Case studies in the management of refractory bleeding in patients with haemophilia A and inhibitors.

In haemophilia patients with well-established high-titer inhibitors, even seemingly minor acute bleeding episodes or surgical procedures may become refractory to treatment and transform into limb- or life-threatening situations. In the absence of evidence-based treatment guidelines, this article presents 10 cases of difficult to control acute and surgical bleeding and offers consensus opinions regarding their management from a panel of experienced haemophilia treaters.

Outcomes of mentored, grant-funded fellowship training in haemostasis /thrombosis: findings from a nested case-control survey study.

Successful strategies by which to effectively recruit and retain academic subspecialists in benign haematology have not been established. To evaluate the effectiveness of a grant-funded, mentored fellowship with respect to retention and early career goals in haemostasis/thrombosis, we sought to compare outcomes for graduates of a grant-funded, mentored fellowship training programme in haemostasis/thrombosis [the National Hemophilia Foundation (NHF)-Baxter Clinical Fellowship Award] during conventional haematology/oncology fellowship training (cases), vs. their training peers who were graduates of conventional haematology/oncology fellowship training alone (controls), via a nested case-control survey study. Survey response rate was 85% (11/13) for cases and 90% (9/10) for controls. All respondents had pursued careers in academic haematology/oncology. Median (range) percent time spent in benign haematology postfellowship was 98% (70-100%) for cases vs. 0% (0-20%) for controls. Time spent in research was significantly greater among cases than controls (median 80% [range: 42-90%] vs. 55% [10-80%], respectively; P = 0.01). By years 3-4 postfellowship, median annual number of peer-reviewed publications was higher for cases than controls (3.5 vs. 1.0; P = 0.01). Cases were also more successful in grant funding (including K-awards). These data suggest that a grant-funded, mentored fellowship training programme in haemostasis/thrombosis may be superior to conventional haematology/oncology fellowship training alone with respect to outcomes of retention in clinical care/research, early-career grant funding and publication productivity.

Inhibitor development and successful immune tolerance in an HIV-infected patient with haemophilia A and after immune reconstitution with HAART.

This is the case of a 28-year-old man with severe congenital haemophilia A, who had a relatively mild bleeding course during early childhood, with limited factor VIII (FVIII) exposure. He was infected with HIV before the age of 7 years, and demonstrated profound immunodeficiency from childhood, with very low CD4+ cell counts for more than a decade. Following initiation of highly active anti-retroviral therapy (HAART) and gradually increasing CD4+ cells, he presented for the first time with a high-titre inhibitor at age 26, despite over 1000 previous FVIII exposures. Subsequently, his inhibitor was successfully eradicated with a standard immune tolerance protocol. It is likely that the effects of chronic HIV infection on T-lymphocyte pathways, and the partial immune reconstitution resulting from HAART, led to this patient's unusual inhibitor course. Such a case serves to augment knowledge gained in animal studies about the immunobiology of FVIII inhibitors.

Quantifying adherence to treatment and its relationship to quality of life in a well-characterized haemophilia population.

It is known that chronically ill patients adhere to medical treatment plans only 50% of the time. Adherence to treatment with factor infusion therapy in haemophilia patients is essential to stop bleeding. It also prevents both acute and chronic life and limb threatening complications. This study, performed in a well-described haemophilia population, was completed in an effort to understand the critical issue of adherence in patients with haemophilia. A major component of the methodology of this study was the development of a unique scoring system to quantify adherence. Adherence scores in patients on On-Demand treatment strategies were then compared to those on High Intensity treatment strategies. Quality of life (QoL) studies were also performed on the study population to assess the association of treatment regimen and adherence scores to QoL measures. Results of this study demonstrated that adherence to On-Demand therapy was significantly greater than adherence to High Intensity treatment regimens and in children, High Intensity treatment regimens, which included prophylaxis, correlated with better QoL scores in body pain. It is envisioned that the development of an objective scoring system for adherence will prove useful in future studies of adherence as well as in the development of intervention strategies that can overcome barriers to adherence in haemophilia patients.

Prophylactic treatment with activated prothrombin complex concentrate (FEIBA) reduces the frequency of bleeding episodes in paediatric patients with haemophilia A and inhibitors.

Orthopaedic complications are among the most disabling sequelae occurring in patients with haemophilia and inhibitors. Recurrent or refractory joint bleeds can lead to joint damage, limiting mobility and causing permanent disability. Activated prothrombin complex concentrates (aPCCs) are effective in controlling acute, intraoperative and postoperative bleeding in patients with haemophilia and inhibitors. The relatively long, dosing interval and safety profile distinguish aPCCs as a well-suited option for prophylaxis. Therefore, it is postulated that long-term routine aPCC administration will decrease the frequency of recurrent bleeds, prevent damage to normal joints, and slow the progression of existing joint disease in patients with inhibitors. To test this hypothesis, a retrospective chart audit was performed. In four treatment centres, five patients were identified who received aPCC [Factor Eight Inhibitor Bypassing Activity, Anti-Inhibitor Coagulant Complex (FEIBA); Baxter AG, Vienna, Austria] prophylactically for > or = 6 months to prevent or reduce further joint deterioration, reduce bleeding and prevent postsurgical bleeding. Median treatment duration was 15 months and included administration of >1300 doses of aPCC. Dosages ranged from 50 to 75 U kg(-1) three times per week in four patients; one patient received 100 U kg(-1) daily. Orthopaedic status was maintained in four patients and improved in one; the frequency of bleeding episodes was reduced in all patients. No adverse events or thrombotic complications were reported. This case series demonstrates that routine aPCC administration may be used safely and effectively to reduce the occurrence of bleeding episodes and to maintain or improve clinical joint status in some patients.

Inhibitor treatment in haemophilias A and B: summary statement for the 2006 international consensus conference.

Participants in an international conference on the management of haemophilia patients with inhibitors developed a jointly authored summary of the findings and conclusions of the conference. Current knowledge of the genetic and immunologic mechanisms underlying inhibitor development was briefly summarized. Concerning the purported treatment-related risk factors, conference participants commented on the limitations of the available evidence and the need for more rigorous prospective research in a fully genotyped population. Other clinical considerations discussed included the unproved utility of routine surveillance, the need for assay standardization, the management of acute bleeding and approaches to joint disease prophylaxis and immune tolerance induction (ITI). A number of issues were identified as needing further investigation in larger prospective studies, ideally through international cooperation. Such studies should enroll cohorts that have been scrupulously defined in terms of mutation status and treatment exposure. Finally, conference participants urged their colleagues to participate in the currently ongoing international trials of ITI.

Prophylaxis in haemophilia patients with inhibitors.

The presence of high titre inhibitors makes the treatment of bleeding episodes in haemophilia patients difficult and increases the risk of uncontrollable bleeding and disability, despite optimum on-demand treatment with bypassing agents. The inability to effectively control joint bleeding leads to progressive joint disease in many patients with inhibitors. Significant mobility impairments are far more prevalent in patients with inhibitors than in those without inhibitors. Emerging data suggest that prophylaxis using bypassing agents may be effective and safe in reducing the incidence of joint bleeding during immune tolerance induction (ITI), and for patients who failed ITI or who were never candidates for ITI. Only controlled clinical trials will ultimately demonstrate whether prophylaxis can prevent joint bleeding and damage, and improve quality of life in patients with inhibitors. This article will review the published data on the use of bypassing agents in the prevention of bleeding, and will discuss ongoing clinical prophylaxis trials in inhibitor patients.

Platelet kinetics in immune thrombocytopenic purpura and human immunodeficiency virus thrombocytopenia.

Platelet kinetics studies are capable of measuring in vivo platelet survival and platelet turnover rates. These studies can be helpful in elucidating mechanisms of thrombocytopenia, particularly in complicated clinical situations. Numerous studies over the past 30 years have established the abnormalities in platelet kinetics associated with immune thrombocytopenic purpura (ITP). It is now well known that many patients infected with HIV type-1 will develop thrombocytopenia, and that at least 10% will develop a thrombocytopenic disorder clinically indistinguishable from immune thrombocytopenic purpura. Platelet kinetics studies in this group of patients may prove of great benefit in understanding the mechanisms underlying thrombocytopenia and in making accurate diagnoses. For all patients with ITP-like disorders, these studies may also prove helpful in understanding and improving current therapies.

Use of prothrombin complex concentrates and activated prothrombin complex concentrates as prophylactic therapy in haemophilia patients with inhibitors.

Haemophilia patients with inhibitors are treated for acute bleeding with prothrombin complex concentrates (PCCs) or activated prothrombin complex concentrates (aPCCs). Despite this therapy, patients with high-level inhibitors are at increased risk of developing devastating joint disease. This paper examines available information that supports the study of PCCs and/or aPCCs as prophylactic therapy for haemophilia patients with inhibitors. This strategy would require that PCCs or aPCCs be administered repetitively in a dose that is sufficient to prevent haemarthrosis without causing thrombogenic events, or causing anamnestic response in inhibitor titre. PCC doses ranging from 30 to 50 U kg-1 every other day for up to 8 months have resulted in subjective improvement both in bleeding associated with target joints and in the management of chronic joint inflammation. aPCC doses as low as 50-100 U kg-1 every other day have been useful in postsurgical prophylaxis. The risk of developing a myocardial infarction or clinically relevant disseminated intravascular coagulation is linked to total dosages of either PCCs or aPCCs greater than 200 U kg-1 day-1. It is uncertain what anamnestic response would result from prophylaxis, but with typical therapy the aPCCs cause such a response in only a small percentage of patients. Based on these findings, a clinical trial of these products used in doses of 50-100 U kg-1 every other day would appear to be warranted in patients who have permanent inhibitors and frequent joint bleeding.

Concurrence of anaphylaxis and acute heparin-induced thrombocytopenia in a patient with heparin-induced antibodies.

We report the occurrence of acute heparin-induced thrombocytopenia in a patient with anaphylaxis that began immediately after an intravenous bolus dose of unfractionated heparin. This case report is the first to document the concurrence of these 2 reactions to heparin. An abrupt fall in platelet count was documented immediately after the anaphylactic response. Study results for antibodies characteristic of heparin-induced thrombocytopenia were positive in 2 assays: serotonin release assay and heparin platelet factor 4 enzyme-linked immunosorbent assay. The patient's antibody was exclusively immunoglobulin G. Any explanation for the relationship between the antibody response observed and the histamine release remains speculative.

Activity of granzyme A, a serine protease in the killing granules of cytotoxic T lymphocytes, is reduced in cells from HIV-infected hemophiliacs.

Cytotoxic CD8+ lymphocytes (CTLs) kill virally infected target cells by releasing cytotoxic granules. The primary objective of this study was to determine whether the activity of granzyme A, a serine protease in the killing granules of CTLs is altered in HIV-infected hemophiliacs. A sensitive colorimetric assay that measures cleavage of a synthetic substrate, N alpha-benzyloxycarbonyl-L-lysine thiobenzyl ester (BLT), was used to quantitate granzyme A activity. Granzyme A activities from hemophiliacs were normalized to to granzyme A activities of healthy donors run concurrently. Granzyme A activity in CD8+ T cells from HIV-seropositive hemophiliacs was significantly lower than granzyme A activity in cells from HIV-seronegative hemophiliacs (0.48 units +/- 0.086/CD8+ T cell and 1.573 +/- 0.434 units/CD8+ T cell, respectively; p < 0.005). These results indicate that cytotoxic cells in HIV-infected hemophiliacs have reduced granzyme A activity, which may result in a defect in CTL-mediated cell killing in these patients.

Role of splenectomy in the management of hemophilic patients with human immunodeficiency virus-associated immunopathic thrombocytopenic purpura.

Immunopathic thrombocytopenic purpura (ITP) can be a life-threatening complication of human immunodeficiency virus (HIV) infection in patients with hemophilia and can seriously compromise quality of life if not managed effectively. We report here complete response to splenectomy in four severe hemophiliacs with HIV-associated ITP. All patients were symptomatic, had platelet counts less than 25,000/mm3, and had failed at least one non-surgical therapy prior to splenectomy. All patients tolerated surgery well and obtained an immediate and durable complete response. In addition to our experience, a review of the literature shows that splenectomy is well tolerated and provides the most effective long-term solution for hemophiliacs with HIV-ITP.

Unbound immunoglobulins are a major source of error in the quantitation of platelet surface-bound immunoglobulin levels.

Analysis of assays for the determination of platelet-associated immunoglobulins (PAIgs) has led to disagreement over the amount of surface-bound Igs in both normal controls and patients with elevated platelet Ig levels. By the use of radiolabeled platelets and platelet counts, it was demonstrated that more than 10(8) platelets are disrupted after each centrifugation during platelet isolation procedures, releasing intraplatelet contents into the fluid phase of resuspended platelets in buffer. It was shown that suspensions of whole washed platelets contain a significant, but generally overlooked, amount of unbound Igs that have been liberated from platelets disrupted during processing. When platelet suspensions are evaluated for Igs with assays that fail to incorporate a final separation of whole platelets from the suspension fluid, unbound Igs as well as those bound to the platelet surface are measured, which yields a logarithmic overestimation of surface-bound Igs. It has been further demonstrated that patients infected with human immunodeficiency virus type 1 can have elevations of PAIgG, PAIgA, and PAIgM in both the thrombocytopenic and nonthrombocytopenic states. These elevations are due to increased internal platelet pools of Igs and not to increased surface-bound Igs.

Evaluation by quantitative acid elution and radioimmunoassay of multiple classes of immunoglobulins and serum albumin associated with platelets in idiopathic thrombocytopenic purpura.

Immunoglobulins (Igs) and serum albumin were eluted from normal platelets and platelets from patients with idiopathic thrombocytopenic purpura (ITP) with a quantitative acid elution procedure followed by solid-phase radioimmunoassay (SPRIA). Acid elution was shown to release a reproducible fraction of platelet-associated Igs, and the amounts released per platelet were independent of the platelet concentration over a wide range of concentrations. This procedure is suitable for sensitive, reproducible, and specific quantitation of large numbers of samples. Washed platelets from 13 normal donors contained the following components (expressed in femtograms per platelet, mean +/- 2 SEM): IgG, 1.40 +/- 0.26; IgA, 0.72 +/- 0.36; IgM 0.078 +/- 0.036; albumin 7.7 +/- 1.5. Immunoglobulins and albumin eluted from the platelets of ten ITP patients (two in remission), expressed as femtograms per platelet, mean (range), were: IgG 104 (0.3 to 750); IgA 90 (0.9 to 715); IgM 162 (1.2 to 1,300); and albumin 34 (6.8 to 199). All platelet-associated Igs from thrombocytopenic ITP patients were found to be elevated twofold to 2,300-fold with one Ig class occasionally elevated 50-fold to 100-fold higher than the others. A similar group of ten thrombocytopenic ITP patients was found to have twofold to 26-fold elevations of platelet-associated albumin. This demonstration of increases in multiple classes of Igs as well as serum albumin associated with platelets from ITP patients suggests that some nonimmune process may be contributing to the phenomenon of increased platelet-associated proteins in ITP.