U. Martinowitz

A new approach to treatment of bleeding episodes in young hemophilia patients: a single bolus megadose of recombinant activated factor VII (NovoSeven®)

Summary.u2002 Recombinant activated factor VII (rFVIIa, NovoSeven®) represents an effective treatment for hemophilia patients with inhibitors, but no consensus as to the best dosing regimen exists. We assessed the efficacy and safety of a rFVIIa ‘megadose’ (300u2003µgu2003kg−1 bolus) as treatment for bleeds in three young inhibitor patients. Of 114 bleeds, 95 responded to a single dose. Pain relief was faster and therapy duration significantly shorter than with continuous infusion (CI) regimens or standard boluses (90u2003µgu2003kg−1 every 3u2003h). Rebleeding occurred in 9.6% of cases and 19/114 episodes required a second bolus injection. Although rFVIIa consumption per bleed (median: 300u2003µgu2003kg−1) was higher than with standard boluses (180–270u2003µgu2003kg−1), patients found single bolus administration more convenient than recurrent injections or CI. With two exceptions, no complications occurred within 3 h of treatment, despite high FVII:C levels (median: 27.4u2003Uu2003mL−1; range: 19.8–54u2003Uu2003mL−1). Treatment of bleeds with a rFVIIa megadose in young inhibitor patients is effective and well tolerated.

Cone and platelet analyser (CPA) : a new test for the prediction of bleeding among thrombocytopenic patients

The risk of bleeding among thrombocytopenic patients was evaluated using our new cone and platelet analyser (CPA) test. Using this test, adherence of platelets was quantitated on extracellular matrix and expressed as percent of surface coverage (SC) and the average size (AS) of aggregates. 42 thrombocytopenic patients with ITP (n=23), post chemotherapy (n=12) and others (n=7) were tested over a total of 82 visits. On each visit, complete blood count and CPA tests were performed and patients were evaluated for evidence of bleeding (found in 40 visits).

Results from a large multinational clinical trial (guardian™1) using prophylactic treatment with turoctocog alfa in adolescent and adult patients with severe haemophilia A: Safety and efficacy

Recombinant factor VIII (rFVIII) products provide a safe and efficacious replacement therapy for prophylaxis and treatment of bleeding episodes in patients with severe haemophilia A. This multinational, open‐label, non‐controlled trial investigated the safety and efficacy of turoctocog alfa, a new rFVIII product. The primary objective was to evaluate safety. A total of 150 patients (24 adolescents and 126 adults) with severe haemophilia A (FVIII activity ≤1%), with at least 150 exposure days (EDs) to any FVIII product and no history of inhibitors were enrolled, and 146 patients (97%) completed the trial. All patients received prophylaxis with turoctocog alfa for approximately 6 months and had a mean of 85 EDs during the trial. None of the patients developed FVIII inhibitors, there were no indications of early FVIII inhibitor development and no safety concerns were identified. A total of 225 adverse events were reported in 100 (67%) patients, with the most common being events associated with dosing procedures, headaches, and nasopharyngitis. A total of 499 bleeding episodes were reported during the trial, the majority (89%) were controlled with 1–2 infusions of turoctocog alfa. Based on patient reports, the success rate (defined as ‘excellent’ or ‘good’ haemostatic response) for treatment of bleeding episodes was 81%. The overall median annualized bleeding rate was 3.7 (interquartile range: 8.7) bleeds/patient/year. In conclusion, turoctocog alfa provides a new, safe and effective alternative for prophylaxis and treatment of bleeding episodes in patients with haemophilia A.

Synoviorthesis with radioactive Yttrium in haemophilia: Israel experience

Radioactive Yttrium‐90 (90Y) was injected into 163 joints. Of these patients 115 were persons with haemophilia and they suffered from recurrent haemarthroses. The median age at the time of the initial exposure to 90Y was between 11 and 15 years and the median follow‐up period 11 years. Over 80% of the patients with haemophilia reported a decrease in the number of haemarthroses and 15% stopped bleeding altogether in the treated articulation. The safety of this modality of management has been reported and hence the patients age should not be regarded as a criteria.

Effects of factor VIII inhibitor bypassing activity (FEIBA), recombinant factor VIIa or both on thrombin generation in normal and haemophilia A plasma

Summary.u2002 Factor VIII inhibitor bypass activity (FEIBA) and recombinant factor VIIa (rFVIIa) are the common bypassing agents for treating haemophilia A or haemophilia B patients who developed an inhibitor to factor VIII or IX, respectively. As these preparations differ in their composition and mode of action, combined therapy, either sequential or simultaneous has recently been used for achieving haemostasis during bleeding episodes in patients who became refractory to FEIBA or rFVIIa when each was given alone. In this in vitro study, we show by a sensitive assay of thrombin generation that phospholipids present in FEIBA and other procoagulants contribute to FEIBA’s activity and that exogenous phospholipids are essential for the activity of rFVIIa. We also demonstrate that the combination of FEIBA and rFVIIa has a marked synergistic effect on thrombin generation in plasma of a haemophilia A patient with a high titre of an inhibitor. It is conceivable that simultaneous administration of small doses of FEIBA and rFVIIa may be beneficial in treating haemophilia A patients, with an inhibitor to FVIII, who are resistant to conventional therapy.

Prerequisites for recombinant factor VIIa‐induced thrombin generation in plasmas deficient in factors VIII, IX or XI

Summary.u2002 Background:u2002Recombinant factor VIIa (rFVIIa) used for the treatment of hemophilia A or B patients with an inhibitor is hemostatically effective because it induces thrombin generation (TG), despite grossly impaired FVIII‐ and FIX‐dependent amplification of FX activation. Tissue factor (TF) and or activated platelets were shown to be essential for the rFVIIa activity. Objective: To evaluate the relative effects of TF and phospholipids on rFVIIa‐induced TG in FVIII‐, FIX‐ and FXI‐deficient plasmas. Methods: Phospholipids had an independent effect that was augmented by TF. The contribution of blood‐borne TF in FVIII‐, FIX‐ and FXI‐deficient plasma to rFVIIa‐induced TG was demonstrated by removing microparticles and use of anti‐TF antibodies. Results: At increasing concentrations of rFVIIa, the dependence of rFVIIa‐induced TG on TF declined, but the presence of phospholipids was essential. rFVIIa was also shown to activate purified FIX and FX in the presence of phospholipids and absence of TF. rFVIIa‐induced TG was dramatically augmented in FVIII‐ or FIX‐deficient plasma in which the level of FVIII or FIX was increased to 1 or 2u2003Uu2003dL−1. Conclusions: The data indicate that rFVIIa‐induced TG is affected by TF, phospholipids, rFVIIa concentration, and the presence of FVIII and FIX.

Current strategy for genetic analysis of haemophilia A families.

Summary. Carrier detection and prenatal diagnosis of haemophilia A, which was based in the last decade mainly on linkage polymorphism analysis, has been greatly facilitated by the recent discovery that two types of inversion disrupting the factor VIII gene are common mutations observed in 42–48% of severe haemophilia A cases. In this study DNA analysis was performed in 64 unrelated severe haemophilia A patients and 173 women belonging to their families, and in four women from a family with a deceased haemophilic relative whose DNA was unavailable (a total of 177 females from 65 unrelated families). Factor VIII gene inversions were found in 32 out of the 65 families (49%), 29 involving recombination with the distal A gene and three with the proximal A gene. Definitive information regarding carriership of haemophilia was provided to all 81 women belonging to the 32 inversion‐positive families, among them one woman previously uninformative for any of the polymorphisms examined, five women who were informative only for extragenic polymorphisms, and four suspected carriers who were relatives of the deceased haemophiliac. In 33 inversion‐negative families, 96 females were examined by analysis of the BclI restriction fragment length polymorphism (RFLP) in intron 18 and of the multiallelic dinucleotide repeats in introns 13 and 22, followed by analysis of other intragenic polymorphisms. This procedure yielded an informativity rate of almost 100%. Of the 96 females examined by linkage polymorphism analysis, 78 belonged to 25 families with more than one haemophiliac and 29 of them were obligate carriers. In 47 of the 49 suspected carriers linkage polymorphism analysis enabled definition of carriership based on intragenic polymorphisms. 18 of the 96 females belonged to eight families with sporadic haemophilia cases and only eight of the 18 suspected carriers could be diagnosed by exclusion.

Surfactant impairs coagulation in-vitro: A risk factor for pulmonary hemorrhage?

BACKGROUNDnPulmonary hemorrhage (PHEM) complicates the hospital course of 3-5% of preterm infants with respiratory distress syndrome (RDS), and bears a high mortality rate. Impaired thrombin generation and poor clot formation in premature neonates affect PHEM severity.nnnOBJECTIVESnWe evaluated the impact of surfactant upon in-vitro clot formation in order to assess the role of surfactant in the pathogenesis of PHEM.nnnMETHODSnBlood samples were obtained from healthy volunteers for measuring complete blood count, PT, PTT, and platelet function. Surfactant at increasing concentrations was added to blood samples, and whole blood clotting assays were performed using rotation thromboelastogram (ROTEM®, Pentapharm Munich, Germany) and whole blood platelet adhesion and aggregation (Impact-R®, Diamed, Switzerland).nnnRESULTSnThe mean PT level increased from 10.05 ± 033 to 11.64 ± 0.85 sec (p=0.06) in the presence of surfactant. Platelet aggregation with the agonists adenosine diphosphate and epinephrine significantly decreased with escalating surfactant concentration (p<0.001). Adhesion, manifested by surface coverage (SC), significantly decreased with increasing surfactant concentration: mean SC 9.25 ± 2.96 compared to 6.1 ± 0.96 and 0.05 ± 0.058 with 0/0.1/5mg/ml surfactant, respectively, p<0.001 Whole blood ROTEM studies showed a trend towards lengthening of clotting time with increased surfactant concentration and lower clot strength.nnnCONCLUSIONnThe presence of surfactant impairs coagulation in-vitro. The risk of PHEM may therefore be greater in extremely premature infants. Future studies are required to assess the clinical significance and relevance of our preliminary findings.

Multifocal pseudotumour in a single limb

A 13‐year‐old boy with severe haemophilia presented at the National Centre with gross swelling of his foot and infrapatella area, and reported that several months previously he had kicked a football and had instantly developed a bleed in his foot. Despite replacement factor the swelling failed to subside. He had ambulated for a while using crutches and when he eventually presented himself the X‐rays revealed two separate pseudotumours. The patient underwent a transfemoral amputation.

Haemophiliac Hands—a Three Year Follow-Up Study

The total absence of literature regarding the affects of haemophilia on the hand prompted this three year study at the Israel National Haemophilia Centre. The hands of all haemophiliacs were examined and X-rayed at the time of their annual check-up. Apart from a number of established Volkmanns contractures in elderly patients and multiple bone cysts of the carpus, surprisingly little pathology was found. When considering the extensive damage done to the musculoskeletal system by this haemarthritic pathogenesis it is astounding how the hand, with its multiple small joints, constant movement and trauma, escapes significant damage.