Today's view of hereditary thrombophilia.

Venous thromboembolism (VTE) is still a serious medical problem with the non-decreasing incidence of new cases despite prophylaxis in risky situations. It is a multifactorial disease, in which the hereditary component is also significantly involved. The aim of the current research is to search for new polymorphisms that are involved in thrombogenesis in addition to classical thrombophilia (deficiency of natural coagulation inhibitors and FVL and FII prothrombin mutations). The article provides an overview of the results of already performed genome-wide association studies of VTE and their use for the calculation of the so-called polygenic risk score, which could be used for individualized prevention of VTE after standardization of the method.

Rivaroxaban - Metabolism, Pharmacologic Properties and Drug Interactions.

BACKGROUND: Rivaroxaban represents a selective direct inhibitor of activated coagulation factor X (FXa) having peroral bioavailability and prompt onset of action. OBJECTIVE: The absorbtion of rivaroxaban is quick, reaching maximum plasma concentration 2-4 hours following its administration. Peroral bioavailability is high (80-100 %) and pharmacokinetic variability is considered to be moderate (coefficient of variation 30-40 %). This review discusses the properties, drug interactions, pharmacokinetics and clinical indications of rivaroxaban. METHOD: Dosing regimen of rivaroxaban was derived from pharmacologic data of the development program aimed to gain strong antithrombotic drug and balance between efficacy and risk of bleeding in patients. Results of doseranging trials, pharmacokinetic models and randomised studies of phase III advocate the use of such schemes in everyday practice. RESULTS: The drug has been manufactured to fulfill clinical requirements in a variety of indications in adults: prophylaxis of venous thromboembolism (VTE) following elective knee or hip replacement surgical intervention, therapy and secondary prophylaxis of VTE, prophylaxis of ischemic stroke and embolism in individuals diagnosed with nonvalvular atrial fibrillation (NVAF) with risky characteristics, and in Europe the prophylaxis of atherothrombotic episodes following an acute coronary syndrome in subjects with increased levels of cardiac biomarkers. CONCLUSION: Rivaroxaban may offer benefit in many clinical situations. In comparison with low molecular weight heparin and fondaparinux requiring subcutaneous way of administration, and with vitamin K antagonists (VKAs), which require regular monitoring of international normalized ratio, rivaroxaban is relatively easy to use. However, adjustments of dose are needed in individuals with impaired renal functions.

Influence of long-term thromboprophylaxis with low-molecular-weight heparin (enoxaparin) on changes of bone metabolism markers in pregnant women.

This is a first descriptive, retrospective, observational study aiming to evaluate the changes in bone turnover markers in pregnant women and to assess the effect of a long-term treatment with low-molecular-weight heparin (LMWH), specifically, enoxaparin. Study involved 50 pregnant Caucasian women with thrombophilia. The patients either received prophylactic enoxaparin once daily subcutaneously (N = 35) or were observed without treatment (N = 15). Concentrations of total serum alkaline phosphatase (total AP), bone alkaline phosphatase (bone AP), osteoprotegerin (OPG), and the receptor activator of nuclear factor κB ligand (RANKL) were measured at 15, 25, and 35 weeks of gestation. Total serum AP increased with gestational age. In the group treated with enoxaparin, the percentage of bone AP concentration was lower (P < .05) than in the control group. Serum OPG also increased with gestational age, but no significant difference was found between the groups with- and without treatment. Despite the OPG increased, RANKL did not change.

FXa inhibition and coagulation changes during DVT prophylaxis by enoxaparin over the course of a 15-day follow-up in septic patients.

The objective of our study was to examine the changes in coagulation parameters and inflammatory reaction over the course of 15 days in patients with severe sepsis. We tried to identify mechanisms by which sepsis-induced pathophysiological changes may influence the effectiveness of subcutaneously (SC) administered enoxaparin 40 mg once daily. A total of 16 patients (8 men, 8 women; age 35-83 years) meeting the inclusion criteria of severe sepsis were enrolled in this study. The follow-up was performed on days 1, 2, 3, 6, 9, 12, and 15 of hospitalization at the intensive care unit (ICU). Blood coagulation (activated partial thromboplastin time [aPTT], prothrombin time [PT], fibrinogen, antithrombin (AT), protein C [PC], D-dimer, fragment 1.2 [F1.2], factor Xa [FXa] inhibition) and inflammatory reactants (interleukin 6 [IL-6], C-reactive protein [CRP], orosomucoid, alpha-1-antitrypsin) were tested. The mean FXa inhibition was 0.17 (+ or - 0.17) IU/mL. The arbitrarily established range of FXa inhibition for prophylaxis, 0.2 to 0.4 IU/mL, was reached in 22 cases (20%), while in 74 cases (68%), it was below and in 13 cases (12%) above the aforementioned range. Factor Xa inhibition positively correlated with AT (r = .42; P < .001) and PC (r = .45; P < .001) activities. A negative correlation was found between the FXa inhibition and alpha-1-antitrypsin concentrations (r = -.33; P = .01) but only in the subgroup with alpha-1-antitrypsin concentrations > or = 2.2 g/L. We confirmed that in most patients with sepsis, the prophylaxis with enoxaparin did not lead to the required FXa inhibition. The inhibition of FXa by enoxaparin depends mainly on the AT and PC activities.

Favorable coagulation profile with fondaparinux after hip surgery in elderly patients.

Twenty-three patients with fondaparinux prophylaxis over 75 years of age who underwent hip fracture surgery were enrolled in the study. Fondaparinux sodium (2.5 mg) was administered subcutaneously 6 h postoperatively and then every 24 h for 28 days. Coagulation and inflammatory parameters were measured preoperatively, then 10 h, 2, 7, and 28 days postoperatively. Increased D-dimers, positive acute phase proteins, and IL-6, and decreased negative acute phase proteins were observed preoperatively (P < 0.05). Maximum values were reached 10 h postoperatively for IL-6 and D-dimer, and on postoperative days 2 and 7 for positive acute phase proteins (P < 0.05). Transferrin, prealbumin and antithrombin levels were lowest 10 h postoperatively and on postoperative day 2 (P < 0.05). Increased D-dimers, IL-6, and positive acute phase proteins, and decreased negative acute phase proteins persisted until postoperative day 28 (P < 0.05). Prothrombin fragments (F1 + 2) reached peak levels preoperatively and decreased gradually until postoperative day 28. Fondaparinux promoted the inhibition of thrombin generation, as documented by negative correlation between F1 + 2 and FXa inhibition (r = -0.46; P < 0.001). Fondaparinux-induced FXa inhibition increased gradually until postoperative day 28. This increase correlated positively with antithrombin activity (r = 0.4; P < 0.05). Fondaparinux prophylaxis counteracted pro-thrombogenic effect associated with hip fracture and subsequent surgery without severe bleeding complications.