Risk Factor For Thromboembolic Complications Research Articles

ANALYSIS OF THE INFLUENCE OF THROMBOEMBOLIC COMPLICATIONS PREVENTION WITH ORAL ANTICOAGULANTS ON BUDGET IN PATIENTS WITH NON-VALVULAR ATRIAL FIBRILLATION

Atrial fibrillation (AF) is a risk factor for thromboembolic complications, requiring administration of vitamin K antagonists (warfarin) or the new oral anticoagulants (apixaban, dabigatran and rivaroxaban). Aim. To assess the influence of apixaban use on the budget as an alternative to warfarin, dabigatran or rivaroxaban use in patients with non-valvular AF in the Russian Federation (RF). Material and methods. The analysis was performed with the perspective of the health care budget with 5 year horizon period and by the pharmacoeconomic model developed by Pharmerit International (Rotterdam, Netherlands) and adapted for the RF. The cardiovascular complications rate in the model was in line with the results of comparative clinical trials: ARISTOTLE, AVERROES, RE-LY, ROCKET-AF. The analysis suggested that 100% of patients with atrial fibrillation were transferred on apixaban instead of warfarin, dabigatran or rivaroxaban. The analysis was based on the assumption that patients were fully committed to the therapy over the horizon of the study, ie, refusal of treatment was not considered. The possibility of episodes of ischemic and hemorrhagic strokes, the severity of which corresponded to previously published data for the Russian population, was considered in the study. The present study was performed based on two scenarios. In the first of them the cost of anticoagulation therapy was determined on the basis of the average weighted prices of public procurement for the period from 04.01.2014 to 01.04.2015. The alternative scenario purported to demonstrate potential savings of the budget of the health care system on the inclusion of apixaban in the list of essential drugs. This scenario took into account that the cost of dabigatran and rivaroxaban corresponded to registered maximum selling price including 10% VAT and 10% of the wholesale allowance and the cost of apixaban - presumed maximum selling price which the producer intends to register in case the drug is included in the essential drugs list, subject to 10% VAT and 10% wholesale mark. The cost of complications treatment corresponded to the rate of compulsory health insurance for the city of St. Petersburg for 2015. Results. The estimated number of patients with non-valvular AF who require anticoagulation therapy in the RF is 1,196,600 people according to the epidemiological data. Treatment with apixaban significantly reduces the incidence of cardiovascular events as compared with warfarin and rivaroxaban. The results of the budget impact analysis, taking into account the price obtained at auction from 01.04.14 through 01.04.15, show a decrease in the load on the budget when the apixaban is included in the therapy regimen of non-valvular atrial fibrillation. Potential savings of resources of the health care system reached 10.9 billion rubles as compared with dabigatran and 39.2 billion rubles as compared with rivaroxaban. This advantage can be explained by both the lower cost of apixaban in comparison with reference drugs, and a reduction of the in-hospital expenses on complications treatment. Switching from warfarin to apixaban increases the budget load in 2.81 times. However, previous data demonstrate the economic feasibility of the additional costs of apixaban, that help to achieve significant advantages from a clinical point of view. The results obtained on the basis of prices, intended to include apixaban in the list of essential drugs, showed that in this case the savings of the budget of the health care system will reach 127-129 bln. rubles for 5 years (average 26%) as compared with dabigatran and rivaroxaban. The comparison of apixaban with warfarin showed an increase in total costs of therapy in 2.72 times. Conclusion. The inclusion of apixaban in the therapy regimen of non-valvular atrial fibrillation can significantly reduce the burden on the budget of the health care system as compared with dabigatran and rivaroxaban, as well as reduce the incidence of cardiovascular events compared with warfarin. This allows recommending the inclusion of the drug in the federal and regional programs for the prevention of thromboembolic complications in this group of patients.

Thromboembolic complications after Zenith® Low Profile Endovascular Graft for infrarenal abdominal aneurysms.

The purpose of this study was to objectify and evaluate risk factors for thromboembolic complications after treatment with a Zenith(®) Low Profile Endovascular Graft (Zenith LP). Results were compared with those in the recent literature on endovascular aortic repair (EVAR) and with the thromboembolic complications in the patient group treated with a Zenith Flex Endovascular Graft in our institute in the period before the use of the Zenith LP. All consecutive patients who were suitable for treatment with a Zenith LP endograft between October 2010 and December 2011 were included. The preprocedural computed tomography scan (CT), procedural angiographic images, and the postprocedural CT scans were evaluated for risk factors for and signs of thromboembolic complications. All patients treated between December 2007 and November 2012 with a Zenith Flex endograft were retrospectively evaluated for thromboembolic complications. In the study period 17 patients were treated with a LP Zenith endograft. Limb occlusion occurred in 35 % of the patients. Limb occlusions occurred in 24 % of the limbs at risk (one limb occluded twice). In one patient two risk factors for limb occlusion were identified. Between December 2007 and November 2012, a total of 43 patients were treated with a Zenith Flex endograft. No limb occlusion or distal embolization occurred. Despite that this was a small retrospective study, the Zenith LP endograft seems to be associated with more frequent thromboembolic complications compared with the known limb occlusion rates in the literature and those of the patients treated with a Zenith Flex endograft in our institute.

Early cerebral thromboembolic complications after radiofrequency catheter ablation of atrial fibrillation: incidence, characteristics, and risk factors.

Thromboembolic complications remain one of the most severe adverse events associated with catheter ablation of atrial fibrillation (AF), but data on such events are limited. The purpose of this study was to evaluate the incidence, characteristics, and risk factors of thromboembolic complications after AF ablation. Cerebral thromboembolic complications occurring within 1 month of 3360 consecutive AF radiofrequency catheter ablations were assessed. Stroke was defined as a neurologic deficit lasting more than 24 hours or with imaging study showing new infarction. Transient ischemic attack (TIA) was defined as a deficit lasting less than 24 hours and without documented infarction. There were 17 peri-interventional cerebral thromboembolic events (0.5%). Nine cases (53%) were diagnosed as strokes and 8 (47%) as TIAs. Sixty percent of the events occurred within 48 hours after the ablation; the rest occurred within 1 week. In univariate analysis, peri-interventional thromboembolism was associated with peripheral vascular disease (P = .010), impaired left ventricular ejection fraction (P = .040), periprocedural bridging with heparin (P = .007), and previous stroke (P = .026). Multivariable analysis demonstrated that peripheral vascular disease (odds ratio [OR] 8.81, confidence interval [CI] 1.61-48.31, P = .012) and previous stroke (OR 6.13, CI 1.18-31.91, P = .031) were independent predictors. In a different model, the CHA2DS2-VASc score was associated with thromboembolism (OR 1.35, CI 1.00-1.80, P = .049). Cerebral thromboembolic complications after AF radiofrequency catheter ablation are rare. They mostly occur within 48 hours after the procedure and remain without lasting neurologic deficits in the majority of cases. Such complications are associated with peripheral vascular disease, previous stroke, and the CHA2DS2-VASc score.

Case series of thromboembolic complications in childhood nephrotic syndrome: Hacettepe experience.

The aim of this study was to describe the incidence and contributory risk factors for thromboembolic complications in children with nephrotic syndrome (NS) and thrombosis. Among 188 children with the diagnosis of NS (80 girls; mean age: 12.6 ± 5.4 years) followed up in our hospital for the last 5 years, 17 (9.0 %) children (16 boys) identified as having thromboembolic complications. All 17 children with NS and thrombosis were screened for laboratory risk factors for thrombosis. The diagnosis was confirmed by cranial magnetic resonance imaging, doppler ultrasonography, and echocardiography. Among 17 children with thrombosis, 14 (82.3 %) were found to have focal segmental glomerulosclerosis (FSGS) as underlying pathology by renal biopsy. The mean age of the thrombotic children was 4.5 ± 3.2 years at the diagnosis of NS and that was 7.1 ± 4.9 years at the time of thrombosis. The mean time from NS diagnosis to the first thrombosis development was 2.6 ± 2.3 years. Thrombosis occurred during the first year of NS in 9/17 (52.9 %) children. Most of the children (88.2 %) had venous thrombosis. Among the screened risk factors, high factor VIII level (64.7 %) was the leading factor followed by decreased antithrombin III level (29.4 %). Furthermore, 4 children had central venous catheters and 2 had infection as clinical risk factors for thrombosis. In this case series, subtype of FSGS, active disease state of NS, central venous catheters, and some inherited and acquired thrombotic risk factors have been identified as contributory factors for the development of thrombosis in children with NS.

Cellular signaling by antiphospholipid antibodies

The presence of antiphospholipid antibodies is one of the most common acquired risk factors for thromboembolic complications and pregnancy morbidity 1. ‘Antiphospholipid antibodies’ is a collective term for a set of autoantibodies with closely related but different specificities. Experiments in which isolated patient antibodies were injected into mice have shown that a specific subset of autoantibodies, those directed against the plasma protein beta2 glycoprotein I, can explain the increased risk of thrombosis 2,3.

Thromboembolic Complications After Cardioversion of Acute Atrial Fibrillation: The FinCV (Finnish CardioVersion) Study

This study sought to explore the incidence and risk factors of thromboembolic complications after cardioversion of acute atrial fibrillation. Anticoagulation therapy is currently recommended after cardioversion of acute atrial fibrillation in patients with risk factors for stroke, but the implementation of these new consensus-based guidelines has been slow. A total of 7,660 cardioversions were performed in 3,143 consecutive patients with atrial fibrillation lasting <48 h in 3 hospitals. For this analysis, embolic complications were evaluated during the 30 days after 5,116 successful cardioversions in 2,481 patients with neither oral anticoagulation nor peri-procedural heparin therapy. There were 38 (0.7%; 95% confidence interval [CI]: 0.5% to 1.0%) definite thromboembolic events (31 strokes) within 30 days (median 2 days, mean 4.6 days) after cardioversion. In addition, 4 patients suffered transient ischemic attack after cardioversion. Age (odds ratio [OR]: 1.05; 95% CI: 1.02 to 1.08), female sex (OR: 2.1; 95% CI: 1.1 to 4.0), heart failure (OR: 2.9; 95% CI: 1.1 to 7.2), and diabetes (OR: 2.3; 95% CI: 1.1 to 4.9) were the independent predictors of definite embolic events. Classification tree analysis showed that the highest risk of thromboembolism (9.8%) was observed among patients with heart failure and diabetes, whereas patients with no heart failure and age <60 years had the lowest risk of thromboembolism (0.2%). The incidence of post-cardioversion thromboembolic complications is high in certain subgroups of patients when no anticoagulation is used after cardioversion of acute atrial fibrillation. (Safety of Cardioversion of Acute Atrial Fibrillation [FinCV]; NCT01380574).

Assessment of genetic risk factors for thromboembolic complications in adults with idiopathic nephrotic syndrome

Nephrotic syndrome (NS) may occur with acquired hypercoagulability, however, the fact that it is accompanied by an underlying hereditary thrombophilia, especially combined hereditary thrombophilia would lead to thrombotic events. In this study, we aimed to evaluate the contribution of genetic thrombophilia to development of thrombotic events in adult patients with NS. Factor V Leiden (FVL), prothrombin, and methylenetetrahydrofolate reductase (MTHFR) gene mutation were studied in 51 newly diagnosed idiopathic NS patients and age- and gender-matched 20 healthy control subjects included in the study. Renal vein Doppler ultrasound was conducted in order to investigate the prevalence of subclinical renal vein thrombosis. Of 51 patients, 6 (11.8%) were established to have thromboembolic (TE) complications at the time of diagnosis (4 symptomatic, 2 subclinical), and no recurring thrombotic episode was observed. Genetic mutation was established in all patients that were found to have TE complications. Acquired hypercoagulability factors were similar in patients without and with TE complication. The coexistence of inherited thrombophilia in NS may facilitate thromboembolic complications. If the cause of thrombosis cannot be explained by the usual factors attributed to the occurrence of thrombosis in NS, screening for the other factors, such as FVL, MTHFR, and prothrombin gene mutation, may be beneficial.

The Current Role of Statin Therapy in the Treatment of Atrial Fibrillation

Atrial fibrillation (AF) is the most common arrhythmia and one of the major causes of morbidity and hospitalization. It is an important risk factor for thromboembolic complications and cerebrovascular disease. In AF, extensive electrical and structural remodeling of atrial tissue takes place with the main underlying mechanisms being inflammation and fibrosis. In recent years it has been shown, that beside conventional antiarrhythmic therapies, modalities aiming at reversal of atrial tissue derangement could be of some benefit in the treatment of AF. In this respect, the main focus was oriented towards drugs such as angiotensin convertase (ACE) inhibitors, angiotensin receptor blockers (ARBs), polyunsaturated fatty acids and statins. Data about the potential beneficial role of statins for AF treatment is continuously growing. It is now evident that statins act on AF mainly through their pleiotropic and not their lipid lowering properties. Several retrospective trials have shown that statins exert antiarrhythmic effects in patients with AF, while data from prospective studies are still conflicting. Thus, the definitive confirmation and explanation of statin's role in AF treatment is still missing. Herein, the current patophysiological concepts providing rationale for the use of statins in AF treatment as well as up-to-date data from retrospective and prospective clinical studies are reviewed and discussed. Particular attention is paid to various clinical settings such as primary prevention, secondary prevention (post-cardioversion) and postoperative setting. We also present our own data regarding the role of statins in prevention of the recurrence of AF after successful cardioversion.

Venous thromboembolic disease in patients with haemophilia

With the availability of efficient and safe clotting factor replacement therapy, elective total joint arthroplasty is increasingly performed in subjects with haemophilia suffering from chronic haemophilic arthropathy. Little has been published addressing the prevalence and the specific risk factors of thromboembolic complications and the role of thromboembolic prophylaxis in this specific population. While the risk of thrombosis in hemophilic patients following hip or knee arthroplasty is considered to be low and probably mitigated by the clotting factor deficiency, cases have been reported of pulmonary embolism and deep vein thrombosis in hemophilic patients. Although most guidelines advocate thromboembolic prophylaxis in the general population undergoing major orthopaedic surgery, no such standard of care is in place for hemophilic patients. This paper discusses the scope of the problem of venous thromboembolism in patients with haemophilia undergoing major orthopaedic surgery and reviews the published approaches to the use of prophylactic anticoagulation in this setting.

Epidemiology and Risk Factors for Thromboembolic Complications of Childhood Nephrotic Syndrome: A Midwest Pediatric Nephrology Consortium (MWPNC) Study

Epidemiology and Risk Factors for Thromboembolic Complications of Childhood Nephrotic Syndrome: A Midwest Pediatric Nephrology Consortium (MWPNC) Study

The Efficacy of Prophylactic Low-Molecular-Weight Heparin to Prevent Pulmonary Thromboembolism in Immediate Breast Reconstruction Using the TRAM Flap

Sir: We read with great interest the recent publication by Kim et al. entitled “The Efficacy of Prophylactic Low-Molecular-Weight Heparin to Prevent Pulmonary Thromboembolism in Immediate Breast Reconstruction Using the TRAM Flap” (Plast Reconstr Surg. 2009;123:9–12). The authors compared a group of 450 patients receiving a free microvascular transverse rectus abdominis musculocutaneous (TRAM) flap without medical prophylaxis with 200 patients receiving low-molecular-weight heparin for prophylaxis of deep vein thrombosis, and found a significant decrease in asymptomatic pulmonary thromboembolism in the latter group. Because antithrombotic therapy may influence not only deep vein thrombosis but also anastomotic patency and the incidence of microvascular anastomosis thrombosis, we would like to ask the authors about the incidence of anastomotic failure, requiring surgical revision, in their series. Did the authors observe a reduction of either venous or arterial anastomotic thrombosis in the heparin group? Finally, did the authors observe a difference in flap survival between the two groups? In large studies of microvascular breast reconstruction, the incidence of anastomotic venous and arterial thrombosis is reported to be 1.5 and 0.6 percent, respectively.1 Arterial anastomotic thrombosis is associated with flap loss in 11.1 percent of the cases, whereas venous anastomotic thrombosis may lead to flap loss in 26.7 percent of these cases.1 In concordance with the results from Kim et al., these data suggest a need for medical prophylaxis of vascular thrombosis following microvascular free tissue transfer. However, postoperative anticoagulation and antiaggregation regimens are not standardized, and it is unclear which thromboembolic risk factors may contribute to anastomotic thrombosis. In this context, we would like to point out the possible role of hereditary thrombophilia in postoperative thrombosis of both deep leg veins and microvascular anastomosis. Factor V Leiden mutation was first described in 1994 and has since been identified as a major risk factor for thromboembolic complications.2 Heterozygous carriers of the gene mutation carry a 5- to 10-fold higher risk for deep vein thrombosis, and the risk is 80-fold higher in homozygous carriers. In the white population, the prevalence of the factor V Leiden mutation is between 2 and 10 percent, thus resembling the most common type of hereditary thrombophilia in the Western world.2 We have recently published a case in which a patient with factor V Leiden mutation suffered from recurrent venous and arterial thrombosis at the microvascular anastomosis following breast reconstruction with a TRAM flap.3 Other authors also suggest a possible impact of factor V Leiden mutation on thrombotic occlusion of microvascular anastomosis.4,5 Because of the relatively high prevalence of factor V Leiden mutation in whites, further research on the impact of this thrombophilic disorder in patients undergoing free microvascular tissue transfer is warranted. Alexander E. Handschin, M.D. Kay Busch, M.D. Peter M. Vogt, M.D., Ph.D. Plastic, Hand, and Reconstructive Surgery Medical School Hannover Hannover, Germany

Epidemiology and Risk Factors for Thromboembolic Complications of Childhood Nephrotic Syndrome: A Midwest Pediatric Nephrology Consortium (MWPNC) Study

To identify clinical variables predictive of the risk of thromboembolism (TE), and to confirm the incidence of TE in primary and secondary childhood nephrotic syndrome (NS). A comprehensive chart review identified 326 children with NS from any cause evaluated between 1999 and 2006. These patients had a total of 1472.8 patient-years of follow-up. Comparison statistics, survival analysis, and logistic regression were used to define TE epidemiology and clinical risk factors. We found that 9.2% of our cohort had experienced at least 1 TE. The overall incidence was 20.4 patients with TEs/1000 patient-years. The median time to the first TE was 70.5 days after diagnosis of NS. Deep venous thrombosis was the most common TE (76%) and was frequently associated with the use of a central venous catheter (45%). Significant independent predictors of TE included age > or = 12 years at onset of NS (P < .0001), severity of proteinuria (P < .0001), and history of TE preceding diagnosis of NS (P < .0001). Life- or limb-threatening TEs represented 23.7% of the events. Children with NS should be carefully followed for TE, particularly those who are age 12 years or older, have severe proteinuria, or have a previous history of TE.

Acquired activated protein C resistance is associated with IgG antibodies to protein S in patients with systemic lupus erythematosus

The objective of this study was to clarify the roles of anti-phospholipid antibodies (aPLs) in the pathogenesis of acquired activated protein C resistance (APC-R) in patients with systemic lupus erythematosus (SLE). We examined several aPLs levels (lupus anticoagulant, anti-cardiolipin antibodies, anti-β2-glycoprotein I antibodies, anti-protein C antibodies, and anti-protein S antibodies), the APC-R test, and the factor V Leiden test in 85 SLE patients. Acquired APC-R, which was not found in any patient with the factor V Leiden mutation, was present in 26 (30.6%) of 85 patients, and confirmed that acquired APC-R was a significant risk factor for thromboembolic complications [odd ratio (OR), 3.36; 95% confidence interval (CI), 1.24-9.11]. Multivariate logistic analysis revealed that both LA and anti-PS strongly associated with the presence of APC-R, and that the correlation between anti-PS and APC-R was much stronger (OR, 46.7; 95%CI, 6.99-311) than that between LA and APC-R (OR, 11.3; 95%CI, 2.26-57.0). Furthermore, the mean value of APC sensitivity ratios was significantly lower in SLE patients with anti-PS (mean ± SD, 1.68 ± 0.37, p < 0.0001) than in those without anti-PS (2.23 ± 0.40). These results suggest that acquired APC-R is most strongly attributable to functional interference of the APC pathway by anti-PS, which contribute to risk of thromboembolic complications.

Thrombosis as a complication of the Klippel-Trénaunay syndrome and other vascular malformations

SummaryThe Klippel-Trénaunay syndrome (KTS) is a congenital disorder of vascular malformations characterized by the clinical trias of naevi flammei, varicosis and hypertrophy of the affected limb. According to its clinical development KTS can be diagnosed directly post partum or becomes apparent in the course of the development particularly regarding incomplete forms. The most described symptoms next to swelling are pain and augmented sweating of the affected extremity. Complications of KTS are bleeding from mechanically traumatised vascular malformations or widened vessels, but also thromboembolic events are reported. We report on two patients with KTS and one patient with angiodysplasia, who developed deep vein thromboses in the affected limb at young age. None of the patients suffered from thrombophilia or other predisposing risk factors for thrombosis. KTS and other angiodysplastic disorders seem to be a risk factor for thromboembolic complications even at young age. A comprehensive counceling of the patients concerning the prevention of complications and especially the symptoms of thromboembolic events is important for early diagnosis and immediate therapy.

Hypoxemia After Total Joint Arthroplasty: A Problem on the Rise

Total joint arthroplasty (TJA) is categorized as a major risk factor for thromboembolic complications. The importance of hypoxemia during the postoperative period is subject of controversy. This prospective study elucidates the incidence and etiology of hypoxemia after TJA. Furthermore, we intended to assess the predictive value of clinical findings in identifying the etiology of hypoxemia after TJA. Of 1971 patients, 78 (4.0%) experienced an acute episode of hypoxemia during their hospitalization after TJA. Hypoxemia as the initial presenting sign, predicted major complications, defined as life-threatening if left untreated, in 32% of the hypoxic population. These diagnoses included pulmonary embolism, pulmonary edema, and pneumonia. Tachypnea was the only independent factor associated with pulmonary embolism. Our study presents the incidence and etiology of hypoxemia after TJA, and we recommend a heightened appreciation for the hypoxemic patient.

Tissue factor expression on monocytes induced by anti-phospholipid antibodies as a strong risk factor for thromboembolic complications in SLE patients

Our aim was to clarify the role of anti-phospholipid antibodies in the pathogenesis of monocyte tissue factor (TF) expression and thromboembolic complications (TE) in patients with SLE. We examined cell surface expression of TF on monocytes in 93 SLE patients. Monocyte TF expression was significantly higher in SLE patients who had TE than in other SLE patients, and confirmed that the high expression of monocyte TF was a strong risk factor for TE. Furthermore, the presence of anti-cardiolipin/β2-glycoprotein I antibodies (anti-CL/β2-GPI) was strongly associated with the high expression of monocyte TF. We therefore studied the in vitro effect of IgG anti-CL/β2-GPI on lipopolysaccharide (LPS)-induced expression of TF on monocytes in healthy peripheral blood and found that purified IgG containing anti-CL/β2-GPI significantly enhanced LPS-induced monocyte TF expression. These results suggest that anti-CL/β2-GPI cause persistently high TF expression on monocyte, which may contribute to the risk of thromboembolic events in SLE patients.

New Pharmacologic Approaches to Prevent Thromboembolism in Patients with Atrial Fibrillation

Atrial fibrillation (AF) is associated with a 6 fold increased risk for ischemic stroke. Observational studies suggest that one in four to five strokes is due to AF. Depending on the risk profile of an individual patient, the yearly risk for ischemic stroke is between 2% and 14%. AF is accompanied by an increased propensity for atrial clot formation due to a combination of decreased atrial blood flow, increased activity of the platelet/plasmatic coagulation system and prothrombotic changes at the atrial endocardium. This review summarizes the current guidelines for thromboembolic prevention in patients with AF. In many cases, continuous oral anticoagulation therapy (OAT) with vitamin K antagonists (VitKAs) is indicated if AF is accompanied by more than one additional risk factor for thromboembolic complications. However, therapeutic range of VitKAs (Phenprocoumon, Warfarin, and others), the most commonly used oral anticoagulants, is narrow and their use requires regular anticoagulation monitoring. Possibly due to these limitations, about one third of eligible patients are not treated with VitKAs. Furthermore, in many treated patients OAT is not well controlled. Thus, in clinical practice anticoagulation therapy in AF is suboptimal. Therefore, new and more convenient pharmacologic approaches to prevent thromboembolism with i.e. direct thrombin inhibitors (DTI), synthetic polysaccharides (factor Xa Inhibitors), and others are discussed, and their possible future role in the treatment of AF is evaluated.

Antikoagulation bei Vorhofflimmern

Atrial fibrillation is associated with a relevant risk for ischemic stroke: Observational studies suggest that one in four to five strokes is due to atrial fibrillation. Depending on the risk profile of an individual patient, the yearly risk for a stroke is between 2% and 14%. Continuous oral anticoagulation is indicated if atrial fibrillation is accompanied by at least one additional risk factor for thromboembolic complications. This recommendation is supported by several large randomized trials. Due to their low therapeutic range, vitamin K antagonists (phenprocoumon, warfarin, and others), the most commonly used oral anticoagulants, require regular anticoagulation monitoring. If well-controlled (international normalized ratio 2-3, in elderly patients preferably 2-2.5), oral anticoagulation prevents more than half of ischemic strokes related to atrial fibrillation, while bleeding complications are rare. In the follow-up of low risk patients (CHADS2-Score 0), oral anticoagulation becomes necessary when risk factors for thromboembolic complications develop. If a stroke occurs during oral anticoagulation and an INR>2 in a patient with atrial fibrillation, other causes than thromboembolic events should be considered. New anticoagulants--especially direct thrombin antagonists--are currently evaluated in clinical trials and may in the future facilitate anticoagulation in patients with atrial fibrillation.

Platelet glycoprotein I(b)alpha and integrin alpha2 beta1 polymorphisms: gene frequencies and linkage disequilibrium in a population diversity panel.

Genetic variants in the GP1BA and ITGA2 genes have been proposed as potential modifiers for arterial vascular disease and bleeding disorders. Since ancestry may play an important role in the prevalence of these variants, we sought to determine their allele frequency and linkage disequilibrium in a collection of 1064 DNA samples from 51 ethnic groups. We studied haplotypes of ITGA2 defined by single nucleotide substitutions at positions -52, 807, and 1648, and GP1BA variants defined by sequence changes in positions -5 (Kozak), 1018 (T145M, HPA-2) and 1285 (VNTR A, B, C and D). Frequency of haplotypes of ITGA2 showed considerable variation across the different groups, with a higher prevalence of the haplotype -52C or T/807C/1648A observed in African compared with caucasian and Asian populations. The haplotypes 52C/807T/1648A and -52T/807T/1648A were not observed in caucasians or South Americans. While relative frequencies of the GP1BA Kozak alleles were comparable across groups, the methionine allele (HPA-2b) showed a higher frequency in Africa (0.26) than in the other groups. We also observed a high prevalence of the VNTR B allele in the African and Israeli populations. Haplotype analysis revealed incomplete linkage disequilibrium between the HPA-2 and VNTR alleles. Incorporation of GP1BA variants into the set of SNPs already genotyped by the HapMap project disrupted the pre-existing haplotype block. These data provide a valuable resource for optimal selection of variants best tailored for association studies of vascular disease or bleeding disorders when examining individuals of different ancestral origins.

Risk Factors for Thromboembolic Complications in Inflammatory Bowel Disease: The Role of Hyperhomocysteinaemia

Inflammatory bowel disease (IBD) is associated with an increased risk for thromboembolic events. Aim of this study was to examine the relationship of hyperhomocysteinemia and thrombosis in IBD patients and to assess the role of this factor in addition to other known prothrombotic abnormalities. IBD patients with a history of thrombosis (n = 22) and sex-, age-, and diagnosis-matched IBD controls (n = 23) were studied. Homocysteine (tHcy) was assessed before and after methionine loading. Plasma levels of protein C, protein S, antithrombin III, and fibrinogen and the presence of anticardiolipin and antiphospholipid antibodies were determined and genetic testing for factor V Leiden and the prothrombin gene mutation was performed. Results showed that fasting homocysteine levels in IBD patients with a history of arterial or venous thrombosis tended to be higher than in IBD controls, although not significantly. The increase in homocysteine levels after methionine loading was significantly higher in IBD patients in the arterial thrombosis group than in IBD controls (40.9 +/- 17.7 vs. 27.2 +/- 9.9 microM; P < 0.05). Among the other prothrombotic factors, only factor V Leiden was significantly associated with a history of venous thrombosis (20 vs. 0%). At least one risk factor was found in 64% of the IBD patients with previous thromboembolic complications. We conclude that there is an association between hyperhomocysteinemia and a history of arterial thrombosis in IBD patients. We confirm the high prevalence of factor V Leiden in IBD patients with a history of venous thrombosis. In the majority of IBD patients with previous thromboembolic complications, at least one prothrombotic risk factor is detected.