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1.  Life-threatening biopsy of an iliopsoas pseudotumour in a patient with haemophilia: a case report 
Iliopsoas pseudotumour is a serious complication of haemophilia. We present the case of a 20-year-old male patient with a six-month history of left leg weakness, limitation of movement and wasting of the muscles. Clinically he was diagnosed as having a psoas muscle rhabdomyosarcoma. During a computed tomography (CT) scan-guided Tru-cut biopsy he developed a serious and life-threatening bleeding from a retroperitoneal muscular haematoma. The patient underwent laparotomy prior to his final diagnosis of an Iliopsoas pseudotumour, which is a serious, as well as rare, complication of haemophilia.
PMCID: PMC2412891  PMID: 18447900
2.  Acquired haemophilia secondary to ivabradine presenting with acute respiratory distress syndrome 
BMJ Case Reports  2012;2012:bcr0120125506.
The authors present the case of a 72-year-old patient who presented with severe dyspnoea, scant haemoptysis, pronounced desaturation and bilateral haematomas on the upper limbs. Chest radiography showed bilateral infiltrates mainly in the lower lobes. The patient’s prothrombin time, and platelet count were normal. However, the activated partial thromboplastin time showed a prolongation that was not reversed on a correction study. Factor VIII (FVIII) levels were very low and evidence of FVIII inhibitor was found. The patient had started taking ivabradine 2 months earlier, and the diagnosis of idiosyncratic acquired haemophilia was established. The patient was treated with volume expansion therapy, high levels of oxygen, multiple transfusions, methylprednisolone, desmopressine and rituximab. On the 3rd day, the patient showed progressive amelioration of his dyspnoea, oxygen needs and chest infiltrates. On the 7th day, the patient was discharged.
PMCID: PMC3339166  PMID: 22604198
3.  Efficacy of Corticosteroids Alone in the Eradication of Factor VIII Inhibitor in an Old Female with Idiopathic Acquired Haemophilia A: Description of a Case 
Case Reports in Rheumatology  2012;2012:310730.
Acquired haemophilia A (AHA) is a rare and serious disorder mainly affecting elderly patients. It is caused by the production of autoantibodies directed against coagulation factors; patients present with spontaneous bleeding, potentially fatal, in the absence of familial or personal history. Autoimmune disorders, infections, solid and hematologic tumors, and drugs are predisposing factors, but up to 50 percent of cases remain unexplained. The diagnosis of AHA is confirmed by specific laboratory tests; and the therapy is a clinical challenge, due to the fact that older patients are often affected by comorbidities. By passing agents may be used when persistent bleeding or haemodynamic instability is observed; corticosteroids, alone or with immunosuppressive therapy, are necessary to inhibit the production of the autoantibodies. We describe a case in which steroids in monotherapy successfully, safely, and persistently inhibited the production of anti-Factor VIII antibodies, in an old patient admitted after rheumatologic consult.
PMCID: PMC3437614  PMID: 22973529
4.  Haemophilia. 
Postgraduate Medical Journal  1997;73(858):201-206.
Although the nature of haemophilia has been understood for thousands of years, knowledge of its molecular genetics is recent. These X-linked bleeding disorders have diverse underlying DNA defects and, in 1992, DNA inversion within the X chromosome was found to explain half of the most serious cases of haemophilia A. The life-span and quality-of-life for patients with haemophilia had improved steadily throughout the early 1980s but the principal cause of death remained intracranial haemorrhage until the epidemic of HIV infection due to contaminated factor concentrates. Infection with hepatitis C virus is almost universal for patients treated with clotting factors before 1985. No curative treatment is available for hepatitis C at present. Knowledge of the transmission of viruses in concentrates has led to important developments in processing techniques to eliminate them. Recombinant technology has produced factor VIII and, more recently, factor IX concentrate which is likely to be very safe. Development of inhibitors to factor concentrates (especially factor VIII) remains one of the most serious complications of haemophilia. The variety of treatments available testifies to the lack of a single universally efficacious one. The use of prophylactic treatment has been conclusively demonstrated to result in a preservation of joint function in severely affected patients who might otherwise develop significant joint problems. The many facets of the care of patients with severe haemophilia, ranging from dental care to genetic counselling, can be advantageously co-ordinated in a haemophilia comprehensive care centre.
PMCID: PMC2431274  PMID: 9156121
5.  Primary Percutaneous Coronary Intervention in a Patient with Haemophilia A 
Case Reports in Medicine  2013;2013:189796.
Haemophilia A is a rare genetic condition leading to coagulation factor VIII deficiency and thus predisposing to bleeding diathesis. Due to advances in treatment, life expectancy of haemophilia A sufferers is increasing, and the incidence and prevalence of coronary artery disease are rising. There have been many reported cases of acute myocardial infarction in such patients, who subsequently undergo elective percutaneous coronary intervention. We present the case of a 55-year-old gentleman presenting with an acute anterior full-thickness myocardial infarction who required emergency primary percutaneous coronary intervention.
PMCID: PMC3880720  PMID: 24454390
6.  Severe Recurrent Achalasia Cardia Responding to Treatment of Severe Autoimmune Acquired Haemophilia 
Case Reports in Gastroenterology  2012;6(3):618-623.
Acquired haemophilia A and severe acquired achalasia are both very rare conditions with unknown aetiology. Haemophilia A is a haemorrhagic disease induced by deficiency or malfunction of coagulation factor VIII. Congenital haemophilia is an inherited disease transmitted by the mother through X-linked inheritance and primarily affects males. However, acquired haemophilia A is a serious, sudden-onset, autoimmune disease that affects either sex. In addition, achalasia is a disease of the oesophagus caused by abnormal function of the nerves and muscles. It causes swallowing difficulties due to the inability of the lower oesophageal sphincter to relax during swallowing, leading to dysphagia, regurgitation and chest pain. In this report, we describe the case of a patient with severe, newly diagnosed, acquired haemophilia A with long-standing, recurrent achalasia; the achalasia had recurred 3 times despite complete and proper surgical fixation. Acquired haemophilia A is treated with immunosuppressive therapy. High-dose steroid therapy was administered for 7 months, during which the patient responded well; moreover, the achalasia did not recur for more than 2 years. The response of the achalasia to immunosuppressive therapy suggests that achalasia may be an autoimmune disorder and that there may be an association between both diseases. The findings of the present case suggest that achalasia may favourably respond to steroid therapy as a first-line treatment prior to surgery.
PMCID: PMC3492964  PMID: 23139652
Recurrent achalasia cardia; Autoimmune acquired haemophilia; Cross-reacting autoantibodies
7.  Intraspinal bleeding in haemophilia: successful treatment with factor VIII concentrate. 
A severely affected haemophilic boy became tetraparetic as a result of a spontaneously occurring intraspinal haematoma. Myelography defined the extent of the lesion and showed it to be extradural in site. Infusion of large doses of factor VIII concentrate led to dramatic improvement and avoided the need to operate.
PMCID: PMC492946  PMID: 591991
8.  Inversions in the factor VIII gene: improvement of carrier detection and prenatal diagnosis in Dutch haemophilia A families. 
Journal of Medical Genetics  1995;32(4):296-300.
Haemophilia A is an X linked bleeding disorder caused by a heterogeneous spectrum of mutations in the factor VIII gene. It has recently been reported that about 50% of severe haemophilia A cases are the result of an iversion in the factor VIII gene. The inversion results from homologous recombination between the A gene located in intron 22 of the FVIII gene and one of the two distal A genes, thus disrupting the coding sequence of the factor VIII gene. The inversion can be detected by conventional Southern blotting and hybridisation techniques. Here we present an analysis of 177 unrelated Dutch haemophilia A cases for the presence of an inversion. In 57% of the patients with severe disease an inversion was found and also in at least one of the 26 patients with moderately severe disease. The majority of inversions (85%) involved the most distal A gene, while in a minority (15%) the more proximal A gene was involved. We show that direct mutation detection greatly improves the assessment of carrier status and prenatal diagnosis for haemophilia A, especially in families with an isolated patient. The inversion is predominantly of grandpaternal origin.
PMCID: PMC1050380  PMID: 7643361
9.  Liver disease complicating severe haemophilia in childhood. 
Archives of Disease in Childhood  1980;55(7):537-540.
Liver biopsies were performed in 5 boys aged between 2 and 9 years with severe classical haemophilia who had persistently abnormal liver function tests. Abnormal histology was present in all; 4 had chronic persistent hepatitis and the fifth chronic aggressive hepatitis with early cirrhosis. Evidence of previous hepatitis B infection was present in one patient, 3 had antibodies to hepatitis, A, and 2 had subnormal levels of alpha-1-antitrypsin. Haemobilia occurred as a late complication of biopsy in one. The significance of these findings in young boys is discussed, as is the role of exposure to factor VIII containing blood products. It is concluded that cryoprecipitate should be used in preference to large pool factor VIII concentrates in children with haemophilia.
PMCID: PMC1626797  PMID: 7436504
10.  Acquired Haemophilia A in the Elderly: Case Reports 
Acquired hemophilia A (AHA) is a very rare disease, caused by the development of autoantibodies, directed against circulating factor VIII of coagulation. Age distribution is bimodal, with a first peak occurring among young women in the postpartum period, and a second major peak of incidence among elderly patients in whom it is frequently associated with malignancy and drugs. This disease often represents a life-threatening bleeding condition, especially in the elderly, thus requiring a prompt therapeutic intervention, including control of acute bleeding and eradication of the inhibitor by immunosuppressive therapy. The diagnosis of AHA should be considered in any elderly patient who presents with bleeding and prolonged activated Partial Thromboplastin Time. Moreover, the coexistence of a series of underlying diseases associated with AHA should be always searched for. An early recognition and an adequate treatment of this coagulation disorder and of the possible associated diseases play a significant role for a favourable outcome, but concomitant morbidities in the elderly may limit aggressive therapy and may complicate the clinical scenario. We report 3 consecutive elderly patients successfully treated with recombinant activated factor VII and standard immunosuppressive regimens, with remission of the disease.
PMCID: PMC2831236  PMID: 20204184
11.  High rate of spontaneous inhibitor clearance during the long term observation study of a single cohort of 524 haemophilia A patients not undergoing immunotolerance 
The natural history of inhibitors in patients with haemophilia A not undergoing immune tolerance induction (ITI) is largely unknown. A recent randomized controlled trial suggests that the higher the FVIII dose used for ITI, the faster the clearance and the lower the rate of bleeding, without any difference in the rate of tolerance. We aimed at assessing the rate of spontaneous inhibitor clearance in a large cohort of patients not undergoing ITI.
A retrospective analysis of anti-FVIII inhibitors of long-term registry data in a single centre cohort of 524 haemophilia A patients considered for synovectomy was performed. Patients were tested for inhibitors before and 15 days after any and each surgical episode and thereafter did not undergo immune tolerance at any time.
The cumulative incidence of inhibitors overall was 34% (180 out of 524) with the highest percentage of 39% (168 out of 434) in severe patients which represented 83% of the cohort. Among the 180 inhibitor patients: 63 had permanent inhibitors; 70 fulfilled current criteria for transient inhibitors but a third category of 47 additional patients cleared the alloantibody spontaneously in >6 months. At logistic regression, both the inhibitor titre and the gene mutation were shown to predict time to clearance.
Spontaneous clearance of inhibitors over variable time in the absence of ITI treatment was found in up to 2/3 of the cases.
PMCID: PMC3766100  PMID: 24001010
Hemophilia A; Inhibitors; ITI
12.  Prevention of spontaneous bleeding in dogs with haemophilia A and haemophilia B 
Dogs with haemophilia A or haemophilia B exhibit spontaneous bleeding comparable with the spontaneous bleeding phenotype that occurs in humans with severe haemophilia. The phenotypic and genotypic characteristics of haemophilic dogs have been well-described, and such dogs are suitable for testing prophylactic protein replacement therapy and gene transfer strategies. In dogs with haemophilia, long-term effects on spontaneous bleeding frequency (measured over years) can be used as an efficacy endpoint in such studies. Although complete correction of coagulopathy has not been achieved, published data show that prophylactic factor replacement therapy and gene transfer can markedly reduce the frequency of spontaneous bleeding in haemophilic dogs. Further studies are currently ongoing.
PMCID: PMC3101869  PMID: 20586797
dogs; haemophilia A; haemophilia B; spontaneous bleeding
13.  Thrombin activatable fibrinolysis inhibitor activation and bleeding in haemophilia A 
Haemophilia  2011;18(3):e316-e322.
Individuals with haemophilia A exhibit bleeding tendencies that are not always predicted by their factor (f)VIII level. It has been suggested that bleeding in haemophilia is due not only to defective prothrombin activation but also aberrant fibrinolysis. Thrombin activatable fibrinolysis inhibitor (TAFI) activation was measured in tissue factor (Tf)-initiated blood coagulation in blood samples of 28 haemophiliacs and 5 controls. Reactions were quenched over time with FPRck and citrate and assayed for TAFIa and thrombin-antithrombin (TAT). The TAFIa potential (TP), TAFI activation rate and the TAFIa level at 20 minutes (TAFIa20min) was extracted from the TAFI activation progress curve. In general, the time course of TAFI activation follows thrombin generation regardless of fVIII activity and as expected the rate of TAFI activation and TP decreases as fVIII decreases. The magnitude of TP was similar among the control subjects and subjects with < 11% fVIII. In severe subjects with < 1% fVIII at the time of blood collection, the TAFIa20min was inversely and significantly correlated with hemarthrosis (-0.77, p=0.03) and total bleeds (-0.75, p=0.03). In all cases, TAFIa20min was more strongly correlated with bleeding than TAT levels at 20 minutes. Overall, this study shows that TAFI activation in whole blood can be quantified and related to the clinical bleeding phenotype. Measuring TAFIa along with thrombin generation can potentially be useful to evaluate the differential bleeding phenotype in haemophilia A.
PMCID: PMC3289731  PMID: 21933309
TAFIa; haemophilia A; factor VIII; bleeding score; thrombin generation; carboxypeptidase U
14.  Lymphocyte subset ratios and factor VIII usage in haemophilia. 
Archives of Disease in Childhood  1985;60(6):530-536.
Type and quantity of replacement treatment, together with haematological and immunological parameters were determined in 37 boys with severe haemophilia A and 41 children with other bleeding disorders. The quantity of factor VIII concentrate given to boys with severe haemophilia A (mean U/year) showed a significant inverse correlation with total white cell counts, lymphocyte counts, platelet counts, and the ratio of monoclonal antibody defined T lymphocyte subsets, T4 and T8 (T4:T8). Of the boys with severe haemophilia A, 49% had inversed T4:T8 ratios and 24% had thrombocytopenia. Treatment with high dose factor VIII concentrate (more than 25 000 U/year) was associated with low platelet counts, low lymphocyte counts, low T4:T8 ratios, and hypergammaglobulinaemia. In addition, six patients with severe haemophilia A and factor VIII inhibitors had inversed T4:T8 ratios. Patients treated exclusively with cryoprecipitate or prothrombin complex concentrates had normal T4:T8 ratios and platelet counts. The severity of the haematological and immunological abnormalities observed seems to be associated with high usage of factor VIII concentrates. Similar abnormalities have been described in patients with the acquired immune deficiency syndrome (AIDS). Prospective study of haemophiliacs is required to assess long term sequelae of factor concentrate usage, including the possible development of AIDS.
PMCID: PMC1777360  PMID: 3925894
15.  Outcome in moderate haemophilia 
Blood Transfusion  2014;12(Suppl 1):s330-s336.
Moderate haemophilia is the rarest form of haemophilia. This study aims to assess short- and long-term outcome, including its association with treatment, in patients with moderate haemophilia.
Material and methods
Seventy-five patients with moderate haemophilia (1–5% factor VIII/ factor IX activity), without a history of inhibitors, treated at the van Creveldkliniek, Utrecht (NL) were included in the study. Life-long data on bleeding and treatment were collected. Joints were evaluated using the Haemophilia Joint Health Score. Adults completed questionnaires on activity (HAL) and quality of life (SF-36, EQ5D).
The median age of the patients was 37 years (IQR 23–52 years) and haemophilia A was diagnosed in 89%. Bleeding frequency was low: the median annual bleeding rate was 2.0 bleeds/ year (IQR 0.8–3.7 bleeds/year), including a median of 0 joint bleeds/year (IQR 0.8–3.7 bleeds/year). Joint function was good: 82% scored <10 out of 126 points of the Haemophilia Joint Health Score (HJHS). Nevertheless, 29% of patients with moderate haemophilia had a history of prophylaxis, because of a high bleeding frequency. Median age at first joint bleed was 4.8 years (IQR 3.5–8.5). Use of prophylaxis was more associated with age at first joint bleed (P <0.01) than with baseline factor activity (P =0.12). Most patients (52%) who suffered their first joint bleed before the age of 5 years required prophylaxis later in life.
The majority of patients with moderate haemophilia have few bleeds and complications; however, a considerable subset of patients with a more severe bleeding pattern need prophylactic treatment. These latter patients may be identified by the onset of joint bleeding before the age of 5 years.
PMCID: PMC3934251  PMID: 23245711
moderate haemophilia; HJHS; physical activity; joint bleed
16.  Need for Prophylactic Treatment in Adult Haemophilia A Patients 
Background and Methods
A single centre study including 52 German patients aged ≥16 years with severe haemophilia A was performed to compare the amount of clotting factor and outcome between on-demand therapy (26 patients) and continuous prophylaxis (26 patients) over 1 year.
Prophylaxis reduced the number of bleeds significantly. Compared to on-demand treatment (20.5 ± 3.0 bleeds/year/patient), under prophylaxis 7.8 ± 1.3 bleeds/year/patient were observed. Joint bleeds were reduced from 12.2 ± 1.5 to 4.7 ± 1.0/year/ patient. In the on-demand group 38% of the patients suffered from more than 2 bleeds/month, whereas in the prophylaxis group no patient was found with more than 2 bleeds/month. Mean annual factor VIII (FVIII) consumption increased from 767 ± 110 IU/kg body weight under on-demand treatment to 2,841 ± 341 IU/kg body weight under continuous prophylaxis, displaying a nearly fourfold increase in FVIII consumption. Furthermore, prophylaxis implies a more than four-fold increase in treatment days which escalated from a mean weekly injection rate of 0.56 ± 0.08 FVIII injections/week when bleeds were treated on demand to 2.52 ± 0.30 FVIII injections/week during prophylaxis.
Even though the results reflect a benefit also for prophylactically treated patients regarding their bleeding frequency, one has to take into account a substantial increase of the costs for coagulation concentrates when all patients with severe haemophilia A switch to continuous prophylaxis.
PMCID: PMC2941834  PMID: 20877667
Haemophilia A; On-demand therapy; Continuous prophylaxis
17.  Acquired haemophilia A as a blood transfusion emergency 
Blood Transfusion  2008;6(1):8-11.
Acquired haemophilia is a rare autoimmune disorder caused by autoantibodies directed in the majority of the cases against clotting factor VIII. This disorder is characterised by the sudden onset of bleeding that not rarely may be life-threatening and need transfusion support. Most reports on this condition describe the need for blood transfusions during the acute, haemorrhagic phase, but the number of transfused red cell units is often unknown.
Patients and methods
In the last 5 years, 14 patients with acquired haemophilia A were identified in the transfusion and haemophilia centres of Verona and Castelfranco Veneto. The transfusion support for these 14 patients was analyzed in this retrospective survey.
The 14 patients required a total of 183 red cell units. The average transfusion requirement was 13 red cells units/patient, with a range from 0 to 38 units.
Eleven of the 14 patients studied needed strong transfusion support to enable any further management of the haemorrhages, as well as for eradication treatment of the autoantibodies to factor VIII. A relevant part of the management of haemorrhagic symptoms as well as the first choice for any further treatment (bleeding or the cure of the underlying disease) is transfusion of red blood cells.
PMCID: PMC2626855  PMID: 18661918
acquired haemophilia; transfusions; autoantibodies; anti-FVIII
18.  Management of dental extraction in patients with Haemophilia A and B: A report of 58 extractions 
Objectives: Patients with inherited bleeding disorders are at high risk of bleeding following oral surgery and present challenges to the oral surgeons. Aim of this study was to report our experience in dental extraction in patients exhibiting Haemophilia A and B between 2007 and 2012. Patient and Methods: 58 dental extractions in 15 patients during 19 interventions were performed. Replacement therapy with recombinant and plasma-derived factor VIII and IX was applied systematically in combination with antifibrinolytic treatment and local haemostatic measures. The following data were recorded: type of surgery, applied local haemostatic measures, general substitution, systemic antifibrinolytic agents and occurrence of postoperative bleeding complications. Results: Two patients presented postoperative bleeding. One had secondary bleeding requiring additional injection of factor concentrates. The other one presented epistaxis which was managed conservatively with a nasal tamponade. Conclusions: Excellent haemostasis is achievable after dental extractions in patients with Haemophilia A and B by following a protocol using defined pre- and postoperative doses of factor concentrates in combination with haemostatic measures.
Key words:Antifibrinolytic treatment, dental extraction, Haemophilia, inherited bleeding disorders, local haemostatic measures.
PMCID: PMC3909433  PMID: 24121912
19.  Patterns of bleeding in adolescents with severe haemophilia A. 
British Medical Journal  1979;1(6161):469-470.
Eighty-two boys with severe haemophilia A who spent some time at Lord Mayor Treloar College during 1973-7 were studied. All episodes of bleeding that occurred during term time were recorded, along with the number of transfusions. The bleeding frequency among these boys, most of them aged 10-17 years, increased steadily from 8,31 episodes/100 days in 1973 to 12,63 episodes/100 days in 1977. At the same time there was a steady fall in bleeding frequency with age. Altogether 24% of bleeding episodes were into the elbow joint, 22% into the knee, and 15% into the ankle. As the boys grew older the proportion of bleeding episodes in the legs declined and that in the arms increased. The overall results reflect the fact that special schools now see only the severest cases of haemophilia. The pattern of bleeding during adolescence suggests that concepts of management of arm bleeding need modifying.
PMCID: PMC1597799  PMID: 427411
20.  Case Report: Cauda Equina Syndrome Associated With an Interspinous Device 
Although postoperative spinal epidural hematoma (SEH) is not uncommon, hematomas that require surgery are rare. Cauda equina syndrome (CES) may be associated with postoperative SEH. In these cases, early recognition and emergency decompression can prevent further damage and better neurologic recovery.
Case Description
A 41-year-old man underwent two-level discectomy with insertion of an interspinous spacer at L3-4 and L4-5 because of low back pain and radiculopathy. Eight hours after the operation, the patient developed CES. MRI revealed SEH compressing posteriorly at the L3-4 level. On emergency decompression and hematoma evacuation, the interspinous spacer had obstructed the laminotomy site at L3-4 completely, blocking drainage to the drain. The patient experienced complete neurologic recovery by 2 months followup.
Literature Review
Many studies report risk factors for SEH. However, postoperative SEH can also be encountered in patients without these risks. One study reported a critical ratio (preoperative versus postoperative cross-sectional area) correlated with postoperative symptoms, especially in those with CES. The propensity to develop CES is likely dependent on a number of patient-specific factors.
Clinical Relevance
Surgeons should be aware that patients without risk factors may develop acute CES. Wider laminotomy (larger than half of the device size) may help to prevent this complication when one uses the compressible type of device, especially in patients with relatively small lamina.
PMCID: PMC3348300  PMID: 21870210
21.  Cyclosporin treatment of a woman with acquired haemophilia due to factor VIII:C inhibitor. 
Postgraduate Medical Journal  1989;65(764):400-402.
A 47 year old woman is reported who had life-threatening bleeding due to the spontaneous development of factor VIII:C inhibitor. Cyclosporin combined with prednisone resulted in a full recovery and complete elimination of antibody even when other therapeutic facilities failed to be effective.
PMCID: PMC2429330  PMID: 2514421
22.  Estimation of transient increases in bleeding risk associated with physical activity in children with haemophilia 
Although it is widely appreciated that vigorous physical activity can increase the risk of bleeding episodes in children with haemophilia, the magnitude of the increase in risk is not known. Accurate risk estimates could inform decisions made by children with haemophilia and their parents about participation in physical activity and aid the development of optimal prophylactic schedules. The aim of this study is to provide an accurate estimate of the risks of bleeding associated with vigorous physical activity in children with haemophilia.
The study will be a case-crossover study nested within a prospective cohort study. Children with moderate or severe haemophilia A or B, recruited from two paediatric haematology departments in Australia, will participate in the study. The child, or the child's parent or guardian, will report bleeding episodes experienced over a 12-month period. Following a bleeding episode, the participant will be interviewed by telephone about exposures to physical activity in the case period (8 hours before the bleed) and 2 control periods (an 8 hour period at the same time on the day preceding the bleed and an 8 hour period two days preceding the bleed). Conditional logistic regression will be used to estimate the risk of participating in vigorous physical activity from measures of exposure to physical activity in the case and control periods.
This case-control study will provide estimates of the risk of participation in vigorous physical activity in children with haemophilia.
PMCID: PMC2443707  PMID: 18582359
23.  Mutations in Intron 1 and Intron 22 Inversion Negative Haemophilia A Patients from Western India 
PLoS ONE  2014;9(5):e97337.
Despite increased awareness and diagnostic facilities, 70–80% of the haemophilia A (HA) patients still remain undiagnosed in India. Very little data is available on prevalent mutations in HA from this country. We report fifty mutations in seventy one Indian HA patients, of which twenty were novel. Ten novel missense mutations [p.Leu11Pro (p.Leu-8Pro), p.Tyr155Ser (p.Tyr136Ser), p.Ile405Thr (p.Ile386Thr), p.Gly582Val (p.Gly563Val) p.Thr696Ile (p.Thr677Ile), p.Tyr737Cys (p.Tyr718Cys), p.Pro1999Arg (p.Pro1980Arg), p.Ser2082Thr (p.Ser2063Thr), p.Leu2197Trp (p.Leu2178Trp), p.Asp2317Glu (p.Asp2298Glu)] two nonsense [p.Lys396* (p.Lys377*), p.Ser2205* (p.Ser2186*)], one insertion [p.Glu1268_Asp1269ins (p.Glu1249_Asp1250)] and seven deletions [p.Leu882del (p.Leu863del), p.Met701del (p.Met682del), p.Leu1223del (p.Leu1204del), p.Trp1961_Tyr1962del (p.Trp1942_Tyr1943del) p.Glu1988del (p.Glu1969del), p.His1841del (p.His1822del), p.Ser2205del (p.Ser2186del)] were identified. Double mutations (p.Asp2317Glu; p.Thr696Ile) were observed in a moderate HA case. Mutations [p. Arg612Cys (p.Arg593Cys), p.Arg2326Gln (p.Arg2307Gln)] known to be predisposing to inhibitors to factor VIII (FVIII) were identified in two patients. 4.6% of the cases were found to be cross reacting material positive (CRM+ve). A wide heterogeneity in the nature of mutations was seen in the present study which has been successfully used for carrier detection and antenatal diagnosis in 10 families affected with severe to moderate HA.
PMCID: PMC4028251  PMID: 24845853
24.  Acquired haemophilia heralded by bleeding into the oral mucosa in a patient with bullous pemphigoid, rheumatoid arthritis, and vitiligo 
Postgraduate Medical Journal  2006;82(963):e3.
Acquired haemophilia is rare and potentially fatal, with a mortality of 20% if left untreated. There is a strong association with other autoimmune diseases. This report describes a patient with rheumatoid arthritis, vitiligo, and bullous pemphigoid where the diagnosis of acquired haemophilia was made after an extensive bleed into a bullous lesion in the buccal mucosa. This case highlights some of the potential complications of acquired haemophilia and its treatment.
PMCID: PMC2563721  PMID: 16397069
acquired haemophilia; bullous pemphigoid; buccal haematoma; factor VIII inhibitor concentration; factor eight inhibitor bypassing activity (FEIBA)
25.  A Novel Missense Mutation, E1623G, in the Human Factor VIII Gene Associated With Moderate Haemophilia A 
Haemophilia A is the most common inherited X-linked recessive bleeding disorder. The severity of the resultant bleeding diathesis depends on the FVIII levels associated with the mutation. Analysis of carrier state can be made indirectly by DNA linkage analysis or directly by identifying the mutation that leads to the disease. The aim of this study was to identification of the causal mutation of the FVIII gene in a haemophilic patient.
Case Report:
Our case is a 16-year-old male haemophilia A patient with some symptoms such as recurrent hemarthrosis in left knee. In this study, we used single-stranded conformational polymorphism (SSCP) and conformational sensitive gel electrophoresis (CSGE) methods and direct sequencing to identify the mutation responsible for haemophilia A in our patient.
We reported a novel missense mutation (GAA→GGA), E1623G, in exon 14 of FVIII gene that is associated with moderate haemophilia A. This new mutation was recorded in GenBank (NCBI) with accession number JF916726.1. This study showed that the use of PCR-CSGE and PCR-SSCP may be useful in detecting most of genetic defects such as point mutations of FVIII gene in haemophilic patients.
PMCID: PMC3964430  PMID: 24719712
Hemophilia A; Mutation, Missense; F8 protein, human

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