Pieter Willem Kamphuisen

Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate A Randomized, Placebo-Controlled, Crossover Study in Healthy Subjects

Background— Rivaroxaban and dabigatran are new oral anticoagulants that specifically inhibit factor Xa and thrombin, respectively. Clinical studies on the prevention and treatment of venous and arterial thromboembolism show promising results. A major disadvantage of these anticoagulants is the absence of an antidote in case of serious bleeding or when an emergency intervention needs immediate correction of coagulation. This study evaluated the potential of prothrombin complex concentrate (PCC) to reverse the anticoagulant effect of these drugs. Methods and Results— In a randomized, double-blind, placebo-controlled study, 12 healthy male volunteers received rivaroxaban 20 mg twice daily (n=6) or dabigatran 150 mg twice daily (n=6) for 2½ days, followed by either a single bolus of 50 IU/kg PCC (Cofact) or a similar volume of saline. After a washout period, this procedure was repeated with the other anticoagulant treatment. Rivaroxaban induced a significant prolongation of the prothrombin time (15.8±1.3 versus 12.3±0.7 seconds at baseline; P<0.001) that was immediately and completely reversed by PCC (12.8±1.0; P<0.001). The endogenous thrombin potential was inhibited by rivaroxaban (51±22%; baseline, 92±22%; P=0.002) and normalized with PCC (114±26%; P<0.001), whereas saline had no effect. Dabigatran increased the activated partial thromboplastin time, ecarin clotting time (ECT), and thrombin time. Administration of PCC did not restore these coagulation tests. Conclusion— Prothrombin complex concentrate immediately and completely reverses the anticoagulant effect of rivaroxaban in healthy subjects but has no influence on the anticoagulant action of dabigatran at the PCC dose used in this study. Clinical Trial Registration— URL: http://www.trialregister.nl. Unique identifier: NTR2272.Background— Rivaroxaban and dabigatran are new oral anticoagulants that specifically inhibit factor Xa and thrombin, respectively. Clinical studies on the prevention and treatment of venous and arterial thromboembolism show promising results. A major disadvantage of these anticoagulants is the absence of an antidote in case of serious bleeding or when an emergency intervention needs immediate correction of coagulation. This study evaluated the potential of prothrombin complex concentrate (PCC) to reverse the anticoagulant effect of these drugs.nnMethods and Results— In a randomized, double-blind, placebo-controlled study, 12 healthy male volunteers received rivaroxaban 20 mg twice daily (n=6) or dabigatran 150 mg twice daily (n=6) for 2½ days, followed by either a single bolus of 50 IU/kg PCC (Cofact) or a similar volume of saline. After a washout period, this procedure was repeated with the other anticoagulant treatment. Rivaroxaban induced a significant prolongation of the prothrombin time (15.8±1.3 versus 12.3±0.7 seconds at baseline; P <0.001) that was immediately and completely reversed by PCC (12.8±1.0; P <0.001). The endogenous thrombin potential was inhibited by rivaroxaban (51±22%; baseline, 92±22%; P =0.002) and normalized with PCC (114±26%; P <0.001), whereas saline had no effect. Dabigatran increased the activated partial thromboplastin time, ecarin clotting time (ECT), and thrombin time. Administration of PCC did not restore these coagulation tests.nnConclusion— Prothrombin complex concentrate immediately and completely reverses the anticoagulant effect of rivaroxaban in healthy subjects but has no influence on the anticoagulant action of dabigatran at the PCC dose used in this study.nnClinical Trial Registration— URL: . Unique identifier: NTR2272.nn# Clinical Perspective {#article-title-32}

Association of V617F Jak2 mutation with the risk of thrombosis among patients with essential thrombocythaemia or idiopathic myelofibrosis: A systematic review

INTRODUCTIONnMany studies evaluated the association of V617F Jak-2 with the risk of thrombosis in patients with essential thrombocythaemia, but the results of these studies were inconsistent. Few studies evaluated the association of V617F Jak-2 mutation with the risk of thrombosis in patients with idiopathic myelofibrosis. Therefore, we performed a systematic review of the studies that assessed the risk of thrombosis associated with V617F Jak-2 in patients with ET or IM.nnnMATERIALS AND METHODSnWe searched MEDLINE and EMBASE databases and reference lists of retrieved articles. Odds ratios (ORs) and 95% confidence intervals (CI) were calculated for each trial and pooled.nnnRESULTSnWe included 21 studies involving patients with essential thrombocythaemia and 6 studies patients with idiopathic myelofibrosis. In essential thrombocythaemia patients, V617F Jak-2 was associated with a significant increased risk of thrombosis (OR 1.92, 95% CI 1.45-2.53), both of venous (OR 2.49, 95% CI 1.71-3.61) and arterial (OR 1.77, 95% CI 1.29-2.43) vessels. In idiopathic myelofibrosis patients, the risk of thrombosis associated with V617F Jak-2 tended to be increased (OR 1.76, 95% CI 0.91-3.41).nnnCONCLUSIONSnOur systematic review suggests that V617F Jak-2 increases the risk of thrombosis in essential thrombocythaemia patients by about two fold while its role in idiopathic myelofibrosis patients is uncertain.

Circulating microparticles in cardiovascular disease: implications for atherogenesis and atherothrombosis

Summary.u2002 The complex and multifactorial nature of atherogenesis and development of atherothrombotic complications involves numerous interactions between various cell types inside the vascular wall (e.g. macrophages and smooth muscle cells) and in the blood (e.g. leukocytes and platelets). One relatively recent advance in this area is the discovery of circulating microparticles and their role in endothelial damage, platelet activation, hypercoagulability and regulation of inter‐cellular interactions. Microparticles are small anucleoid phospholipid vesicles released from different cells, such as platelets, erythrocytes, leukocytes and endothelial cells. Microparticles carry surface proteins and include cytoplasmic material of the parental cells responsible for the exertion of microparticle‐mediated biological effects. About 25% of the procoagulant activity of stimulated platelet suspensions is associated with microparticles released upon platelet activation and their surface may be approximately 50–100‐fold more procoagulant than the surface of activated platelets per se. The available lines of evidence indicate that shedding of microparticles from the parental cells is not just a passive process accompanying cellular dysfunction and apoptosis, but a tightly regulated mechanism implicated in the interactions between various cell types. The role of microparticles as biological messengers is supported by their differential and specific involvement in the pathophysiology of different cardiovascular disorders, including atherogogenesis and thrombosis.

Bleeding risk and reversal strategies for old and new anticoagulants and antiplatelet agents

Summary.u2002 The most important adverse effect of antithrombotic treatment is the occurrence of bleeding. In the case of severe bleeding in a patient who uses anticoagulant agents or when a patient on anticoagulants needs to undergo an urgent invasive procedure, it may be useful to reverse anticoagulant treatment. Conventional anticoagulants such as vitamin K antagonists may be neutralized by administration of vitamin K or prothrombin complex concentrates, whereas heparin and heparin derivatives can be counteracted by protamine sulphate. The anti‐hemostatic effect of aspirin and other antiplatelet strategies can be corrected by the administration of platelet concentrate and/or desmopressin, if needed. Recently, a new generation of anticoagulants with a greater specificity towards activated coagulation factors as well as new antiplatelet agents have been introduced and these drugs show promising results in clinical studies. A limitation of these new agents may be the lack of an appropriate strategy to reverse the effect if a bleeding event occurs, although experimental studies show hopeful results for some of these agents.

Risk factors for upper limb deep vein thrombosis associated with the use of central vein catheter in cancer patients

Deep vein thrombosis of upper limb is a common complication of CVC in patients with cancer. In these patients the risk factors for CVC-related thrombosis are not completely defined. The purpose of this study was to identify the risk factors for CVC-related thrombosis in patients included in a randomized, double-blind, placebo-controlled study aimed at assessing the efficacy and safety of enoxaparin for the prophylaxis of CVC-related thrombosis. CVC-related thrombosis was screened by mandatory venography after 6xa0weeks of study treatment. A number of patient baseline characteristics were assessed as potential risk factors for CVC-related deep vein thrombosis. Crude associations between risk factors and clinical outcomes were assessed by χ2 test or Fisher’s exact test. Multiple logistic regression analysis was used to identify independent risk factors. A CVC-related thrombosis was found in 50 out of 310 patients (16.1%). At multiple logistic regression analysis, CVC tip misplaced in the upper half of superior vena cava (OR 4.05, 95%CI 1.64–10.02), left-sided CVC insertion (OR 2.29, 95%CI 1.01–5.51) and chest radiotherapy (OR 7.01, 95%CI 1.42–34.66) were independent risk factors for thrombosis. In addition to these risk factors, the presence of distant metastases (OR 9.36, 95%CI 1.53–57.05) increased the risk of thrombosis in patients who received placebo. An inadequate position of the CVC tip, left-sided CVC insertion and chest radiotherapy are independent risk factors for CVC-related thrombosis in cancer patients. Patients with distant metastases have an increased risk for thrombosis in absence of antithrombotic prophylaxis.

Obesity: a new disaster for haemophilic patients? A nationwide survey

Summary.u2002 The prevalence of obesity, an important risk factor for both cardiovascular disease and arthropathy, is strongly increasing in the general population, but data for the haemophilia population are scarce. Obesity may have a more profound effect on arthropathy and on cardiovascular disease in patients with haemophilia. To assess the prevalence of obesity in haemophilia patients and install adequate measures, if necessary. We performed a nationwide postal survey to measure the prevalence of overweight and obesity in Dutch haemophilia patients in 1992 (nu2003=u2003980) and 2001 (nu2003=u20031066). A random sample of the Dutch male population served as the control group. In adult haemophiliacs, the prevalence of overweight (BMI 25–30u2003kgu2003m−2) increased from 27% to 35% (95% CI 31.1–38.0) and the prevalence of obesity (BMI ≥30u2003kgu2003m−2) doubled from 4% to 8% (95% CI 6.0–10.1), which was comparable with the general population. The increased prevalence of obesity in boys with haemophiliacs, which tripled in 10u2003years, is alarming. The increased prevalence of overweight and obesity in patients with haemophilia may have a profound effect on morbidity and quality of life of haemophilia patients by aggravating pre‐existing arthropathy and predisposing aged patients to cardiovascular disease. Measures to prevent overweight in haemophiliacs are therefore urgently needed.

Prevention of venous thromboembolism after acute ischemic stroke

Summary.u2002 Venous thromboembolism (VTE) is a common complication after acute ischemic stroke. When screened by 125I fibrinogen scanning or venography, the incidence of deep‐vein thrombosis (DVT) in stroke patients is comparable with that seen in patients undergoing hip or knee replacement. Most stroke patients have multiple risk factors for VTE, like advanced age, low Barthel Index severity score or hemiplegia. As pulmonary embolism is a major cause of death after acute stroke, the prevention of this complication is of crucial importance. Prospective trials have shown that both unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are effective in reducing DVT and pulmonary embolism in stroke patients. Current guidelines recommend the use of these agents in stroke patients with risk factors for VTE. Some clinicians are concerned that the rate of intracranial bleeding associated with thromboprophylaxis may outweigh the benefit of prevention of VTE. Low‐dose LMWH and UFH seem, however, safe in stroke patients. Higher doses clearly increase the risk of cerebral bleeding and should be avoided for prophylactic use. Both aspirin and mechanical prophylaxis are suboptimal to prevent VTE. Graduated compression stockings should be reserved to patients with a clear contraindication to antithrombotic agents.

Statins, fibrates, and venous thromboembolism: a meta-analysis.

AIMSnThe aim is to make a systematic review of the literature to assess the effect of lipid-lowering drugs on venous thromboembolism (VTE) occurrence.nnnMETHODS AND RESULTSnMEDLINE and EMBASE databases were searched to identify studies that evaluated the effect of lipid-lowering drugs, in particular statins and fibrates, on VTE risk until April 2009. A scoring system was used to divide studies into two quality categories. Odds ratios (ORs) and 95% confidence intervals (CIs) were then calculated and pooled using a fixed and a random-effects model. Statistical heterogeneity was evaluated through the use of I(2) statistics. Three randomized controlled trials (RCTs), three cohort, and eight case-control studies were included in our systematic review, for a total of 863 805 patients. Statins use significantly reduced VTE risk [OR, 0.81; 95% CI, 0.66-0.99, random-effect model)]. There was a very high heterogeneity among the studies (I(2) > 80%). The use of fibrates was associated with a significant increase in the risk of VTE (OR, 1.58; 95% CI, 1.23-2.02), without heterogeneity (I(2) = 0%). Data on other lipid-lowering drugs were lacking.nnnCONCLUSIONnThis meta-analysis of available literature suggests that statins may lower the risk of VTE, whereas fibrates may increase this risk. Due to several methodological limitations, this conclusion should be considered with caution, and additional, specifically designed RCTs are warranted.

Heritability of elevated factor VIII antigen levels in factor V Leiden families with thrombophilia.

Factor VIII activity (factor VIII:C) and factor VIII antigen (factor VIII:Ag) levels above150u2003IU/dl are associated with a five‐ to sixfold increased risk of venous thrombosis compared with levels <u200a100u2003IU/dl. These high levels are present in 25% of patients with a first episode of deep‐vein thrombosis and in 11% of healthy controls. von Willebrand factor (VWF) and blood group are important determinants of the factor VIII level in plasma and therefore contribute to thrombotic risk, while factor VIII appears to be the final effector. Previously, we found familial clustering of factor VIII:C levels in women, which remained after adjustment for VWF and blood group. In the present study, we analysed the familial influence on factor VIII:Ag levels exceeding 150u2003IU/dl in 12 large families with thrombophilia in which high factor VIII:Ag levels contribute to thrombotic risk. As expected, blood group was a main determinant of the plasma factor VIII level: 58 relatives (32%) had factor VIII levels above 150u2003IU/dl and 50 (86%) of these had blood group non‐O. After adjustment for blood group and age, we found an association between factor VIII:Ag levels in sister pairs (0·35, Pu2003=u20030·003), brother pairs (0·35, Pu2003=u20030·003), brother–sister pairs (0·35, Pu2003<u20030·001) and in mother–son pairs (0·45, Pu2003=u20030·02), but not in father–daughter or father–son pairs. The familial aggregation test was strongly positive for factor VIII:Ag levels (Pu2003<u20030·001) and remained so after adjustment for the influence of blood group. We conclude that high factor VIII:Ag levels are a highly prevalent risk factor for venous thrombosis and contribute to risk in families with thrombophilia, and that these high levels are likely to be genetically determined by factors other than just blood group.

Detection of lupus anticoagulant in the presence of rivaroxaban using Taipan snake venom time

G. M. A . VAN O S ,* B . DE LA AT , * § P . W. KAMPHUISEN ,– J . C . M. ME I J ERS – and P H. G . D E GRO O T* *Laboratory of Clinical Chemistry and Haematology, University Medical Center, Utrecht; Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam; Sanquin Research, Amsterdam; §Synapse, CARIM, Maastricht University Medical Center, Maastricht; and –Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands