also increases blood coagulability. The study participants also completed a questionnaire about acquired risk factors for venous thrombosis. The researchers divided the participants into four equal-sized groups (quartiles) based on their CLT and used the quartile with the lowest CLT as the reference group for their statistical analyses; hypofibrinolysis was defined as a CLT in the highest quartile (the longest times). Participants with hypofibrinolysis alone were twice as likely to develop venous thrombosis as those with a CLT in the lowest quartile (the shortest times). Oral contraceptive use alone increased the risk of venous thrombosis 2.5-fold, whereas the combination of oral contraceptive use and hypofibrinolysis increased the risk 20-fold. The researchers also found synergistic effects on thrombosis risk for hypofibrinolysis combined with immobilization or with the factor V Leiden mutation but not with the prothrombin mutation.
What Do These Findings Mean?
These findings confirm that persons with hypofibrinolysis and hence longer CLTs have a greater risk of developing venous thrombosis than those with short CLTs. Because CLTs were measured after venous thrombosis had occurred, hypofibrinolysis could be an effect rather than a cause of this condition. However, this is unlikely because there was no association between how long after the venous thrombosis the blood sample was taken and the measured CLT. These findings also show that the combination of hypofibrinolysis with immobilization, the factor V Leiden mutation, and oral contraceptive use greatly increases the risk of venous thrombosis. This new information about the risk factors for venous thrombosis should help physicians to advise patients about reducing their chances of developing this life-threatening condition.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050097.
The MedlinePlus encyclopedia has pages on blood clots, deep vein thrombosis, and pulmonary embolism (in English and Spanish)
The US National Heart Lung and Blood Institute provides information on deep vein thrombosis, including an animation about how DVT causes pulmonary embolisms
The UK National Health Service Direct health encyclopedia provides information for patients on deep vein thrombosis (in several languages)
More information about the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) study is available on the Leiden University Medical Center Web site
Wikipedia has pages on coagulation and on fibrinolysis (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.0050097
PMCID: PMC2365975  PMID: 18462012
3.  Next-Generation Sequencing and In Vitro Expression Study of ADAMTS13 Single Nucleotide Variants in Deep Vein Thrombosis 
PLoS ONE  2016;11(11):e0165665.
Background
Deep vein thrombosis (DVT) genetic predisposition is partially known.
Objectives
This study aimed at assessing the functional impact of nine ADAMTS13 single nucleotide variants (SNVs) previously reported to be associated as a group with DVT in a burden test and the individual association of selected variants with DVT risk in two replication studies.
Methods
Wild-type and mutant recombinant ADAMTS13 were transiently expressed in HEK293 cells. Antigen and activity of recombinant ADAMTS13 were measured by ELISA and FRETS-VWF73 assays, respectively. The replication studies were performed in an Italian case-control study (Milan study; 298/298 patients/controls) using a next-generation sequencing approach and in a Dutch case-control study (MEGA study; 4306/4887 patients/controls) by TaqMan assays.
Results
In vitro results showed reduced ADAMTS13 activity for three SNVs (p.Val154Ile [15%; 95% confidence interval [CI] 14–16], p.Asp187His [19%; 95%[CI] 17–21], p.Arg421Cys [24%; 95%[CI] 22–26]) similar to reduced plasma ADAMTS13 levels of patients carriers for these SNVs. Therefore these three SNVs were interrogated for risk association. The first replication study identified 3 heterozygous carriers (2 cases, 1 control) of p.Arg421Cys (odds ratio [OR] 2, 95%[CI] 0.18–22.25). The second replication study identified 2 heterozygous carriers (1 case, 1 control) of p.Asp187His ([OR] 1.14, 95%[CI] 0.07–18.15) and 10 heterozygous carriers (4 cases, 6 controls) of p.Arg421Cys ([OR] 0.76, 95%[CI] 0.21–2.68).
Conclusions
Three SNVs (p.Val154Ile, p.Asp187His and p.Arg421Cys) showed reduced ex vivo and in vitro ADAMTS13 levels. However, the low frequency of these variants makes it difficult to confirm their association with DVT.
doi:10.1371/journal.pone.0165665
PMCID: PMC5089687  PMID: 27802307
4.  Human genome meeting 2016 
Srivastava, A. K. | Wang, Y. | Huang, R. | Skinner, C. | Thompson, T. | Pollard, L. | Wood, T. | Luo, F. | Stevenson, R. | Polimanti, R. | Gelernter, J. | Lin, X. | Lim, I. Y. | Wu, Y. | Teh, A. L. | Chen, L. | Aris, I. M. | Soh, S. E. | Tint, M. T. | MacIsaac, J. L. | Yap, F. | Kwek, K. | Saw, S. M. | Kobor, M. S. | Meaney, M. J. | Godfrey, K. M. | Chong, Y. S. | Holbrook, J. D. | Lee, Y. S. | Gluckman, P. D. | Karnani, N. | Kapoor, A. | Lee, D. | Chakravarti, A. | Maercker, C. | Graf, F. | Boutros, M. | Stamoulis, G. | Santoni, F. | Makrythanasis, P. | Letourneau, A. | Guipponi, M. | Panousis, N. | Garieri, M. | Ribaux, P. | Falconnet, E. | Borel, C. | Antonarakis, S. E. | Kumar, S. | Curran, J. | Blangero, J. | Chatterjee, S. | Kapoor, A. | Akiyama, J. | Auer, D. | Berrios, C. | Pennacchio, L. | Chakravarti, A. | Donti, T. R. | Cappuccio, G. | Miller, M. | Atwal, P. | Kennedy, A. | Cardon, A. | Bacino, C. | Emrick, L. | Hertecant, J. | Baumer, F. | Porter, B. | Bainbridge, M. | Bonnen, P. | Graham, B. | Sutton, R. | Sun, Q. | Elsea, S. | Hu, Z. | Wang, P. | Zhu, Y. | Zhao, J. | Xiong, M. | Bennett, David A. | Hidalgo-Miranda, A. | Romero-Cordoba, S. | Rodriguez-Cuevas, S. | Rebollar-Vega, R. | Tagliabue, E. | Iorio, M. | D’Ippolito, E. | Baroni, S. | Kaczkowski, B. | Tanaka, Y. | Kawaji, H. | Sandelin, A. | Andersson, R. | Itoh, M. | Lassmann, T. | Hayashizaki, Y. | Carninci, P. | Forrest, A. R. R. | Semple, C. A. | Rosenthal, E. A. | Shirts, B. | Amendola, L. | Gallego, C. | Horike-Pyne, M. | Burt, A. | Robertson, P. | Beyers, P. | Nefcy, C. | Veenstra, D. | Hisama, F. | Bennett, R. | Dorschner, M. | Nickerson, D. | Smith, J. | Patterson, K. | Crosslin, D. | Nassir, R. | Zubair, N. | Harrison, T. | Peters, U. | Jarvik, G. | Menghi, F. | Inaki, K. | Woo, X. | Kumar, P. | Grzeda, K. | Malhotra, A. | Kim, H. | Ucar, D. | Shreckengast, P. | Karuturi, K. | Keck, J. | Chuang, J. | Liu, E. T. | Ji, B. | Tyler, A. | Ananda, G. | Carter, G. | Nikbakht, H. | Montagne, M. | Zeinieh, M. | Harutyunyan, A. | Mcconechy, M. | Jabado, N. | Lavigne, P. | Majewski, J. | Goldstein, J. B. | Overman, M. | Varadhachary, G. | Shroff, R. | Wolff, R. | Javle, M. | Futreal, A. | Fogelman, D. | Bravo, L. | Fajardo, W. | Gomez, H. | Castaneda, C. | Rolfo, C. | Pinto, J. A. | Akdemir, K. C. | Chin, L. | Futreal, A. | Patterson, S. | Statz, C. | Mockus, S. | Nikolaev, S. N. | Bonilla, X. I. | Parmentier, L. | King, B. | Bezrukov, F. | Kaya, G. | Zoete, V. | Seplyarskiy, V. | Sharpe, H. | McKee, T. | Letourneau, A. | Ribaux, P. | Popadin, K. | Basset-Seguin, N. | Chaabene, R. Ben | Santoni, F. | Andrianova, M. | Guipponi, M. | Garieri, M. | Verdan, C. | Grosdemange, K. | Sumara, O. | Eilers, M. | Aifantis, I. | Michielin, O. | de Sauvage, F. | Antonarakis, S. | Likhitrattanapisal, S. | Lincoln, S. | Kurian, A. | Desmond, A. | Yang, S. | Kobayashi, Y. | Ford, J. | Ellisen, L. | Peters, T. L. | Alvarez, K. R. | Hollingsworth, E. F. | Lopez-Terrada, D. H. | Hastie, A. | Dzakula, Z. | Pang, A. W. | Lam, E. T. | Anantharaman, T. | Saghbini, M. | Cao, H. | Gonzaga-Jauregui, C. | Ma, L. | King, A. | Rosenzweig, E. Berman | Krishnan, U. | Reid, J. G. | Overton, J. D. | Dewey, F. | Chung, W. K. | Small, K. | DeLuca, A. | Cremers, F. | Lewis, R. A. | Puech, V. | Bakall, B. | Silva-Garcia, R. | Rohrschneider, K. | Leys, M. | Shaya, F. S. | Stone, E. | Sobreira, N. L. | Schiettecatte, F. | Ling, H. | Pugh, E. | Witmer, D. | Hetrick, K. | Zhang, P. | Doheny, K. | Valle, D. | Hamosh, A. | Jhangiani, S. N. | Akdemir, Z. Coban | Bainbridge, M. N. | Charng, W. | Wiszniewski, W. | Gambin, T. | Karaca, E. | Bayram, Y. | Eldomery, M. K. | Posey, J. | Doddapaneni, H. | Hu, J. | Sutton, V. R. | Muzny, D. M. | Boerwinkle, E. A. | Valle, D. | Lupski, J. R. | Gibbs, R. A. | Shekar, S. | Salerno, W. | English, A. | Mangubat, A. | Bruestle, J. | Thorogood, A. | Knoppers, B. M. | Takahashi, H. | Nitta, K. R. | Kozhuharova, A. | Suzuki, A. M. | Sharma, H. | Cotella, D. | Santoro, C. | Zucchelli, S. | Gustincich, S. | Carninci, P. | Mulvihill, J. J. | Baynam, G. | Gahl, W. | Groft, S. C. | Kosaki, K. | Lasko, P. | Melegh, B. | Taruscio, D. | Ghosh, R. | Plon, S. | Scherer, S. | Qin, X. | Sanghvi, R. | Walker, K. | Chiang, T. | Muzny, D. | Wang, L. | Black, J. | Boerwinkle, E. | Weinshilboum, R. | Gibbs, R. | Karpinets, T. | Calderone, T. | Wani, K. | Yu, X. | Creasy, C. | Haymaker, C. | Forget, M. | Nanda, V. | Roszik, J. | Wargo, J. | Haydu, L. | Song, X. | Lazar, A. | Gershenwald, J. | Davies, M. | Bernatchez, C. | Zhang, J. | Futreal, A. | Woodman, S. | Chesler, E. J. | Reynolds, T. | Bubier, J. A. | Phillips, C. | Langston, M. A. | Baker, E. J. | Xiong, M. | Ma, L. | Lin, N. | Amos, C. | Lin, N. | Wang, P. | Zhu, Y. | Zhao, J. | Calhoun, V. | Xiong, M. | Dobretsberger, O. | Egger, M. | Leimgruber, F. | Sadedin, S. | Oshlack, A. | Antonio, V. A. A. | Ono, N. | Ahmed, Z. | Bolisetty, M. | Zeeshan, S. | Anguiano, E. | Ucar, D. | Sarkar, A. | Nandineni, M. R. | Zeng, C. | Shao, J. | Cao, H. | Hastie, A. | Pang, A. W. | Lam, E. T. | Liang, T. | Pham, K. | Saghbini, M. | Dzakula, Z. | Chee-Wei, Y. | Dongsheng, L. | Lai-Ping, W. | Lian, D. | Hee, R. O. Twee | Yunus, Y. | Aghakhanian, F. | Mokhtar, S. S. | Lok-Yung, C. V. | Bhak, J. | Phipps, M. | Shuhua, X. | Yik-Ying, T. | Kumar, V. | Boon-Peng, H. | Campbell, I. | Young, M. -A. | James, P. | Rain, M. | Mohammad, G. | Kukreti, R. | Pasha, Q. | Akilzhanova, A. R. | Guelly, C. | Abilova, Z. | Rakhimova, S. | Akhmetova, A. | Kairov, U. | Trajanoski, S. | Zhumadilov, Z. | Bekbossynova, M. | Schumacher, C. | Sandhu, S. | Harkins, T. | Makarov, V. | Doddapaneni, H. | Glenn, R. | Momin, Z. | Dilrukshi, B. | Chao, H. | Meng, Q. | Gudenkauf, B. | Kshitij, R. | Jayaseelan, J. | Nessner, C. | Lee, S. | Blankenberg, K. | Lewis, L. | Hu, J. | Han, Y. | Dinh, H. | Jireh, S. | Walker, K. | Boerwinkle, E. | Muzny, D. | Gibbs, R. | Hu, J. | Walker, K. | Buhay, C. | Liu, X. | Wang, Q. | Sanghvi, R. | Doddapaneni, H. | Ding, Y. | Veeraraghavan, N. | Yang, Y. | Boerwinkle, E. | Beaudet, A. L. | Eng, C. M. | Muzny, D. M. | Gibbs, R. A. | Worley, K. C. C. | Liu, Y. | Hughes, D. S. T. | Murali, S. C. | Harris, R. A. | English, A. C. | Qin, X. | Hampton, O. A. | Larsen, P. | Beck, C. | Han, Y. | Wang, M. | Doddapaneni, H. | Kovar, C. L. | Salerno, W. J. | Yoder, A. | Richards, S. | Rogers, J. | Lupski, J. R. | Muzny, D. M. | Gibbs, R. A. | Meng, Q. | Bainbridge, M. | Wang, M. | Doddapaneni, H. | Han, Y. | Muzny, D. | Gibbs, R. | Harris, R. A. | Raveenedran, M. | Xue, C. | Dahdouli, M. | Cox, L. | Fan, G. | Ferguson, B. | Hovarth, J. | Johnson, Z. | Kanthaswamy, S. | Kubisch, M. | Platt, M. | Smith, D. | Vallender, E. | Wiseman, R. | Liu, X. | Below, J. | Muzny, D. | Gibbs, R. | Yu, F. | Rogers, J. | Lin, J. | Zhang, Y. | Ouyang, Z. | Moore, A. | Wang, Z. | Hofmann, J. | Purdue, M. | Stolzenberg-Solomon, R. | Weinstein, S. | Albanes, D. | Liu, C. S. | Cheng, W. L. | Lin, T. T. | Lan, Q. | Rothman, N. | Berndt, S. | Chen, E. S. | Bahrami, H. | Khoshzaban, A. | Keshal, S. Heidari | Bahrami, H. | Khoshzaban, A. | Keshal, S. Heidari | Alharbi, K. K. R. | Zhalbinova, M. | Akilzhanova, A. | Rakhimova, S. | Bekbosynova, M. | Myrzakhmetova, S. | Matar, M. | Mili, N. | Molinari, R. | Ma, Y. | Guerrier, S. | Elhawary, N. | Tayeb, M. | Bogari, N. | Qotb, N. | McClymont, S. A. | Hook, P. W. | Goff, L. A. | McCallion, A. | Kong, Y. | Charette, J. R. | Hicks, W. L. | Naggert, J. K. | Zhao, L. | Nishina, P. M. | Edrees, B. M. | Athar, M. | Al-Allaf, F. A. | Taher, M. M. | Khan, W. | Bouazzaoui, A. | Harbi, N. A. | Safar, R. | Al-Edressi, H. | Anazi, A. | Altayeb, N. | Ahmed, M. A. | Alansary, K. | Abduljaleel, Z. | Kratz, A. | Beguin, P. | Poulain, S. | Kaneko, M. | Takahiko, C. | Matsunaga, A. | Kato, S. | Suzuki, A. M. | Bertin, N. | Lassmann, T. | Vigot, R. | Carninci, P. | Plessy, C. | Launey, T. | Graur, D. | Lee, D. | Kapoor, A. | Chakravarti, A. | Friis-Nielsen, J. | Izarzugaza, J. M. | Brunak, S. | Chakraborty, A. | Basak, J. | Mukhopadhyay, A. | Soibam, B. S. | Das, D. | Biswas, N. | Das, S. | Sarkar, S. | Maitra, A. | Panda, C. | Majumder, P. | Morsy, H. | Gaballah, A. | Samir, M. | Shamseya, M. | Mahrous, H. | Ghazal, A. | Arafat, W. | Hashish, M. | Gruber, J. J. | Jaeger, N. | Snyder, M. | Patel, K. | Bowman, S. | Davis, T. | Kraushaar, D. | Emerman, A. | Russello, S. | Henig, N. | Hendrickson, C. | Zhang, K. | Rodriguez-Dorantes, M. | Cruz-Hernandez, C. D. | Garcia-Tobilla, C. D. P. | Solorzano-Rosales, S. | Jäger, N. | Chen, J. | Haile, R. | Hitchins, M. | Brooks, J. D. | Snyder, M. | Jiménez-Morales, S. | Ramírez, M. | Nuñez, J. | Bekker, V. | Leal, Y. | Jiménez, E. | Medina, A. | Hidalgo, A. | Mejía, J. | Halytskiy, V. | Naggert, J. | Collin, G. B. | DeMauro, K. | Hanusek, R. | Nishina, P. M. | Belhassa, K. | Belhassan, K. | Bouguenouch, L. | Samri, I. | Sayel, H. | moufid, FZ. | El Bouchikhi, I. | Trhanint, S. | Hamdaoui, H. | Elotmani, I. | Khtiri, I. | Kettani, O. | Quibibo, L. | Ahagoud, M. | Abbassi, M. | Ouldim, K. | Marusin, A. V. | Kornetov, A. N. | Swarovskaya, M. | Vagaiceva, K. | Stepanov, V. | De La Paz, E. M. Cutiongco | Sy, R. | Nevado, J. | Reganit, P. | Santos, L. | Magno, J. D. | Punzalan, F. E. | Ona, D. | Llanes, E. | Santos-Cortes, R. L. | Tiongco, R. | Aherrera, J. | Abrahan, L. | Pagauitan-Alan, P. | Morelli, K. H. | Domire, J. S. | Pyne, N. | Harper, S. | Burgess, R. | Zhalbinova, M. | Akilzhanova, A. | Rakhimova, S. | Bekbosynova, M. | Myrzakhmetova, S. | Gari, M. A. | Dallol, A. | Alsehli, H. | Gari, A. | Gari, M. | Abuzenadah, A. | Thomas, M. | Sukhai, M. | Garg, S. | Misyura, M. | Zhang, T. | Schuh, A. | Stockley, T. | Kamel-Reid, S. | Sherry, S. | Xiao, C. | Slotta, D. | Rodarmer, K. | Feolo, M. | Kimelman, M. | Godynskiy, G. | O’Sullivan, C. | Yaschenko, E. | Xiao, C. | Yaschenko, E. | Sherry, S. | Rangel-Escareño, C. | Rueda-Zarate, H. | Tayubi, I. A. | Mohammed, R. | Ahmed, I. | Ahmed, T. | Seth, S. | Amin, S. | Song, X. | Mao, X. | Sun, H. | Verhaak, R. G. | Futreal, A. | Zhang, J. | Whiite, S. J. | Chiang, T. | English, A. | Farek, J. | Kahn, Z. | Salerno, W. | Veeraraghavan, N. | Boerwinkle, E. | Gibbs, R. | Kasukawa, T. | Lizio, M. | Harshbarger, J. | Hisashi, S. | Severin, J. | Imad, A. | Sahin, S. | Freeman, T. C. | Baillie, K. | Sandelin, A. | Carninci, P. | Forrest, A. R. R. | Kawaji, H. | Salerno, W. | English, A. | Shekar, S. N. | Mangubat, A. | Bruestle, J. | Boerwinkle, E. | Gibbs, R. A. | Salem, A. H. | Ali, M. | Ibrahim, A. | Ibrahim, M. | Barrera, H. A. | Garza, L. | Torres, J. A. | Barajas, V. | Ulloa-Aguirre, A. | Kershenobich, D. | Mortaji, Shahroj | Guizar, Pedro | Loera, Eliezer | Moreno, Karen | De León, Adriana | Monsiváis, Daniela | Gómez, Jackeline | Cardiel, Raquel | Fernandez-Lopez, J. C. | Bonifaz-Peña, V. | Rangel-Escareño, C. | Hidalgo-Miranda, A. | Contreras, A. V. | Polfus, L. | Wang, X. | Philip, V. | Carter, G. | Abuzenadah, A. A. | Gari, M. | Turki, R. | Dallol, A. | Uyar, A. | Kaygun, A. | Zaman, S. | Marquez, E. | George, J. | Ucar, D. | Hendrickson, C. L. | Emerman, A. | Kraushaar, D. | Bowman, S. | Henig, N. | Davis, T. | Russello, S. | Patel, K. | Starr, D. B. | Baird, M. | Kirkpatrick, B. | Sheets, K. | Nitsche, R. | Prieto-Lafuente, L. | Landrum, M. | Lee, J. | Rubinstein, W. | Maglott, D. | Thavanati, P. K. R. | de Dios, A. Escoto | Hernandez, R. E. Navarro | Aldrate, M. E. Aguilar | Mejia, M. R. Ruiz | Kanala, K. R. R. | Abduljaleel, Z. | Khan, W. | Al-Allaf, F. A. | Athar, M. | Taher, M. M. | Shahzad, N. | Bouazzaoui, A. | Huber, E. | Dan, A. | Al-Allaf, F. A. | Herr, W. | Sprotte, G. | Köstler, J. | Hiergeist, A. | Gessner, A. | Andreesen, R. | Holler, E. | Al-Allaf, F. | Alashwal, A. | Abduljaleel, Z. | Taher, M. | Bouazzaoui, A. | Abalkhail, H. | Al-Allaf, A. | Bamardadh, R. | Athar, M. | Filiptsova, O. | Kobets, M. | Kobets, Y. | Burlaka, I. | Timoshyna, I. | Filiptsova, O. | Kobets, M. N. | Kobets, Y. | Burlaka, I. | Timoshyna, I. | Filiptsova, O. | Kobets, M. N. | Kobets, Y. | Burlaka, I. | Timoshyna, I. | Al-allaf, F. A. | Mohiuddin, M. T. | Zainularifeen, A. | Mohammed, A. | Abalkhail, H. | Owaidah, T. | Bouazzaoui, A.
Human Genomics  2016;10(Suppl 1):12.
Table of contents
O1 The metabolomics approach to autism: identification of biomarkers for early detection of autism spectrum disorder
A. K. Srivastava, Y. Wang, R. Huang, C. Skinner, T. Thompson, L. Pollard, T. Wood, F. Luo, R. Stevenson
O2 Phenome-wide association study for smoking- and drinking-associated genes in 26,394 American women with African, Asian, European, and Hispanic descents
R. Polimanti, J. Gelernter
O3 Effects of prenatal environment, genotype and DNA methylation on birth weight and subsequent postnatal outcomes: findings from GUSTO, an Asian birth cohort
X. Lin, I. Y. Lim, Y. Wu, A. L. Teh, L. Chen, I. M. Aris, S. E. Soh, M. T. Tint, J. L. MacIsaac, F. Yap, K. Kwek, S. M. Saw, M. S. Kobor, M. J. Meaney, K. M. Godfrey, Y. S. Chong, J. D. Holbrook, Y. S. Lee, P. D. Gluckman, N. Karnani, GUSTO study group
O4 High-throughput identification of specific qt interval modulating enhancers at the SCN5A locus
A. Kapoor, D. Lee, A. Chakravarti
O5 Identification of extracellular matrix components inducing cancer cell migration in the supernatant of cultivated mesenchymal stem cells
C. Maercker, F. Graf, M. Boutros
O6 Single cell allele specific expression (ASE) IN T21 and common trisomies: a novel approach to understand DOWN syndrome and other aneuploidies
G. Stamoulis, F. Santoni, P. Makrythanasis, A. Letourneau, M. Guipponi, N. Panousis, M. Garieri, P. Ribaux, E. Falconnet, C. Borel, S. E. Antonarakis
O7 Role of microRNA in LCL to IPSC reprogramming
S. Kumar, J. Curran, J. Blangero
O8 Multiple enhancer variants disrupt gene regulatory network in Hirschsprung disease
S. Chatterjee, A. Kapoor, J. Akiyama, D. Auer, C. Berrios, L. Pennacchio, A. Chakravarti
O9 Metabolomic profiling for the diagnosis of neurometabolic disorders
T. R. Donti, G. Cappuccio, M. Miller, P. Atwal, A. Kennedy, A. Cardon, C. Bacino, L. Emrick, J. Hertecant, F. Baumer, B. Porter, M. Bainbridge, P. Bonnen, B. Graham, R. Sutton, Q. Sun, S. Elsea
O10 A novel causal methylation network approach to Alzheimer’s disease
Z. Hu, P. Wang, Y. Zhu, J. Zhao, M. Xiong, David A Bennett
O11 A microRNA signature identifies subtypes of triple-negative breast cancer and reveals MIR-342-3P as regulator of a lactate metabolic pathway
A. Hidalgo-Miranda, S. Romero-Cordoba, S. Rodriguez-Cuevas, R. Rebollar-Vega, E. Tagliabue, M. Iorio, E. D’Ippolito, S. Baroni
O12 Transcriptome analysis identifies genes, enhancer RNAs and repetitive elements that are recurrently deregulated across multiple cancer types
B. Kaczkowski, Y. Tanaka, H. Kawaji, A. Sandelin, R. Andersson, M. Itoh, T. Lassmann, the FANTOM5 consortium, Y. Hayashizaki, P. Carninci, A. R. R. Forrest
O13 Elevated mutation and widespread loss of constraint at regulatory and architectural binding sites across 11 tumour types
C. A. Semple
O14 Exome sequencing provides evidence of pathogenicity for genes implicated in colorectal cancer
E. A. Rosenthal, B. Shirts, L. Amendola, C. Gallego, M. Horike-Pyne, A. Burt, P. Robertson, P. Beyers, C. Nefcy, D. Veenstra, F. Hisama, R. Bennett, M. Dorschner, D. Nickerson, J. Smith, K. Patterson, D. Crosslin, R. Nassir, N. Zubair, T. Harrison, U. Peters, G. Jarvik, NHLBI GO Exome Sequencing Project
O15 The tandem duplicator phenotype as a distinct genomic configuration in cancer
F. Menghi, K. Inaki, X. Woo, P. Kumar, K. Grzeda, A. Malhotra, H. Kim, D. Ucar, P. Shreckengast, K. Karuturi, J. Keck, J. Chuang, E. T. Liu
O16 Modeling genetic interactions associated with molecular subtypes of breast cancer
B. Ji, A. Tyler, G. Ananda, G. Carter
O17 Recurrent somatic mutation in the MYC associated factor X in brain tumors
H. Nikbakht, M. Montagne, M. Zeinieh, A. Harutyunyan, M. Mcconechy, N. Jabado, P. Lavigne, J. Majewski
O18 Predictive biomarkers to metastatic pancreatic cancer treatment
J. B. Goldstein, M. Overman, G. Varadhachary, R. Shroff, R. Wolff, M. Javle, A. Futreal, D. Fogelman
O19 DDIT4 gene expression as a prognostic marker in several malignant tumors
L. Bravo, W. Fajardo, H. Gomez, C. Castaneda, C. Rolfo, J. A. Pinto
O20 Spatial organization of the genome and genomic alterations in human cancers
K. C. Akdemir, L. Chin, A. Futreal, ICGC PCAWG Structural Alterations Group
O21 Landscape of targeted therapies in solid tumors
S. Patterson, C. Statz, S. Mockus
O22 Genomic analysis reveals novel drivers and progression pathways in skin basal cell carcinoma
S. N. Nikolaev, X. I. Bonilla, L. Parmentier, B. King, F. Bezrukov, G. Kaya, V. Zoete, V. Seplyarskiy, H. Sharpe, T. McKee, A. Letourneau, P. Ribaux, K. Popadin, N. Basset-Seguin, R. Ben Chaabene, F. Santoni, M. Andrianova, M. Guipponi, M. Garieri, C. Verdan, K. Grosdemange, O. Sumara, M. Eilers, I. Aifantis, O. Michielin, F. de Sauvage, S. Antonarakis
O23 Identification of differential biomarkers of hepatocellular carcinoma and cholangiocarcinoma via transcriptome microarray meta-analysis
S. Likhitrattanapisal
O24 Clinical validity and actionability of multigene tests for hereditary cancers in a large multi-center study
S. Lincoln, A. Kurian, A. Desmond, S. Yang, Y. Kobayashi, J. Ford, L. Ellisen
O25 Correlation with tumor ploidy status is essential for correct determination of genome-wide copy number changes by SNP array
T. L. Peters, K. R. Alvarez, E. F. Hollingsworth, D. H. Lopez-Terrada
O26 Nanochannel based next-generation mapping for interrogation of clinically relevant structural variation
A. Hastie, Z. Dzakula, A. W. Pang, E. T. Lam, T. Anantharaman, M. Saghbini, H. Cao, BioNano Genomics
O27 Mutation spectrum in a pulmonary arterial hypertension (PAH) cohort and identification of associated truncating mutations in TBX4
C. Gonzaga-Jauregui, L. Ma, A. King, E. Berman Rosenzweig, U. Krishnan, J. G. Reid, J. D. Overton, F. Dewey, W. K. Chung
O28 NORTH CAROLINA macular dystrophy (MCDR1): mutations found affecting PRDM13
K. Small, A. DeLuca, F. Cremers, R. A. Lewis, V. Puech, B. Bakall, R. Silva-Garcia, K. Rohrschneider, M. Leys, F. S. Shaya, E. Stone
O29 PhenoDB and genematcher, solving unsolved whole exome sequencing data
N. L. Sobreira, F. Schiettecatte, H. Ling, E. Pugh, D. Witmer, K. Hetrick, P. Zhang, K. Doheny, D. Valle, A. Hamosh
O30 Baylor-Johns Hopkins Center for Mendelian genomics: a four year review
S. N. Jhangiani, Z. Coban Akdemir, M. N. Bainbridge, W. Charng, W. Wiszniewski, T. Gambin, E. Karaca, Y. Bayram, M. K. Eldomery, J. Posey, H. Doddapaneni, J. Hu, V. R. Sutton, D. M. Muzny, E. A. Boerwinkle, D. Valle, J. R. Lupski, R. A. Gibbs
O31 Using read overlap assembly to accurately identify structural genetic differences in an ashkenazi jewish trio
S. Shekar, W. Salerno, A. English, A. Mangubat, J. Bruestle
O32 Legal interoperability: a sine qua non for international data sharing
A. Thorogood, B. M. Knoppers, Global Alliance for Genomics and Health - Regulatory and Ethics Working Group
O33 High throughput screening platform of competent sineups: that can enhance translation activities of therapeutic target
H. Takahashi, K. R. Nitta, A. Kozhuharova, A. M. Suzuki, H. Sharma, D. Cotella, C. Santoro, S. Zucchelli, S. Gustincich, P. Carninci
O34 The undiagnosed diseases network international (UDNI): clinical and laboratory research to meet patient needs
J. J. Mulvihill, G. Baynam, W. Gahl, S. C. Groft, K. Kosaki, P. Lasko, B. Melegh, D. Taruscio
O36 Performance of computational algorithms in pathogenicity predictions for activating variants in oncogenes versus loss of function mutations in tumor suppressor genes
R. Ghosh, S. Plon
O37 Identification and electronic health record incorporation of clinically actionable pharmacogenomic variants using prospective targeted sequencing
S. Scherer, X. Qin, R. Sanghvi, K. Walker, T. Chiang, D. Muzny, L. Wang, J. Black, E. Boerwinkle, R. Weinshilboum, R. Gibbs
O38 Melanoma reprogramming state correlates with response to CTLA-4 blockade in metastatic melanoma
T. Karpinets, T. Calderone, K. Wani, X. Yu, C. Creasy, C. Haymaker, M. Forget, V. Nanda, J. Roszik, J. Wargo, L. Haydu, X. Song, A. Lazar, J. Gershenwald, M. Davies, C. Bernatchez, J. Zhang, A. Futreal, S. Woodman
O39 Data-driven refinement of complex disease classification from integration of heterogeneous functional genomics data in GeneWeaver
E. J. Chesler, T. Reynolds, J. A. Bubier, C. Phillips, M. A. Langston, E. J. Baker
O40 A general statistic framework for genome-based disease risk prediction
M. Xiong, L. Ma, N. Lin, C. Amos
O41 Integrative large-scale causal network analysis of imaging and genomic data and its application in schizophrenia studies
N. Lin, P. Wang, Y. Zhu, J. Zhao, V. Calhoun, M. Xiong
O42 Big data and NGS data analysis: the cloud to the rescue
O. Dobretsberger, M. Egger, F. Leimgruber
O43 Cpipe: a convergent clinical exome pipeline specialised for targeted sequencing
S. Sadedin, A. Oshlack, Melbourne Genomics Health Alliance
O44 A Bayesian classification of biomedical images using feature extraction from deep neural networks implemented on lung cancer data
V. A. A. Antonio, N. Ono, Clark Kendrick C. Go
O45 MAV-SEQ: an interactive platform for the Management, Analysis, and Visualization of sequence data
Z. Ahmed, M. Bolisetty, S. Zeeshan, E. Anguiano, D. Ucar
O47 Allele specific enhancer in EPAS1 intronic regions may contribute to high altitude adaptation of Tibetans
C. Zeng, J. Shao
O48 Nanochannel based next-generation mapping for structural variation detection and comparison in trios and populations
H. Cao, A. Hastie, A. W. Pang, E. T. Lam, T. Liang, K. Pham, M. Saghbini, Z. Dzakula
O49 Archaic introgression in indigenous populations of Malaysia revealed by whole genome sequencing
Y. Chee-Wei, L. Dongsheng, W. Lai-Ping, D. Lian, R. O. Twee Hee, Y. Yunus, F. Aghakhanian, S. S. Mokhtar, C. V. Lok-Yung, J. Bhak, M. Phipps, X. Shuhua, T. Yik-Ying, V. Kumar, H. Boon-Peng
O50 Breast and ovarian cancer prevention: is it time for population-based mutation screening of high risk genes?
I. Campbell, M.-A. Young, P. James, Lifepool
O53 Comprehensive coverage from low DNA input using novel NGS library preparation methods for WGS and WGBS
C. Schumacher, S. Sandhu, T. Harkins, V. Makarov
O54 Methods for large scale construction of robust PCR-free libraries for sequencing on Illumina HiSeqX platform
H. DoddapaneniR. Glenn, Z. Momin, B. Dilrukshi, H. Chao, Q. Meng, B. Gudenkauf, R. Kshitij, J. Jayaseelan, C. Nessner, S. Lee, K. Blankenberg, L. Lewis, J. Hu, Y. Han, H. Dinh, S. Jireh, K. Walker, E. Boerwinkle, D. Muzny, R. Gibbs
O55 Rapid capture methods for clinical sequencing
J. Hu, K. Walker, C. Buhay, X. Liu, Q. Wang, R. Sanghvi, H. Doddapaneni, Y. Ding, N. Veeraraghavan, Y. Yang, E. Boerwinkle, A. L. Beaudet, C. M. Eng, D. M. Muzny, R. A. Gibbs
O56 A diploid personal human genome model for better genomes from diverse sequence data
K. C. C. Worley, Y. Liu, D. S. T. Hughes, S. C. Murali, R. A. Harris, A. C. English, X. Qin, O. A. Hampton, P. Larsen, C. Beck, Y. Han, M. Wang, H. Doddapaneni, C. L. Kovar, W. J. Salerno, A. Yoder, S. Richards, J. Rogers, J. R. Lupski, D. M. Muzny, R. A. Gibbs
O57 Development of PacBio long range capture for detection of pathogenic structural variants
Q. Meng, M. Bainbridge, M. Wang, H. Doddapaneni, Y. Han, D. Muzny, R. Gibbs
O58 Rhesus macaques exhibit more non-synonymous variation but greater impact of purifying selection than humans
R. A. Harris, M. Raveenedran, C. Xue, M. Dahdouli, L. Cox, G. Fan, B. Ferguson, J. Hovarth, Z. Johnson, S. Kanthaswamy, M. Kubisch, M. Platt, D. Smith, E. Vallender, R. Wiseman, X. Liu, J. Below, D. Muzny, R. Gibbs, F. Yu, J. Rogers
O59 Assessing RNA structure disruption induced by single-nucleotide variation
J. Lin, Y. Zhang, Z. Ouyang
P1 A meta-analysis of genome-wide association studies of mitochondrial dna copy number
A. Moore, Z. Wang, J. Hofmann, M. Purdue, R. Stolzenberg-Solomon, S. Weinstein, D. Albanes, C.-S. Liu, W.-L. Cheng, T.-T. Lin, Q. Lan, N. Rothman, S. Berndt
P2 Missense polymorphic genetic combinations underlying down syndrome susceptibility
E. S. Chen
P4 The evaluation of alteration of ELAM-1 expression in the endometriosis patients
H. Bahrami, A. Khoshzaban, S. Heidari Keshal
P5 Obesity and the incidence of apolipoprotein E polymorphisms in an assorted population from Saudi Arabia population
K. K. R. Alharbi
P6 Genome-associated personalized antithrombotical therapy for patients with high risk of thrombosis and bleeding
M. Zhalbinova, A. Akilzhanova, S. Rakhimova, M. Bekbosynova, S. Myrzakhmetova
P7 Frequency of Xmn1 polymorphism among sickle cell carrier cases in UAE population
M. Matar
P8 Differentiating inflammatory bowel diseases by using genomic data: dimension of the problem and network organization
N. Mili, R. Molinari, Y. Ma, S. Guerrier
P9 Vulnerability of genetic variants to the risk of autism among Saudi children
N. Elhawary, M. Tayeb, N. Bogari, N. Qotb
P10 Chromatin profiles from ex vivo purified dopaminergic neurons establish a promising model to support studies of neurological function and dysfunction
S. A. McClymont, P. W. Hook, L. A. Goff, A. McCallion
P11 Utilization of a sensitized chemical mutagenesis screen to identify genetic modifiers of retinal dysplasia in homozygous Nr2e3rd7 mice
Y. Kong, J. R. Charette, W. L. Hicks, J. K. Naggert, L. Zhao, P. M. Nishina
P12 Ion torrent next generation sequencing of recessive polycystic kidney disease in Saudi patients
B. M. Edrees, M. Athar, F. A. Al-Allaf, M. M. Taher, W. Khan, A. Bouazzaoui, N. A. Harbi, R. Safar, H. Al-Edressi, A. Anazi, N. Altayeb, M. A. Ahmed, K. Alansary, Z. Abduljaleel
P13 Digital expression profiling of Purkinje neurons and dendrites in different subcellular compartments
A. Kratz, P. Beguin, S. Poulain, M. Kaneko, C. Takahiko, A. Matsunaga, S. Kato, A. M. Suzuki, N. Bertin, T. Lassmann, R. Vigot, P. Carninci, C. Plessy, T. Launey
P14 The evolution of imperfection and imperfection of evolution: the functional and functionless fractions of the human genome
D. Graur
P16 Species-independent identification of known and novel recurrent genomic entities in multiple cancer patients
J. Friis-Nielsen, J. M. Izarzugaza, S. Brunak
P18 Discovery of active gene modules which are densely conserved across multiple cancer types reveal their prognostic power and mutually exclusive mutation patterns
B. S. Soibam
P19 Whole exome sequencing of dysplastic leukoplakia tissue indicates sequential accumulation of somatic mutations from oral precancer to cancer
D. Das, N. Biswas, S. Das, S. Sarkar, A. Maitra, C. Panda, P. Majumder
P21 Epigenetic mechanisms of carcinogensis by hereditary breast cancer genes
J. J. Gruber, N. Jaeger, M. Snyder
P22 RNA direct: a novel RNA enrichment strategy applied to transcripts associated with solid tumors
K. Patel, S. Bowman, T. Davis, D. Kraushaar, A. Emerman, S. Russello, N. Henig, C. Hendrickson
P23 RNA sequencing identifies gene mutations for neuroblastoma
K. Zhang
P24 Participation of SFRP1 in the modulation of TMPRSS2-ERG fusion gene in prostate cancer cell lines
M. Rodriguez-Dorantes, C. D. Cruz-Hernandez, C. D. P. Garcia-Tobilla, S. Solorzano-Rosales
P25 Targeted Methylation Sequencing of Prostate Cancer
N. Jäger, J. Chen, R. Haile, M. Hitchins, J. D. Brooks, M. Snyder
P26 Mutant TPMT alleles in children with acute lymphoblastic leukemia from México City and Yucatán, Mexico
S. Jiménez-Morales, M. Ramírez, J. Nuñez, V. Bekker, Y. Leal, E. Jiménez, A. Medina, A. Hidalgo, J. Mejía
P28 Genetic modifiers of Alström syndrome
J. Naggert, G. B. Collin, K. DeMauro, R. Hanusek, P. M. Nishina
P31 Association of genomic variants with the occurrence of angiotensin-converting-enzyme inhibitor (ACEI)-induced coughing among Filipinos
E. M. Cutiongco De La Paz, R. Sy, J. Nevado, P. Reganit, L. Santos, J. D. Magno, F. E. Punzalan , D. Ona , E. Llanes, R. L. Santos-Cortes , R. Tiongco, J. Aherrera, L. Abrahan, P. Pagauitan-Alan; Philippine Cardiogenomics Study Group
P32 The use of “humanized” mouse models to validate disease association of a de novo GARS variant and to test a novel gene therapy strategy for Charcot-Marie-Tooth disease type 2D
K. H. Morelli, J. S. Domire, N. Pyne, S. Harper, R. Burgess
P34 Molecular regulation of chondrogenic human induced pluripotent stem cells
M. A. Gari, A. Dallol, H. Alsehli, A. Gari, M. Gari, A. Abuzenadah
P35 Molecular profiling of hematologic malignancies: implementation of a variant assessment algorithm for next generation sequencing data analysis and clinical reporting
M. Thomas, M. Sukhai, S. Garg, M. Misyura, T. Zhang, A. Schuh, T. Stockley, S. Kamel-Reid
P36 Accessing genomic evidence for clinical variants at NCBI
S. Sherry, C. Xiao, D. Slotta, K. Rodarmer, M. Feolo, M. Kimelman, G. Godynskiy, C. O’Sullivan, E. Yaschenko
P37 NGS-SWIFT: a cloud-based variant analysis framework using control-accessed sequencing data from DBGAP/SRA
C. Xiao, E. Yaschenko, S. Sherry
P38 Computational assessment of drug induced hepatotoxicity through gene expression profiling
C. Rangel-Escareño, H. Rueda-Zarate
P40 Flowr: robust and efficient pipelines using a simple language-agnostic approach;ultraseq; fast modular pipeline for somatic variation calling using flowr
S. Seth, S. Amin, X. Song, X. Mao, H. Sun, R. G. Verhaak, A. Futreal, J. Zhang
P41 Applying “Big data” technologies to the rapid analysis of heterogenous large cohort data
S. J. Whiite, T. Chiang, A. English, J. Farek, Z. Kahn, W. Salerno, N. Veeraraghavan, E. Boerwinkle, R. Gibbs
P42 FANTOM5 web resource for the large-scale genome-wide transcription start site activity profiles of wide-range of mammalian cells
T. Kasukawa, M. Lizio, J. Harshbarger, S. Hisashi, J. Severin, A. Imad, S. Sahin, T. C. Freeman, K. Baillie, A. Sandelin, P. Carninci, A. R. R. Forrest, H. Kawaji, The FANTOM Consortium
P43 Rapid and scalable typing of structural variants for disease cohorts
W. Salerno, A. English, S. N. Shekar, A. Mangubat, J. Bruestle, E. Boerwinkle, R. A. Gibbs
P44 Polymorphism of glutathione S-transferases and sulphotransferases genes in an Arab population
A. H. Salem, M. Ali, A. Ibrahim, M. Ibrahim
P46 Genetic divergence of CYP3A5*3 pharmacogenomic marker for native and admixed Mexican populations
J. C. Fernandez-Lopez, V. Bonifaz-Peña, C. Rangel-Escareño, A. Hidalgo-Miranda, A. V. Contreras
P47 Whole exome sequence meta-analysis of 13 white blood cell, red blood cell, and platelet traits
L. Polfus, CHARGE and NHLBI Exome Sequence Project Working Groups
P48 Association of adipoq gene with type 2 diabetes and related phenotypes in african american men and women: The jackson heart study
S. Davis, R. Xu, S. Gebeab, P Riestra, A Gaye, R. Khan, J. Wilson, A. Bidulescu
P49 Common variants in casr gene are associated with serum calcium levels in koreans
S. H. Jung, N. Vinayagamoorthy, S. H. Yim, Y. J. Chung
P50 Inference of multiple-wave population admixture by modeling decay of linkage disequilibrium with multiple exponential functions
Y. Zhou, S. Xu
P51 A Bayesian framework for generalized linear mixed models in genome-wide association studies
X. Wang, V. Philip, G. Carter
P52 Targeted sequencing approach for the identification of the genetic causes of hereditary hearing impairment
A. A. Abuzenadah, M. Gari, R. Turki, A. Dallol
P53 Identification of enhancer sequences by ATAC-seq open chromatin profiling
A. Uyar, A. Kaygun, S. Zaman, E. Marquez, J. George, D. Ucar
P54 Direct enrichment for the rapid preparation of targeted NGS libraries
C. L. Hendrickson, A. Emerman, D. Kraushaar, S. Bowman, N. Henig, T. Davis, S. Russello, K. Patel
P56 Performance of the Agilent D5000 and High Sensitivity D5000 ScreenTape assays for the Agilent 4200 Tapestation System
R. Nitsche, L. Prieto-Lafuente
P57 ClinVar: a multi-source archive for variant interpretation
M. Landrum, J. Lee, W. Rubinstein, D. Maglott
P59 Association of functional variants and protein physical interactions of human MUTY homolog linked with familial adenomatous polyposis and colorectal cancer syndrome
Z. Abduljaleel, W. Khan, F. A. Al-Allaf, M. Athar , M. M. Taher, N. Shahzad
P60 Modification of the microbiom constitution in the gut using chicken IgY antibodies resulted in a reduction of acute graft-versus-host disease after experimental bone marrow transplantation
A. Bouazzaoui, E. Huber, A. Dan, F. A. Al-Allaf, W. Herr, G. Sprotte, J. Köstler, A. Hiergeist, A. Gessner, R. Andreesen, E. Holler
P61 Compound heterozygous mutation in the LDLR gene in Saudi patients suffering severe hypercholesterolemia
F. Al-Allaf, A. Alashwal, Z. Abduljaleel, M. Taher, A. Bouazzaoui, H. Abalkhail, A. Al-Allaf, R. Bamardadh, M. Athar
doi:10.1186/s40246-016-0063-5
PMCID: PMC4896275  PMID: 27294413
5.  Venous Thrombosis Risk after Cast Immobilization of the Lower Extremity: Derivation and Validation of a Clinical Prediction Score, L-TRiP(cast), in Three Population-Based Case–Control Studies 
PLoS Medicine  2015;12(11):e1001899.
Background
Guidelines and clinical practice vary considerably with respect to thrombosis prophylaxis during plaster cast immobilization of the lower extremity. Identifying patients at high risk for the development of venous thromboembolism (VTE) would provide a basis for considering individual thromboprophylaxis use and planning treatment studies.
The aims of this study were (1) to investigate the predictive value of genetic and environmental risk factors, levels of coagulation factors, and other biomarkers for the occurrence of VTE after cast immobilization of the lower extremity and (2) to develop a clinical prediction tool for the prediction of VTE in plaster cast patients.
Methods and Findings
We used data from a large population-based case–control study (MEGA study, 4,446 cases with VTE, 6,118 controls without) designed to identify risk factors for a first VTE. Cases were recruited from six anticoagulation clinics in the Netherlands between 1999 and 2004; controls were their partners or individuals identified via random digit dialing. Identification of predictor variables to be included in the model was based on reported associations in the literature or on a relative risk (odds ratio) > 1.2 and p ≤ 0.25 in the univariate analysis of all participants. Using multivariate logistic regression, a full prediction model was created. In addition to the full model (all variables), a restricted model (minimum number of predictors with a maximum predictive value) and a clinical model (environmental risk factors only, no blood draw or assays required) were created. To determine the discriminatory power in patients with cast immobilization (n = 230), the area under the curve (AUC) was calculated by means of a receiver operating characteristic. Validation was performed in two other case–control studies of the etiology of VTE: (1) the THE-VTE study, a two-center, population-based case–control study (conducted in Leiden, the Netherlands, and Cambridge, United Kingdom) with 784 cases and 523 controls included between March 2003 and December 2008 and (2) the Milan study, a population-based case–control study with 2,117 cases and 2,088 controls selected between December 1993 and December 2010 at the Thrombosis Center, Fondazione IRCCS Ca’ Granda–Ospedale Maggiore Policlinico, Milan, Italy.
The full model consisted of 32 predictors, including three genetic factors and six biomarkers. For this model, an AUC of 0.85 (95% CI 0.77–0.92) was found in individuals with plaster cast immobilization of the lower extremity. The AUC for the restricted model (containing 11 predictors, including two genetic factors and one biomarker) was 0.84 (95% CI 0.77–0.92). The clinical model (consisting of 14 environmental predictors) resulted in an AUC of 0.77 (95% CI 0.66–0.87). The clinical model was converted into a risk score, the L-TRiP(cast) score (Leiden–Thrombosis Risk Prediction for patients with cast immobilization score), which showed an AUC of 0.76 (95% CI 0.66–0.86). Validation in the THE-VTE study data resulted in an AUC of 0.77 (95% CI 0.58–0.96) for the L-TRiP(cast) score. Validation in the Milan study resulted in an AUC of 0.93 (95% CI 0.86–1.00) for the full model, an AUC of 0.92 (95% CI 0.76–0.87) for the restricted model, and an AUC of 0.96 (95% CI 0.92–0.99) for the clinical model. The L-TRiP(cast) score resulted in an AUC of 0.95 (95% CI 0.91–0.99).
Major limitations of this study were that information on thromboprophylaxis was not available for patients who had plaster cast immobilization of the lower extremity and that blood was drawn 3 mo after the thrombotic event.
Conclusions
These results show that information on environmental risk factors, coagulation factors, and genetic determinants in patients with plaster casts leads to high accuracy in the prediction of VTE risk. In daily practice, the clinical model may be the preferred model as its factors are most easy to determine, while the model still has good predictive performance. These results may provide guidance for thromboprophylaxis and form the basis for a management study.
Using three population-based case-control studies, Banne Nemeth and colleagues derive and validate a clinical prediction score (L-TRiP(cast)) for venous thrombosis risk.
Editors' Summary
Background
Blood normally flows smoothly around the human body, but when a cut or other injury occurs, proteins called clotting factors make the blood gel (coagulate) at the injury site. The resultant clot (thrombus) plugs the wound and prevents blood loss. Sometimes, however, a thrombus forms inside an uninjured blood vessel and partly or completely blocks the blood flow. Clot formation inside one of the veins deep in the body (usually in a leg) is called deep vein thrombosis (DVT). DVT, which can cause pain, swelling, and redness in the affected limb, is treated with anticoagulants, drugs that stop the clot growing. If left untreated, part of the clot can break off and travel to the lungs, where it can cause a life-threatening pulmonary embolism. DVT and pulmonary embolism are known collectively as venous thromboembolism (VTE). Risk factors for VTE include age, oral contraceptive use, having an inherited blood clotting disorder, and prolonged inactivity (for example, being bedridden). An individual’s lifetime risk of developing VTE is about 11%; 10%–30% of people die within 28 days of diagnosis of VTE.
Why Was This Study Done?
Clinicians cannot currently accurately predict who will develop VTE, but it would be very helpful to be able to identify individuals at high risk for VTE because the condition can be prevented by giving anticoagulants before a clot forms (thromboprophylaxis). The ability to predict VTE would be particularly useful in patients who have had a lower limb immobilized in a cast after, for example, breaking a bone. These patients have an increased risk of VTE compared to patients without cast immobilization. However, their absolute risk of VTE is not high enough to justify giving everyone with a leg cast thromboprophylaxis because this therapy increases the risk of major bleeds. Here, the researchers investigate the predictive value of genetic and environmental factors and levels of coagulation factors and other biomarkers on VTE occurrence after cast immobilization of the lower leg and develop a clinical tool for the prediction of VTE in patients with plaster casts.
What Did the Researchers Do and Find?
The researchers used data from the MEGA study, a study of risk factors for VTE, to build a prediction model for a first VTE in patients with a leg cast; the prediction model included 32 predictors (the full model). They also built a restricted model, which included only 11 predictors but had maximum predictive value, and a clinical model, which included 14 environmental predictors that can all be determined without drawing blood or undertaking any assays. They then determined the ability of each model to distinguish between patients with a leg cast who did and did not develop VTE using receiver operating characteristic (ROC) curve analysis. The area under the curve (AUC) for the full model was 0.85, for the restricted model it was 0.85, and for the clinical model it was 0.77. (A predictive test that discriminates perfectly between individuals who do and do not subsequently develop a specific condition has an AUC of 1.00; a test that is no better at predicting outcomes than flipping a coin has an AUC of 0.5.) Similar or higher AUCs were obtained for all the models using data collected in two independent studies. Finally, the researchers converted the clinical model into a risk score by giving each variable in the model a numerical score. The sum of these scores was used to stratify individuals into categories of low or high risk for VTE. With a cutoff of 9 points, the risk score correctly identified 80.8% of the patients in the MEGA study with a plaster cast who developed VTE and 60.8% of the patients who did not develop VTE.
What Do These Findings Mean?
Some aspects of this study may limit the accuracy of its findings. For example, no information was available about which patients with a plaster cast received thromboprophylaxis. Nevertheless, these findings suggest that information on environmental risk factors, coagulation factors, and genetic determinants can be used to predict VTE risk in patients with a leg cast with high accuracy. Importantly, the risk score derived and validated by the researchers, which includes only predictors that can be easily determined in clinical practice, may help clinicians decide which patients with a leg cast should receive thromboprophylaxis and which should not be exposed to the risk of anticoagulant therapy, until an unambiguous guideline for these patients becomes available.
Additional Information
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001899.
The US National Heart, Lung, and Blood Institute provides information on deep vein thrombosis (including an animation about how DVT causes pulmonary embolisms) and on pulmonary embolism
The UK National Health Service Choices website has information on deep vein thrombosis (including personal stories) and on pulmonary embolism
The US non-profit organization National Blood Clot Alliance provides detailed information about deep vein thrombosis and pulmonary embolism for patients and professionals and includes a selection of personal stories about these conditions
MedlinePlus has links to further information about deep vein thrombosis and pulmonary embolism (in English and Spanish)
Wikipedia has a page on ROC curve analysis (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
More information about the MEGA study is available
doi:10.1371/journal.pmed.1001899
PMCID: PMC4640574  PMID: 26554832
6.  Plasma DNA is Elevated in Patients with Deep Vein Thrombosis 
Objective
To investigate if plasma DNA is elevated in patients with deep vein thrombosis (DVT) and to determine whether there is a correlation with other biomarkers of DVT.
Background
Leukocytes release DNA to form extracellular traps (ETs), which have recently been linked to experimental DVT. In baboons and mice, extracellular DNA co-localized with von Willebrand factor (VWF) in the thrombus and DNA appeared in circulation at the time of thrombus formation. ETs have not been associated with clinical DVT.
Setting
From December 2008 to August 2010, patients were screened through the University of Michigan Diagnostic Vascular Unit and were divided into three distinct groups: 1) the DVT positive group, consisting of patients who were symptomatic for DVT, which was confirmed by compression duplex ultrasound (n=47); 2) the DVT negative group, consisting of patients that present with swelling and leg pain but had a negative compression duplex ultrasound, (n=28); and 3) a control group of healthy non-pregnant volunteers without signs or symptoms of active or previous DVT (n=19). Patients were excluded if they were less than 18 years of age, unwillingness to consent, pregnant, on an anticoagulant therapy, or diagnosed with isolated calf vein thrombosis.
Methods
Blood was collected for circulating DNA, CRP, D-dimer, VWF activity, myeloperoxidase (MPO), ADAMTS13 and VWF. The Wells score for a patient’s risk of DVT was assessed. The Receiver Operating Characteristic (ROC) curve was generated to determine the strength of the relationship between circulating DNA levels and the presence of DVT. A Spearman correlation was performed to determine the relationship between the DNA levels and the biomarkers and the Wells score. Additionally the ratio of ADAMTS13/VWF was assessed.
Results
Our results showed that circulating DNA (a surrogate marker for NETs) was significantly elevated in DVT patients, compared to both DVT negative patients (57.7±6.3 vs. 17.9±3.5ng/mL, P<.01) and controls (57.7±6.3 vs. 23.9±2.1ng/mL, P<.01). There was a strong positive correlation with CRP (P<.01), D-dimer (P<.01), VWF (P<.01), Wells score (P<.01) and myeloperoxidase (MPO) (P<.01), along with a strong negative correlation with ADAMTS13 (P<.01) and the ADAMTS13/VWF ratio. The logistic regression model showed a strong association between plasma DNA and the presence of DVT (ROC curve was determined to be 0.814).
Conclusions
Plasma DNA is elevated in patients with deep vein thrombosis and correlates with biomarkers of DVT. A strong correlation between circulating DNA and MPO suggests that neutrophils may be a source of plasma DNA in patients with DVT.
doi:10.1016/j.jvsv.2012.12.002
PMCID: PMC3810974  PMID: 24187669
7.  Management of Venous Thromboembolisms: Part I. The Consensus for Deep Vein Thrombosis  
Acta Cardiologica Sinica  2016;32(1):1-22.
Deep vein thrombosis (DVT) is a potentially catastrophic condition because thrombosis, left untreated, can result in detrimental pulmonary embolism. Yet in the absence of thrombosis, anticoagulation increases the risk of bleeding. In the existing literature, knowledge about the epidemiology of DVT is primarily based on investigations among Caucasian populations. There has been little information available about the epidemiology of DVT in Taiwan, and it is generally believed that DVT is less common in Asian patients than in Caucasian patients. However, DVT is a multifactorial disease that represents the interaction between genetic and environmental factors, and the majority of patients with incident DVT have either inherited thrombophilia or acquired risk factors. Furthermore, DVT is often overlooked. Although symptomatic DVT commonly presents with lower extremity pain, swelling and tenderness, diagnosing DVT is a clinical challenge for physicians. Such a diagnosis of DVT requires a timely systematic assessment, including the use of the Wells score and a D-dimer test to exclude low-risk patients, and imaging modalities to confirm DVT. Compression ultrasound with high sensitivity and specificity is the front-line imaging modality in the diagnostic process for patients with suspected DVT in addition to conventional invasive contrast venography. Most patients require anticoagulation therapy, which typically consists of parenteral heparin bridged to a vitamin K antagonist, with variable duration. The development of non-vitamin K oral anticoagulants has revolutionized the landscape of venous thromboembolism treatment, with 4 agents available,including rivaroxaban, dabigatran, apixaban, and edoxaban. Presently, all 4 drugs have finished their large phase III clinical trial programs and come to the clinical uses in North America and Europe. It is encouraging to note that the published data to date regarding Asian patients indicates that such new therapies are safe and efficacious. Ultimately, our efforts to improve outcomes in patients with DVT rely on the awareness in the scientific and medical community regarding the importance of DVT.
PMCID: PMC4804936  PMID: 27122927
Combination therapy; Hypertension; α1-blocker
8.  Hematologic Genetic Testing in High-risk Patients Before Knee Arthroplasty: A Pilot Study 
Background
Patients with a personal or familial history of thromboembolism are considered at higher risk for thromboembolic disease after knee arthroplasty. While it remains unclear why some patients develop deep vein thrombosis (DVT) or pulmonary embolism (PE) despite similar operative procedures and the same prophylactic regimen, we presume one explanation would be genetic predisposition.
Questions/purposes
We determined the frequency of 12 factors including antithrombin III activity, prothrombin gene mutations, and the presence of phospholipid antibodies in a high-risk patient cohort and compared those findings with the known prevalence in the population at large.
Patients and Methods
Patients identified preoperatively as having a personal or familial history of DVT and/or PE were referred for hemostatic serum and genetic tests, including % antithrombin III activity (ATIII), protein C and protein S activities, APC resistance, Factor V gene (Leiden) mutations, prothrombin gene mutations, lupus anticoagulant antibody presence, cardiolipin antibody presence, phosphatidyl antibody presence, β2-glycoprotein antibody presence, and serum homocysteine and lipoprotein(a) levels The frequencies of varying abnormalities were identified and compared to the prevalence reported in the literature.
Results
Forty-three of 1944 patients undergoing knee arthroplasty had a history of DVT or PE. Sixteen of 43 (37%) patients had an abnormality and eight of these (19%) had two or more abnormalities. The frequency of nine of the 12 tests appeared to be greater in this cohort than in the population at large.
Conclusions
Patients with a personal or familial history of DVT or PE appear to have a high frequency of hereditary prothrombotic abnormalities. Preoperative evaluation by a hematologist may be warranted in patients with a personal or familial history of DVT or PE as the postoperative anticoagulation protocols may be altered and identification of these abnormalities may affect a patient’s risk for other disease states.
Level of Evidence
Level IV, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence.
doi:10.1007/s11999-010-1514-2
PMCID: PMC3008871  PMID: 20824408
9.  Effect of Statins on Venous Thromboembolic Events: A Meta-analysis of Published and Unpublished Evidence from Randomised Controlled Trials 
PLoS Medicine  2012;9(9):e1001310.
A systematic review and meta-analysis conducted by Kazem Rahimi and colleagues re-evaluates the hypothesis, generated in previous studies, that statins may reduce the risk of venous thromboembolic events. Their meta-analysis does not support the previous findings.
Background
It has been suggested that statins substantially reduce the risk of venous thromboembolic events. We sought to test this hypothesis by performing a meta-analysis of both published and unpublished results from randomised trials of statins.
Methods and Findings
We searched MEDLINE, EMBASE, and Cochrane CENTRAL up to March 2012 for randomised controlled trials comparing statin with no statin, or comparing high dose versus standard dose statin, with 100 or more randomised participants and at least 6 months' follow-up. Investigators were contacted for unpublished information about venous thromboembolic events during follow-up. Twenty-two trials of statin versus control (105,759 participants) and seven trials of an intensive versus a standard dose statin regimen (40,594 participants) were included. In trials of statin versus control, allocation to statin therapy did not significantly reduce the risk of venous thromboembolic events (465 [0.9%] statin versus 521 [1.0%] control, odds ratio [OR] = 0.89, 95% CI 0.78–1.01, p = 0.08) with no evidence of heterogeneity between effects on deep vein thrombosis (266 versus 311, OR 0.85, 95% CI 0.72–1.01) and effects on pulmonary embolism (205 versus 222, OR 0.92, 95% CI 0.76–1.12). Exclusion of the trial result that provided the motivation for our meta-analysis (JUPITER) had little impact on the findings for venous thromboembolic events (431 [0.9%] versus 461 [1.0%], OR = 0.93 [95% CI 0.82–1.07], p = 0.32 among the other 21 trials). There was no evidence that higher dose statin therapy reduced the risk of venous thromboembolic events compared with standard dose statin therapy (198 [1.0%] versus 202 [1.0%], OR = 0.98, 95% CI 0.80–1.20, p = 0.87). Risk of bias overall was small but a certain degree of effect underestimation due to random error cannot be ruled out.
Please see later in the article for the Editors' Summary.
Conclusions
The findings from this meta-analysis do not support the previous suggestion of a large protective effect of statins (or higher dose statins) on venous thromboembolic events. However, a more moderate reduction in risk up to about one-fifth cannot be ruled out.
Editors' Summary
Background
Blood normally flows smoothly throughout the human body, supplying its organs and tissues with oxygen and nutrients. But, when an injury occurs, proteins called clotting factors make the blood gel (coagulate) at the injury site. The resultant blood clot (thrombus) plugs the wound and prevents blood loss. Occasionally, however, a thrombus forms inside an uninjured blood vessel and partly or completely blocks the blood flow. A clot inside one of the veins (vessels that take blood towards the heart) deep within the body is called a deep vein thrombosis (DVT). Symptoms of DVT (which usually occurs in the leg) include pain, swelling, and redness in the affected limb. DVT is treated with heparin and warfarin, two anticoagulant drugs that stop the blood clot growing. If left untreated, part of the clot (an embolus) can break off and travel to the lungs, where it can cause a pulmonary embolism (PE), a life-threatening condition characterized by chest pain, breathlessness, coughing, and dizziness. Little is known about how to prevent DVTs and PEs but risk factors for these venous thromboembolic events include having an inherited blood clotting disorder, oral contraceptive use, having surgery, and prolonged inactivity (on long-haul plane flights, for example).
Why Was This Study Done?
In 2009, a secondary (add-on) analysis of data from a randomized controlled trial (RCT, a study that randomly assigns individuals to receive different treatments and compares the outcomes associated with each treatment) called the JUPITER trial reported that rosuvastatin—a cholesterol-lowering drug (statin)—halved the risk of venous thromboembolic events among apparently healthy adults. The JUPITER trial was initiated to test whether statins reduce the risk of strokes, heart attacks, and other cardiovascular diseases (conditions that involve the heart and the blood vessels) among adults with raised levels of a predictor for these diseases called C-reactive protein; statins reduce the levels of this protein as well as those of cholesterol. Because fewer than 100 of the participants in the JUPITER trial developed a DVT or PE, the reduction in the risk of a venous thromboembolic event among the participants who took rosuvastatin could have happened by chance. In this systematic review and meta-analysis of 29 RCTs of statins that collected information on many more venous thromboembolic events, the researchers test the hypothesis that statins substantially reduce the risk of such events. A systematic review uses predefined criteria to identify all the research on a given topic; a meta-analysis is a statistical approach that combines the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 22 RCTs (105,759 participants) that compared the effects of statins with control (dummy) tablets and seven (40,594 participants) that compared an intensive statin regimen with a standard regimen. They then obtained largely unpublished information about the venous thromboembolic events that occurred during these trials (about 1,000 DVTs and PEs) from the original investigators. In the trials of statin versus control, allocation to statin therapy did not significantly reduce the risk of venous thromboembolic events. Thus, although events occurred in 465 participants who were given statins (0.9% of the participants) and in 521 participants who were given control tablets (1% of the participants), this difference in outcomes was not statistically significant—it could have happened by chance. Exclusion of the JUPITER trial results from the meta-analysis did not alter this finding. The researchers also found no evidence that intensive statin therapy reduced the risk of venous thromboembolic events compared to standard therapy.
What Do These Findings Mean?
The findings of this meta-analysis do not support the suggestion that statins, either at the standard dose or at higher doses, reduce the risk of venous thromboembolic events substantially among healthy adults. It is possible that the effect of statins has been underestimated in this meta-analysis because of missing data or because of some other source of bias. Furthermore, because the total number of events in this meta-analysis is still relatively modest, these findings do not rule out the possibility that statins may reduce the risk of venous thromboembolic events by up to about one-fifth in some or all individuals. Additional large RCTs are now needed to investigate whether statin treatment does in fact reduce the risk of venous thromboembolic events in adults and, if it does, whether all statins have a similar effect and whether statin treatment is beneficial in everyone or only in specific subgroups of people.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001310.
This study is further discussed in a PLOS Medicine Perspective by Frits Rosendaal
The US National Heart Lung and Blood Institute provides information on deep vein thrombosis (including an animation about how DVT causes pulmonary embolisms), and information on pulmonary embolism
The UK National Health Service Choices website has information on deep vein thrombosis, including personal stories, on pulmonary embolism, and on statins; a Behind the Headlines article describes the JUPITER trial and its implications
The non-profit organization US National Blood Clot Alliance provides detailed information about deep vein thrombosis and pulmonary embolism for patients and professionals and includes a selection of personal stories about these conditions
MedlinePlus has links to further information about deep vein thrombosis, pulmonary embolism, and statins (in English and Spanish)
doi:10.1371/journal.pmed.1001310
PMCID: PMC3445446  PMID: 23028261
10.  Emergency Department Management of Suspected Calf-Vein Deep Venous Thrombosis: A Diagnostic Algorithm 
Introduction
Unilateral leg swelling with suspicion of deep venous thrombosis (DVT) is a common emergency department (ED) presentation. Proximal DVT (thrombus in the popliteal or femoral veins) can usually be diagnosed and treated at the initial ED encounter. When proximal DVT has been ruled out, isolated calf-vein deep venous thrombosis (IC-DVT) often remains a consideration. The current standard for the diagnosis of IC-DVT is whole-leg vascular duplex ultrasonography (WLUS), a test that is unavailable in many hospitals outside normal business hours. When WLUS is not available from the ED, recommendations for managing suspected IC-DVT vary. The objectives of the study is to use current evidence and recommendations to (1) propose a diagnostic algorithm for IC-DVT when definitive testing (WLUS) is unavailable; and (2) summarize the controversy surrounding IC-DVT treatment.
Discussion
The Figure combines D-dimer testing with serial CUS or a single deferred FLUS for the diagnosis of IC-DVT. Such an algorithm has the potential to safely direct the management of suspected IC-DVT when definitive testing is unavailable. Whether or not to treat diagnosed IC-DVT remains widely debated and awaiting further evidence.
Conclusion
When IC-DVT is not ruled out in the ED, the suggested algorithm, although not prospectively validated by a controlled study, offers an approach to diagnosis that is consistent with current data and recommendations. When IC-DVT is diagnosed, current references suggest that a decision between anticoagulation and continued follow-up outpatient testing can be based on shared decision-making. The risks of proximal progression and life-threatening embolization should be balanced against the generally more benign natural history of such thrombi, and an individual patient’s risk factors for both thrombus propagation and complications of anticoagulation.
doi:10.5811/westjem.2016.5.29951
PMCID: PMC4944794  PMID: 27429688
11.  Current and Former Smoking and Risk for Venous Thromboembolism: A Systematic Review and Meta-Analysis 
PLoS Medicine  2013;10(9):e1001515.
In a meta-analysis of 32 observational studies involving 3,966,184 participants and 35,151 events, Suhua Wu and colleagues found that current, ever, and former smoking was associated with risk of venous thromboembolism.
Please see later in the article for the Editors' Summary
Background
Smoking is a well-established risk factor for atherosclerotic disease, but its role as an independent risk factor for venous thromboembolism (VTE) remains controversial. We conducted a meta-analysis to summarize all published prospective studies and case-control studies to update the risk for VTE in smokers and determine whether a dose–response relationship exists.
Methods and Findings
We performed a literature search using MEDLINE (source PubMed, January 1, 1966 to June 15, 2013) and EMBASE (January 1, 1980 to June 15, 2013) with no restrictions. Pooled effect estimates were obtained by using random-effects meta-analysis. Thirty-two observational studies involving 3,966,184 participants and 35,151 VTE events were identified. Compared with never smokers, the overall combined relative risks (RRs) for developing VTE were 1.17 (95% CI 1.09–1.25) for ever smokers, 1.23 (95% CI 1.14–1.33) for current smokers, and 1.10 (95% CI 1.03–1.17) for former smokers, respectively. The risk increased by 10.2% (95% CI 8.6%–11.8%) for every additional ten cigarettes per day smoked or by 6.1% (95% CI 3.8%–8.5%) for every additional ten pack-years. Analysis of 13 studies adjusted for body mass index (BMI) yielded a relatively higher RR (1.30; 95% CI 1.24–1.37) for current smokers. The population attributable fractions of VTE were 8.7% (95% CI 4.8%–12.3%) for ever smoking, 5.8% (95% CI 3.6%–8.2%) for current smoking, and 2.7% (95% CI 0.8%–4.5%) for former smoking. Smoking was associated with an absolute risk increase of 24.3 (95% CI 15.4–26.7) cases per 100,000 person-years.
Conclusions
Cigarette smoking is associated with a slightly increased risk for VTE. BMI appears to be a confounding factor in the risk estimates. The relationship between VTE and smoking has clinical relevance with respect to individual screening, risk factor modification, and the primary and secondary prevention of VTE.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Blood normally flows throughout the human body, supplying its organs and tissues with oxygen and nutrients. But, when an injury occurs, proteins called clotting factors make the blood gel (coagulate) at the injury site. The resultant clot (thrombus) plugs the wound and prevents blood loss. Occasionally, a thrombus forms inside an uninjured blood vessel and partly or completely blocks the blood flow. Clot formation inside one of the veins deep within the body, usually in a leg, is called deep vein thrombosis (DVT) and can cause pain, swelling, and redness in the affected limb. DVT can be treated with drugs that stop the blood clot from getting larger (anticoagulants) but, if left untreated, part of the clot can break off and travel to the lungs, where it can cause a life-threatening pulmonary embolism. DVT and pulmonary embolism are collectively known as venous thromboembolism (VTE). Risk factors for VTE include having an inherited blood clotting disorder, oral contraceptive use, prolonged inactivity (for example, during a long-haul plane flight), and having surgery. VTEs are present in about a third of all people who die in hospital and, in non-bedridden populations, about 10% of people die within 28 days of a first VTE event.
Why Was This Study Done?
Some but not all studies have reported that smoking is also a risk factor for VTE. A clear demonstration of a significant association (a relationship unlikely to have occurred by chance) between smoking and VTE might help to reduce the burden of VTE because smoking can potentially be reduced by encouraging individuals to quit smoking and through taxation policies and other measures designed to reduce tobacco consumption. In this systematic review and meta-analysis, the researchers examine the link between smoking and the risk of VTE in the general population and investigate whether heavy smokers have a higher risk of VTE than light smokers. A systematic review uses predefined criteria to identify all the research on a given topic; meta-analysis is a statistical method for combining the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 32 observational studies (investigations that record a population's baseline characteristics and subsequent disease development) that provided data on smoking and VTE. Together, the studies involved nearly 4 million participants and recorded 35,151 VTE events. Compared with never smokers, ever smokers (current and former smokers combined) had a relative risk (RR) of developing VTE of 1.17. That is, ever smokers were 17% more likely to develop VTE than never smokers. For current smokers and former smokers, RRs were 1.23 and 1.10, respectively. Analysis of only studies that adjusted for body mass index (a measure of body fat and a known risk factor for conditions that affect the heart and circulation) yielded a slightly higher RR (1.30) for current smokers compared with never smokers. For ever smokers, the population attributable fraction (the proportional reduction in VTE that would accrue in the population if no one smoked) was 8.7%. Notably, the risk of VTE increased by 10.2% for every additional ten cigarettes smoked per day and by 6.1% for every additional ten pack-years. Thus, an individual who smoked one pack of cigarettes per day for 40 years had a 26.7% higher risk of developing VTE than someone who had never smoked. Finally, smoking was associated with an absolute risk increase of 24.3 cases of VTE per 100,000 person-years.
What Do These Findings Mean?
These findings indicate that cigarette smoking is associated with a statistically significant, slightly increased risk for VTE among the general population and reveal a dose-relationship between smoking and VTE risk. They cannot prove that smoking causes VTE—people who smoke may share other unknown characteristics (confounding factors) that are actually responsible for their increased risk of VTE. Indeed, these findings identify body mass index as a potential confounding factor that might affect the accuracy of estimates of the association between smoking and VTE risk. Although the risk of VTE associated with smoking is smaller than the risk associated with some well-established VTE risk factors, smoking is more common (globally, there are 1.1 billion smokers) and may act synergistically with some of these risk factors. Thus, smoking behavior should be considered when screening individuals for VTE and in the prevention of first and subsequent VTE events.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001515.
The US National Heart Lung and Blood Institute provides information on deep vein thrombosis (including an animation about how DVT causes pulmonary embolism), and information on pulmonary embolism
The UK National Health Service Choices website has information on deep vein thrombosis, including personal stories, and on pulmonary embolism; SmokeFree is a website provided by the UK National Health Service that offers advice on quitting smoking
The non-profit organization US National Blood Clot Alliance provides detailed information about deep vein thrombosis and pulmonary embolism for patients and professionals and includes a selection of personal stories about these conditions
The World Health Organization provides information about the dangers of tobacco (in several languages)
Smokefree.gov, from the US National Cancer Institute, offers online tools and resources to help people quit smoking
MedlinePlus has links to further information about deep vein thrombosis, pulmonary embolism, and the dangers of smoking (in English and Spanish)
doi:10.1371/journal.pmed.1001515
PMCID: PMC3775725  PMID: 24068896
12.  The Absolute Risk of Venous Thrombosis after Air Travel: A Cohort Study of 8,755 Employees of International Organisations 
PLoS Medicine  2007;4(9):e290.
Background
The risk of venous thrombosis is approximately 2- to 4-fold increased after air travel, but the absolute risk is unknown. The objective of this study was to assess the absolute risk of venous thrombosis after air travel.
Methods and Findings
We conducted a cohort study among employees of large international companies and organisations, who were followed between 1 January 2000 and 31 December 2005. The occurrence of symptomatic venous thrombosis was linked to exposure to air travel, as assessed by travel records provided by the companies and organisations. A long-haul flight was defined as a flight of at least 4 h and participants were considered exposed for a postflight period of 8 wk. A total of 8,755 employees were followed during a total follow-up time of 38,910 person-years (PY). The total time employees were exposed to a long-haul flight was 6,872 PY. In the follow-up period, 53 thromboses occurred, 22 of which within 8 wk of a long-haul flight, yielding an incidence rate of 3.2/1,000 PY, as compared to 1.0/1,000 PY in individuals not exposed to air travel (incidence rate ratio 3.2, 95% confidence interval 1.8–5.6). This rate was equivalent to a risk of one event per 4,656 long-haul flights. The risk increased with exposure to more flights within a short time frame and with increasing duration of flights. The incidence was highest in the first 2 wk after travel and gradually decreased to baseline after 8 wk. The risk was particularly high in employees under age 30 y, women who used oral contraceptives, and individuals who were particularly short, tall, or overweight.
Conclusions
The risk of symptomatic venous thrombosis after air travel is moderately increased on average, and rises with increasing exposure and in high-risk groups.
In a cohort study of 8,755 employees of large international organizations followed for 38,910 person-years, Suzanne Cannegieter and colleagues find a risk of one thrombosis per 4,656 long-haul flights.
Editors' Summary
Background.
Blood normally flows smoothly throughout the human body, supplying the brain and other vital organs with oxygen and nutrients. When an injury occurs, proteins called clotting factors make the blood gel or coagulate at the injury site. The resultant blood clot (thrombus) plugs the wound and prevents blood loss. Sometimes, however, a thrombus forms inside an uninjured blood vessel and partly or completely blocks the blood flow. A clot inside one of the veins (vessels that take blood to the heart) deep within the body is called a deep vein thrombosis (DVT). Symptoms of DVT (which usually occurs in the deep veins of the leg) include pain, swelling, and redness in one leg. DVT is usually treated with heparin and warfarin, two anticoagulant drugs that stop the blood clot growing. If left untreated, part of the clot (an embolus) can break off and travel to the lungs, where it can cause a life-threatening condition called pulmonary embolism (PE). Fortunately, DVT and PE are rare but having an inherited blood clotting disorder, taking an oral contraceptive, and some types of surgery are all risk factors for them. In addition, long-haul plane travel increases the risk of DVT and PE, known collectively as venous thrombosis (VT) 2- to 4-fold, in part because the enforced immobilization during flights slows down blood flow.
Why Was This Study Done?
Although the link between air travel and VT was first noticed in the 1950s, exactly how many people will develop DVT and PE (the absolute risk of developing VT) after a long flight remains unknown. This information is needed so that travelers can be given advice about their actual risk and can make informed decisions about trying to reduce that risk by, for example, taking small doses of anticoagulant medicine before a flight. In this study, the researchers have determined the absolute risk of VT during and after long-haul air travel in a large group of business travelers.
What Did the Researchers Do and Find?
The researchers enrolled almost 9,000 employees from several international companies and organizations and followed them for an average of 4.4 years. The details of flights taken by each employee were obtained from company records, and employees completed a Web-based questionnaire about whether they had developed VT and what risk factors they had for the condition. Out of 53 thrombi that occurred during the study, 22 occurred within eight weeks of a long-haul flight (a flight of more than four hours). From this and data on the total time employees spent on long-haul flights, the researchers calculated that these flights tripled the risk of developing VT, and that the absolute risk (the probability of something occurring in a certain time period) of a VT occurring shortly after such travel was one event per 4,656 flights. They also calculated that the risk of VT was increased by exposure to more flights during a short period and to longer flights and was greatest in the first two weeks after a flight. In addition, the risk of VT was particularly high in young employees, women taking oral contraceptives, and people who were short, tall or overweight.
What Do These Findings Mean?
The main finding of this study is that the absolute risk of VT after of a long-haul flight is low—only one passenger out of nearly 5,000 is likely to develop VT because of flying. However, the study included only healthy people without previous VT whose average age was 40 years, so the absolute risk of VT after long-haul flights might be higher in the general traveling population. Even so, this finding strongly suggests that prophylactic (preventative) use of anticoagulants by all long-haul travelers may not be justified because these drugs have potentially dangerous side effects (for example, they can cause uncontrolled bleeding). Subgroups of travelers with additional risk factors for VT might, however, benefit from the use of this and other prophylactic measures, but randomized trials are needed to find out who would benefit most from which prophylactic measure.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040290.
MedlinePlus encyclopedia pages on blood clots, deep vein thrombosis, and pulmonary embolism (in English and Spanish)
Information from the US National Heart Lung and Blood Institute on deep vein thrombosis, including an animation of how DVT causes pulmonary embolisms
Information for patients from the UK National Health Service Direct health encyclopedia on deep vein thrombosis (in several languages)
Information for travelers on DVT from the US Centers for Disease Control and Prevention and from the UK National Travel Health Network and Centre
This study came out of the WHO Research Into Global Hazards of Travel (WRIGHT) project, and WHO's WRIGHT project on Air Travel and Venous Thromboembolism, of which his study forms a part, has a Web site
doi:10.1371/journal.pmed.0040290
PMCID: PMC1989755  PMID: 17896862
13.  Deep venous thrombosis in the antenatal period in a large cohort of pregnancies from western India 
Thrombosis Journal  2007;5:9.
Background
Deep venous thrombosis (DVT) is an important complication in the peripartal and postpartal period.
Methods
We followed up prospectively the prevalence of DVT in 34720 prenatal mothers between June 2002 and July 2006 attending the antenatal clinics of two major hospitals in Mumbai, India. Thirty two women (0.1%) presented for the first time with symptomatic DVT i.e. 17 in the first trimester, 6 in the second and 9 in the third trimester of pregnancy. Nine had history of fetal loss while in the remaining twenty three there was no history of fetal loss.
Results
The evaluation of both acquired and heritable thrombophilia showed a conglomeration of thrombophilia in this group when compared to 100 normal pregnant women who have given birth to at least one healthy baby with no history of fetal death, DVT or other obstetrical complications. The relative risks for all the antiphospholipid antibodies (APA) studied i.e lupus anticoagulant (LA), IgG/IgM antibodies for cardiolipin (ACA), β2 glycoprotein 1 (β2 GP 1) and annexin V were significantly higher in women with pregnancy associated DVT (RR 7.4 95% CI 4.3–11.3 P < 0.05). Among the genetic thrombophilia markers studied, Protein S (PS) deficiency was the strongest risk factor (RR 5.00 95% CI 3.02–5.00 P < 0.05) followed by factor V Leiden (FVL) mutation (RR 4.57 95% CI 2.23–4.57 P < 0.05) and PAI 4G/4G homozygosity (RR 3.24 95% CI 1.85–5.12 P < 0.05). Protein C (PC) and endothelial protein C receptor (EPCR) 23 bp insertion polymorphism was also increased in the patient group as compared to controls but the difference was not statistically significant. The MTHFR C677T, fibrinogen gene β448 Arg/Lys polymorphisms were not significantly different from the normal controls, while antithrombin III (AT III) deficiency and PT G20210A polymorphism were absent in both controls and patients. Two or more risk factors were present in 22 out of 32 cases (68.75%).
Conclusion
We conclude that the prevalence of DVT in India is more or less similar to other reports published and both acquired and heritable thrombophilia show strong association with DVT associated with pregnancy.
doi:10.1186/1477-9560-5-9
PMCID: PMC1950495  PMID: 17610719
14.  Incidence and Risk Factors of Deep Venous Thrombosis in Asymptomatic Iliac Vein Compression: A Prospective Cohort Study 
Chinese Medical Journal  2016;129(18):2149-2152.
Background:
Deep vein thrombosis (DVT) may be associated with iliac vein compression. Up to now, the majority of data has come from a retrospective study about the correlation between DVT and iliac vein compression. This prospective study was to determine the incidence of DVT in individuals with iliac vein compression and identify risk factors predictive of DVT.
Methods:
A total of 500 volunteers without symptoms of venous diseases of lower extremities and overt risk factors of deep venous thrombosis between October 2011 and September 2012 in Shijitan Hospital were enrolled in this cohort study. All the participants underwent contrast-enhanced abdominal computed tomography (CT) to evaluate iliac vein compression. Baseline demographic information and degree of iliac vein compression were collected. They were categorized into ≥50% or <50% iliac vein compression group. Ultrasound examination was performed to screen DVT at the time of CT examination and 3, 6, 9, and 12 months after the examination. Primary event was DVT of ipsilateral lower extremity. Correlation between DVT and iliac vein compression was estimated by multivariate Logistic regression after adjusting for age, gender, malignancy, surgery/immobilization, chemotherapy/hormonal therapy, and pregnancy.
Results:
In 500 volunteers, 8.8% (44) had ≥50% iliac vein compression and 91.2% (456) had <50% iliac vein compression. Ipsilateral DVT occurred in six volunteers including two in iliofemoral vein, two in popliteal vein, and two in calf vein within 1 year. Univariate analysis showed that the incidence of DVT was 6.8% in ≥50% compression group, significantly higher than that in <50% compression group (0.7%) (χ2 = 12.84, P = 0.01). Patients with malignancy had significantly higher incidence of DVT than those without malignancy (χ2 = 69.60, P < 0.01). Multivariate Logistic regression indicated that iliac vein compression and malignancy were independent risk factors of DVT. After adjustment for malignancy, patients with ≥50% iliac vein compression had 10-fold increased risk of developing DVT (adjusted relative risk [RR] = 10.162, 95% confidence interval [CI]: 1.149–89.865, P = 0.037). In subgroup analysis, patients with malignancy and ≥50% iliac vein compression had 12-fold increased the risk of DVT than those without malignance and ≥50% compression (RR = 12.389, 95% CI: 2.327–65.957, P = 0.003).
Conclusions:
Iliac vein compression is common, but the incidence of DVT is low. Only individuals with ≥50% iliac vein compression or compression combined with other risk factors might have significantly increased the risk of DVT. Further study is recommended to improve prevention strategies for DVT in significant iliac vein compression.
doi:10.4103/0366-6999.189918
PMCID: PMC5022332  PMID: 27625083
Deep Venous Thrombosis; Iliac Vein Compression; Logistic Models
15.  Traumatic deep vein thrombosis in a soccer player: A case study 
Thrombosis Journal  2004;2:8.
A 42 year-old male former semi-professional soccer player sustained a right lower extremity popliteal contusion during a soccer game. He was clinically diagnosed with a possible traumatic deep vein thrombosis (DVT), and sent for confirmatory tests. A duplex doppler ultrasound was positive for DVT, and the patient was admitted to hospital for anticoagulation (unfractionated heparin, warfarin). Upon discharge from hospital the patient continued oral warfarin anticoagulation (six months), and the use of compression stockings (nine months). He followed up with his family doctor at regular intervals for serial coagulation measurements, and ultrasound examinations. The patient's only identified major thrombotic risk factor was the traumatic injury. One year after the initial deep vein thrombosis (DVT) the patient returned to contact sport, however he continued to have intermittent symptoms of right lower leg pain and right knee effusion.
Athletes can develop vascular injuries in a variety of contact and non-contact sports. Trauma is one of the most common causes of lower extremity deep vein thrombosis (DVT), however athletic injuries involving lower extremity traumatic DVT are seldom reported. This diagnosis and the associated risk factors must be considered during the initial physical examination. The primary method of radiological diagnosis of lower extremity DVT is a complete bilateral duplex sonography, which can be augmented by other methods such as evidence-based risk factor analysis. Antithrombotic medication is the current standard of treatment for DVT. Acute thrombolytic treatment has demonstrated an improved therapeutic efficacy, and a decrease in post-DVT symptoms.
There is a lack of scientific literature concerning the return to sport protocol following a DVT event. Athletic individuals who desire to return to sport after a DVT need to be fully informed about their treatment and risk of reoccurrence, so that appropriate decisions can be made.
doi:10.1186/1477-9560-2-8
PMCID: PMC526763  PMID: 15485571
16.  Diagnosis of deep vein thrombosis, and prevention of deep vein thrombosis recurrence and the post-thrombotic syndrome in the primary care medicine setting anno 2014 
The requirement for a safe diagnostic strategy of deep vein thrombosis (DVT) should be based on an overall objective post incidence of venous thromboembolism (VTE) of less than 1% during 3 mo follow-up. Compression ultrasonography (CUS) of the leg veins has a negative predictive value (NPV) of 97%-98% indicating the need of repeated CUS testing within one week. A negative ELISA VIDAS safely excludes DVT and VTE with a NPV between 99% and 100% at a low clinical score of zero. The combination of low clinical score and a less sensitive D-dimer test (Simplify) is not sensitive enough to exclude DVT and VTE in routine daily practice. From prospective clinical research studies it may be concluded that complete recanalization within 3 mo and no reflux is associated with a low or no risk of PTS obviating the need of MECS 6 mo after DVT. Partial and complete recanalization after 3 to more than 6 mo is usually complicated by reflux due to valve destruction and symptomatic PTS. Reflux seems to be a main determinant for PTS and DVT recurrence, the latter as a main contributing factor in worsening PTS. This hypothesis is supported by the relation between the persistent residual vein thrombosis (RVT = partial recanalization) and the risk of VTE recurrence in prospective studies. Absence of RVT at 3 mo post-DVT and no reflux is predicted to be associated with no recurrence of DVT (1.2%) during follow-up obviating the need of wearing medical elastic stockings and anticoagulation at 6 mo post-DVT. The presence or absence of RVT but with reflux at 3 to 6 mo post-DVT is associated with both symptomatic PTS and an increased risk of VTE recurrence in about one third in the post-DVT period after regular discontinuation of anticoagulant treatment. To test this hypothesis we designed a prospective DVT and postthrombotic syndrome (PTS) Bridging the Gap Study by addressing at least four unanswered questions in the treatment of DVT and PTS. Which DVT patient has a clear indication for long-term compression stocking therapy to prevent PTS after the initial anticoagulant treatment in the acute phase of DVT? Is 3 mo the appropriate point in time to determine candidates at risk to develop DVT recurrence and PTS? Which high risk symptomatic PTS patients need extended anticoagulant treatment?
doi:10.5492/wjccm.v4.i1.29
PMCID: PMC4326761  PMID: 25685720
Deep Venous thrombosis; Ultrasonography; Post-thrombotic syndrome; ELISA VIDAS D-dimer; Medical elastic stockings; Anticoagulation
17.  Elevated risk of thrombophilia in agenesis of the vena cava as a factor for deep vein thrombosis 
Background
Congenital absence of the inferior vena cava (AIVC) is a rare malformation which may be associated with an increased risk for deep vein thrombosis (DVT). However, the role of thrombophilia in AIVC and DVT is unknown.
Methods
Between 1982 and 2013 41 patients (12 female, 29 male, mean age 28 S.D. 11 years) were detected at the University of Düsseldorf, Germany, with AIVC. Based on medical history, clinical examination, imaging and coagulation studies, we performed on this collective a risk characterisation. Extensive literature research added further 123 published cases during 1993 and 2013. AIVC-patients were compared with iliocaval DVT-patients without AIVC (n = 168) treated during the same period in our clinic (90 female, 78 male, mean age 38 S.D. 17 years).
Results
In contrast to classical DVT younger men were more often affected. Factor-V-Leiden-mutation, 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism and hyperhomocysteinemia individually are associated with an increased risk of DVT in patients with AIVC. Aplasia/hypoplasia of the right or left kidney is also associated with IVCA.
Conclusions
AIVC should be considered in young patients who present with DVT involving the vena cava. Analysis of publications with AIVC and our patients yielded a typical spectrum of AIVC-associated DVT characteristics: AIVC occurs in young male adults, is revealed by proximal DVT, not necessarily accused by precipitating factors like immobilisation, and is mostly located bilateral. Hereditary coagulation abnormalities seem to be more often a contributing factor for DVT in AIVC.
Electronic supplementary material
The online version of this article (doi:10.1186/s13023-014-0223-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s13023-014-0223-4
PMCID: PMC4308084  PMID: 25604085
Vena cava anomaly; Agenesis; Deep venous thrombosis; Thrombophilia
18.  Deep vein thrombosis in primary care: possible malignancy? 
Background
The increased prevalence of unrecognised malignancy in patients with deep vein thrombosis (DVT) has been well established in secondary care settings. However, data from primary care settings, needed to tailor the diagnostic workup, are lacking.
Aim
To quantify the prevalence of unrecognised malignancy in primary care patients who have been diagnosed with DVT.
Design
Prospective follow-up study.
Setting
All primary care physicians affiliated/associated with a non-teaching hospital in a geographically circumscribed region participated in the study.
Method
A total of 430 consecutive patients without known malignancy, but with proven DVT were included in the study and compared with a control group of 442 primary care patients, matched according to age and sex. Previously unrecognised, occult malignancy was considered present if a new malignancy was diagnosed within 2 years following DVT diagnosis (DVT group) or inclusion in the control group. Patients with DVT were categorised in to those with unprovoked idiopathic DVT and those with risk factors for DVT (that is, secondary DVT).
Results
During the 2-year follow-up period, a new malignancy was diagnosed 3.6 times more often in patients with idiopathic DVT than in the control group (2-year incidence: 7.4% and 2.0%, respectively). The incidence in patients with secondary DVT was 2.6%; only slightly higher than in control patients.
Conclusion
Unrecognised malignancies are more common in both primary and secondary care patients with DVT than in the general population. In particular, patients with idiopathic DVT are at risk and they could benefit from individualised case-finding to detect malignancy.
PMCID: PMC1876636  PMID: 16954002
deep vein thrombosis; idiopathic; neoplasms; primary health care
19.  Should symptomatic, isolated distal deep vein thrombosis be treated with anticoagulation? 
BACKGROUND:
During the past two decades, the diagnosis of deep venous thrombosis (DVT) has made considerable progress. The term distal or calf vein thrombosis includes thrombosis in infrapopliteal veins, including the posterior tibial, peroneal, anterior tibial and muscular calf veins. The necessity of treating of distal DVT is debatable.
OBJECTIVE:
To determine whether treatment of isolated, distal DVT with anticoagulation versus no treatment affects patient outcome.
METHODS:
All patients discharged with a diagnosis of distal DVT from Tan Tock Seng Hospital, Singapore, between January 1, 2006, and December 31, 2007, were identified by the medical records office of the hospital. Compression of the intraluminal thrombus by duplex scan was used to diagnose distal DVT. Excluded were patients who either had both distal and proximal DVT, or had distal DVT along with pulmonary embolism (PE) at presentation.
Complete resolution of distal DVT on repeat duplex scan was used to measure the primary outcome. Repeat follow-up scans were performed at two weeks, one month, three months and six months, or on subsequent follow-up until the distal DVT had resolved completely.
Secondary outcome measures were complete improvement of symptoms, progression of thrombosis, or PE or death during the follow-up period.
The study included 68 patients with distal DVT; however, 17 patients with PE, two of whom had proximal DVT (in the iliac and common femoral veins) at the first presentation along with distal DVT, were excluded from the study. In total, 51 patients were included for analysis. The follow-up scan was available in 35 patients; therefore, the primary analysis was performed in 35 patients (47 incidences of distal DVT). However, the secondary analysis was available in all 51 patients.
Of the 35 patients available for follow-up scans, 17 patients (25 incidences of distal DVT) received anticoagulation and 18 patients (22 incidences of distal DVT) received no anticoagulation.
Of the 17 patients who were treated with anticoagulation, nine patients (13 incidences of distal DVT) received enoxaparin at a dose of 1 mg/kg twice a day for two weeks and eight patients (12 incidences of distal DVT) received warfarin for a period of three months with initial overlap of enoxaparin 1 mg/kg twice a day for three to five days. Once the prothrombin time international normalized ratio of a patient on warfarin was between 2 and 3, enoxaparin was discontinued. The 18 patients who did not receive anticoagulation received follow-up with regular duplex scan.
RESULTS:
There were no statistically significant differences among the groups in the resolution of distal DVT or symptom improvement with or without treatment. In the group that received no treatment, one death occurred. Proximal extension and PE were not recorded in any of the patients.
CONCLUSION:
Distal DVT may not require treatment with anticoagulation. If leg symptoms worsen, or if there is an extension of distal DVT on the follow-up scan, treatment with anticoagulation is recommended.
PMCID: PMC2780853  PMID: 22477500
Anticoagulation; Distal; DVT; Symptomatic; Ultrasound
20.  Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo 
Deep vein thrombosis initiation is mediated by cross talk between monocytes, neutrophils, and platelets.
Deep vein thrombosis (DVT) is a major cause of cardiovascular death. The sequence of events that promote DVT remains obscure, largely as a result of the lack of an appropriate rodent model. We describe a novel mouse model of DVT which reproduces a frequent trigger and resembles the time course, histological features, and clinical presentation of DVT in humans. We demonstrate by intravital two-photon and epifluorescence microscopy that blood monocytes and neutrophils crawling along and adhering to the venous endothelium provide the initiating stimulus for DVT development. Using conditional mutants and bone marrow chimeras, we show that intravascular activation of the extrinsic pathway of coagulation via tissue factor (TF) derived from myeloid leukocytes causes the extensive intraluminal fibrin formation characteristic of DVT. We demonstrate that thrombus-resident neutrophils are indispensable for subsequent DVT propagation by binding factor XII (FXII) and by supporting its activation through the release of neutrophil extracellular traps (NETs). Correspondingly, neutropenia, genetic ablation of FXII, or disintegration of NETs each confers protection against DVT amplification. Platelets associate with innate immune cells via glycoprotein Ibα and contribute to DVT progression by promoting leukocyte recruitment and stimulating neutrophil-dependent coagulation. Hence, we identified a cross talk between monocytes, neutrophils, and platelets responsible for the initiation and amplification of DVT and for inducing its unique clinical features.
doi:10.1084/jem.20112322
PMCID: PMC3328366  PMID: 22451716
21.  Genetic risk factors in patients with deep venous thrombosis, a retrospective case control study on Iranian population 
Thrombosis Journal  2015;13:35.
Background
Venous thromboembolism (VTE) could be manifested as deep venous thrombosis (DVT) or pulmonary embolism (PE). DVT is usually the more common manifestation and is usually formation of a thrombus in the deep veins of lower extremities. DVT could occur without known underlying cause (idiopathic thrombosis) which could be a consequence of an inherited underlying risk factor or could be a consequence of provoking events, such as trauma, surgery or acute illness (provoked thrombosis). Our aim in this study was to assess the impact of some previously reported genetic risk factors including, methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, plasminogen activator inhibitor-1(PAI-1) 4G/5G, prothrombin 20210 and FV Leiden on occurrence of DVT in a population of Iranian patients.
Methods
This long-term study was conducted on 182 patients with DVT and also 250 age and sex matched healthy subjects as control group. The diagnosis of DVT was based on patient’s history, clinical findings, D-dimer test, and confirmed by Doppler ultrasonography. After confirmation of DVT, both groups were assessed for the five mentioned mutations. The relationship between mutations and predisposition to DVT was calculated by using logistic regression and expressed as an OR with a 95 % confidence interval (CI).
Results
Our results revealed that FV Leiden (OR 6.7; 95 % CI = 2.2 to 20.3; P = 0.001), MTHFR C677T (OR 6.0; 95 % CI = 2.2 to 16.4; P < 0.001), MTHFR A1298C (OR 8.3; 95 % CI = 4.4 to 15.8; P < 0.001), and PAI-1 4G/5G (OR 3.8; 95 % CI = 2.1 to 7.2; P < 0.001) mutations were all significantly associated with an increased risk of DVT. Prothrombin 20210 was found in none of the patients and controls.
Conclusion
Our findings suggest that genetic risk factors have a contributory role on occurrence of DVT.
doi:10.1186/s12959-015-0064-y
PMCID: PMC4640381  PMID: 26557789
Deep venous thrombosis; Plasminogen activator inhibitor-1; FV Leiden; Prothrombin20210; Methylenetetrahydrofolate reductase
22.  Incidence of Deep Venous Thrombosis After Tibial Tubercle Osteotomy 
Orthopaedic Journal of Sports Medicine  2014;2(8):2325967114544457.
Background:
Tibial tubercle osteotomy (TTO) is performed in a predominantly young and often female population due to the prevalence of patellofemoral disorders in this group. While considered a procedure that falls within the realm of sports surgeries, the procedure can carry significant morbidity, including infection, fracture, and deep vein thrombosis (DVT). The incidence of postoperative DVT in this population has not been described in the literature, although it has been mentioned anecdotally, and current guidelines do not address the issue of DVT prophylaxis in postoperative TTO patients.
Purpose:
To describe the incidence of DVT after TTO and identify any predisposing factors.
Study Design:
Case series; Level of evidence, 4.
Methods:
Subjects who had undergone TTO by the senior author from 2002 to 2013 were identified, and a retrospective chart review was performed. Those who presented with symptomatic DVT confirmed with ultrasonography were reported. Demographic data, as well as potential risk factors such as body mass index, family history of bleeding/clotting disorders, duration of the nonweightbearing period, total tourniquet time, use of contraceptive medication, smoking status, and use of anticoagulants, were collected from the chart and analyzed for correlation with development of DVT.
Results:
A total of 156 patients were included in this study. Six patients were found to have developed symptomatic DVT during the first 6 weeks after surgery. The mean age at the time of surgery in the DVT group was 34.94 ± 6.57 years, compared with 26.26 ± 10.20 years in the non-DVT group (P = .04). Due to the small number of patients with positive findings, there was no statistically significant correlation between the development of DVT and factors such as nonweightbearing duration, tourniquet time, or the use of contraceptives.
Conclusion:
The incidence of postoperative DVT in arthroscopic and sports procedures has been thought to be low. This case series reported a rate of 3.8% with symptomatic DVT after TTO, and patients diagnosed with DVT were significantly older than unaffected patients. It is anticipated that the actual rate including asymptomatic DVT would be higher, as only 60% of patients with DVT are symptomatic. More studies are needed to define the actual incidence in this population. Given the number of common risk factors in this population, including nonweightbearing duration and the use of oral contraceptive pills, future studies may show the advantage of chemical prophylaxis for DVT in this group.
doi:10.1177/2325967114544457
PMCID: PMC4555576  PMID: 26535355
tibial tubercle osteotomy; patellofemoral instability; deep vein thrombosis; age
23.  Deep vein thrombosis in patients with advanced liver cirrhosis: a rare condition? 
Hepatology International  2010;4(1):433-438.
Purpose
Patients with liver cirrhosis are generally considered to be “auto-anticoagulated” because of coagulopathy and thrombocytopenia. However, deep vein thrombosis (DVT) has been reported in patients with liver cirrhosis. The objectives of this study were to know the prevalence of DVT among cirrhotic patients and to compare clinical pictures between cirrhotic patients with and without DVT.
Methods
A case–control study was performed on the basis of medical record data of patients with liver cirrhosis admitted between August 2004 and July 2007 in Medistra hospital in Jakarta. Diagnosis of DVT was established by duplex Doppler ultrasonography of the lower extremities. Patients with splanchnic thrombosis were excluded from this study. Diagnosis of liver cirrhosis was based on history and clinical manifestation, consistent with liver cirrhosis and confirmed by ultrasonography or computed tomography.
Results
A total of 256 patients with liver cirrhosis were included in this study; 164 (64.1%) among them were men. Patients’ mean age was 60.5 ± 12.5 years, ranging from 16 to 88 years. Viral hepatitis accounted for 74.6% of patients with liver cirrhosis. DVT was found in 12 (4.7%) patients. There was no significant laboratory difference between cirrhotic patients with and without DVT (serum albumin, platelet count, aminotransferases, γ-glutamyl transpeptidase, alkaline phosphatase, total bilirubin levels, and prothrombin time). Diabetes mellitus was significantly higher in the DVT group than that in the control group (66.6 vs. 34.0%, P = 0.025). Multivariate analysis confirmed diabetes mellitus as an independent risk factor for the occurrence of DVT (odds ratio = 4.26; 95% confidence interval = 1.206–15.034; P = 0.024).
Conclusions
The prevalence of DVT in patients with liver cirrhosis was 4.7%, and Deep vein thrombosis is not a rare condition in cirrhotic patients with coagulopathy and warrants further studies on the mechanisms and prevention.
doi:10.1007/s12072-010-9166-6
PMCID: PMC2836440  PMID: 20305762
DVT; Liver cirrhosis; Autoanticoagulated; Coagulopathy
24.  Deep Vein Thrombosis in Patients with Severe Motor and Intellectual Disabilities, Especially Diagnosis and Prevention of Recurrence for Chronic Thrombosis—Serial Changes of Sonography and D-Dimer 
Annals of Vascular Diseases  2015;8(4):290-296.
Most patients with severe motor and intellectual disabilities (SMID) have restricted mobility capability and have been bedridden for long periods because of paralysis of the extremities caused by abnormal muscular tonicity due to cerebral palsy and developmental disabilities. Such patients are associated with a high risk of complications like deep vein thrombosis (DVT). Here, we report twelve patients (42.9%) with DVT among 28 patients with SMID during prolonged bed rest. However, we did not detect thrombosis in the soleal veins, finding it mostly in the femoral and common femoral veins. We applied anticoagulant therapy (warfarin), and carefully followed up the cases with DVT, regulating the warfarin dosage at prothrombin time-international normalized ratio (PT-INR) values around two to prevent recurrence of chronic thrombosis. Regarding laboratory data for the coagulation system, there were no cases above 5 µg/ml for the D-dimer and there were significant differences between the DVT and non-DVT groups in the D-dimer levels. The plasma levels of D-dimer in patients with DVT diminished to less than 1.0 µg/ml after warfarin treatment. Concerning sudden death (4.2%) in patients with SMID, we have to be very careful of the possibility of pulmonary thromboembolism due to DVT. Therefore, we should consider the particularity of the underdeveloped vascular system from underlying diseases for the evaluation of DVT. A detailed study of DVT as a vascular complication is very important for the smooth medical care of SMID, and serial assessment of compression Doppler ultrasonography of the lower extremities, as a noninvasive examination and measurement of D-dimer, is very helpful. (This article is a translation of Jpn J Phlebol 2014; 25: 34–42.)
doi:10.3400/avd.oa.15-00102
PMCID: PMC4691502  PMID: 26730253
severe motor and intellectual disabilities (SMID); chronic deep vein thrombosis (DVT); D-dimer; ultrasonography
25.  Deep vein thrombosis: validation of a patient-reported leg symptom index 
Introduction
Deep vein thrombosis (DVT) is a serious health problem that affects more than 2 million people annually in the United States. Many of these patients develop asymptomatic DVT, but months to years later may experience symptomatic post-thrombotic syndrome (PTS). It is not known how many cases of PTS can be traced to "asymptomatic" DVT because venography is no longer routinely done and ultrasonography (US) may miss some asymptomatic clots. As a result, a clinical tool in addition to US to detect symptom emergence or exacerbation in patients after DVT would be of value.
Methods
Seventy-seven patients hospitalized with an acute DVT interviewed by telephone at 3–7 days, 30–40 days, and 12-months following discharge were included in this report. All were treated with a standard anticoagulation "Clinical Pathway Protocol" between April 1999 and January 2000. Using a 14-item Deep Vein Thrombosis Leg Symptom Index (DVT-LSI), patients were queried regarding leg pain, swelling, skin discoloration, cosmetic appearance, activity tolerance, emotional distress, and leg-related sleep problems.
Results
The DVT-LSI for each leg was reliable at all assessments, with instrument reliability (alpha coefficients) greater than 0.70 at all time points (range 0.71–0.87). DVT-LSI scores, and the percentage of patients exhibiting symptoms, were higher in the DVT-affected leg at all time points. Among patients with unilateral disease, symptom severity ratings were significantly worse for patients in the affected leg compared to the normal leg at all time points, with the exception of those with a right-leg DVT at 12 months. Patients with bilateral thrombi did not have different scores on one leg compared to the other.
Conclusion
The DVT-LSI is useful in assessing symptomatic clinical outcomes in patients after diagnosis of DVT, and may represent a surrogate marker for DVT otherwise presumed to be asymptomatic.
doi:10.1186/1477-7525-1-76
PMCID: PMC317368  PMID: 14675486

Results 1-25 (1601143)