Roel Vink

Recombinant factor VIIa reverses the anticoagulant effect of the long‐acting pentasaccharide idraparinux in healthy volunteers

We investigated whether the anticoagulant effect of idraparinux, a selective long‐acting factor Xa inhibitor, could be neutralized by recombinant factor VIIa (rFVIIa) in healthy male volunteers. We performed a randomized, placebo‐controlled trial, comparing idraparinux [7·5 mg subcutaneous (s.c.)] followed at 3 h by rFVIIa [90 μg/kg intravenous (i.v.)] (n = 6), or idraparinux (7·5 mg s.c) followed after 1 week by rFVIIa (90 μg/kg i.v.)(n = 6). rFVIIa, given 3 h after idraparinux, significantly reversed the increased thrombin generation time (TGT), the increased activated partial thromboplastin time (aPTT) and prothrombin time (PT), and the reduced prothrombin fragment 1+2 (F1+2) levels caused by idraparinux, although no clear effect of rFVIIa on the endogenous thrombin potential (ETP) was observed. One week after idraparinux, injection of rFVIIa resulted in a similar relative reduction of the remaining increased aPTT, PT and TGT, with correction to pre‐idraparinux values. A clear increase of F1+2 was observed, together with a small increase in ETP. We conclude that rFVIIa has significant effects on the idraparinux‐inhibited thrombin generation and clotting parameters. These results suggest that rFVIIa may be useful in serious bleeding complications in idraparinux treated patients.

Transfusion of fresh-frozen plasma in critically ill patients with a coagulopathy before invasive procedures: a randomized clinical trial (CME).

Prophylactic use of fresh‐frozen plasma (FFP) is common practice in patients with a coagulopathy undergoing an invasive procedure. Evidence that FFP prevents bleeding is lacking, while risks of transfusion‐related morbidity after FFP have been well demonstrated. We aimed to assess whether omitting prophylactic FFP transfusion in nonbleeding critically ill patients with a coagulopathy who undergo an intervention is noninferior to a prophylactic transfusion of FFP.

Management of bleeding disorders by prohemostatic therapy.

Pro-hemostatic therapy aims at an improvement of hemostasis, which may be achieved by amelioration of primary hemostasis, stimulation of fibrin formation or inhibition of fibrinolysis. These treatment strategies may be applied to specifically correct a defect in one of the pathways of coagulation, but have in some, situations also been shown to be effective in reducing bleeding in patients without a primary defect in coagulation. Besides the transfusion of platelets in case of thrombocytopenia or severe platelet disorders, a pharmacological improvement of primary hemostasis may be achieved by the administration of desmopressin., The administration of DDAVP results in a marked increase in the plasma concentration of Von Willebrand factor (and associated coagulation factor VIII) and (also by yet unexplained additional mechanisms) a remarkable potentiation of primary hemostasis as a consequence. DDAVP is used for the prevention and treatment of bleeding in patients with von Willebrand disease or mild hemophilia A, and further in patients with an impaired function of primary hemostasis, such as in patients with uremia, liver cirrhosis or in patients with aspirin-associated bleeding. Based on the current insight that activation of coagulation in vivo predominantly proceeds by the tissue factor/factor VII(a) pathway, recombinant factor VIIa has been developed as a prohemostatic agent and has recently become available for clinical use. Indeed, in uncontrolled clinical studies this compound has been shown to exert a potent procoagulant activity and appeared to be highly effective in the prevention and treatment of bleeding, although most experience so far has been obtained in patients with severe and complicated coagulation defects. At present, a more general use of this agent for bleeding patients without an apparent coagulation defect is the subject of a number of ongoing clinical trials. Agents that exert anti-fibrinolytic activity are aprotinin and the group of lysine analogues. The pro-hemostatic effect of these agents proceeds not only by the inhibition of fibrinolysis (thereby shifting the procoagulant/anticoagulant balance towards a more procoagulant state), but also due to a protective effect on platelets, as has been demonstrated at least for aprotinin. The mechanism, of this platelet-protective effect has, besides a potential prevention of plasmin-mediated loss of platelet receptors not been elucidated. Whether the pro-hemostatic effect of the anti-fibrinolytic agents will eventually result in a higher incidence of thromboembolic complications is still a matter of debate (see further), however, this has so far not been shown in straightforward clinical trials.

Individualized duration of oral anticoagulant therapy for deep vein thrombosis based on a decision model

Summary.  Background: The optimal duration of oral anticoagulant therapy for patients with a first episode of deep vein thrombosis (DVT) is still a matter of debate. However, according to the ACCP consensus strategy a limited stratification in treatment duration is advocated, i.e. 3 months for patients with a transient risk factor and 1 year or longer for patients with recurrent disease or a consistent risk factor such as thrombophilia or cancer. This consensus strategy is founded on the mean optimal duration of therapy obtained in large cohorts of patients and is mainly based on the risk of recurrent venous thromboembolism (VTE), with only minimal consideration for the patients bleeding risk. Objective: The aim of this study is to optimize the anticoagulant treatment strategy with vitamin K antagonists for the individual patient with DVT. Methods: Based on an extensive literature study, a mathematical model was constructed to balance the risk of recurrent VTE against the risk of major hemorrhagic complications. The following parameters are incorporated in the model: baseline estimates and risk factors for recurrent VTE and bleeding, clinical course of DVT, and efficacy of treatment with vitamin K antagonists. With the use of these parameters, the risk for a recurrent VTE and a bleeding episode can be calculated for the individual patient. The optimal duration of anticoagulant therapy can be defined as the timepoint at which the benefit of treatment (prevention of VTE) is counterbalanced by its risk (bleeding). Results/conclusions: How long a patient should receive anticoagulant treatment is a matter of balancing the benefits and risks of treatment. The model shows that the optimal treatment duration varies greatly from patient to patient according to the patients unique bleeding and recurrence risk.

In vivo treatment of rats with unfractionated heparin (UFH) or low molecular weight heparin (LMWH) does not affect experimentally induced colon carcinoma metastasis

Recent randomized trials have suggested that treatment with low molecular weight heparin (LMWH) improves survival of cancer patients with venous thromboembolism, as compared to treatment with unfractionated heparin (UFH). Experimental studies have shown that UFH has activities besides its anticoagulant function which may affect progression of malignancy, including stimulation of new blood vessel formation. In contrast, LMWH has been suggested to inhibit angiogenesis. In the present study, we compared quantitatively the effects of treatment with UFH, LMWH or placebo on the development of experimentally induced colon carcinoma metastases in rat liver and on tumor-associated angiogenesis. It is shown that UFH and LMWH in therapeutic dosages neither affect development of metastases nor tumor blood vessel formation in this animal model. These results indicate that heparins do not affect colon cancer metastasis in liver. Further studies in other animal models are required to establish the mechanisms by which heparins potentially affect cancer.

Prevention and Treatment of Bleeding by Pro-hemostatic Treatment Strategies

SummaryPro-hemostatic therapy may achieve an improvement of hemostasis, by amelioration of primary hemostasis, stimulation of fibrin formation or inhibition of fibrinolysis. Pro-hemostatic interventions appear to be effective in reducing peri-operative blood loss and reducing transfusion requirements in specific situations and may be helpful adjuncts in the management of severe spontaneous and post-operative bleeding. The risk of a higher incidence of thrombotic complications associated with the use of pro-hemostatic therapy is unknown but seems not to be very high in clinical practice. There is a need for more systematic and adequately controlled clinical observations to better establish the efficacy and safety of pro-hemostatic interventions.ZusammenfassungPro-hämostatische Therapie kann eine Verbesserung der Hämostase durch Verbesserung der primären Hämostase, Stimulation der Fibrinbildung oder Hemmung der Fibrinolyse bewirken. Pro-hämostatische Interventionen scheinen effektiv den peri-operativen Blutverlust und die notwendigen Transfusionen in bestimmten klinischen Situationen zu vermindern. Darüberhinaus können sie nützliche Hilfsmittel in der Behandlung von schweren spontanen, sowie post-operativen Blutungen sein. Das Risiko für thrombotische Komplikationen dieser Therapien ist unbekannt, aber erscheint in klinischer Praxis nicht sehr hoch zu sein. Es gibt einen Bedarf an systematischen und adäquat kontrollierten klinischen Studien, um die Wirksamkeit und die Sicherheit dieser pro-hämostatischen Interventionen besser zu etablieren.

Challenges in managing anticoagulant therapy in patients with heart valve prostheses

There is a wide array of recommendations for the management of anticoagulant therapy in patients with mechanical heart valves. The optimal intensity of vitamin K antagonists, management of patients during noncardiac surgery and use of anticoagulants during pregnancy are all ongoing matters of debate. In this review, we discus the various studies on these topics and the different guidelines. Based on these, literature recommendations for daily clinical practice are formulated.