Patients with liver disease frequently develop coagulopathy, and fresh frozen plasma is traditionally used for correction of coagulopathy to manage and prevent bleeding. Prothrombin complex concentrates (PCCs) offer an attractive alternative because they are more readily available and avoid large‐volume transfusion. This retrospective, single‐center study reviewed clinical use of PCC in patients with acute/chronic liver disease. A total of 105 patients with 194 episodes of PCC administration were reviewed. Data pertaining to indication, dosing, effectiveness, and safety were collected. The effect of PCC on coagulation was analyzed in patients for whom coagulation results were available 7 hours before and after PCC. Data on thromboembolic events and mortality within 4 weeks of PCC administration were captured. Most patients (77%) had chronic liver disease; the remainder had acute liver failure. Indications for PCC were preprocedure prophylaxis and treatment for active/recent bleeding in 48% and 52% of 194 treatment episodes, respectively. The median dose of PCC administered was 22 IU/kg (interquartile range, 16‐29 IU/kg). Before PCC administration, 45% of patients had an international normalized ratio (INR) greater than 2.0, and 36% had fibrinogen levels of at least 1.5 g/L. PCC produced statistically significant reductions in prothrombin time and INR (coadministration with fibrinogen or cryoprecipitate: 3.1 versus 1.9; P < 0.001; no coadministration: 2.3 versus 1.8; P < 0.001). Three patients with multiple risk factors developed thrombotic events (hepatic artery thrombosis, incidental bilateral pulmonary embolism, nonocclusive portal vein thrombosis); there were no cardiovascular or cerebrovascular adverse events. Overall, 46 patients died of causes unrelated to PCC treatment. Conclusion: In patients with liver disease, PCC therapy was effective in improving coagulation test results without an excess of thrombotic events. Further assessment of PCC as hemostatic therapy in this setting is required.

Acquired haemophilia A (AHA) is a rare, serious bleeding disorder most often encountered in elderly patients. The mainstay of haemostatic management is with bypassing agents (BPAs) including recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrates (aPCCs). Their major limitation is incomplete efficacy, potential risk for thrombosis and the lack of routine laboratory assays for monitoring treatment response. Plasma-derived porcine FVIII (pd-pFVIII, Hyate C), first used in the 1950s for the management of congenital haemophilia, has sufficient sequence homology to be haemostatic in humans, but the lack of complete homology facilitates efficacy even in the presence of human allo- and autoantibodies against human FVIII (hFVIII). In a small phase II/III study, recombinant porcine FVIII (rpFVIII, Obizur, OBI-1, susoctocog alfa) was shown to be safe and effective for the management of bleeding episodes in patients with AHA with anti-porcine FVIII (anti-pFVIII) antibody levels of 20 BU/ml or less. Treatment outcome was judged on clinical response and FVIII levels after an initial fixed dose of 200 IU/kg. The rise in FVIII levels showed considerable inter-individual variability and was significantly influenced by the presence of anti-pFVIII antibodies. Based on the baseline levels of anti-pFVIII antibodies and response to treatment, three potential patient groups were identifiable. In the first group, the absence of cross-reacting antibodies was associated with supra-therapeutic FVIII levels, fewer infusions and lower rpFVIII utilization per treatment episode. The second group had patients with low levels of cross-reacting anti-pFVIII antibodies (0.8-5 BU/ml) with near-normal response to rpFVIII. The last group had higher titres of anti-pFVIII antibody (10-30 BU/ml) associated with lower FVIII levels, more infusions and higher consumption of rpFVIII. We propose a new treatment algorithm for the haemostatic management of AHA that includes the potential first-line clinical use of rpFVIII that takes into account availability of anti-pFVIII antibody results, titre of anti-pFVIII antibodies and severity of bleeding episode.

rFVIIIFc (efraloctocog alfa, Eloctate®) is an extended half-life (EHL) factor VIII licensed for use in patients with hemophilia A for prophylaxis and treatment of bleeding and surgical episodes. Pharmacokinetic studies in adults have shown a mean 1.5-fold increase in half-life compared to full-length factor VIII. When compared to adults, the half-life is decreased by 8% in adolescents between 12 and 17 years, by 18% in children 6 to <12 years, and by 33% in children between the ages of 2 and <6 years. There is a considerable interindividual variation in the prolongation of the half-life particularly in children and across the age groups, the range extending from no increase to a 2.5-fold increase. In addition to age, von willebrand factor (VWF) antigen level has demonstrated a significant impact on rFVIIIFc half-life, with higher VWF levels associated with greater prolongation of half-life. The pivotal and pediatric clinical trials have demonstrated the efficacy and safety of rFVIIIFc for use in regular prophylaxis and in management of bleeds and surgery. In these studies, just under half the participants showed a zero annualized bleed rate (ABR), and the median ABR (1.6 in the pivotal study for the individualized prophylaxis arm) showed a further decrease in the extension study. On average, the patients required fewer infusions (reduced by at least a third), and the mean weekly consumption seems to be in keeping with standard recombinant factor VIII. EHL rFVIIIFc has made decreased infusion frequency a possibility. However, the interindividual variability in dose and infusion frequency highlights the need for a personalized approach based on individual patient’s half-life and/or response to treatment.

Wilms tumour (WT) is the commonest primary malignant renal tumour of childhood. Acquired von Willebrand syndrome (avWS) is a well-described paraneoplastic phenomenon, but it is uncommon and may not be detected until clinically significant bleeding is encountered during interventional procedures. Previous studies on small cohorts of patients have determined an incidence of between 4 and 8%. We have performed a retrospective study on cases of WT presenting over an 11.5-year period to a paediatric haematology/oncology unit in a tertiary referral centre to review the incidence of avWS, bleeding phenotype, management, and response to treatment of the primary pathology.

Background: Severe hemophilia A and B patients with inhibitors experience serious musculoskeletal hemorrhage as well as high risk of limb and life threatening bleeds. However, lack of effect of FVIII or FIX substitution therapy and short functional half-life of by-passing agents, leave these patients with very limited bleed preventive treatment options. ALN-AT3 (Alnylam Pharmaceuticals, Cambridge, MA, USA), a subcutaneously administered investigational RNAi therapeutic targeting reduction of antithrombin for potential treatment of hemophilia is currently in phase 1 clinical development in hemophilia A and B patients without inhibitors. Initial data from that ongoing study in 12 patients suggest an AT KD dependent correction of thrombin generation. This study aims to assess changes in peak thrombin generation in samples from patients with severe hemophilia A and B with inhibitors following in vitro reduction of antithrombin. Materials and methods: Citrated plasma samples were obtained from patients with severe hemophilia A and B with high responding inhibitors. Samples were spiked in vitro with isotype specific control IgG or a monoclonal antibody (Haemtech Inc, Essex Junction, VT, USA) targeting antithrombin knockdown of 50% and 90%. Dynamic formation of thrombin was measured by calibrated automated thrombin generation using 1pM tissue factor PPP reagent and 4μM phospholipid (Thrombinoscope, Maastricht, The Nederlands). The primary effect measure was peak thrombin (nM). Data were tested by a 1-way ANOVA and p<0.05 was considered statistically significant. Results: A total of 12 inhibitor hemophilia samples were investigated; 9 hemophilia A and 3 hemophilia B. All the control samples demonstrated a profound defect in thrombin generation with a median peak thrombin of 19.9 nM (range 6.7 - 42.4). Patients with severe hemophilia A and inhibitors had a median peak thrombin generation of 19.7 nM (range 6.7 - 42.4), whereas patients with severe hemophilia B and inhibitors had a median peak thrombin generation of 19.2nM (range 19.4 - 38.1). An AT reduction dependent improvement in peak thrombin generation was observed in all 12 tested plasma samples (Figure 1). In the first 12 subjects, peak thrombin generation was increased up to 363% from a mean of 22nM (control) to 39 nM (50% AT reduction) and 80nM (90% AT reduction) (p<0.05); levels comparable to thrombin generation observed in healthy male volunteers and in hemophilia patients treated with ALN-AT3. Conclusions: These in vitro data suggest that reduction of AT is a promising approach for restoring hemostatic balance and correcting thrombin generation in hemophilia patients with inhibitors. Furthermore, the present laboratory data compare well with clinical data generated with ALN-AT3 administered to patients with hemophilia A or B. Thus, both laboratory and emerging clinical data suggest that targeting antithrombin could be a promising approach for restoring hemostatic balance in hemophilia. The potential for low volume subcutaneous administration, infrequent dosing, and applicability to persons with hemophilia who have inhibitors, make ALN-AT3 a particularly encouraging investigational therapy. Figure 1. Figure 1. Disclosures Kenet: Bayer, Novo Nordisk: Other: Advisory Boards, Speakers Bureau; Opko Biologics: Consultancy, Other: Advisory Boards; BPL; Baxelta: Research Funding; Pfizer: Honoraria. Off Label Use: ALN-AT3 is an investigational RNAi therapeutic targeting the endogenous anticoagulant antithrombin.. Chowdary:Sobi: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta: Membership on an entity's Board of Directors or advisory committees; Biogen: Membership on an entity's Board of Directors or advisory committees. Sehgal:Alnylam Pharmaceuticals: Employment, Equity Ownership. Akinc:Alnylam Pharmaceuticals: Employment, Equity Ownership. Sorensen:Alnylam Pharmaceuticals: Employment, Equity Ownership.

A 43-year-old man with no history of bleeding or bruising had a routine blood count performed prior to angiography. The automated platelet count on an impedance-based instrument was 108 3 10 9 L 21. The rest of the blood count was normal. Because of the unexpected thrombocytopenia, a blood film was examined. This showed extensive phagocytosis of platelets (Image 1). There was limited platelet satellitism, suggesting that this may have been the first stage of the process (top left image). In some cells, phagocytic vacuoles were clearly apparent (bottom right image). An in vitro phenomenon was suspected. A repeat blood sample was therefore taken, and a film prepared with no exposure to anticoagulant showed no phagocytosis. After a brief exposure to EDTA, occasional neutrophils showed satellitism and phagocytosis, and the platelet count was 158 3 10 9 L 21. By 4 hr, phagocytosis was extensive. The patient proceeded to an uneventful angiogram.

No abstract

Healthy, term neonates rarely encounter problems with bleeding, despite physiological differences in their levels of clotting factors, reflected in prolongation of the prothrombin time (PT), activated partial thromboplastin time (APTT) and thrombin time (TT). Their risk of bleeding, however, is significantly increased by the presence of a severe congenital bleeding disorder. Establishing such a diagnosis can present a particular challenge, given the rarity of these conditions and the difficulty in performing and interpreting laboratory assays in this age group. However, a delay in diagnosis and implementation of appropriate treatment can result in catastrophic sequelae. Therefore, the presentation of a healthy child at birth, whose condition rapidly deteriorates as a result of bleeding, should prompt the urgent investigation of a congenital haemostatic defect and involvement of expert haematological advice. We describe a very unusual presentation of a severe bleeding disorder in the first few days of life to highlight these issues.