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The new oral anticoagulants (NOACs) represent alternative antithrombotic agents for prophylaxis and therapy of thromboembolic diseases. They act either by inhibition of the clotting factor Xa or IIa (thrombin). As a consequence, they influence several coagulation assays (for example prothrombin time, activated partial thromboplastin time). Because of the short half-life of these new agents, these changes show great variations in the course of 24 hours. Furthermore, there are significant differences of laboratory results depending on the used reagents. We explain the influence of apixaban, rivaroxaban (factor Xa inhibitors) and dabigatran (thrombin inhibitor) on the most commonly used coagulation assays. Besides we show that this influence depends on the way of action of the drug as well as on the principle of the coagulation assay. Being aware of this relationships helps to interpret the results of coagulation assays under influence of NOACs correctly., (© Georg Thieme Verlag KG Stuttgart · New York.)

New oral anticoagulants promise to overcome essential drawbacks of traditional substances. They have a predictable therapeutic effect, a wide therapeutic window, only limited interaction with food and drugs and can be administered p.o. with a fixed dose. On the other hand, knowledge on the laboratory management of new anticoagulants is limited. In the present article we discuss possible indications and available assays for monitoring of Rivaroxaban, Apixaban and Dabigatran. Furthermore, we discuss interpretation of routine coagulation tests during therapy with these new drugs.

To further elucidate the debated role of hereditary FXII deficiency as a thrombophilic risk factor this follow-up study on 65 subjects out of 12 Swiss families was undertaken (follow-up: 6 yrs). Fifteen severely FXII deficient subjects (FXII:C < 1%), 35 partially FXII deficient subjects (FXII:C > or = 1-59%), 10 with normal FXII values (FXII:C > or = 70%), and 5 non-classifiable subjects (FXII:C > or = 60-69%) were reevaluated. Eight subjects (4 severely and 3 partially FXII deficient, 1 non-classifiable) were newly enrolled. Four instances of deep vein thrombosis, one superficial vein thrombosis and one myocardial infarction were noted in 2 out of 19 severely FXII deficient subjects during a total life-time period of 866.6 patient-years. In 38 partially FXII deficient subjects (1862.8 patient-years) one ischemic cerebrovascular stroke and one superficial vein thrombosis were recorded in 2 individuals. The 10 subjects with normal FXII values (498.2 patient-years) remained thrombosis-free. One superficial vein thrombosis occurred in an unclassifiable woman. None of the 3 different FXII gene defects revealed in our patients was specifically associated with thromboembolic complications. Kaplan-Meier analysis of thrombosis-free survival suggests that hereditary partial (and probably severe) FXII deficiency does not constitute a thrombophilic condition.

Homocysteine is a sulfur-containing amino acid intermediate involved in two metabolic pathways, in the remethylation to methionine and in the transsulfuration to cysteine. Severe hyperhomocysteinemia (> 100 mumol/l) is found in congenital homocystinuria. Moderate (15-30 mumol/l) or intermediate (> 30-100 mumol/l) hyperhomocysteinemia is caused by defects in genes encoding for enzymes of homocysteine metabolism or by inadequate intake of those vitamins that are involved in homocysteine metabolism (folic acid, cobalmin, and vitamin B6). Today, hyperhomocysteinemia should be considered an important risk factor for atherosclerotic vascular and venous thromboembolic diseases. Homocysteine-plasma levels above the 95th percentile were found to be associated with a 2 to 3-fold elevated relative risk for deep-vein thrombosis and pulmonary embolism. Moreover, mild hyperhomocysteinemia has been shown to be associated with a 2 to 4-fold increased relative risk for coronary artery disease, cerebrovascular disease, and peripheral arterial occlusive disease. Several mechanisms have been proposed by which hyperhomocysteinemia contributes to atherogenesis and thrombogenesis. Several studies have shown that hyperhomocysteinemia can be corrected by supplementation of folic acid, cobalamin and vitamin B6. Clinical trials are urgently needed which investigate the preventive effect of supplementation of these vitamins on thrombotic diseases.

The role of plasminogen (plg) deficiency in the pathogenesis of venous thromboembolism is debated in the literature. In the present study we evaluated the prevalence of plg deficiency in our thrombophilia patients and aimed to elucidate the thrombosis risk of plg deficiency as a single defect or in combination with other defects, with special focus on APC resistance. The study cohort included 1192 consecutive patients with a history of clinically or objectively diagnosed venous and/or arterial thromboembolism and/or positive family history who were referred to our department for thrombophilia investigation from 02/1988 to 03/1997. All available family members of patients with plg deficiency were tested for plg, APC resistance and other thrombophilic defects that were established in the propositus. 23/1192 propositi were plg-deficient corresponding to an overall prevalence of 1.9%, i.e. 2.2% in patients with venous thrombosis and 1.4% in those with arterial events. Out of the 23 plg-deficient propositi, 8 showed one or multiple additional thrombophilic defects, and in 4 patients relevant circumstantial risk factors were present. Of the 53 available family members, 28 were plg-deficient including 5 with additional APC resistance, and 4 subjects had isolated APC resistance. Ten of the 53 family members had already suffered thromboembolic events, i.e. 5 (18%) in the plg-deficient group and 5 (20%) in the non-deficient group, both groups showing an almost identical median age at the time of investigation (28.9 years and 27.1 years, respectively). Based on our data, plg deficiency is a rare defect in thrombophilic patients and as a single defect it does not seem to be a strong thrombotic risk factor, as 11 of 23 propositi had additional thrombophilic defects or circumstantial risk factors, and in the family members thrombotic events were equally frequent in the plg-deficient and non-deficient subjects.

Resistance against the anticoagulatory effect of activated protein C (APC resistance) is the most prevalent hereditary risk factor for venous thromboembolism known today. In this short review, an exemplary casuistic observation from our thrombophilia outpatient ward is presented. The discovery by Dahlbäck et al. in 1993 of hereditary APC resistance as a basis of familial thrombophilia and the molecular characterization of this defect as point mutation in the coagulation factor V gene (FV R506Q- or FV Leiden-mutation) by Bertina and coworkers are discussed. The clinical implications of this thrombophilia and relevant knowledge for daily practice are briefly summarized.

Individuals with severe factor XII (FXII) deficiency may be prone to thromboembolic disease and this thrombophilic state may be due to insufficient contact activation dependent fibrinolysis. According to our previous study (Thromb Haemostas 1991; 65: 117-121), however, heterozygous FXII deficiency is not a strong prethrombotic risk factor, only one out of 45 obligatory or possible heterozygotes having sustained a thrombotic event. In the present study, FXII clotting activity (FXII:C) and antigen concentration (FXII:AG) were measured in 200 patients having suffered from idiopathic thromboembolism and compared with the values in 200 healthy controls. Mean FXII levels were not significantly different in thrombophilic patients and controls, and subnormal FXII values were not more frequently encountered in patients than in controls. Specific FXII activity, i.e. the ratio of FXII:C to FXII:AG, showed considerable variation in each of the two groups, but patients and controls had a similar distribution of specific FXII activity. Variations in specific FXII activity were not explained by differences in beta 2-glycoprotein I levels. In conclusion, heterozygous FXII deficiency is not a strong prethrombotic risk factor and subnormal FXII values are not more common in thrombophilic patients than in healthy individuals.

In order to assess the clinical implications of hereditary F XII deficiency, all available members of Swiss families with F XII deficiency were investigated. Based on the F XII:C values and the family pedigree, the 74 subjects, aged 8-82 years, were classified as homozygotes/double heterozygotes for F XII deficiency (n = 18), as obligatory (n = 20) or possibly (n = 25) heterozygotes, respectively, and as normals (n = 11). None of the 18 subjects with F XII:C less than 0.01 U/ml and only one possibly heterozygous woman had an abnormal bleeding tendency, confirming the notion that Hageman trait generally does not result in a hemorrhagic diathesis. Two of the 18 subjects with severe F XII deficiency had suffered from venous thromboembolic disease at age less than 40 years. One heterozygous woman had a leg ulcer probably due to venous thrombosis. Thus, whereas homozygous F XII deficiency may be associated with an increased risk for venous thromboembolic disease, partial F XII deficiency is not, by itself, a strong risk factor for thrombosis. Whereas 17 of the 18 subjects with F XII:C less than 0.01 U/ml had no detectable F XII:Ag, one cross reacting material-positive F XII deficient subject (F XII:Ag = 0.11 U/ml) was identified. The dysfunctional F XII, present in this subject's plasma and tentatively called F XII Bern, is the fourth abnormal F XII molecule identified so far.

Chopard P, Dörffler-Melly J, Hess U, Wuillemin WA, Hayoz D, Gallino A, Bachli EB, Canova CR, Isenegger J, Rubino R, Bounameaux H (University Hospitals, Geneva; Inselspital, Bern; Kantonsspital, St Gall; Kantonsspital, Lucerne; CHUV, Lausanne; Ente Ospedaliero Cantonale Bellinzona-Locarno; Universitätsspital, Zurich; Angiologie Spitäler, Chur; and Aventis Pharma, Zurich; Switzerland). Venous thromboembolism prophylaxis in acutely ill medical patients: definite need for improvement.J Intern Med2005;257:352–357.To examine the frequency and adequacy of thromboprophylaxis in acutely ill medical patients hospitalized in eight Swiss medical hospitals.A cross-sectional study of 1372 patients from eight Swiss hospitals was carried out. After exclusion of patients (275) given therapeutic anticoagulation, 1097 patients were audited. The adequacy of thromboprophylaxis was assessed by comparison with predefined explicit criteria.Of 1097 patients, 542 (49.4%) received thromboprophylaxis. According to the explicit criteria, 644 (58.7%) should have been on prophylaxis (P < 0.001, when compared with the rate observed). The rate of prevention differed widely between hospitals (from 29.4 to 88.6%) with no difference between teaching and nonteaching hospitals. According to the explicit criteria, a substantial proportion (44.9%) of the patients who should have been treated were not. Conversely, 41.3% of the patients were unnecessarily treated.Even though the appropriateness of the explicit criteria used could be challenged, our data suggest that the current practice is associated with important uncertainty leading to both overuse and underuse of thromboprophylaxis in patients hospitalized in medical wards. More efforts are urgently needed to develop new or endorse existing explicit, evidence-based criteria and guidelines for thromboprophylaxis in this population of patients. [ABSTRACT FROM AUTHOR]