Recurrent abortions in Asian Indians: no role of factor V Leiden Hong Kong/Cambridge mutation and MTHFR polymorphism.

Recurrent fetal loss is a frequent health problem. Data accumulated over the past few years have suggested a possible correlation between thrombophilia and fetal loss. Although a clear association has been established between fetal loss and certain thrombophilic states, such as antiphospholipid antibody syndromes, antithrombin deficiency, and combined defects, reports on the prevalence of inherited prothrombotic defects such as factor V Leiden mutation and methylene tetrahydrofolate reductase C677T polymorphism in fetal loss are contradictory. The prevalence of these 2 mutations in Asian Indians with recurrent fetal loss has not yet been studied. In light of this, the present study looked at the prevalence of these mutations in 85 patients with spontaneous recurrent abortion and 31 controls. The authors did not find any significant role of these mutations in the development of recurrent abortion.

Hairy cell leukemia: clinical, pathological and ultrastructural findings in Asian-Indians.

BACKGROUND: Hairy-cell leukemia (HCL), lymphoproliferative disease of older age, is characterized by projections from surface of abnormal cells. AIM: The aim was to study the clinical presentation and ultrastructural changes in hairy cells (HCs) following cladribine treatment. SETTINGS AND DESIGN: Clinical presentation, peripheral smear, bone marrow aspiration and biopsy of HCL cases diagnosed over a period of three years were reviewed. MATERIALS AND METHODS: Consecutive HCL cases in Hematology clinic of a tertiary care center were enrolled. Tartarate-resistant acid phosphatase (TRAP) test was done to detect HCs and electron microscopy was done to demonstrate initial ultrastructural changes and alterations following cladribine therapy. RESULTS: Fifteen cases of HCL, aged 32-57 years (median 47 years) were studied. The clinical presentation included splenomegaly in 15 (100%), fever in 10 (67%), hepatomegaly and pain abdomen in eight (53%), fatigue in nine (60 %) cases. The commonest laboratory features were monocytopenia in 13 (87%), neutropenia in 12 (80%), anemia in 10 (67 %) and pancytopenia in nine (60%). All patients showed symptomatic improvement on cladribine therapy. Electron microscopy after treatment (three months) showed loss of the finger like projections, characteristic bald lymphocytes, loss of ribosomal lamellar complexes, as well as decrease in mitochondria and vacuoles. CONCLUSIONS: Indian patients with HCL are younger. Cladribine is an effective therapy for these patients and leads to complete response in most of the patients. There is a significant improvement in the ultrastructural features following cladribine therapy.

Zoledronic Acid for Treatment of Low Bone Mineral Density in Patients with Beta Thalassemia Major.

To determine the efficacy of zoledronic acid (ZA) in thalassemia major associated low bone mineral density. Prospective, open label, single arm trial. Bone mineral density (BMD) at lumbar, hip and forearm region were performed at baseline and after 1 year of therapy. Initial, 9 patients received a first dose of 4 mg. Due to severe adverse effects, further doses for these patients and all new recruited patients were 1 mg once every 3 months for 4 doses. All patients were receiving 500 mg of calcium carbonate twice daily and 0.25 µg alfacalcidol once daily before and during the entire study period. Dual energy X-ray absoptiometry was performed at baseline and after 1 year. Twenty-seven patients with transfusion dependent thalassemia with a median age 19.5 year (15-38 years) were eligible for ZA treatment. Seven patients had bony pains. Four patients developed grade 4 hypocalcemia (3 developed tetany) and 2 developed infusion related toxicity with initial dose of 4 mg. One mg dose was well tolerated. At the end of 1 year, bone pains had completely resolved. There was significant increase in BMD at lumbar (p = 0.002) and forearm regions (p = 0.04) and intertrochantric area (p = 0.041). The % change in BMD at 1 year was +3.7 ± 3.2%. ZA is an efficacious agent in treatment of low BMD in these patients. ZA produces significant adverse reactions at 4 mg dose but 1 mg dose is well tolerated and is efficacious.

Disseminated intravascular coagulation in acute leukemia at presentation and during induction therapy.

Between January 2001 and December 2003, 67 patients with acute leukemia were evaluated prospectively for hemostatic abnormality at presentation, of which 43 (64.2%) had acute lymphoblastic leukemia and 24 (35.8%) had acute myelogenous leukemia. At presentation, 27 patients (40.3%) had bleeding manifestations. Thrombocytopenia was present in 57 patients (85%), and 33(49.3%) had some abnormality of global coagulation markers. Disseminated intravascular coagulation was defined by International Society of Thrombosis and Hemostasis criteria. Disseminated intravascular coagulation was more often associated with bleeding manifestations in acute myelogenous leukemia cases than in acute lymphoblastic leukemia cases. Two patients presented disseminated intravascular coagulation on day 7 of chemotherapy, without any bleeding manifestations. Four of 15 evaluated cases who had a bleeding or infection complication after day 7 of induction therapy also had disseminated intravascular coagulation. It is recommended that all patients with leukemia be investigated for disseminated intravascular coagulation at presentation.

Is it safe to avoid bone marrow examination in suspected itp?

Two children with suspected ITP are described. One child was treated outside with corticosteroids and was diagnosed acute lymphoblastic leukemia. Another child was fresh and diagnosed as acute myeloid leukemia on bone marrow aspirate examination. Both the children had no physical or peripheral smear finding suggestive of leukemia. We suggest that a bone marrow examination is required in developing countries for evaluation of thrombocytopenia before labeling it an immune thrombocytopenic purpura.

Autoimmune hemolytic anemia in children.

The clinical and hematological profile and treatment outcome of children with warm autoimmune hemolytic anemia (AIHA) were assessed using retrospective case record analysis. There were 26 (17 idiopathic; 9 secondary) patients with a median age of 11 years. Pallor (100%), fever (39%), and jaundice (59%) were the main presenting complaints. Jaundice was much more common in idiopathic (70%) compared to secondary (44%). Direct antiglobulin test was negative in 3 patients. Oral prednisolone produced remission in 81% patients. Four patients relapsed after a median period of 7 months (2 months to 2 year) after response. All responded to a second course of steroids in median 14 days. One child required cyclosporin A in addition. No correlation was found between response and parameters such as age, sex, jaundice, low pretreatment hemoglobin, reticulocyte count, total leukocyte count, platelet count, subtype of AIHA, and hepatosplenomegaly. Relapse correlated with increased duration between the onset of symptoms and treatment. This study indicates that oral prednisolone is an effective therapy for autoimmune hemolytic anemia. In refractory cases cyclosporine A may be useful.

Fludarabine, cyclophosphamide and horse antithymocyte globulin conditioning regimen for allogeneic peripheral blood stem cell transplantation performed in non-HEPA filter rooms for multiply transfused patients with severe aplastic anemia.

Multiply transfused patients of severe aplastic anemia are at increased risk of graft rejection. Five such patients underwent peripheral blood stem cell transplantation from HLA-identical siblings with a fludarabine-based protocol. The conditioning consisted of fludarabine 30 mg/m(2)/day x 6 days, cyclophosphamide 60 mg/kg/day x 2 days and horse antithymocyte globulin (ATG) x 4 days. Two different ATG preparations were used: ATGAM (dose 30 mg/kg/day x 4 days) or Thymogam (dose 40 mg/kg/day x 4 days). Engraftment: median time to absolute neutrophil count (ANC) >0.5 x 10(9)/l was 11 days (range: 8-17) and median time to platelet count >20 x 10(9)/l was 11 days (range: 9-17). At a median follow-up of 171 days (range: 47-389), there has been no graft rejection and all patients are in complete remission. Acute GVHD (grade 1) occurred in one patient only. Chronic GVHD developed in two patients (extensive in one and limited in another). The transplants were performed in non-HEPA filter rooms. In only one patient, systemic antifungal therapy (voriconazole) was used. The use of Thymogam brand of ATG for conditioning is being reported for the first time. Our experience suggests that this fludarabine-based protocol allows rapid sustained engraftment in high-risk patients without significant immediate toxicity.

Congenital vitamin K-dependent coagulation factor deficiency: a case report.

Congenital vitamin K-dependent coagulation factor deficiency is a very rare bleeding disorder, which usually presents with episodes of intracerebral bleed in the first few weeks of life, sometimes leading to a fatal outcome. We report a case of combined factor deficiency of vitamin K-dependent factors in which the patient presented with both intracerebral bleeding, and possibly also thrombosis, and responded to a vitamin K supplement along with fresh frozen plasma.

Spectrum of inherited bleeding disorders in Indians.

The incidence of hereditary hemorrhagic disorders may vary according to the country and ethnic origin. Von Willebrand disease has emerged as the most common hereditary hemorrhagic disease in the industrialized world. In this series of 966 patients diagnosed to have inherited bleeding disorders, hemophilia A was the most common and was seen in 410 (42.4%) of the patients followed by platelet function defects seen in 380 (39.4%) of the patients. It is thus concluded that, similar to the white population, hemophilia A remains the most common bleeding disorder in the Indian population, although this is closely followed by platelet function defects in India, which are quite rare in whites. Von Willebrand disease is relatively rare in the Indian population.

Clinicohematologic spectrum in patients with lupus anticoagulant.

A retrospective analysis of clinicohematologic parameters of 25 patients with lupus anticoagulant was carried out. The hematologic tests included dilute Russel viper venom test (dRVVT), kaolin clotting time (KCT), activated partial thromboplastin time, and prothrombin time. The diagnosis of lupus anticoagulants was based on the presence of prolonged KCT/dRVVT, its absence of correction with normal plasma and correction by phospholipids. Specific factor assays and platelet aggregation studies were performed wherever required. Ten patients (40%) had thrombosis, which was venous in 5 (50%) and arterial in 4 (40%). One patient (10%) had both arterial and venous thrombosis and presented with catastrophic antiphospholipid syndrome. Eighteen female patients conceived. Four (22%) of these had recurrent first trimester abortion. Five (20%) patients had bleeding manifestations. One (4%) of these had hypoprothrombinemia and was diagnosed to have hypoprothrombinemia lupus anticoagulant syndrome. However in two of these patients, no cause of bleeding could be identified other than the presence of lupus anticoagulants. It is concluded that patients with lupus anticoagulant have a varied spectrum of hemostatic disorders. Bleeding may sometimes occur in these patients due to associated thrombocytopenia or associated factor inhibitors. Rarely, it may occur due to presence of lupus anticoagulants alone.

Clinico-hematologic profile of factor XIII-deficient patients.

A retrospective analysis of clinico-hematologic parameters of 18 factor XIII-deficient patients was carried out. The hematologic tests included activated partial thromboplastin time (APTT), prothrombin time (PT), and clot solubility. Laboratory diagnosis of FXIII deficiency was made where bleeding time, PT, APTT, and thrombin time were normal and the clot solubility test result with 5M urea was positive. Factor XIII level with family screening was performed using commercially available kits. History of prolonged bleeding from the umbilical stump was present in four (22.2%) patients. The most common site of bleeding was the skin (11 of 18 patients). Three patients were given prophylaxis (FFP in two, factor XIII in one). A high prevalence of recurrent abortion in female patients with FXIII deficiency (two of the three patients in this study) was observed.

Inherited heterogenous defect in platelet aggregation selectively with ADP and epinephrine--a series of 25 cases.

Inherited heterogeneous defects of platelet function caused by impairment of platelet responses to weak agonists as ADP, epinephrine and others as low concentration collagen and platelet activating factor (PAF) have been described, though quite rarely. We describe here 25 cases of this defect with impairment in response to ADP and epinephrine. Subjects with a history of generalized bleeding and a prolonged bleeding time, PF3 availability or prothrombin consumption index and a normal platelet count, prothrombin time, activated partial thromboplastin time and clot solubility were subjected to platelet aggregation. Those of these which showed a normal aggregation with collagen and arachidonic acid and an absent or reduced aggregation with ADP and epinephrine were included in our study group. Subjects with history or findings suggestive of antiplatelet drug intake or any acquired condition affecting platelet functions were excluded from this study. 76% of the patients had onset of recurrent bleeding manifestations since childhood with a mean age at onset of 9.2 years. A positive family history was present in 36% of the patients. Majority of the patients (88%) presented with mild bleeding manifestations, the commonest symptom being appearance of recurrent ecchymotic spots. We present here a series of patients with a hereditary platelet aggregation defect selectively with ADP and epinephrine.

Tritiated thymidine labeling index in Indian childhood acute lymphoblastic leukemia.

Tritiated thymidine labeling index (LI) was determined in 25 unselected children with cytochemically proved ALL, at various stages of the disease. All the cases were treated by a uniform therapeutic protocol. Pretreatment LI determined in 15 cases showed an inverse correlation with the duration of first complete remission. LI was also studied during remission in 23 patients. Six out of these 23 patients relapsed within subsequent 90 days, while the rest continued to be in remission. Mean LI of the nonerythroid cells in later group of patients was found to be significantly higher than that of the patients who relapsed.

A study of serum ferritin in beta thalassemia. Iron deficiency and overload.

Serum ferritin, serum iron, and unsaturated iron binding capacity were studied in 64 patients with beta homozygous thalassemia (BHT), 120 patients with beta heterozygous thalassemia, and 46 normal subjects. Incidence of iron overload seen in 32 BHT cases was similar in untransfused and transfused cases. Among heterozygotes, iron stores were depleted in 24 (20%), mostly females (70.8%). Only male heterozygotes but not normals were iron deficient. In 18 (75%) heterozygotes with depleted iron stores, transferrin saturation (TS) was normal. It was also normal in 8 (25%) BHT patients and 5 (100%) heterozygotes with iron overload. In 13 (35.1%) BHT patients, it was raised in the absence of iron overload. It was concluded that iron deficiency in heterozygotes is of greater magnitude, especially in females, than hitherto known in India. Transferrin saturation is not a good indicator of either iron depletion or overload. Iron supplementation is recommended in heterozygous beta thalassemia in infants, children, and expectant mothers in geographic areas with high incidence of iron deficiency.

Vinblastine and danazol therapy in steroid resistant childhood chronic idiopathic thrombocytopenic purpura.

Various drugs such as vinca alkaloids, immunoglobulins and immunosuppressant drugs have been used with variable benefits in patients with chronic idiopathic thrombocytopenic purpura (CITP) refractory to steroid therapy. Vinblastine and danazol have been shown to decrease the expression of Fc (IgG) receptors on macrophages by different mechanisms. These two drugs were used in combination, with the presumption that they will have an additive effect in the treatment of CITP. Sixteen patients with CITP between 2 and 17 years of age, resistant to steroids, were treated with vinblastine given as an intravenous bolus dose at weekly intervals for 8 weeks (the induction phase), followed at monthly intervals for the next 6 months (the maintenance phase). Danazol was given daily in doses of 2-3 mg/kg body weight during both phases. Ten of the 16 (62.5%) patients had partial to complete response and 5 of these 10 patients had sustained remission after cessation of therapy. The initial outcome with the combination of these two drugs in CITP appears to be quite promising and requires further evaluation in a larger controlled study.

Hypertension as a paraneoplastic phenomenon in childhood Hodgkin's disease.

A 14 year old girl with Hodgkin's disease presented with hypertension as an unusual paraneoplastic phenomenon. The elevated plasma renin activity recorded in this patient was possibly a result of Hodgkin's disease. Hypertension as well as plasma renin activity declined to normal values following her successful response to chemotherapy.

Asymptomatic visceral leishmaniasis in a child with acute lymphoblastic leukaemia.

Visceral leishmaniasis was detected incidentally in a patient with acute lymphoblastic leukaemia in remission, during maintenance therapy. Absence of fever, a normal haemogram, normal serum globulins, a negative serology and testicular involvement were the hallmarks of the case. Treatment with sodium stibogluconate (20 mg/kg for 55 days) failed. Subsequent therapy with pentamidine resulted in complete parasite clearance. Prolonged therapy with pentavalent antimony compounds or a higher dose of second line drugs such as pentamidine are recommended for complete clearance.

Etiology of febrile episodes in children with acute lymphocytic leukaemia.

In 53 children (aged 5 months to 11 yr) with acute lymphoblastic leukemia, 68 febrile episodes were investigated for determining the etiology. Microbial organisms were isolated in 33 episodes. Bacteraemia was seen in 24 patients and in three of them Clostridium species were isolated. Escherichia coli was the commonest isolate and was seen in 11 (18.6%) febrile episodes. Other common organisms isolated were Staphylococcus aureus in nine (15.2%), and Klebsiella pneumoniae and coagulase negative Staph. in 6 (10.2%) episodes each. Pseudomonas aeruginosa and Acinetobactor were isolated in 5 (8.5%) episodes each.

Hemophilia A: role of FVIIIC/vWF Ag in assisting linkage analysis for carrier detection.

Carrier detection for hemophilia A was carried out in 52 females from 30 families presenting to the Haematology Department AIIMS, using linkage analysis and factor VIIIC (FVIIIC)-von Willebrand factor (vWF) antigen assay. The allelic frequency for the marker Bcl 1 and Xba 1 was 0.58 and 0.54, respectively, for the positive alleles and 0.42 and 0.46, respectively, for the negative alleles. The heterozygosity frequency of Bcl I and Xba 1 was 0.65 and 0.55, respectively. Of the 52 females, 30 were mothers of hemophilic patients and 22 were sisters of hemophilic patients. Of the 30 mothers, positive family history was present in 14. In these patients, the defective X chromosome was tracked in 10, and in four the defective X chromosome could not be tracked because the mothers were homozygous for the marker used. Of the 16 mothers without a family history of disease, three were observed to be carriers based on linkage analysis and reduced factor VIII levels in mother/sister. Possible defective X chromosome was tracked in 11 mothers and five were noninformative because they did not show heterozygosity for the markers used. Using linkage analysis, nine of the 22 sisters were found to be definite carriers, 10 noncarriers, and three were noninformative. It is thus concluded that using Bcl 1 and Xba 1 linkage analysis, carrier status can be definitely ascertained in 50% females and this level of information can be increased to 61.5% by measuring FVIIIC/vWF antigen levels in them.