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1.  Upper-Extremity Transplantation Using a Cell-Based Protocol to Minimize Immunosuppression 
Annals of surgery  2013;257(2):345-351.
Objective
To minimize maintenance immunosuppression in upper-extremity transplantation to favor the risk-benefit balance of this procedure.
Background
Despite favorable outcomes, broad clinical application of reconstructive transplantation is limited by the risks and side effects of multidrug immunosuppression. We present our experience with upper-extremity transplantation under a novel, donor bone marrow (BM) cell-based treatment protocol (“Pittsburgh protocol”).
Methods
Between March 2009 and September 2010, 5 patients received a bilateral hand (n = 2), a bilateral hand/forearm (n = 1), or a unilateral (n = 2) hand transplant. Patients were treated with alemtuzumab and methylprednisolone for induction, followed by tacrolimus monotherapy. On day 14, patients received an infusion of donor BM cells isolated from 9 vertebral bodies. Comprehensive follow-up included functional evaluation, imaging, and immunomonitoring.
Results
All patients are maintained on tacrolimus monotherapy with trough levels ranging between 4 and 12 ng/mL. Skin rejections were infrequent and reversible. Patients demonstrated sustained improvements in motor function and sensory return correlating with time after transplantation and level of amputation. Side effects included transient increase in serum creatinine, hyperglycemia managed with oral hypoglycemics, minor wound infection, and hyperuricemia but no infections. Immunomonitoring revealed transient moderate levels of donor-specific antibodies, adequate immunocompetence, and no peripheral blood chimerism. Imaging demonstrated patent vessels with only mild luminal narrowing/occlusion in 1 case. Protocol skin biopsies showed absent or minimal perivascular cellular infiltrates.
Conclusions
Our data suggest that this BM cell-based treatment protocol is safe, is well tolerated, and allows upper-extremity transplantation using low-dose tacrolimus monotherapy.
doi:10.1097/SLA.0b013e31826d90bb
PMCID: PMC4162482  PMID: 23001085
bone marrow; cell therapy; composite tissue allotransplantation; hand transplantation; immunomodulation; immunomonitoring; immunosuppression; reconstructive transplantation; rejection; vascularized composite allotransplantation
2.  Laboratory variables for assessing iron deficiency in REDS-II Iron Status Evaluation (RISE) blood donors 
Transfusion  2013;53(11):2766-2775.
BACKGROUND
Iron deficiency is common in regular blood donors. We evaluated the diagnostic sensitivity and specificity of red blood cell (RBC) hematology analyzer indices to assess iron status as a part of donor management.
STUDY DESIGN AND METHODS
A total of 1659 male and female donors from the Retrovirus Epidemiology Donor Study-II (REDS-II) Donor Iron Status Evaluation (RISE) study who were either first-time/reactivated (FT/ RA; no donations for 2 years) or frequent donors were recruited into a longitudinal study of regular donation of RBCs. Of these, 1002 donors returned 15 to 24 months later for a final assessment. Absent iron stores (AIS) was defined as plasma ferritin level of less than 12 µ.g/L. Logarithm of the ratio of soluble transferrin receptor to ferritin of at least 2.07 (≥97.5% in FT/RA males) was used to define iron-deficient erythropoiesis (IDE). Receiver operating characteristics analysis was performed to assess selected RBC indices (e.g., percentage of hypochromic mature RBCs, proportion of hypochromic mature RBCs [HYPOm], and hemoglobin [Hb] content of reticulocytes [CHr]) in identifying AIS and IDE.
RESULTS
HYPOm and CHr detected IDE with comparable sensitivity, 72% versus 69%, but differed in specificity: HYPOm 68% and CHr 53%. For detecting AIS, sensitivity was improved to 85% for HYPOm and 81% for CHr but specificity was reduced for both. Venous Hb had high specificity but poor sensitivity for IDE and AIS. A plasma ferritin level of less than 26.7 u.g/L was a good surrogate for assessing IDE.
CONCLUSION
RBC indices correlate with AIS and IDE and are more informative than Hb measurement, but lack sufficient sensitivity and specificity to be used as diagnostic tools in blood donors at risk for iron deficiency.
doi:10.1111/trf.12209
PMCID: PMC3895107  PMID: 23617531
3.  Restless Legs Syndrome, pica, and iron status in blood donors 
Transfusion  2013;53(8):1645-1652.
BACKGROUND
The association of blood donation related iron deficiency with pica or Restless Leg Syndrome (RLS) remains poorly elucidated. This study evaluated the prevalence of RLS and pica in blood donors completing the REDS-II Iron Status Evaluation (RISE) Study.
STUDY DESIGN AND METHODS
RISE enrolled 2425 blood donors in a prospective cohort study; 1334 donors provided blood samples to characterize iron status and answered a questionnaire inquiring into symptoms of RLS and pica at a final visit after 15–24 months of follow-up. Associations between both conditions and iron status were evaluated.
RESULTS
There were 9% and 20% of donors reporting symptoms of Probable or Probable/Possible RLS, respectively. Iron depletion and donation intensity were not predictive of RLS. Pica was reported by 65 donors (5.5%), half of whom reported daily cravings. Prevalence of pica increased with degree of iron depletion in women (2% in iron replete females, 13% in those with ferritin < 12ng/mL), but not in men. Probable RLS and pica co-expressed in 8 individuals, but no more frequently than expected by chance.
CONCLUSION
RLS and pica have been associated with iron deficiency in non-donor populations. This study indicates a potentially high prevalence of RLS in frequent blood donors but shows no association with iron status or donation intensity. Low iron stores were associated with higher prevalence of pica, but only in females. Furthermore, the results are incompatible with RLS and pica sharing a common pathophysiology.
doi:10.1111/trf.12260
PMCID: PMC4226336  PMID: 23763445
blood donor; iron depletion; donation interval; pica; Restless Legs Syndrome
4.  Ticlopidine-, Clopidogrel-, and Prasugrel-Associated Thrombotic Thrombocytopenic Purpura: A 20-Year Review from the Southern Network on Adverse Reactions (SONAR) 
Thienopyridine-derivatives (ticlopidine, clopidogrel, and prasugrel) are the primary antiplatelet agents. Thrombotic thrombocytopenic purpura (TTP) is a rare drug-associated syndrome, with the thienopyridines being the most common drugs implicated in this syndrome. We reviewed 20 years of information on clinical, epidemiologic, and laboratory findings for thienopyridine-associated TTP. Four, 11, and 11 cases of thienopyridine-associated TTP were reported in the first year of marketing of ticlopidine (1989), clopidogrel (1998), and prasugrel (2010), respectively. As of 2011, the FDA received reports of 97 ticlopidine-, 197 clopidogrel-, and 14 prasugrel-associated TTP cases. Severe deficiency of ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) was present in 80% and antibodies to 100% of these TTP patients on ticlopidine, 0% of the patients with clopidogrel-associated TTP (p < 0.05), and an unknown percentage of patients with prasugrel-associated TTP. TTP is associated with use of each of the three thienopyridines, although the mechanistic pathways may differ.
doi:10.1055/s-0032-1328894
PMCID: PMC3804561  PMID: 23111862
thrombotic thrombocytopenic purpura; ticlopidine; clopidogrel; prasugrel; adverse event
6.  The Role of Plasmapheresis in Critical Illness 
Critical Care Clinics  2012;28(3):453-468.
Synopsis
In this chapter, we will review the current recommendations from the American Society for Apheresis regarding the use of plasmapheresis in many of the diseases that intensivists commonly encounter in critically ill patients. Recent experience indicates that therapeutic plasma exchange (TPE) may be useful in a wide spectrum of illnesses characterized by microvascular thrombosis, the presence of auto-antibodies, immune activation with dysregulation of immune response, and in some infections.
doi:10.1016/j.ccc.2012.04.009
PMCID: PMC3381605  PMID: 22713617
therapeutic plasma exchange; thrombotic microangiopathy; microvascular thrombosis; auto-antibodies; liver failure; hemophagocytic lymphohistiocytosis; rapidly progressive glomerulo nephritis; vasculitides; solid organ transplantation
7.  Population-based screening for anemia using first-time blood donors 
American journal of hematology  2012;87(5):496-502.
Background
Anemia is an important public health concern. Data from population-based surveys such as the National Health and Nutrition Examination Survey (NHANES) are the gold standard, but are obtained infrequently and include only small samples from certain minority groups.
Objectives
We assessed whether readily available databases of blood donor hemoglobin values could be used as a surrogate for population hemoglobin values from NHANES.
Design
Blood donor venous and fingerstick hemoglobin values were compared to 10,254 NHANES 2005-2008 venous hemoglobin values using demographically stratified analyses and ANOVA. Fingerstick hemoglobins or hematocrits were converted to venous hemoglobin estimates using regression analysis.
Results
Venous hemoglobin values from 1,609 first time donors correlated extremely well with NHANES data across different age, gender and demographic groups. Cigarette smoking increased hemoglobin by 0.26 to 0.59 g/dL depending on intensity. Converted fingerstick hemoglobin from 36,793 first time donors agreed well with NHANES hemoglobin (weighted mean hemoglobin of 15.53 g/dL for donors and 15.73 g/dL for NHANES) with similar variation in mean hemoglobin by age. However, compared to NHANES, the larger donor dataset showed reduced differences in mean hemoglobin between Blacks and other races/ethnicities.
Conclusions
Overall, first-time donor fingerstick hemoglobins approximate U.S. population data and represent a readily available public health resource for ongoing anemia surveillance.
doi:10.1002/ajh.23171
PMCID: PMC3525330  PMID: 22460662
Erythrocyte count; Hematologic tests; Anemia; United States; blood donors; African Continental Ancestry Group
8.  The difference between fingerstick and venous hemoglobin and hematocrit varies by sex and iron stores 
Transfusion  2011;52(5):1031-1040.
BACKGROUND
Fingerstick blood samples are used to estimate donor venous hemoglobin (Hb).
STUDY DESIGN AND METHODS
Fingerstick Hb or hematocrit (Hct) was determined routinely for 2425 selected donors at six blood centers, along with venous Hb. Using sex and measures of iron status including absent iron stores (AIS; ferritin < 12 ng/mL), linear regression models were developed to predict venous Hb from fingerstick.
RESULTS
Across all subjects, fingerstick Hb was higher than venous Hb in the higher part of the clinical range, but lower in the lower part of the range. The relationship varied by sex and iron status. Across centers, a female donor had on average a venous Hb result 0.5 to 0.8 g/dL lower than a male donor with the same fingerstick Hb and iron status. Similarly, a donor with AIS had on average a venous Hb result 0.3 to 1.1 g/dL lower than an iron-replete donor with the same fingerstick value and sex. An iron-replete male donor with a fingerstick result at the cutoff (Hb 12.5 g/dL) had an acceptable expected venous Hb (12.8 to 13.8 g/dL). A female donor with AIS with a fingerstick result at the cutoff had an expected venous Hb below 12.5 g/dL (11.7 to 12.4 g/dL). Of females with AIS, 40.2% donated blood when their venous Hb was less than 12.5 g/dL.
CONCLUSIONS
Fingerstick is considered a useful estimator of venous Hb. However, in some donor groups, particularly female donors with AIS, fingerstick overestimates venous Hb at the donation cutoff. This significant limitation should be considered in setting donor fingerstick Hb or Hct requirements.
doi:10.1111/j.1537-2995.2011.03389.x
PMCID: PMC3623687  PMID: 22014071
9.  Iron Deficiency in Blood Donors: The REDS-II Donor Iron Status Evaluation (RISE) Study 
Transfusion  2011;52(4):702-711.
Background
Blood donors are at risk of iron deficiency. We evaluated the effects of blood donation intensity on iron and hemoglobin in a prospective study.
Methods
Four cohorts of frequent and first time or reactivated blood donors (no donation in 2 years), female and male, totaling 2425 were characterized and followed as they donated blood frequently. At enrollment and the final visit, ferritin, soluble transferrin receptor (sTfR), and hemoglobin were determined. Models to predict iron deficiency and hemoglobin deferral were developed. Iron depletion was defined at two levels: Iron Deficient Erythropoiesis (IDE) [log (soluble transferrin receptor/ferritin ≥ 2.07)] and Absent Iron Stores (AIS) (ferritin < 12 ng/mL).
Results
Among returning female first time/reactivated donors, 20% and 51% had AIS and IDE at their final visit, respectively; corresponding proportions for males were 8% and 20%. Among female frequent donors who returned, 27% and 62% had AIS and IDE, respectively, while corresponding proportions for males were 18% and 47%. Predictors of IDE and/or AIS included a higher frequency of blood donation in the last 2 years, a shorter interdonation interval, and being female and young; conversely, taking iron supplements reduced the risk of iron depletion. Predictors of hemoglobin deferral included female gender, Black race and a shorter interdonation interval.
Conclusions
There is a high prevalence of iron depletion in frequent blood donors. Increasing the interdonation interval would reduce the prevalence of iron depletion and hemoglobin deferral. Alternatively, replacement with iron supplements may allow frequent donation without the adverse outcome of iron depletion.
doi:10.1111/j.1537-2995.2011.03401.x
PMCID: PMC3618489  PMID: 22023513
Donors; Hematology – Red Cells; Blood Center Operations
10.  Spermatogonial stem cell transplantation into Rhesus testes regenerates spermatogenesis producing functional sperm 
Cell stem cell  2012;11(5):715-726.
Summary
Spermatogonial stem cells (SSCs) maintain spermatogenesis throughout a man’s life and may have application for treating some cases of male infertility, including those caused by chemotherapy before puberty. We performed autologous and allogeneic SSC transplantations into the testes of 18 adult and 5 prepubertal recipient macaques that were rendered infertile with alkylating chemotherapy. After autologous transplant, the donor genotype from lentivirus-marked SSCs was evident in the ejaculated sperm of 9/12 adult and 3/5 prepubertal recipients after they reached maturity. Allogeneic transplant led to donor-recipient chimerism in sperm from 2/6 adult recipients. Ejaculated sperm from one recipient transplanted with allogeneic donor SSCs were injected into 85 rhesus oocytes via intracytoplasmic sperm injection. Eighty-one oocytes were fertilized, producing embryos ranging from 4-cell to blastocyst with donor paternal origin confirmed in 7/81 embryos. This demonstration of functional donor spermatogenesis following SSC transplantation in primates is an important milestone for informed clinical translation.
doi:10.1016/j.stem.2012.07.017
PMCID: PMC3580057  PMID: 23122294
Spermatogonial stem cells; adult tissue stem cells; primates; transplantation; regeneration; fertility preservation
11.  The impact of HFE mutations on haemoglobin and iron status in individuals experiencing repeated iron loss through blood donation 
British journal of haematology  2011;156(3):388-401.
Summary
Frequent blood donors become iron deficient. HFE mutations are present in over 30% of donors. A 24-month study of 888 first time/reactivated donors and 1537 frequent donors measured haemoglobin and iron status to assess how HFE mutations impact the development of iron deficiency erythropoiesis. Donors with two HFE mutations had increased baseline haemoglobin and iron stores as did those with one mutation, albeit to a lesser extent. Over multiple donations haemoglobin and iron status of donors with HFE mutations paralleled those lacking mutations. The prevalence of HFE mutations was not increased in higher intensity donors. Thus, in general, HFE mutations do not temper donation-induced changes in haemoglobin and iron status. However, in Black donors there was an increase of H63D carriers at baseline, from 3.7% in first time/reactivated donors to 15.8% in frequent donors, suggesting that the relative effects of HFE mutations on iron absorption may vary between racial/ethnic groups. In secondary analyses, venous haemoglobin decreased more slowly in donors with ferritin ≥ 12 μg/l; and haemoglobin recovery time was shorter in donors with reticulocyte haemoglobin (CHr) ≥ 32.6 pg, indicating that these biochemical measures are better indicators of a donor’s response to phlebotomy than their HFE mutation status.
doi:10.1111/j.1365-2141.2011.08952.x
PMCID: PMC3508695  PMID: 22118647
HFE; blood donor; iron deficiency; haemoglobin; ferritin
12.  Iron Deficiency in Blood Donors: Analysis of Enrollment Data from the REDS-II Donor Iron Status Evaluation (RISE) Study 
Transfusion  2010;51(3):511-522.
Background
Regular blood donors are at risk of iron deficiency, but characteristics which predispose to this condition are poorly defined.
Methods
2425 red cell donors, either first time (FT) or reactivated donors (no donations for 2 years) or frequent donors were recruited for follow-up. At enrollment, ferritin, soluble transferrin receptor (sTfR), and hemoglobin were determined. Donor variables included demographics, smoking, dietary intake, use of iron supplements, and menstrual/pregnancy history. Models to predict two measures of iron deficiency were developed: Absent iron stores (AIS) were indicated by ferritin < 12 ng/mL and iron deficient erythropoiesis (IDE) by log (sTfR/ferritin) ≥ 2.07.
Results
15.0% of donors had AIS, 41.7% IDE. In frequent donors, 16.4% and 48.7% of males had AIS and IDE, respectively, with corresponding proportions of 27.1% and 66.1% for females. Donation intensity was most closely associated with AIS/IDE (ORs from 5.3 to 52.2 for different donation intensity compared to FT donors). Being female, younger, and/or menstruating also increased the likelihood of having AIS/IDE, as did having a lower weight. Marginally significant variables for AIS and/or IDE were being a non-smoker, previous pregnancy and not taking iron supplements. Dietary variables were in general unrelated to AIS/IDE, as was race/ethnicity.
Conclusion
A large proportion of both female and male frequent blood donors have iron depletion. Donation intensity, gender/menstrual status, weight, and age are important independent predictors of AIS/IDE. Reducing the frequency of blood donation is likely to reduce the prevalence of iron deficiency among blood donors, as might implementing routine iron supplementation.
doi:10.1111/j.1537-2995.2010.02865.x
PMCID: PMC3050998  PMID: 20804527
Donors; Hematology–Red Cells; Blood Center Operations
13.  Two Mechanistic Pathways for Thienopyridine-Associated Thrombotic Thrombocytopenic Purpura 
Objectives
We sought to describe clinical and laboratory findings for a large cohort of patients with thienopyridine-associated thrombotic thrombocytopenic purpura (TTP).
Background
The thienopyridine derivatives, ticlopidine and clopidogrel, are the 2 most common drugs associated with TTP in databases maintained by the U.S. Food and Drug Administration (FDA).
Methods
Clinical reports of TTP associated with clopidogrel and ticlopidine were identified from medical records, published case reports, and FDA case reports (n = 128). Duration of thienopyridine exposure, clinical and laboratory findings, and survival were recorded. ADAMTS13 activity (n = 39) and inhibitor (n = 30) were measured for a subset of individuals.
Results
Compared with clopidogrel-associated TTP cases (n = 35), ticlopidine-associated TTP cases (n = 93) were more likely to have received more than 2 weeks of drug (90% vs. 26%), to be severely thrombocytopenic (84% vs. 60%), and to have normal renal function (72% vs. 45%) (p < 0.01 for each). Compared with TTP patients with ADAMTS13 activity >15% (n = 13), TTP patients with severely deficient ADAMTS13 activity (n = 26) were more likely to have received ticlopidine (92.3% vs. 46.2%, p < 0.003). Among patients who developed TTP >2 weeks after thienopyridine, therapeutic plasma exchange (TPE) increased likelihood of survival (84% vs. 38%, p < 0.05). Among patients who developed TTP within 2 weeks of starting thienopyridines, survival was 77% with TPE and 78% without.
Conclusions
Thrombotic thrombocytopenic purpura is a rare complication of thienopyridine treatment. This drug toxicity appears to occur by 2 different mechanistic pathways, characterized primarily by time of onset before versus after 2 weeks of thienopyridine administration. If TTP occurs after 2 weeks of ticlopidine or clopidogrel therapy, therapeutic plasma exchange must be promptly instituted to enhance likelihood of survival.
doi:10.1016/j.jacc.2007.04.093
PMCID: PMC3167088  PMID: 17868804
14.  Liver Transplantation: Intraoperative Changes in Coagulation Factors in 100 First Transplants 
Hepatology (Baltimore, Md.)  1989;9(5):710-714.
Six intraoperative blood samples were obtained at intervals from each of 100 individuals undergoing their first liver transplants. The patients fell into the following diagnostic categories: postnecrotic cirrhosis 28, primary biliary cirrhosis 20, sclerosing cholangitis 19, miscellaneous diseases 14, carcinoma/neoplasia 12 and fulminant hepatitis 7. Coagulation factor values in the initial (baseline) blood samples varied by patient diagnosis. In general, all factor levels were reduced except factor VIII:C, which was increased to almost twice normal. The slight intraoperative changes in factors II, VII, IX, X, XI and XII suggested that a steady-state relationship existed between depletion (consumption/bleeding) and repletion (transfusion, transit from extra- to intravascular space), even in the anhepatic state. In contrast, there were rapid and very significant falls in factor VIII and fibrinogen and a less pronounced decrease in factor V, all reaching their nadirs in early to mid-Stage III. The cause of these coagulation changes appears to be activation of the fibrinolytic system.
PMCID: PMC3032392  PMID: 2651269
15.  Intensive Plasma Exchange Increases ADAMTS-13 Activity And Reverses Organ Dysfunction In Children With Thrombocytopenia-Associated Multiple Organ Failure 
Critical care medicine  2008;36(10):2878-2887.
Thrombocytopenia-associated multiple organ failure (TAMOF) is a poorly understood syndrome in critically ill children. ADAMTS-13, formerly known as von Willebrand factor (VWF) cleaving protease, is decreased in adults with VWF mediated thrombotic microangiopathy, and intensive plasma exchange (PEx) both replenishes ADAMTS-13 and improves outcome in these patients. We hypothesized that children with TAMOF syndrome have decreased ADAMTS-13 activity which can be replenished with PEx. In the first of two consecutive studies, relationships between platelet count, VWF multimers, ADAMTS-13 activity, plasminogen activator inhibitor-1 (PAI-1) and prothrombin time (PT) were analyzed in children with and without TAMOF. In the second study, children with severe TAMOF (platelet counts<100,000/mm3 and ≥3 organ failure) were randomized to PEx or standard therapy. In the first study, children with TAMOF (n=28) had decreased ADAMTS-13 activity, but similar PAI-1 activity and PT compared to children with MOF without thrombocytopenia (n=9) (p<0.05). All non-survivors (n=7) had TAMOF, reduced ADAMTS 13 activity, and VWF-rich microvascular thromboses at autopsy. In the second study, PEx (n=5, median 12 days, 4–28 days) restored ADAMTS-13 activity and organ function, compared to standard therapy (n=5) (p<0.05). Children with TAMOF syndrome can have VWF mediated thrombotic microangiopathy. Similar to adult experience, PEx can replenish ADAMTS-13 activity and reverse organ failure in these children.
PMCID: PMC2772176  PMID: 18828196
ADAMTS-13; von Willebrand factor; thrombocytopenia; multiple organ failure; plasma exchange; thrombotic microangiopathy

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