Individualized prophylaxis for optimizing hemophilia care: can we apply this to both developed and developing nations?

Prophylaxis is considered optimal care for hemophilia patients to prevent bleeding and to preserve joint function thereby improving quality of life (QoL). The evidence for prophylaxis is irrefutable and is the standard of care in developed nations. Prophylaxis can be further individualized to improve outcomes and cost effectiveness. Individualization is best accomplished taking into account the bleeding phenotype, physical activity/lifestyle, joint status, and pharmacokinetic handling of specific clotting factor concentrates, all of which vary among individuals. Patient acceptance should also be considered. Assessment tools (e.g. joint status imaging and function studies/scores, QoL) for determining and monitoring risk factors and outcome, as well as population PK profiling have been developed to assist the individualization process. The determinants of optimal prophylaxis include (1) factor dose/dosing frequency, hence, cost/affordability (2) bleeding triggers (physical activity/lifestyle, chronic arthropathy and synovitis) and (3) bleeding rates. Altering one determinant results in adjustment of the other two. Thus, the trough level to protect from spontaneous bleeding can be increased in patients who have greater bleeding risks; and prophylaxis to achieve zero joint bleeds is achievable through optimal individualization. Prophylaxis in economically constrained nations is limited by the ill-affordability of clotting factor concentrates. However, at least 5 studies on children and adults from Thailand, China and India have shown superiority of low dose (~5–10 IU kg^?1 2-3× per week) prophylaxis over episodic treatment in terms of bleed reduction, and quality of life, with improved physical activity, independent functioning, school attendance and community participation. In these nations, the prophylaxis goals should be for improved QoL rather than “zero bleeds” and perfect joints. Prophylaxis can still be individualized to affordability. Higher protective trough level can be achieved by using smaller doses given more frequently without an increase in consumption/cost. The bleeding trigger can also be down-regulated by avoiding unnecessary injury, and by engaging in judicious strengthening exercises appropriate to the joint status to improve balance and joint stabilization. Central to the success of prophylaxis are clinics with comprehensive care that provide the necessary professional expertise, support, and counseling, to educate patients, families, and other healthcare professionals, and to support research for improved hemophilia care.     

The international,prospective Glanzmann Thrombasthenia Registry: treatment modalities and outcomes of non-surgical bleeding episodes in patients with Glanzmann thrombasthenia

Standard treatment for Glanzmann thrombasthenia is platelet transfusion. Recombinant activated factor VII has been shown to be successful in patients with Glanzmann thrombasthenia with platelet antibodies or who are refractory to platelet transfusions. The Glanzmann Thrombasthenia Registry prospectively collected worldwide information on the effectiveness and safety of platelet transfusion, recombinant activated factor VII and/or antifibrinolytics for the treatment of bleeds in patients with Glanzmann thrombasthenia. Data relating to 829 non-surgical bleeding episodes were entered into the Glanzmann Thrombasthenia Registry (severe/moderate: 216/613; spontaneous/post-traumatic: 630/199). Recombinant activated factor VII alone was used in 124/829 bleeds, recombinant activated factor VII+antifibrinolytics in 107/829, platelets±antifibrinolytics in 312/829, antifibrinolytics alone in 219/829, and recombinant activated factor VII+platelets±antifibrinolytics in 67/829. The proportion of successful treatments to stop bleeding was 91.0% in cases treated with recombinant activated factor VII only, 82.7% for recombinant activated factor VII+antifibrinolytics, 72.7% for treatment with recombinant activated factor VII+platelets±antifibrinolytics, 78.8% for platelets±antifibrinolytics and 84.7% for antifibrinolytics alone. Treatment failure was documented in 18 bleeding events (2% of the total treatments), the majority of which were in patients receiving treatment with antifibrinolytics; bleeding re-started in 6% of bleeds after initial effective treatment. Thirty-five adverse events were reported, none of which was a thromboembolic event. Among treatments that included recombinant activated factor VII, only one patient reported three possibly drug-related non-serious adverse events (nausea, dyspnea and headache). To conclude, non-surgical bleeds were common and often severe in Glanzmann thrombasthenia; both platelets and recombinant activated factor VII appeared to be effective, and with good safety profiles, for the treatment of non-surgical bleeds. This trial was registered at clinicaltrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT01476423","term_id":"NCT01476423"}}NCT01476423.     

Low oxygen saturation by pulse oximetry may be associated with a low oxygen affinity hemoglobin variant, hemoglobin Titusville

The authors describe a 10-year-old Caucasian boy who presented with abnormally low oxygen saturation values on pulse oximetry after a routine tonsillectomy. He was asymptomatic and there was no personal or family history of respiratory, cardiac, or hematologic disorders. Multiple initial investigations were completed without diagnostic yield. Eventually, hemoglobinopathy studies identified the presence of a low oxygen affinity hemoglobin variant, characterized as hemoglobin Titusville. Hemoglobinopathies remain highly prevalent worldwide, with more than 65 low oxygen affinity hemoglobin variants identified to date. Early recognition of abnormal hemoglobin variants in asymptomatic patients may avoid extensive, unnecessary medical investigations.     

Aminoglycoside suppression of nonsense mutations in severe hemophilia

Aminoglycoside antibiotics exhibit their bactericidal effect by interfering with normal ribosomal activity. In this pilot study, we have evaluated the effect of the aminoglycoside antibiotic gentamicin on the factor VIII (FVIII) and IX levels of severe hemophiliacs with known nonsense mutations. Five patients were enrolled and each patient was given 3 consecutive days of gentamicin at a dose of 7 mg/kg intravenously every 24 hours. Two patients (patient no. 1: hemophilia A, Ser1395Stop; and patient no. 5: hemophilia B, Arg333Stop) showed a decrease in their activated partial thromboplastin time (aPTT), an increase in their FVIII (0.016 IU/mL, 1.6%) or FIX (0.02 IU/mL, 2%) levels, and an increase in thrombin generation. The remaining 3 patients (patient no. 2: hemophilia B, Arg252Stop; patient no. 3: hemophilia A, Arg2116Stop; and patient no. 4: hemophilia A, Arg427Stop) showed no response in the aPTTs or factor levels, but one (patient no. 2: hemophilia B, Arg252Stop) showed an increase in the factor IX antigen level (2%-5.5%) that persisted throughout the period of the study and was concordant with an increase in thrombin generation. Gentamicin is unlikely to be an effective treatment for severe hemophilia due to its potential toxicities and the minimal response documented in this report. This study, however, does provide a proof of principle, suggesting that ribosomal interference with a less toxic agent may be a potential therapeutic mechanism for severe hemophilia patients with nonsense mutations.     

Helicobacter pylori eradication: Novel therapy for immune thrombocytopenic purpura? A review of the literature

Eradication of Helicobacter pylori (H. pylori ) from the gastric mucosa has been associated with improvement of several systemic diseases, including immune thrombocytopenic purpura (ITP). Over the last 5 years, several studies have reported improved platelet counts in H. pylori-positive ITP patients following standard triple H. pylori eradication therapy. Review of published studies in which eradication of H. pylori has been performed in the ITP population indicates an overall response rate of 52% in 193 subjects in whom H. pylori was eradicated. Cohorts from Japan and Italy report higher response rates. There is no established mechanism to explain how this organism, which does not invade the gastric mucosa, could be implicated in the pathogenesis of this immune-based platelet disorder. Several theories including molecular mimicry, platelet aggregation, and immunomodulatory effects of macrolides have been proposed to explain the platelet response to anti-H. pylori therapy. Large randomized-controlled studies enrolling patients from various ethnic backgrounds will be necessary to determine the response rate and mechanism of response and to gain a better understanding of the pathogenesis of ITP.     

Mutations in the paralogous human α-globin genes yielding identical hemoglobin variants

The human α-globin genes are paralogues, sharing a high degree of DNA sequence similarity and producing an identical α-globin chain. Over half of the α-globin structural variants reported to date are only characterized at the amino acid level. It is likely that a fraction of these variants, with phenotypes differing from one observation to another, may be due to the same mutation but on a different α-globin gene. There have been very few previous examples of hemoglobin variants that can be found at both HBA1 and HBA2 genes. Here, we report the results of a systematic multicenter study in a large multiethnic population to identify such variants and to analyze their differences from a functional and evolutionary perspective. We identified 14 different Hb variants resulting from identical mutations on either one of the two human α-globin paralogue genes. We also showed that the average percentage of hemoglobin variants due to a HBA2 gene mutation (α2) is higher than the percentage of hemoglobin variants due to the same HBA1 gene mutation (α1) and that the α2/α1 ratio varied between variants. These α-globin chain variants have most likely occurred via recurrent mutations, gene conversion events, or both. Based on these data, we propose a nomenclature for hemoglobin variants that fall into this category. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy

Familial platelet disorder with propensity to myeloid malignancy (FPD/AML) is an autosomal dominant syndrome characterized by platelet abnormalities and a predisposition to myelodysplasia (MDS) and/or acute myeloid leukemia (AML). The disorder, caused by inherited mutations in RUNX1, is uncommon with only 14 pedigrees reported. We screened 10 families with a history of more than one first degree relative with MDS/AML for inherited mutations in RUNX1. Germ- line RUNX1 mutations were identified in 5 pedigrees with a 3:2 predominance of N-terminal mutations. Several affected members had normal platelet counts or platelet function, features not previously reported in FPD/AML. The median incidence of MDS/AML among carriers of RUNX1 mutation was 35%. Individual treatments varied but included hematopoietic stem cell transplantation from siblings before recognition of the inherited leukemogenic mutation. Transplantation was associated with a high incidence of complications including early relapse, failure of engraftment, and posttransplantation lymphoproliferative disorder. Given the small size of modern families and the clinical heterogeneity of this syndrome, the diagnosis of FPD/AML could be easily overlooked and may be more prevalent than previously recognized. Therefore, it would appear prudent to screen young patients with MDS/AML for RUNX1 mutation, before consideration of sibling hematopoietic stem cell transplantation.     

Treatment of an aggressive non-Hodgkin's lymphoma during pregnancy with MACOP-B chemotherapy

Non-Hodgkin's lymphoma occurring during pregnancy is a rare event. A young woman at 18 weeks gestation with twins presented with a B-cell immunoblastic lymphoma. Combination chemotherapy with methotrexate, DO xorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) was instituted after limited staging. There was excellent response and the 12 weekly chemotherapy protocol was completed in 13 weeks. Twin male infants were born at 28 weeks gestation by cesarean section for premature labor. There was no evidence of any congenital malformations or hematologic suppressions. We believe this to be the first report of aggressive weekly chemotherapy during pregnancy; this approach to treatment in aggressive non-Hodgkin's lymphoma is both efficacious and safe.