Jacob Luboshitz

Recombinant activated factor VII for adjunctive hemorrhage control in trauma.

BACKGROUNDnRecombinant activated factor VII (rFVIIa) was approved for treatment of hemorrhages in patients with hemophilia who develop inhibitors to factors VIII or IX. Conditions with increased thromboembolic risk, including trauma with or without disseminated intravascular coagulation, were considered a contraindication for the drug. The mechanism of action of rFVIIa suggests enhancement of hemostasis limited to the site of injury without systemic activation of the coagulation cascade. Therefore, use of the drug in trauma patients suffering uncontrolled hemorrhage appears to be rational.nnnMETHODSnSeven massively bleeding, multitransfused (median, 40 units [range, 25-49 units] of packed cells), coagulopathic trauma patients were treated with rFVIIa (median, 120 microg/kg [range, 120-212 microg/kg]) after failure of conventional measures to achieve hemostasis.nnnRESULTSnAdministration of rFVIIa resulted in cessation of the diffuse bleed, with significant decrease of blood requirements to 2 units (range, 1-2 units) of packed cells (p < 0.05); shortening of prothrombin time and activated partial thromboplastin time from 24 seconds (range, 20-31.8 seconds) to 10.1 seconds (range, 8-12 seconds) (p < 0.005) and 79 seconds (range, 46-110 seconds) to 41 seconds (range, 28-46 seconds) (p < 0.05), respectively; and an increase of FVII level from 0.7 IU/mL (range, 0.7-0.92 IU/mL) to 23.7 IU/mL (range, 18-44 IU/mL) (p < 0.05). Three of the seven patients died of reasons other than bleeding or thromboembolism.nnnCONCLUSIONnThe results of this report suggest that in trauma patients rFVIIa may play a role as an adjunctive hemostatic measure, in addition to surgical hemostatic techniques, and provides the motivation for controlled animal and clinical trials.

Non-invasive biomarkers of liver fibrosis in haemophilia patients with hepatitis C: can you avoid liver biopsy?

Summary.u2002 Introduction:u2002 Liver biopsy remains the gold standard for the evaluation of fibrosis despite its risks and limitations, especially in haemophilia patients. Recently, non‐invasive biomarkers have been used to assess histological features. The most thoroughly evaluated biomarker is the FibroTest (FT) (AUROC 0.80 for fibrosis stages F2F3F4 vs. F0F1).

Lower doses of rFVIIa therapy are safe and effective for surgical interventions in patients with severe FXI deficiency and inhibitors

Summary.u2002 Severe FXI deficiency is a rare injury‐related bleeding disorder. In patients with FXI inhibitors, surgeries may be treated using recombinant activated factor VII; however, treatment safety is a major concern and the best dosing regimen as well as mode of administration is still to be defined. We describe four patients with severe factor XI deficiency and inhibitors to FXI, undergoing eight (four major) surgical procedures treated with continuous infusion of rFVIIa. Following acute MI that evolved after surgery of our first patient, all other patients were treated with low‐dose bolus rFVIIa followed by low‐dose continuous infusion of rFVIIa. Haemostasis was successfully achieved and no further thrombotic complications occurred. To support our clinical results ex‐vivo thromboelastography studies were performed, demonstrating the differences of clot formation and lysis between patients with FXI deficiency and healthy controls and suggesting that low‐dose rFVIIa corrects coagulation similarly to high‐dose rFVIIa in FXI deficiency. Recombinant FVIIa at low doses may effectively induce haemostasis and seems to be a safe treatment mode in patients with FXI deficiency and inhibitors undergoing surgeries.

Recombinant factor concentrates may increase inhibitor development: a single centre cohort study.

Summary.u2002 Recent reports have raised concerns regarding potential risk factors for inhibitor development. In Israel, all haemophilia patients (nu2003=u2003479) are followed by the National Hemophilia Center. Most children are neonatally exposed to factor concentrate (due to circumcision performed at the age of 8u2003days). The impact of early exposure and recombinant FVIII products (rFVIII) administration (approved in Israel since 1996) upon inhibitor occurrence in our cohort of haemophilia A (HA) patients was analysed. Two hundred ninety‐two consecutive paediatric cases with a first symptomatic onset of HA were enrolled and followed over a median time of 7u2003years [min–max: 9u2003months to 17u2003years]. Study endpoint was inhibitor development against factor VIII. In addition, the treatment regimens applied, i.e. bolus administration or ‘continuous infusion’ and the family history of inhibitor development were investigated. During the follow‐up period 31/292 children (10.6%) developed high titre inhibitors. Inhibitors occurred in 14/43 (32.5%) HA patients neonatally exposed to rFVIII, as compared to 22/249 previously treated with Plasma Derived (PD) products (8.8%). The odds ratio for inhibitor formation in rFVIII treated HA patients was 3.43 (95% CI: 1.36–8.65). Transient inhibitor evolved among 2/43 paediatric HA patients, only among those treated with rFVIII. The risk of inhibitor detection significantly increased among HA children treated by continuous infusion (Pu2003=u20030.025). Our experience shows that the risk of inhibitor formation may be increased by early exposure to recombinant concentrates. The multiple variables affecting inhibitor incidence deserve further attention by larger prospective studies.

Hepatitis C at the Israeli National Hemophilia Center

Summary.u2002 Haemophilia patients who received non‐virucidally treated large pool clotting factors before 1987 have a high rate of chronic hepatitis C viral infection (HCV). Some patients are coinfected with HIV. Haemophilia patients and other coagulation disorders were treated at one centre since the beginning of the 1970, and the Israeli National Hemophilia Center (INHC) was officially founded in 1987. To characterize patients with HCV as well as patients with HCV/HIV coinfection at the INHC. Patients with haemophilia and other coagulation disorders positive for HCV antibodies were evaluated between 2001 and 2004. Demographic data, type and severity of coagulation disorder, frequency of coagulation factor usage and treatment with concentrated clotting factors prior to 1987 were recorded. Liver enzymes, viral load, genotype and data supporting advanced liver disease were evaluated. About 179 of 239 haemophilia patients (75%) tested positive for anti‐HCV antibodies. Our cohort consisted of 165 patients in whom clinical, biochemical and virological data were available. About 117 patients had active HCV infection with HCV‐RNA‐positive, and 27 were HCV/HIV coinfected. Twenty‐one patients (13%) persistently tested HCV‐RNA‐negative, hence were considered to clear their HCV infection. There was no former USSR immigrants among HCV/HIV coinfected compared with HCV‐infected or HCV‐RNA‐negative groups (0 vs. 30% and 38%, respectively; Pu2003<u20030.001). HCV‐RNA‐negative patients used concentrated coagulation factor less frequently than HCV or HCV/HIV‐infected patients (48% vs. 73%; Pu2003=u20030.023, and 48% vs. 74%; Pu2003=u20030.043, respectively). The use of concentrated clotting factors before 1987 was significantly more frequent in HCV/HIV than in either HCV‐infected or HCV‐RNA‐negative patients (96% vs. 49% and 48%, respectively; Pu2003<u20030.001). Compared with HCV/HIV subjects, patients with HCV monoinfection were characterized by a higher proportion of infection with genotype 1 (80% vs. 61%; Pu2003=u20030.027). The rate of persistently normal liver enzymes in these patients was higher (24% vs. 7%; Pu2003=u20030.05) than in the HCV/HIV‐coinfected patients. Advanced liver disease was significantly more common in patients with HCV/HIV‐coinfection than in HCV‐monoinfected patients (11% vs. 3%; Pu2003=u20030.045). The majority of haemophilia patients are infected with HCV. Viral clearance occurred in a minority of these patients. HCV monoinfected and HCV/HIV coinfected differ clinically and prognostically.

Efficacy and safety of a factor VIII–von Willebrand factor concentrate 8Y: stability, bacteriological safety, pharmacokinetic analysis and clinical experience

Summary.u2002 The present study was undertaken to evaluate stability, pharmacokinetic profile and efficacy of continuous infusion of 8Y in patients with different types of von Willebrand disease (vWD). Following reconstitution, 8Y levels of von Willebrand factor ristocetin cofactor (vWF:Rco), vWF antigen and factor VIII coagulant activity (FVIII:C) decreased to about 80% of the baseline levels; addition of low molecular weight heparin decreased the level of FVIII:C even further. Reconstituted 8Y was found to be sterile for up to 6u2003days postreconstitution. Ten vWD patients (four with type 2A, three with type 3, two with type 1 and one with 2N) underwent pharmacokinetic analysis. The recovery of vWF: RCo was significantly lower in patients with type 3 vWD (1.4u2003±u20030.05%u2003U−1u2003kg−1) compared withthat of the patients with types 1 (2.3u2003± 0.52%u2003U−1u2003kg−1) or 2A (2.0u2003± 0.06%u2003U−1u2003kg−1) vWD (Pu2003=u20030.015). Type 3 vWD patients exhibited significantly higher vWF:RCo clearance (5.1u2003± 1.1u2003mLu2003kg−1u2003h−1) compared with that of patients with type 2A (2.8u2003±u20030.7 mLu2003kg−1u2003h−1) and type 1 (2.6u2003±u20031.0u2003mLu2003kg−1u2003h−1) vWD (Pu2003=u20030.028). Accordingly, terminal half‐life was lower in patients with type 3 vWD (8.0u2003±u20030.6u2003h−1) compared with type 2A (12.7u2003±u20035.9u2003h−1) or type 1 (14u2003±u20031.2u2003h−1) vWD patients. Multimeric pattern of vWF from patients plasma was similar to that of 8Y. In two patients treated with 8Y by continuous infusion for prevention or treatment of bleeding haemostasis was achieved. Thus, 8Y is suitable and haemostatically effective for continuous infusion treatment in patients with vWD.

Infusion rates of recombinant FVIII-FS with PEGylated liposomes in haemophilia A.

The recently published Joint Outcome Study is a significant addition to the previous studies that show reduction in bleeding frequency with prophylactic therapy compared with episodic treatment, resulting in improved joint and quality-of-life outcomes [1]. This evidence has led major haemophilia and medical organizations to recommend prophylactic therapy for patients with severe haemophilia A [3,4]. A common approach to dose-determination for prophylaxis is based on maintenance of circulating factor VIII (FVIII) levels above the threshold for severe disease (i.e. 0.01 IU mL). Because the halflife of human FVIII in the circulation is approximately 10–12 h, prophylactic infusions often need to be repeated every 2–3 days. A longer-acting FVIII product could greatly improve patient compliance and quality of life. A full-length sucrose-formulated preparation of recombinant human FVIII (rFVIII-FS; Kogenate FS; Bayer HealthCare Pharmaceuticals, Berkeley, CA, USA) non-covalently associated with PEGylated liposomes (PEGLip-FVIII-FS) demonstrated prolonged haemostatic activity compared to the same with standard rFVIII-FS in an animal model [2]. This finding is supported by clinical data indicating a statistically significant prolongation of the bleed-free period following prophylactic administration of PEGLip-FVIII-FS compared to the same with standard rFVIII-FS [3]. This study and other earlier clinical evaluations [3–5], have shown a promising safety and tolerability profile for PEGLip-FVIII-FS. However, in these studies PEGLip-FVIII-FS (also referred to as BAY 79-4980) was infused at a slow rate according to current practice for the administration of approved liposome-coated drugs (e.g. amphotericin B liposome or liposomal doxorubicin), which are typically administered over a much longer infusion time than factor concentrates on account of concerns of toxicity related to the active drug (rather than the liposome carrier). In contrast, FVIII concentrates are typically infused by fast infusion over approximately 5 min, most often performed by the patients themselves in the home setting. We describe the results of a randomized, openlabel, single-centre study evaluating the safety and tolerability of PEGLip-FVIII-FS administered over infusion periods as short as 5 min. The study enrolled patients with severe haemophilia A (£1% of FVIII activity) between the ages of 18 and 70 years. Subjects were required to have had ‡250 cumulative exposure days (CEDs) to coagulation factor replacement products prior to enrolment, with at least 25 exposures occurring within 1 year prior to the commencement of the study. Subjects, who were HIV positive were included if their CD4 lymphocyte count was ‡400 cells lL. Subjects with FVIII inhibitors or a history of inhibitors, platelet count <90 000 cells lL, concomitant debilitating disease (e.g. cancer, uncontrolled diabetes, heart insufficiency and renal failure), or a symptomatic infection were excluded. All subjects provided written informed consent. Subjects were randomized to one or the other of two groups that received PEGLip-FVIII-FS at slow (Group A) or fast (Group B) infusion rates at a ratio of 1:2. Each subject received a total of three infusions of PEGLip-FVIII-FS. The first 0.5–1 mL of each infusion was infused slowly, after which the infusion rate increased for the remaining volume. The total infusion time was reduced for each consecutive infusion within the series. The first infusion for both groups lasted 20 min and the fastest infusion lasted 5 min (third infusion for Group B). All Correspondence: U. Martinowitz, Chaim Sheba Medical Center, The Institute of Thrombosis, Hemostasis and the National Hemophilia Center. Tel Hashomer 52621, Israel. Tel.: +972 3 5302 950; fax: +972 3 5351 806; e-mail: martinur@bezeqint.net

Treatment tailoring for factor V deficient patients and perioperative management using global hemostatic coagulation assays

INTRODUCTIONnCongenital factor V deficiency (FVD) is a rare bleeding disorder with an estimated incidence of 1 in 1000,000 in the general population. Since the common coagulation tests do not correlate with the bleeding tendency there is an unmet need to predict FVD patients bleeding hazard prior to surgical interventions.nnnAIMnTo optimize treatment prior to surgical interventions, using global coagulation assays, thrombin generation (TG) and rotating thromboelastogram (ROTEM).nnnMETHODSnOur cohort included 5 patients with FVD, 4 severe and one mild. Two of them underwent TG and ROTEM prior to surgical interventions, including ex vivo spiking assays using bypass agents and platelets spiking.nnnRESULTSnAll five patients exhibited prolonged PT and PTT, non-dependent on their bleeding tendency. Patient 1, who demonstrated severe bleeding phenotype, underwent surgery treated by combination of APCC (FEIBA) and platelet transfusion. Therapy was guided by global tests (TG as well as ROTEM) results. During the pre and post-operative period neither excessive bleeding nor any thrombosis was noted. In contrast, TG and ROTEM analysis of patient 4 has lead us to perform the surgery without any blood products support. Indeed, the patient did not encounter any bleeding.nnnCONCLUSIONnGlobal coagulation assays may be useful ancillary tools guiding treatment decisions in FVD patients undergoing surgical procedures.

From thrombasthenia to next generation thrombocytopenia: Neonatal alloimmune thrombocytopenia induced by maternal Glanzmann thrombasthenia

Glanzmann thrombasthenia (GT) is a rare autosomal recessive disorder of platelet function caused by mutations in the genes coding for integrin αIIbβ3. The aim of this study was to examine the outcome of newborns of GT mothers, with emphasis on thrombocytopenia and bleeding manifestations and their relation to maternal antiplatelet antibodies.

Chronic iliofemoral vein obstruction – an under-recognized cause of exercise limitation†

Abstract Local symptoms of chronic venous insufficiency after deep vein thrombosis (DVT) are well described, but little is known about the effect of residual venous obstruction on exercise capacity. We tested our hypothesis that chronic residual iliofemoral vein occlusion (IFVO) after DVT may impair exercise capacity. Nine post-DVT patients with residual IFVO and effort intolerance were studied; a comparison cohort consisted of 11 healthy volunteers. Exercise tolerance was assessed by bimodality incremental symptom-limited cardiopulmonary testing, using leg and arm ergometers. In healthy subjects, leg vein obstruction was modelled by application to the thighs of cuff tourniquets inflated to 30–40u2005mmHg. Leg exercise tolerance as measured by oxygen uptake at peak exercise (peak ⩒’O2) was reduced in patients (median 50% predicted (range 36–83%) vs. 88% predicted (67–129%) in normal subjects, pu2009<u20090.001). Arm exercise tolerance was also reduced in patients, but less severely than in the legs – the median arm: leg ratio of peak ⩒’O2 was 0.95 (0.77–1.43) in patients vs. a normal ratio of 0.73 (0.6–1.0) in healthy subjects (pu2009<u20090.003). In healthy subjects, bilateral leg vein obstruction by tourniquets reduced peak ⩒’O2 in leg exercise to 76% predicted (range 55–108%; pu2009<u20090.001 vs. standard test). In conclusion, the comparison of arm vs. leg exercise capacity in post-DVT patients with residual IFVO and the effect of experimental venous obstruction (thigh tourniquets) in healthy subjects suggest that reduced exercise capacity in patients was at least partially caused by reduced venous return. Chronic venous obstruction should be recognized as a cause of exercise limitation.