Manoranjan Mahapatra

Intracranial haemorrhage in patients with congenital haemostatic defects

Summary.  We investigated 52 of 457 patients with congenital factor deficiencies with 57 episodes of intracranial haemorrhage (ICH) between 1998 and 2007. There were 38 severe haemophiliacs, 6 with factor XIII deficiency, 5 with factor X deficiency, 2 factor V‐deficient patients, and 1 with type 3 von Willebrand disease (VWD). The median age was 8 years (range 1 month–22 years). Most patients were below 15 years of age (86.5%). All patients with factor X deficiency were between 1 and 5 months of age. ICH was the primary bleeding episode leading to detection of factor deficiency in 19.2% (five patients with severe haemophilia and all patients with factor X deficiency). Trauma caused bleeding in 66%. None of the patients with factor X deficiency had history of prior trauma. Surgery was performed in five patients with subdural haematomas, all of whom survived. Conservative factor replacement with 100% correction for 3 days followed by 50–60% correction for 7 days was possible in 60% patients. Seizures requiring prolonged therapy were noted in eight patients. Death was recorded in 15 patients (29%). Inadequate therapy in the form of delay or insufficient replacement was noted in 7/15 deaths. ICH was seen in 11.3% of all patients with coagulation factor deficiencies. Factor X deficiency presented with ICH at an earlier age. Inadequate replacement therapy including delayed treatment caused nearly 50% of all deaths. Most patients can be managed satisfactorily with adequate replacement therapy alone, with surgery being reserved for those with worsening neurological conditions.

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/m2/day × 6 days, cyclophosphamide 60 mg/kg/day × 2 days and horse antithymocyte globulin (ATG) × 4 days. Two different ATG preparations were used: ATGAM (dose 30 mg/kg/day × 4 days) or Thymogam (dose 40 mg/kg/day × 4 days). Engraftment: median time to absolute neutrophil count (ANC) >0.5 × 109/l was 11 days (range: 8–17) and median time to platelet count >20 × 109/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.

Imatinib-induced Stevens–Johnson syndrome: recurrence after re-challenge with a lower dose

Dear Editor, Imatinib mesylate (STI-571), a selective BCR–ABL (BCR, breakpoint cluster region) tyrosine kinase inhibitor, has been found to be effective in the treatment of different phases of chronic myeloid leukemia (CML). Cutaneous reactions to imatinib therapy are known, with 5% of these reactions being severe [1]. Although a variety of skin manifestations have been described, the occurrence of Stevens–Johnson syndrome (SJS) is rare. A 60-year-old woman was diagnosed as Philadelphiapositive CML in the chronic phase. She had a splenomegaly of 20 cm below costal margin. Her initial hemogram revealed the following: hemoglobin, 12.6 gm/dl; white blood cell count, 196×10/l; and platelet count, 420×10/l with 8% myeloblasts. She was started on imatinib at a dose of 400 mg daily. On the 12th day of therapy, she developed pruritic maculopapular erythematous rash together with mild periorbital edema. The following day, these lesions had progressed into a disseminated rash with confluent areas over the neck, chest, and upper abdomen. In addition, there were oral and vaginal mucosal erosions. The hemogram showed hemoglobin at 12.1 gm/dl, total leukocyte count of 4,300/mm, and platelet count of 470× 10/l with no blasts. The skin biopsy from lesions on the upper abdomen showed parakeratosis, mild irregular acanthosis of the epidermis along with perivascular and periappendigeal lymphohistiocytic infiltration in the dermis. A diagnosis of SJS was made, and imatinib was stopped immediately. She was not on any other medication; therefore, imatinib was the most probable cause for the reaction. Healing started within few days of stoppage of the drug, and in 10 days, the lesions were completely cleared. Her baseline variables put her in the Sokal highrisk group. Therefore, 2 weeks after complete clearance of the rash, imatinib was restarted at a lower dose of 200 mg daily. The following day, she again developed a perioral pruritic erythematous eruption that suggested an early recurrence of the similar adverse drug reaction. The drug was stopped again, and the patient was given fexofenadine and oral prednisolone (40 mg/day). The rash quickly resolved. The patient was started on hydroxyurea, and imatinib was stopped for 1 month. Imatinib was again restarted at 100 mg together with prednisolone 40 mg/day (1 mg/kg). There was no further recurrence of the rash. In the next 6 weeks, the prednisolone was slowly reduced and stopped while dose of imatinib was increased to 300 mg. The patient has now been on treatment for 6 months with no further recurrence of the rash. Imatinib is the most active agent for the treatment of CML, and skin rashes are quite common with this agent [2]. Imatinib is associated with a variety of adverse cutaneous reactions, including urticaria, maculopapular exanthem, generalized exanthematous pustulosis, exfoliative dermatitis, and SJS [1–4]. In our patient, the lesions reappeared on re-challenge with imatinib, which was also reported earlier [5, 6]. Brouard and Saurat [2] have shown that the incidence of cutaneous reactions with imatinib increases with escalating doses of the drug. Valeyrie et al. [1] have reported female sex and imatinib dosage as being independent risk factors for the development of rashes in a multivariate analysis. Most cutaneous eruptions caused by imatinib do not necessitate discontinuance of imatinib and are usually self-limited despite continued treatment. Administration of oral or topical corticosteroids can ameliorate Ann Hematol (2007) 86:537–538 DOI 10.1007/s00277-007-0265-y

Do alpha deletions influence hydroxyurea response in thalassemia intermedia

Abstract Thalassemia intermedia patients show variable phenotypes. Hydroxyurea (HU) may benefit some of the thalassemia intermedia cases (1), however, the parameters influencing the response to HU have not been reported. In this study, the molecular parameters, a-globin and ß-globin genotype and the Xmn I polymorphism, were correlated with the HU response. Twenty patients with thalassemia intermedia were given HU (10–20?mg/kg) and responses were evaluated over a one year period. Twelve patients (60%) showed a good response to therapy with a significant increase in Hb and HbF levels and with elimination of the transfusion requirement in four patients. Four out of the twelve (33%) patients were positive for -a 3.7 deletions whereas none of the 8 non-responders were positive for alpha deletions. One each of the responders and non-responders were positive for aaa anti-3.7 triplication. Three (25%) responsive and one non-responsive patients were homozygous for the IVS1-1 (G?T) mutation. Three of the responsive patients with alpha deletions were also homozygous positive for Xmn I polymorphism. Thus, in addition to acting in synergy with the XmnI polymorphism, alpha deletions may be an independent factor predicting good response to HU in thalassemia intermedia, although this needs to be confirmation in larger studies.

Intracranial hemorrhage in childhood immune thrombocytopenic purpura

We retrospectively analyzed 750 patients with ITP for development of intracranial hemorrhage (ICH). Seventeen cases with age range of 10 months to 18 years were studied. Ten patients were of acute ITP and seven had chronic ITP. Nine patients developed ICH one month after the onset of ITP and five patients had ICH on presentation. ICH was precipitated by trauma in four patients and possibly the use of NSAIDs in one patient. Median platelets counts at the time of ICH were 12 × 109/L (range 2–50 × 109/L). Most patients were treated with corticosteroids. Four patients (24%) died due to ICH. Pediatr Blood Cancer 2009;52:529–531.

Tuberculosis in acute leukemia: A clinico-hematological profile

Abstract We studied 130 consecutive cases of acute leukemia over a 2-year period and identified 9 cases (6.9%) with active tuberculosis (TB). Eight patients with TB had acute myeloid leukemia (AML). Patients with AML were more likely to develop TB as compared to patients with acute lymphoblastic leukemia (ALL) despite the wider use of steroids and radiotherapy in ALL protocols {OR 4.41 (CI 0.53–36.44)}. Only 1 patient died of disseminated TB during post induction neutropenia. All other patients were successfully managed using current anti-tuberculous therapy (ATT). On the whole, TB did not cause any undue delay in chemotherapy and did not flare up during subsequent chemotherapy cycles. However it is not a commonly described infection in acute leukemia and a high index of suspicion is warranted especially in areas endemic for TB.

Hypercoagulable state in five thalassemia intermedia patients.

Fifty-three patients of thalassemia intermedia and 40 controls were studied for clinical evidence of thrombosis and laboratory evidence of hypercoagulable state. Thrombotic episodes were detected in 5 (9.4%) patients. Two of these 5 patients with thrombosis were splenectomized. Laboratory evaluation showed presence of thrombocytosis in 8 (15%), 5 of these were splenectomized. Platelet hyperaggregation was detected in 12 (22.2%) patients. Although rate of aggregation was slow in 7 (13.2%) patients, degree of aggregation was normal in these 7 patients and platelet hypoaggregation was not detected in any patient. Level of coagulation inhibitors protein C and protein S, and antithrombin III were decreased in 31 (58.4%) patients. There was no correlation between low level of protein C and protein S with hepatic dysfunction and iron overload. Antithrombin III level was decreased only in 8 (15%) patients. There was a statistically significant association between the lower level of this inhibitor and hepatic dysfunction. In conclusion, this study provides evidence for the existence of a chronic hypercoagulable state in patients with β thalassemia intermedia, and suggests that expression of a procoagulant surface by thalassemia intermedia red blood cells may be the major underlying factor giving rise to platelet and coagulation inhibitor abnormalities in these patients. These alterations are not related to iron overload or hepatic dysfunction.

Allogeneic hematopoietic SCT performed in non-HEPA filter rooms: initial experience from a single center in India

In developing countries, it is important to ascertain the safety of performing allogeneic hematopoietic SCT (HSCT) in single rooms without high-efficiency particulate air (HEPA) filters. We present our experience of performing 40 such transplants from July 2004 to November 2007. Source of stem cells was peripheral blood in 33, bone marrow in six and combined in one. G-CSF started from day +1. The indications were SAA-18, CML-7, AML-7, ALL-2, myelodysplastic syndrome-2 and thalassemia major-4. The median age was 19 years (range 2.2–46) with 29 male and 11 female participants. Antibacterial and antifungal prophylaxis was administered along with conditioning, and at the onset of fever, systemic antibiotics were started. Antifungal agents were added if fever persisted for 3 days. Median time for neutrophil engraftment was 10 days (range 8–17). Fever occurred in 38 (95%) for a median of 5 days (range 1–38), and blood cultures were positive in seven (17.5%). Systemic antibiotics were used in 95% and antifungals in 57.5% cases. The 30-day mortality was nil, and 100-day mortality was 1 (2.5%). After day 100, there were eight fatalities (20%) due to chronic GVHD-3, relapse-2, graft rejection-2, disseminated tuberculosis and aspergillosis-1. Our experience suggests that allogeneic HSCT can be safely performed in non-HEPA filter rooms in India.

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 pa tients with FXIII deficiency (two of the three patients in this study) was observed.