F. Jijina

Venous thromboembolism in young patients from western India: a study.

The goal of this article is to study the association of known markers of thrombophilia with venous thrombosis in young patients (< 45 years) from the Western part of India. A prospective study of 432 patients (252 males and 180 females, age 1-45 years) was conducted between 1994 and 2000 (6 years). The diagnosis was confirmed in all the patients by ultrasound with Doppler or by a computed tomograph (CT) scan of the brain with or without contrast depending on the case. Detailed clinical examination, and family history was taken to establish recurrent thrombosis and familial occurrence of thrombosis. The markers studied were protein C, protein S, antithrombin (AT) III, factor V Leiden mutation, prothrombin gene G20210A polymorphism, and the thermolabile MTHFR variant C677T polymorphism, using appropriate techniques. Lupus inhibitor was tested in the first 72 patients using Dilute Russel Viper Venom Time (DRVVT) test, and anticardiolipin antibodies were tested by enzyme-linked immunosorbent assay. Protein C, protein S, and AT III deficiency was detected in 9.5%, 6.5%, and 2.6%, respectively, among the patients. Anticardiolipin antibody was present in 9.9% of the patients, whereas lupus anticoagulant was present in 8.3% of patients; factor V Leiden mutation was detected in 3% of patients; thermolabile variant of MTHFR C677T polymorphism was present in 14.9% of patients with 1.2% homozygotes. Prothrombin G20210A polymorphism was not detected in any sample in this population. One hundred and four patients of 432 (24.9%) had recurrent attacks of thrombosis without any proximate precipitating cause, whereas 7.5 % of the patients had another close member of the family with a history of deep venous thrombosis. Eighty-six members from 28 families (out of 32 families giving family history of thrombosis) were investigated and found to have protein C and protein S deficiency in seven each; factor V Leiden was present in 6, and MTHFR C677T polymorphism was present in 5 cases. Hence, 25 of 86 members (28%) from the family of patients with familial history deep venous thrombosis had positive markers for thrombophilia. Thus, we could show that in young patients presenting with thrombosis, at least 34% of them had a demonstrable cause for thrombophilia. Prothrombin gene polymorphism G20210A seems to be nonexistent in our population and AT III deficiency also appears to be low compared to other markers of thrombophilia. There is a high prevalence of variant MTHFR C677T in our series, but the incidence of MTHFR C677T in our general population is also high. Hence, the significance of this finding in our cases of deep venous thrombosis remains to be seen, but we did not see any homozygotes when we tested 70 randomly selected asymptomatic persons, whereas in the present series, 1.8% of the patients had homozygosity for the MTHFR C677T polymorphism.

Role of epsilon amino caproic acid in the management of haemophilic patients with inhibitors.

Summary.  We managed bleeding crisis in 10 consecutive severe haemophilic patients with inhibitors (eight had an inhibitor level of >5 BU mL−1) mainly with the antifibrinolytic agent, i.e. epsilon amino caproic acid (EACA). EACA was used by local, oral or intravenous routes either in combination or separately. Five patients developed inhibitors postoperatively and among the remaining five, four had recurrent haemarthrosis or soft tissue bleeds and one patient presented with severe gastrointestinal bleeding without demonstrable lesion. In all the patients, addition of EACA to their management protocol resulted in stoppage and/or reduced frequency of bleeding. In six of 10 patients, the results were excellent; of these six patients, five developed inhibitors postoperatively. Although a reduction in the frequency of bleeding was observed in patients with haemarthrosis and soft tissue bleed, it was not spectacular and the patients required additional therapy. Hence the results could be described as poor. No patient needed to stop the medicine because of the side‐effect of EACA. Symptoms like mild nausea and vertigo were seen as the side‐effects of this medicine when high intravenous dosage was administered. EACA thus appears to be an excellent adjuvant therapy for haemophilic patients with inhibitors. Besides its well‐recognized antifibrinolytic activity, EACA may have additional mechanisms of action in haemophilic patients with inhibitors . More extensive use of this cheap and safe product is warranted in haemophilic patients with inhibitors. If larger studies confirm this observation, then using antifibrinolytics will allow substantial reduction of FEIBA or activated prothrombin complex (APCC) usage in such patients without necessarily increasing the thrombotic complications or reduction of the clinical efficacy, when compared with higher dosage of FEIBA or APCC alone. This will lead to substantial financial savings in countries where up to 35% of severe haemophilia A patients develop inhibitors.

First‐time development of FVIII inhibitor in haemophilia patients during the postoperative period

Summary. Development of inhibitor to FVIII in haemophilia patients is well‐known and is not uncommon. However, their development for the first time during the postoperative period has hardly been reported. In a developing country such as India, where resources are limited, development of such an eventuality may prove disastrous. However, as many of our patients are sparingly treated, therefore, even if they test negative for the inhibitor preoperatively, they may get the requisite FVIII antigenic stimulation during the preoperative and immediate postoperative period, leading to the development of inhibitors during this critical time of wound healing. We describe here six patients who developed such an inhibitor, from a group of 35 patients with haemophilia A who underwent various surgical procedures (19%). We stress that such an eventuality may not remain rare in developing countries as more patients of severe haemophilia undergo surgery and are therefore challenged for the first time in their life with large amounts of FVIII concentrate during their preoperative period.

Intracranial haemorrhage in severe haemophilia: prevalence and outcome in a developing country.

Summary.  Intracranial haemorrhage (ICH) is a common cause of morbidity and mortality in haemophilic patients all over the world. From 1995 to 2004, we have investigated 37 patients with 43 episodes of ICH at our Comprehensive Haemophilia Care Center from a total of 600 registered patients. Diagnosis of ICH in the patients was confirmed by clinical, haematological and computed tomographic imaging data. Three patients died despite replacement therapy while one child who had a ventriculo‐atrial shunt for acute hydrocephalus also died before further intervention. One of the four patients who died also had severe aplastic anaemia for 6 years in addition to severe haemophilia. Detailed history obtained from 143 families with haemophilia attending the Genetic Diagnosis Clinic at our Center showed a positive history of cerebral bleed in 39 episodes in 37 patients. Sixteen families gave a history of death in the family of haemophilic patients due to ICH, while in the remaining 21 families, the patients had survived the episode after treatment elsewhere. However, the ICH was not confirmed by image data in these cases. The treatment protocols were also not available in these cases. Conservative factor replacement therapy 100% correction for 3 days followed by 50–60% correction for 7 days) coupled with the epsilon amino caproic acid, the antifibrinolytic agent at least for 30 days led to a mortality (10.8%) similar to that of the western countries and almost no morbidity. Surgery was not required in any of these patients except in one elderly patient with HIV infection on antiretroviral therapy.

Effect of hydroxyurea on the transfusion requirements in patients with severe HbE-β-thalassaemia: a genotypic and phenotypic study

Background Haemoglobin E (HbE)-β-thalassaemia has a very variable clinical presentation. The management of severe cases that are often transfusion dependent is similar to that of cases of β-thalassaemia major; however, this is often not possible in India because of its high cost and the lack of availability of safe blood at many places. Thus there was a need for a drug such as hydroxyurea, which is known to reduce the transfusion requirements of patients with thalassaemia intermedia. This study was undertaken to evaluate the response of Indian patients with HbE-β-thalassaemia to hydroxyurea. Materials and methods 11 patients with HbE-β-thalassaemia receiving regular transfusion plus two less frequently transfused patients were selected for hydroxyurea therapy. Clinical and haematological evaluation was performed before and after treatment for 2 years. Molecular studies included β-globin genotype, β-globin gene haplotype, Xmn I polymorphism and α-genotyping. Results Four clinically severe patients became transfusion independent (responders) after hydroxyurea therapy, four patients showed a reduction in their transfusion requirements (partial responders), and three patients were non-responders. Responders showed a statistically significant increase in Hb, mean corpuscular volume, mean cell Hb, fetal Hb and F cells with a reduction in their transfusion requirements. A reduction in serum ferritin concentration was also seen in responders and non-responders. Conclusions Genetic markers such as Xmn I polymorphism and α-gene deletions were not always beneficial for the response to hydroxyurea therapy. Thus many more markers and a larger cohort need to be studied to predict the response in these patients.

Recurrent haemoperitoneum in a female patient with type III von Willebrand’s disease responded to administration of oral contraceptive

This article reports the success of oral contraceptive intervention in the prevention of hemoperitoneum among women with type III von Willebrand factor (vWF) deficiency. Discussion includes a case of a 29-year-old married female with one child who had a known severe von Willebrand disease and presented with blood in the pouch of Douglas as observed by ultrasonography and CT scan examination. She was managed with 30 g of ethinyl estradiol (Ovral-30) which was maintained for 2 years. The addition of tranexamic acid at 2 g/day starting the day before her expected date of menstruation and thereafter for 5 days minimized menstrual blood loss. Though the severity of vWF disease has not changed in the same patient hemoperitoneum occurs only on certain ovulations which may be explained by occasional higher levels of FSH/LH surge and greater vascularity of the Graafian follicle because of its larger size. If pregnancy is desired it remains to be seen whether only tranexamic acid is capable of stopping the midcycle Graafian follicle bleed.

Fractures of long bones in severe haemophilia

Dear Editor, Patients with severe haemophilia in developing countries still get crippling arthropathies and joint deformities. This has been highlighted in several previous studies [1]. The Comprehensive Hemophilia Care Center, Mumbai, has 700 patients of hemophilia registered. Out of these, 500 patients have severe haemophilia. None of these patients are on the prophylactic factor replacement therapy. For many of these patients, joint bleeds are treated with only symptomatic measures like immobilization, local ice application and analgesics owing to either non-availability or non-affordability of the factor concentrates. Out of these 500 cases reviewed over the last 5 years, 20 patients had long-bone fractures (22 episodes). These patients were treated in consultation with orthopaedic surgeons, haematologists and physiotherapists, depending on the site of fracture, nature of fracture, and inhibitor status of the patient. Twenty out of the 500 cases of severe haemophilia sustained fracture during the last 5 years. two patients had two episodes of fracture each. The average age at the time of sustaining fracture was 28 years (14–46). Fifteen patients were <35 years of age. All these patients had severe haemophilia, 19 with factor VIII <1% and one with factor IX <1%. Nine patients had inhibitors positive ranging from 4.2 to 465 BU mL. The details of the site of fracture, nature of injury, inhibitor status and time taken or fracture union are given in Table 1. Seventeen patients had fractured femur (two had fractured neck, five supracondylar and 10 shaft femur); three had fracture of upper end of tibia; one had fracture humerus; and one had fracture of radius and ulna. Six patients with fractured femur required surgery for internal fixation, whereas others were managed conservatively with closed reduction and plaster cast. Liver function tests, including total and conjugated bilirubin, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase and serum albumin, were normal in all the 20 patients, indicating the absence of active liver disease, either acute or chronic. Bone density assessment by DEXA (Dual Energy Xray Absorptiometry) scan was done in six of these patients. They showed bone mineral density (BMD) (Z score) of )2.5 to )4.9 in lumbar spine and )1.4 to )3.8 in the femoral neck. Osteoporosis of lumbar spine was observed in all the six patients. Both the patients who sustained fracture of neck femur had osteoporosis of the hip area. Osteopaenia of the hip was observed in the remaining four patients. Table 2 shows the results of DEXA scan in these six cases. The severity of osteoporosis can be gauged from Figs 1 and 2. The review of literature on fractures in haemophilia showed that there is very little information on the magnitude of this problem, and most of the literature is on the management of these cases [2]. Spontaneous fracture with trivial trauma is normally not seen in young healthy individuals. All the patients, except four, in this group sustained fracture after a fall from standing position following tripping, much like the patients of old age with fracture of femoral neck. In a recent study in patients with severe haemophilia in children, the mean BMD z score was )0.92, which was significantly reduced, compared with that for control subjects [3]. It has also been shown that weight-bearing exercises are crucial in acquiring adequate bone mass in childhood [4]. Correspondence: Dr Kanjaksha Ghosh MD, MRCP, FRC Path, FACP, FNASc, Deputy Director, Institute of Immunohaematology, 13th Floor, NMS Bldg, KEM Hospital Campus, Parel, Mumbai – 12, India. Tel.: 24138518/19; fax: 24138521; e-mail: kanjakshaghosh@hotmail.com

Use of the dual force system to correct chronic knee deformities due to severe haemophilia

In this study, the use of the dual force system to correct recent or relatively longstanding knee deformities in ten patients is described. (Nine of the patients had severe haemophilia and one had severe von Willebrand’s disease.) The mean duration of deformity in these patients was 10 months. The mean range of movement at the affected knee joints increased from 50° at pre‐intervention to 110° following 6 weeks of application of the dual force system. In nine of ten patients (90%) the residual flexion deformity ranged from 0° to 10°. The dual force system offers an easily affordable and effective means of correcting a flexion deformity of the knee joint in severely affected haemophilia and allied disorders. More extensive use of this technique in different centres is required to determine its place in the day‐to‐day management of such patients.

The effect of UGT1A1 promoter polymorphism on bilirubin response to hydroxyurea therapy in hemoglobinopathies.

OBJECTIVES Hydroxyurea is known to reduce ineffective erythropoiesis and thereby hemolysis leading to a reduction in bilirubin levels in patients with hemoglobinopathies. However, the effect of hydroxyurea on hyperbilirubinemia in relation to the UGT1A1 gene promoter polymorphism is not known in Indian patients with different hemoglobinopathies. DESIGN AND METHODS We studied 112 patients (77 sickle cell anemia, 22 β-thalassemia intermedia and 13 HbE-β-thalassemia) who were on hydroxyurea therapy for 2 years for their response towards hyperbilirubinemia associated with UGT1A1 promoter polymorphism. RESULTS The patients with (TA)(7)/(TA)(7) repeats had significantly higher serum bilirubin levels than those with (TA)(6)/(TA)(6) repeats in all the groups and the reduction in serum bilirubin after hydroxyurea therapy was still higher among patients with (TA)(7)/(TA)(7) repeats when compared with (TA)(6)/(TA)(6) repeats. CONCLUSIONS Higher bilirubin levels were associated with the (TA)(7)/(TA)(7) sequence however they did not come down to normal levels after hydroxyurea therapy.

Diffuse alveolar haemorrhage with severe haemophilia

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