Cindy Leissinger

Dose of Prophylactic Platelet Transfusions and Prevention of Hemorrhage

BACKGROUND We conducted a trial of prophylactic platelet transfusions to evaluate the effect of platelet dose on bleeding in patients with hypoproliferative thrombocytopenia. METHODS We randomly assigned hospitalized patients undergoing hematopoietic stem-cell transplantation or chemotherapy for hematologic cancers or solid tumors to receive prophylactic platelet transfusions at a low dose, a medium dose, or a high dose (1.1x10(11), 2.2x10(11), or 4.4x10(11) platelets per square meter of body-surface area, respectively), when morning platelet counts were 10,000 per cubic millimeter or lower. Clinical signs of bleeding were assessed daily. The primary end point was bleeding of grade 2 or higher (as defined on the basis of World Health Organization criteria). RESULTS In the 1272 patients who received at least one platelet transfusion, the primary end point was observed in 71%, 69%, and 70% of the patients in the low-dose group, the medium-dose group, and the high-dose group, respectively (differences were not significant). The incidences of higher grades of bleeding, and other adverse events, were similar among the three groups. The median number of platelets transfused was significantly lower in the low-dose group (9.25x10(11)) than in the medium-dose group (11.25x10(11)) or the high-dose group (19.63x10(11)) (P=0.002 for low vs. medium, P<0.001 for high vs. low and high vs. medium), but the median number of platelet transfusions given was significantly higher in the low-dose group (five, vs. three in the medium-dose and three in the high-dose group; P<0.001 for low vs. medium and low vs. high). Bleeding occurred on 25% of the study days on which morning platelet counts were 5000 per cubic millimeter or lower, as compared with 17% of study days on which platelet counts were 6000 to 80,000 per cubic millimeter (P<0.001). CONCLUSIONS Low doses of platelets administered as a prophylactic transfusion led to a decreased number of platelets transfused per patient but an increased number of transfusions given. At doses between 1.1x10(11) and 4.4x10(11) platelets per square meter, the number of platelets in the prophylactic transfusion had no effect on the incidence of bleeding. (ClinicalTrials.gov number, NCT00128713.)

Anti-Inhibitor Coagulant Complex Prophylaxis in Hemophilia with Inhibitors

BACKGROUND Patients with severe hemophilia A and factor VIII inhibitors are at increased risk for serious bleeding complications and progression to end-stage joint disease. Effective strategies to prevent bleeding in such patients have not yet been established. METHODS We enrolled patients with hemophilia A who were older than 2 years of age, had high-titer inhibitors, and used concentrates known as bypassing agents for bleeding in a prospective, randomized, crossover study comparing 6 months of anti-inhibitor coagulant complex (AICC), infused prophylactically at a target dose of 85 U per kilogram of body weight (±15%) on 3 nonconsecutive days per week, with 6 months of on-demand therapy (AICC at a target dose of 85 U per kilogram [±15%] used for bleeding episodes). The two treatment periods were separated by a 3-month washout period, during which patients received on-demand therapy for bleeding. The primary outcome was the number of bleeding episodes during each 6-month treatment period. RESULTS Thirty-four patients underwent randomization; 26 patients completed both treatment periods and could be evaluated per protocol for the efficacy analysis. As compared with on-demand therapy, prophylaxis was associated with a 62% reduction in all bleeding episodes (P<0.001), a 61% reduction in hemarthroses (P<0.001), and a 72% reduction in target-joint bleeding (≥3 hemarthroses in a single joint during a 6-month treatment period) (P<0.001). Thirty-three randomly assigned patients received at least one infusion of the study drug and were evaluated for safety. One patient had an allergic reaction to the study drug. CONCLUSIONS AICC prophylaxis at the dosage evaluated significantly and safely decreased the frequency of joint and other bleeding events in patients with severe hemophilia A and factor VIII inhibitors. (Funded by Baxter BioScience; Pro-FEIBA ClinicalTrials.gov number, NCT00221195.).

Pharmacokinetic analysis of plasma-derived and recombinant F IX concentrates in previously treated patients with moderate or severe hemophilia B

BACKGROUND: Hemophilia B is an X‐linked bleeding disorder that affects approximately 1 in 25,000 males. Therapy for acute bleeding episodes consists of transfusions of plasma‐derived (pd‐F IX) or recombinant (r‐F IX) concentrates.

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

Summary.  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 enrol 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.

Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia

Recombinant adeno-associated virus (rAAV) is a promising gene delivery vector and has recently been used in patients with hemophilia. One limitation of AAV application is that most humans have experienced wild-type AAV serotype 2 exposure, which frequently generates neutralizing antibodies (NAbs) that may inhibit rAAV2 vector transduction. Employing alternative serotypes of rAAV vectors may circumvent this problem. We investigated the development of NAbs in early childhood by examining sera gathered prospectively from 62 children with hemophilia A, participating in a multi-institutional hemophilia clinical trial (the Joint Outcome Study). Clinical applications in hemophilia therapy have been suggested for serotypes AAV2, AAV5 and AAV8, therefore NAbs against these serotypes were serially assayed over a median follow-up of 4 years. NAbs prevalence increased during early childhood for all serotypes. NAbs against AAV2 (43.5%) were observed more frequently and at higher titers compared with both AAV5 (25.8%) and AAV8 (22.6%). NAbs against AAV5 or AAV8 were rarely observed in the absence of co-prevalent and higher titer AAV2 NAbs, suggesting that NAbs to AAV5 and AAV8 were detected following AAV2 exposure due to partial cross-reactivity of AAV2-directed NAbs. The results may guide rational design of clinical trials using alternative AAV serotypes and suggest that younger patients who are given AAV gene therapy will benefit from the lower prevalence of NAbs.

High-dose DDAVP intranasal spray (Stimate®) for the prevention and treatment of bleeding in patients with mild haemophilia A, mild or moderate type 1 von Willebrand disease and symptomatic carriers of haemophilia A

An open‐label multicentre trial was conducted to evaluate high‐dose DDAVP (desmopressin acetate) intranasal spray (Stimate®; 1.5 mg mL–1), for the control of bleeding in 333 patients with mild haemophilia A, mild or moderate type 1 von Willebrand disease, or symptomatic carriers of haemophilia A. Overall, 278 patients received 2170 doses of high‐dose DDAVP intranasal spray (1.5 mg mL–1). Using study‐defined guidelines, patients evaluated the efficacy of high‐dose DDAVP intranasal spray (1.5 mg mL–1) as ‘excellent’ or ‘good’ in 743 (95%) of 784 bleeding episodes. It demonstrated ‘excellent’ results in 384 (93%) of 413 administrations for prophylaxis and in eight of eight uses prior to acute surgical or dental procedures. When used for the treatment of menorrhagia, the efficacy of high‐dose DDAVP intranasal spray (1.5 mg mL–1) was rated as ‘excellent’ after 655 (92%) of 721 daily uses. Of 2170 doses of high‐dose DDAVP intranasal spray (1.5 mg mL–1), 172 (8%) were associated with adverse events. A total of 272 adverse events were reported among 80 patients. Of these, 239 (88%) were mild or moderate in intensity and only one patient was removed from the study due to an adverse event. These results demonstrate the safety and efficacy of high‐dose DDAVP intranasal spray (1.5 mg mL–1) for control of bleeding episodes in patients with mildly decreased levels of factor VIII, von Willebrand factor, or both.

A systematic approach to controlling problem bleeds in patients with severe congenital haemophilia A and high-titre inhibitors

Summary.  The presence of inhibitory antibodies to clotting factors complicates the treatment of bleeding in haemophilia patients. For patients with high‐titre inhibitors, bypassing agents are essential to haemostatic management. To determine optimal treatment practices, an international panel of physicians convened to develop a systematic treatment approach for problem bleeds (i.e. bleeds that are unresponsive to initial therapy with a single agent within a reasonable amount of time) in haemophilia patients with inhibitors. Aim: The goal of this panel was to develop a consensus algorithm that would aid physicians in considering a variety of treatment approaches to optimize patient care by preventing extensive therapy with inadequate treatments that may lead to suboptimal patient outcomes and unnecessary costs. Methods: Consensus opinions were analyzed for clinical preferences at different time periods, depending on patient response to treatment. Decision‐making points were defined based on the type of bleed: every 8–12 h for the first 24 h, then every 24 h thereafter for limb‐threatening bleeds; every 2–4 h for 2–7 days for life‐threatening bleeds. Results: The resultant consensus guidelines provide a generalized methodology to guide the treatment of problem bleeds in patients with severe haemophilia A and inhibitors, and emphasize changing treatment at the first sign of an inadequate haemostatic response. The treatment algorithms apply to both paediatric and adult patients, although the differences between the two groups were reviewed. Conclusion: These guidelines are focused on optimising the timing of treatment decisions, which may lead to faster responses and improved outcomes.

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

Summary.  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 ≥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.

VWF mutations and new sequence variations identified in healthy controls are more frequent in the African-American population

Diagnosis and classification of VWD is aided by molecular analysis of the VWF gene. Because VWF polymorphisms have not been fully characterized, we performed VWF laboratory testing and gene sequencing of 184 healthy controls with a negative bleeding history. The controls included 66 (35.9%) African Americans (AAs). We identified 21 new sequence variations, 13 (62%) of which occurred exclusively in AAs and 2 (G967D, T2666M) that were found in 10%-15% of the AA samples, suggesting they are polymorphisms. We identified 14 sequence variations reported previously as VWF mutations, the majority of which were type 1 mutations. These controls had VWF Ag levels within the normal range, suggesting that these sequence variations might not always reduce plasma VWF levels. Eleven mutations were found in AAs, and the frequency of M740I, H817Q, and R2185Q was 15%-18%. Ten AA controls had the 2N mutation H817Q; 1 was homozygous. The average factor VIII level in this group was 99 IU/dL, suggesting that this variation may confer little or no clinical symptoms. This study emphasizes the importance of sequencing healthy controls to understand ethnic-specific sequence variations so that asymptomatic sequence variations are not misidentified as mutations in other ethnic or racial groups.

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

Summary.  It is known that chronically ill patients adhere to medical treatment plans only 50% of the time [ 1 ]. 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.