Wolfgang Schramm

Consensus perspectives on prophylactic therapy for haemophilia: summary statement

Summary.  Participants in an international conference on prophylactic therapy for severe haemophilia developed a consensus summary of the findings and conclusions of the conference. In the consensus, participants agreed upon revised definitions for primary and secondary prophylaxis and also made recommendations concerning the need for an international system of pharmacovigilance. Considerations on starting prophylaxis, monitoring outcomes, and individualizing treatment regimens were discussed. Several research questions were identified as needing further investigation, including when to start and when to stop prophylaxis, optimal dosing and dose interval, and methods for assessment of long‐term treatment effects. Such studies should include carefully defined cohorts, validated orthopaedic and quality‐of‐life assessment instruments, and cost‐benefit analyses.

Influence of high-dose aprotinin treatment on blood loss and coagulation patterns in patients undergoing myocardial revascularization.

Intraoperative administration of the proteinase inhibitor aprotinin causes reduction in blood loss and homologous blood requirement in patients undergoing cardiac surgery. To ascertain the blood-saving effect of aprotinin and to obtain further information about the mode of action, 40 patients undergoing primary myocardial revascularization were randomly assigned to receive either aprotinin or placebo treatment. Aprotinin was given as a bolus of 2 x 10(6) kallikrein inactivator units (KIU) before surgery followed by a continuous infusion of 5 x 10(5) KIU/h during surgery. Additionally, 2 x 10(6) KIU were added to the pump prime. Strict criteria were used to obtain a homogeneous patient selection. Total blood loss was reduced from 1,431 +/- 760 ml in the control group to 738 +/- 411 ml in the aprotinin group (P less than 0.05) and the homologous blood requirement from 838 +/- 963 ml to 163 +/- 308 ml (P less than 0.05). In the control group, 2.3 +/- 2.2 U of homologous blood or blood products were given, and in the aprotinin group, 0.63 +/- 0.96 U were given (P less than 0.05). Twenty-five percent of patients in the control group and 63% in the aprotinin group did not receive banked blood or homologous blood products. The activated clotting time as an indicator of inhibition of the contact phase of coagulation was significantly increased before heparinization in the aprotinin group (141 +/- 13 s vs. 122 +/- 25 s) and remained significantly increased until heparin was neutralized after cardiopulmonary bypass (CPB).(ABSTRACT TRUNCATED AT 250 WORDS)

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.).

Practical guidelines for the clinical use of plasma

Despite differences in the composition of fresh frozen plasma (FFP) and solvent/detergent-treated plasma, prospective controlled clinical trials have not revealed any significant difference in clinical efficacy and tolerance between the two types of plasma. Evidence of the clinical efficacy of plasma is mainly based on expert opinion, case reports, and on controlled and uncontrolled observational studies. The application of plasma without laboratory analysis to verify the coagulopathy is normally not justified. With the exception of emergency situations when timely clotting assay results are not available, the administration of plasma in coagulopathy must be verified both clinically and by laboratory analysis before plasma is administered. The rapid infusion of at least 10 ml plasma/kg of body weight is required to increase the respective plasma protein levels significantly. Based on the present state of knowledge, plasma is indicated for complex coagulopathy associated with manifest or imminent bleeding in massive transfusion, disseminated intravascular coagulation, and liver disease. Therapeutic plasma exchange with 40 ml plasma/kg of body weight is the treatment of first choice in acute thrombotic-thrombocytopenic purpura-adult hemolytic uremic syndrome (TTP-HUS). A rare indication is the treatment or prevention of bleeding in congenital factor V or factor XI deficiency, plasma exchange in neonates with severe hemolysis or hyperbilirubinemia, and filling of the oxygenator in extracorporeal membrane oxygenation (ECMO) in neonates. Prothrombin complex concentrates should be preferred to plasma for the reversal of oral anticoagulation in emergency situations, since controlled studies have shown a minor efficacy of plasma. Side effects resulting from the administration of plasma are rare but have to be considered.

Relationship between ABO and Secretor genotype with plasma levels of factor VIII and von Willebrand factor in thrombosis patients and control individuals.

In contrast to earlier reports, this study examined the relationship between plasma levels of factor VIII (FVIII) and von Willebrand factor (VWF) and ABO blood group and secretor status at the genetic level in 355 patients with venous thrombosis as well as in 236 controls. ABO glycosyl transferase alleles A1 and B were more frequent in the thrombosis collective and alleles O1, O2 and A2 were more frequent in the controls. A low‐risk group for venous thrombosis of individuals with genotypes O1O1, O1O2 and O1A2 (H‐antigen rich) could be distinguished from a high‐risk group with genotypes A1A1, A1B, O1A1 and O1B (H‐antigen poor). In both the thrombosis and control groups, the H‐antigen rich group showed significantly lower levels of FVIII coagulant activity (FVIII:C) and VWF antigen (VWF:Ag) than the H‐antigen poor group. The frequency of the different secretor genotypes in the thrombosis group was not different from that in the control group. No significant differences of FVIII:C and VWF:Ag levels were seen between SeSe, Sese and sese individuals in the thrombosis and in the control group. Thus the risk of venous thrombosis is associated with the ABO blood group genotype but not with secretor status.

Socioeconomic impact of haemophilia care: results of a pilot study.

Summary. Fifty consecutive haemophiliacs were entered into a pilot study of socioeconomic impact of haemophilia treatment. The Short Form 36 was used as an instrument for the assessment of quality of life. Direct and indirect costs were analysed. Incremental cost‐effectiveness was expressed as additional costs per joint bleed avoided by prophylactic treatment over on‐demand treatment. Thirtynine patients (mean age 35.14 years) were substituting factor VIII according to an on‐demand and 11 patients according to a modified prophylactic regimen. There were an average of 9.84 joint bleeds per patient across all patients during the 6‐month observation period: on‐demand group 10.74 bleeds, prophylactic group 6.64 bleeds. This difference was not statistically different. Significant differences between haemophiliac patients and healthy men were seen in the assessment of their limitations of physical activities, limiting pain and general health. The total cost per patient during the 6 months was DM 24 601 in all patients, DM 17 253 in those on an on‐demand base and DM 28 245 in the modified prophylactic group. Patients experienced an average 4.71 days off work: on demand 5.81 days, prophylactic regimen 0 days. The total indirect cost per patient was DM 683; therapy cost per patient was DM 25 284; cost per avoided bleed DM 1680 for on‐demand therapy and DM 4228 on prophylaxis. The incremental cost‐effectiveness, i.e. the additional costs to avoid one additional joint bleed by prophylactic treatment, was DM 2536. In conclusion, patients receiving prophylactic clotting factor therapy require less additional health care resources, mainly due to the reduction in the number of joint bleeds.

Absence of Anti-Human Immunodeficiency Virus Types 1 and 2 Seroconversion after the Treatment of Hemophilia A or von Willebrand's Disease with Pasteurized Factor VIII Concentrate

Patients with hemophilia A or von Willebrands disease who are treated with concentrated preparations of human factor VIII made from unscreened pooled plasma are at substantial risk of contracting human immunodeficiency virus (HIV) infection. The purpose of this study was to investigate whether by treating such patients with a pasteurized factor VIII concentrate that had been heated in aqueous solution at 60 degrees C for 10 hours, HIV infection could be avoided. Eleven hemophilia centers in the Federal Republic of Germany and two in Austria identified 155 eligible patients who had been treated exclusively with pasteurized factor VIII concentrate and had not received any other blood products. Between February 1979 and December 1986 they received a total of 15,916,260 IU of pasteurized factor VIII. The United States was the source of 80 percent of the plasma from which the concentrate was made. By September 1988, these 155 patients had been screened for antibody to HIV type 1 (anti-HIV-1) with a total of 657 tests; all were negative. Sixty-seven patients were also tested once for antibody to HIV type 2 (anti-HIV-2); all these tests were negative as well. It appears that pasteurization effectively inactivates HIV, even in plasma that is likely to be highly contaminated with the virus.

HIV-1 reproduction is inhibited by peptides derived from the N- and C-termini of HIV-1 protease

Two octapeptides derived from the sequence of the N- and C-termini of HIV-1 protease were tested for their ability to inhibit HIV-1 reproduction. Weak inhibitory activity was found with each of the two peptides. It is assumed that HIV-1 protease is the target of the inhibitory action. In spite of the moderate inhibitory activity the results are encouraging since they may be improved by various means.

Disturbances of selected plasma proteins in hyperdynamic septic shock.

This study was performed on patients (n=18) suffering from strictly defined hyperdynamic septic shock. Plasma factors (C-reactive protein, acid α1-glycoprotien, fibrinogen, fibrinopeptide A, fibrinogen-fibrin split products, factor XIII, antithrobin III, complement factors C3 and C4, inter-α-trypsin-inhibitor and α2-macroglobulin) measured during hyperdynamic septic shock were highly abnormal. The activation and consumption of clotting, fibrinolytic and complement factors due to system-specific proteinases (such as thrombokinase or plasminogen activators) seemed to be intensified by the nonspecific proteolytic activity of granulocytic proteinases probably released by the action of endotoxins. Possible therapeutic measures to maintain the endogeneous defence mechanism against enhanced proteolysis during septic shock are discussed.

Cross-cultural development and psychometric evaluation of a patient-reported health-related quality of life questionnaire for adults with haemophilia.

Summary.  Co‐morbidities of haemophilia, such as arthropathy and blood‐borne infections, can adversely affect the quality of life of adult patients with haemophilia. The purpose of this study was to develop and validate a haemophilia‐specific health‐related quality of life questionnaire for adults (HAEMO‐QoL‐A). Subjects with varying severities of haemophilia completed the HAEMO‐QoL‐A at baseline and 4 weeks. Other assessments included the SF‐36 and Health Assessment Questionnaire – Functional Disability Index (HAQ‐FDI). Two‐hundred and twenty‐one participants completed the 41‐item HAEMO‐QoL‐A covering six domains (Physical Functioning, Role Functioning, Worry, Consequences of Bleeding, Emotional Impact and Treatment Concerns) and four independent items. Internal consistency was good‐to‐excellent (Cronbach’s α‐range: 0.75–0.95). Test–retest reproducibility was good, with intraclass correlation coefficients >0.80 except for the Emotional Impact domain (0.79). Concurrent validity between the HAEMO‐QoL‐A total and subscale scores and all SF‐36 subscale scores were generally good (correlations range: 0.13–0.87). Significant correlations between the HAEMO‐QoL‐A and the HAQ‐FDI ranged from −0.14 to −0.69. There were non‐significant correlations with the Treatment Concerns subscale and with the Worry subscale. The HAEMO‐QoL‐A discriminated significantly between adults with haemophilia by severity and HIV status. The Physical Functioning subscale discriminated between patients receiving prophylactic or on‐demand therapy. The HAEMO‐QoL‐A is a valid and reliable instrument for assessing quality of life in haemophilia patients.