Mario von Depka

NovoSeven: mode of action and use in acquired haemophilia

Recombinant activated factor VII (rFVIIa, ‘NovoSeven’) is indicated for the treatment of spontaneous and surgical bleeding in patients with haemophilia A or B with antibodies to factors VIII or IX (FVIII or FIX) worldwide, and in patients with acquired haemophilia in Europe. In vitro cell models have demonstrated that rFVIIa can bind to activated platelets and generate small amounts of Fxa, independent of the presence of tissue factor. The amount of platelet-surface Fxa formed increases with rising concentrations of FVIIa and, at levels of rFVII a that are effective in patients, sufficient platelet surface Fxa is generated partially to restore platelet surface thrombin generation. Acquired haemophilia is a rare but potentially life-threatening condition, caused by the autoimmune reduction of clotting factor levels as a result of the spontaneous development of auto-antibodies directed against the deficient factor. Bleeding into the skin or muscles is common in acquired haemophilia and the associated mortality rate is approximately 20%. rFVIIa has reported efficacy in the treatment of major bleeding episodes in patients with acquired haemophilia, which may be explained by its distinct mechanism of action that induces haemostasis at the site of injury, independent of the presence of FVIII or FIX. Also, the localisation of the action of rFVIIa at the site of injury may explain why it is well tolerated in these patients.

Clinical and prognostic role of plasma coagulation factor XIII activity for bleeding disorders and 6-year survival in patients with chronic liver disease

Abstract: Background/Aims: Alterations of plasma coagulation factor XIII may contribute to bleeding disorders in patients with liver cirrhosis. As standard clotting tests such as prothrombin time or activated thromboplastin time (aPTT) cannot detect factor XIII deficiency, this may often be overlooked in clinical practice. We aimed to define factor XIIIs clinical and prognostic role in chronic liver disease.

Antithrombin alfa in hereditary antithrombin deficient patients: A phase 3 study of prophylactic intravenous administration in high risk situations

During surgery and childbirth, patients with hereditary antithrombin (AT) deficiency are at high risk for thrombosis, and heparin prophylaxis may not be sufficiently efficacious. In these patients, exogenous AT may be used in association with heparin. A recombinant human AT (generic name: antithrombin alfa) has been developed. This multi-center study assessed the efficacy and safety of prophylactic intravenous administration of antithrombin alfa to hereditary AT deficient patients in high risk situations, including elective surgery, childbirth, or cesarean section. Antithrombin alfa was administered prior to and during the high risk period for restoration and maintenance of AT activity at 100% of normal. Heparin, low-molecular-weight heparin, and/or vitamin K antagonists were used according to standard of care. The primary efficacy endpoint was the incidence of acute deep vein thrombosis (DVT) from baseline up to day 30 post dosing as assessed by independent central review of duplex ultrasonograms and/or venograms. Safety was assessed based on adverse events (AEs) and laboratory evaluations. Five surgical and nine obstetrical hereditary AT deficiency patients received antithrombin alfa for a mean period of seven days. No clinically overt DVT occurred. Central review of ultrasonograms identified signs of acute DVT in two out of 13 evaluable patients. No antithrombin alfa-related AEs were reported. No patient developed anti-antithrombin alfa antibodies. In conclusion, this study suggests that antithrombin alfa is a safe and effective alternative to human plasma-derived AT for treating hereditary AT deficiency patients at high risk for thromboembolic events.

Plasma P-selectin levels are elevated in patients with chronic liver disease.

P-selectin is a leukocyte receptor and platelet activation marker that has been shown to be involved in thrombogenesis as well as bleeding disorders and may represent a possible link between inflammation and thrombosis. In animal models, high plasma levels correlated with a procoagulant tendency. In acute liver damage models such as hepatic ischaemia–reperfusion-injury, P-selectin was found to be a key mediator of liver injury. In order to investigate the clinical and pathogenetic role of P-selectin in chronic liver diseases, plasma P-selectin levels were measured in 111 patients with chronic liver diseases. P-Selectin was significantly elevated in patients (median 56 ng/ml, range 0–180) compared with controls (n = 38, median 20 ng/ml, range 3.3–42, P < 0.001). Current clinical bleeding symptoms were common, whereas thrombotic events occurred rarely. P-selectin levels were not associated with haemorrhagic or thromboembolic complications. P-selectin correlated with platelet and white-blood-cell counts, but not with endothelial injury markers thrombomodulin and tissue factor or coagulation factors. Interestingly, P-selectin levels were not associated with Childs stage of cirrhosis or disease aetiology, but were generally elevated in chronic liver diseases. Severe hepatic leukocyte infiltration in liver histology was associated with a tendency towards higher P-selectin levels. In line with its role in acute liver damage, P-selectin elevation in chronic liver disease may suggest a possible pathogenetic role in the course of liver cirrhosis.

Prevalence of a 23bp Insertion in Exon 3 of the Endothelial Cell Protein C Receptor Gene in Venous Thrombophilia

BACKGROUND The endothelial cell protein C receptor (EPCR) enhances protein C activation by the thrombin-thrombomodulin complex. As evidence is accumulating that EPCR is an important component of the protein C anticoagulant pathway, polymorphisms in the EPCR gene might be candidate risk factors predisposing to venous thromboembolism (VTE). Recently, a 23bp insertion in exon 3 of the EPCR gene has been identified, which duplicates the preceding 23 bases and results in a STOP codon downstream from the insertion point. However, the clinical significance of this mutation in VTE remains to be clarified. METHODS AND RESULTS In this study we evaluated the EPCR 23bp insertion in 889 patients with documented VTE and in 500 healthy controls. The prevalence of the EPCR insertion among patients was 0.1%, which was not significantly different compared to controls (0.6%, p = 0.1). CONCLUSIONS Our findings showed that the EPCR 23bp insertion is very rare in both patients with VTE and the general population and failed to support an association between the EPCR 23bp insertion and an increased risk of VTE.