Prolonged Anticoagulant Therapy Research Articles

Persistent high factor VIII activity leading to increased thrombin generation – A prospective cohort study

IntroductionA persistently elevated level of factor VIII (FVIII) is an independent risk factor for venous thromboembolism (VTE). Although the pathophysiology of VTE is unclear, the involvement of thrombin generation (TG) has been postulated. Consequently this study was designed to (i) investigate the relationships between FVIII, Thrombin generation test (TGT) parameters and D-dimer in VTE patients, (ii) determine whether elevated levels of FVIII and increased TG in these patients are transient or sustained. Patients and MethodsAfter an initial period of anticoagulation had been completed 91 VTE patients and 52 healthy controls were recruited. FVIII levels were determined by one-stage clotting (FVIII:C) and chromogenic (FVIII:Ch) assays. The potential to generate thrombin was measured using the Calibrated Automated Thrombogram (CAT) and D-Dimer was by immuno-turbidometric assay. ResultsPatients' FVIII:C levels and FVIII:Ch, exhibited good agreement (rs=0.94; p<0.0001), although FVIII:C exhibited a mean bias of -6%. FVIII:Ch show a significant correlation with TGT Peak Thrombin (rs=0.30; p=0.004) and Peak Thrombin was found to be significantly higher (p=0.04) in patients with FVIII>200iu/dL. Furthermore elevated levels of FVIII and increased thrombin generation parameters appeared to be consistent over time. ConclusionOur data suggests that high FVIII leading to increased TG confers a significant risk of recurrent VTE and therefore we speculate that these patients may benefit from prolonged anticoagulation therapy.

Best Practice for Deep Vein Thrombosis Prophylaxis

Much has been written about the impact of deep vein thrombosis (DVT) on the current health system. Recommendations have been developed and implemented for prophylaxis and treatment of DVT, but in spite of these, it continues to significantly contribute to patient morbidity and mortality, creating a large burden on people and systems. Despite evidence available from numerous trials of thromboprophylactic methods comparing anticoagulants and mechanical therapies, debate still exists about what is the safest and most cost-effective intervention. If used appropriately, prophylaxis prevents the hospital and patient from costly diagnostic procedures and prolonged anticoagulation therapy.

What is the Optimal Duration of Treatment for DVT? An Update on Evidence-Based Medicine of Treatment for DVT

Venous thromboembolism, including deep venous thrombosis (DVT) and pulmonary embolism, represent a major source of morbidity and mortality today. Incidence of DVT is estimated to be 56 to 160/100,000 population per year. Systemic anticoagulation with low molecular weight heparin or unfractionated heparin with initiation of oral vitamin K antagonist therapy has been shown to be beneficial in preventing pulmonary embolism and reducing extension and recurrence of DVT. The duration of anticoagulation following an episode of DVT is determined by the greatest predictors of recurrence. These include the presence of reversible risk factors, nonreversible risk factors, and no risk factors (idiopathic or unprovoked DVT). Short durations of anticoagulation are only appropriate for calf DVTs in patients with reversible risk factors. Patients with nonreversible risk factors, such as malignancy and certain inherited thrombophilias with a strong family history of venous thromboembolism will require lifelong anticoagulation. Those with proximal DVT due to reversible risk factors require 3 to 6 months of anticoagulation. Patients with idiopathic DVT require reassessment of risk-to-benefit ratio of hemorrhage from oral vitamin K antagonist therapy compared to reducing risk of recurrence and frequently require prolonged oral anticoagulant therapy. Monitoring with d-dimer and serial ultrasounds may offer an individualized approach to therapy.

Maladie des exostoses multiples révélée par une thrombose poplitée veineuse et artérielle

We report a 38-year-old man who presented successively a thrombosis of the right popliteal vein and the right popliteal artery, responsible of a painful edema of the leg. There was no known thrombophilic predisposing condition. Radiologic assessment, guided by clinical findings, evidenced bilateral femoral and tibial exostosis resulting in a diagnosis of hereditary multiples exostosis. Although anticoagulant treatment with unfractioned heparin was instituted, distal ischemia of the right lower limb developed. Resection of the compressive osteochondroma and an arterial femorotibial bypass venous graft were performed in addition to prolonged anticoagulant therapy. Outcome was eventually favorable. Hereditary multiple exostosis may be asymptomatic for long time. Compression of adjacent vascular structures by an osteochondroma is a rare and potentially serious complication.

International Recommendations for the Prevention and Treatment of Venous Thromboembolism Associated with Cancer

Venous thromboembolism (VTE) is a common complication and a leading cause of death in oncological patients. Recent guidelines have been established for the treatment and prevention of VTE in oncological patients in various clinical situations. These guidelines recommend: (a) prophylactic anticoagulation in all hospitalized oncological patients in whom there are no contraindications; (b) prophylactic anticoagulation in patients scheduled for major oncological surgery in whom there are no contraindications; (c) prolonged (>or=6 months) anticoagulant therapy in oncological patients with manifest VTE in order to prevent a new episode; (d) no routine prophylactic anticoagulation in ambulatory patients without VTE receiving chemotherapy, except when they are receiving treatment with anti-cancer agents with a high risk of thrombogenicity, such as thalidomide- or lenalidomide-based chemotherapeutic regimens; and (e) no use of prophylactic anticoagulants to improve survival in patients with cancer without manifest VTE. Although vitamin K antagonists, unfractionated heparin and in some cases fondaparinux sodium could be used for the treatment of VTE, low molecular weight heparins are recommended for initial and continuous anticoagulant treatment in oncological patients with VTE, as well as for its prevention.

Survival and Recurrence in Patients With Splanchnic Vein Thromboses

Hepatic, splenic, portal, and mesenteric veins are confluent elements within the splanchnic system. It is therefore unclear whether thromboses of isolated segments represent unique entities. We compared etiologies, recurrence, and survival of patients with thromboses of different splanchnic venous segments. An inception cohort of individuals was identified with first lifetime incident of splanchnic vein thrombosis between 1980 and 2000. We performed a case-controlled comparison of recurrent thrombosis and survival data with those of patients with deep venous thrombosis (DVT). The study (832 patients; mean age, 53 +/- 17 years; 42% women) included patients with isolated portal (n = 329), mesenteric (n = 76), splenic (n = 62), and hepatic (n = 45) vein thrombosis and patients with multisegment involvement (n = 320). Malignancy (27%) and cirrhosis (24%) were the most common etiologies. Recurrence-free survival 10 years after splanchnic vein thrombosis (76%) was comparable with that after DVT (68%) and not improved by anticoagulant therapy. Hormone therapy was the only independent predictor of recurrence (hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.09-4.45; P = .03). Major bleeding was 6.9/100 patient-years. Gastroesophageal varices (HR, 2.63; 95% CI, 1.72-4.03; P < .001) and warfarin therapy (HR, 1.91, 95% CI, 1.25-2.92; P = .003) were independent predictors of bleeding. The 10-year survival rate of patients with splanchnic vein thrombosis (60%) was lower than that of patients with DVT (68%, P < .05). Older age (HR, 1.03; 95% CI, 1.02-1.03), active cancer (HR, 2.23; 95% CI, 1.78-2.78), and myeloproliferative disorder (HR, 1.92; 95% CI, 1.41-2.61) were independent determinants of mortality (P < .001). Splanchnic vein thrombosis depends on the pathology of the organ supplied. On the basis of the low rate of recurrence and substantial rate of major hemorrhage, prolonged anticoagulant therapy does not appear to be justified.

Anticoagulants for preventing recurrence following presumed non-cardioembolic ischaemic stroke or transient ischaemic attack.

After a first ischaemic stroke, further vascular events due to thromboembolism are common and often fatal. Anticoagulants could potentially reduce the risk of such events, but any benefits could be offset by an increased risk of fatal or disabling haemorrhages. To assess the effect of prolonged anticoagulant therapy compared with placebo or open control following presumed non-cardioembolic ischaemic stroke or transient ischaemic attack. We searched the Cochrane Stroke Group Trials Register in May 2008. In June 2008 we searched three online trial registers, used Web of Science Cited Reference Search to identify new citations of previously included studies, contacted a pharmaceutical company, and also contacted authors for additional information on included trials. Randomised and quasi-randomised trials comparing at least one month of anticoagulant therapy with control in people with previous, presumed non-cardioembolic, ischaemic stroke or transient ischaemic attack. Two review authors independently selected trials for inclusion, assessed trial quality and extracted the data. Eleven trials involving 2487 participants were included. The quality of the nine trials which predated routine computerised tomography (CT) scanning and the use of the International Normalised Ratio to monitor anticoagulation was poor. There was no evidence of an effect of anticoagulant therapy on either the odds of death or dependency (two trials, odds ratio (OR) 0.83, 95% confidence interval (CI) 0.52 to 1.34) or of 'non-fatal stroke, myocardial infarction, or vascular death' (four trials, OR 0.96, 95% CI 0.68 to 1.37). Death from any cause (OR 0.95, 95% CI 0.73 to 1.24) and death from vascular causes (OR 0.86, 95% CI 0.66 to 1.13) were not significantly different between treatment and control. The inclusion of two recently completed trials did not alter these conclusions. There was no evidence of an effect of anticoagulant therapy on the risk of recurrent ischaemic stroke (OR 0.85, 95% CI 0.66 to 1.09). However, anticoagulants increased fatal intracranial haemorrhage (OR 2.54, 95% CI 1.19 to 5.45), and major extracranial haemorrhage (OR 3.43, 95% CI 1.94 to 6.08). This is equivalent to anticoagulant therapy causing about 11 additional fatal intracranial haemorrhages and 25 additional major extracranial haemorrhages per year for every 1000 patients given anticoagulant therapy. Compared with control, there was no evidence of benefit from long-term anticoagulant therapy in people with presumed non-cardioembolic ischaemic stroke or transient ischaemic attack, but there was a significant bleeding risk.

Preventing recurrent venous thromboembolism

Someone who has had a first episode of venous thromboembolism (VTE) is about 40 times more likely to have an episode in the future than a person who has never...

Prolonged anticoagulation therapy adjunctive to aspirin after successful fibrinolysis: From early reduction in reocclusion to improved long-term clinical outcome

Long-term addition of antithrombotics (clopidogrel, anticoagulants) to aspirin has improved outcome after acute coronary syndromes. Data on the impact after fibrinolysis are scarce. In Antithrombotics in the Prevention of Reocclusion In COronary Thrombolysis-2 (APRICOT-2), adjunctive moderate-intensity coumarin (median international normalized ratio 2.6) conferred a marked reduction in 3-month reocclusion and ischemic events. Given the association between reocclusion and long-term outcome, we performed long-term clinical follow-up. Patients with thrombolysis in myocardial infarction (TIMI) 3 flow <48 hours after fibrinolysis for ST-elevation myocardial infarction were randomized to aspirin plus coumarin, with prolonged heparinization until the target international normalized ratio (2-3) was reached, or aspirin with standard heparinization. Three-month follow-up angiography (reocclusion rates 15% vs 28%) and long-term clinical follow-up (median 7.3 years, interquartile range 5.9-8.6 years) were performed. Patients randomized to adjunctive anticoagulation (n = 123) received coumarin for a median of 280 days (113-387 days). Survival was 94% versus 88% in patients on aspirin alone (n = 128, P = .12). Infarct-free survival was 86% versus 71% (P = .01). Thrombolysis in myocardial infarction bleeding was 4% in both groups. Patients with reocclusion had impaired survival: 80% versus 94% (P < .01). In a multivariable model without reocclusion, combination therapy independently predicted survival (hazard ratio [HR] 0.36, 95% confidence interval [CI] 0.13-1.00) and infarct-free survival (HR 0.51, 95% CI 0.28-0.95). When adjusted for reocclusion, combination therapy did not predict outcome. Reocclusion independently predicted death (HR 2.56, 95% CI 1.02-6.43) and reinfarction. Moderate-intensity oral anticoagulation added to aspirin improved 8-year clinical outcome after successful fibrinolysis. The beneficial effect was largely attributed to a reduction in reocclusion, which independently predicted death and reinfarction. This study provides a mechanistic rationale for prolonged adjunctive anticoagulation after fibrinolysis.

Thrombophilia Due to Factor V and Factor II Mutations and Formation of a Dural Arteriovenous Fistula: Case Report and Review of a Rare Entity

Genetic mutations underlying thrombophilia are often recognized in patients with thromboembolic episodes. However, the clinical and therapeutic implications of such findings often remain unclear. We report the first case of a dural arteriovenous fistula (DAVF) in a patient with a combined factor II and factor V Leiden mutation. A 40-year-old man presented with a large left temporal and intraventricular hemorrhage. An initial angiogram showed thrombosis of the left sigmoid sinus but no evidence of a vascular malformation. One year after the hemorrhage, an angiographic study showed the appearance of a right DAVF. During the follow-up period, the patient was found to harbor heterozygosity for a mutation of factor V and a mutation of factor II. Recognition of the patient's thrombophilia led to prolonged oral anticoagulation therapy to reduce the risk of a recurrent thrombotic episode. Despite the increased risk of bleeding, the therapy was considered justified. DAVFs may occur after sinus thrombosis in patients with combined factor II and factor V mutations. This observation indicates the association of multiple hematological disorders with DAVFs in individual patients. Moreover, it raises the clinical conundrum of how to manage patients with thrombophilia, intracranial hemorrhage, and DAVFs.

Treatment of extensive subacute portal, mesenteric and ileocolic vein thrombosis with recombinant tissue plasminogen activator

Portal or/and mesenteric vein thrombosis is a rare condition with high mortality in an acute form. Therapy of thrombosis is not well defined, although there are some general guidelines that differ according to disease onset and clinical presentation. In acute thrombosis with bowel infarction, surgical resection with possible thrombolysis is advised. The best therapy for the subacute form is not known and the approach differs between centers. For chronic disease, prolonged anticoagulant therapy is recommended. Thrombolysis is well recognized in the treatment of acute ischemic coronary or cerebral diseases. Success of treatment is better if therapy is introduced within a few hours after symptoms have begun. We describe a 25-year-old patient with the subacute form of extensive portal, mesenteric and ileocolic vein thrombosis in the setting of underlying liver cirrhosis due to autoimmune disease. An aggressive therapeutic approach is advised, especially in patients who will eventually undergo liver transplantation, since portal and/or mesenteric vein thrombosis is relative contraindication for liver transplantation in the majority of transplant centers.

463 Left atrial thrombi and thrombus-like artifacts in patients with atrial fibrillation candidate to cardioversion: prevalence and response to prolonged anticoagulation therapy

463 Left atrial thrombi and thrombus-like artifacts in patients with atrial fibrillation candidate to cardioversion: prevalence and response to prolonged anticoagulation therapy

Recurrent Cerebral Venous Thrombosis Associated with Elevated Factor VIII

Cerebral venous thrombosis (CVT) rarely recurs, and the factors associated with a recurrence remain unclear. Recently, however, elevated plasma coagulation factor VIII has been considered a factor related to recurrent venous thromboembolism. Here we report a patient who had recurrent CVT associated with significantly elevated levels of factor VIII despite the chronic use of an antiplatelet agent. Factor IX was also elevated in this patient. These findings suggest that elevated factor VIII is a factor underlying the recurrence of CVT, and that prolonged anticoagulation therapy may have to be considered in patients with elevated coagulation factor levels.

Evolving Consensus in Portal Hypertension Report of the Baveno IV Consensus Workshop on methodology of diagnosis and therapy in portal hypertension

Portal hypertension is associated with the most severe complications of cirrhosis, including ascites, hepatic encephalopathy, and bleeding from gastro-esophageal varices. Despite the progress achieved over the last decades, the 6-week mortality associated with variceal bleeding is still in the order of 10–20%. Awareness of the difficulty inherent to the evaluation of diagnostic tools and the design and conduct of good clinical trials for the treatment of portalhypertensionhas led to theorganization, since1986,of a series of consensus meetings. The first one was organized by Andrew Burroughs in Groningen, The Netherlands [1]. After Groningen, other meetings followed, in Baveno in 1990 (Baveno I) [2] and in 1995 (Baveno II) [3,4], in Milan in 1992 [5], in Reston, USA, in 1996 [6], in Stresa in 2000 (Baveno III) [7,8], again in Baveno in 2005 (Baveno IV) [9,10], and in Atlanta in 2007 [11]. The aims of these meetings were to develop definitions of key events in portal hypertension and variceal bleeding, to review the existing evidence on the natural history, the diagnosis and the therapeutic modalities of portal hypertension, and to issue evidence-based recommendations for the conduct of clinical trials and the management of patients. All these meetings were successful and produced consensus statements on some important points, although some issues remained unsettled. To continue the work of the previous meetings, a Baveno V workshop was held on May 21–22, 2010. The workshop was attended by many of the experts responsible for most of the major achievements of the last years in this field. Many of them had attended the previous meetings as well. The main fields of discussion of the Baveno V workshop were the same as in Baveno I–IV, i.e. the definitions of key events concerning the bleeding episode and the therapeutic options in patients with portal hypertension. For each of these topics, a series of consensus statements were discussed and agreed upon. As in Baveno IV, whenever applicable, the level of existing evidence was evaluated and the recommendations were ranked according to the Oxford System [12] (i.e.: level of evidence from 1 = highest

What’s New for DVT Prophylaxis for the Medically Ill

Much has been written about the impact of deep vein thrombosis (DVT) on the current health system. Recommendations have been developed and implemented for prophylaxis and treatment of DVT, but in spite of these, it continues to significantly contribute to patient morbidity and mortality, creating a large burden on people and systems. Despite evidence available from numerous trials of thromboprophylactic methods comparing anticoagulants and mechanical therapies, debate still exists about what is the safest and most cost-effective intervention. If used appropriately, prophylaxis prevents the hospital and patient from costly diagnostic procedures and prolonged anticoagulation therapy.

The safety of low-molecular weight heparins for the prevention of thromboembolic events after cardioversion of atrial fibrillation.

Transesophageal echocardiography (TEE) guided early cardioversion (CV) in conjunction with short-term anticoagulation has been shown to be safe, and an alternative to prolonged conventional anticoagulation therapy. Recently, low molecular weight heparins (LMWHs) have been used successfully as an alternative to standard heparin therapy obviating the need for hospitalization and APTT monitoring. The aim of this study was to determine the feasibility and safety of TEE guided early cardioversion in conjunction with short-term LMWH use in patients with nonvalvular atrial fibrillation (NVAF). The study group consisted of 172 consecutive patients with NVAF. Before TEE, 90 patients received LMWH (Dalteparin 2 x 5,000U) and 82 patients received standard heparin (UFH) (5,000U bolus followed by infusion to raise APTT to 1.5 times control). TEE was performed and the left atrium and left atrial appendage were examined thoroughly for the presence of thrombus. One patient from each group was excluded due to detection of a left atrial thrombus by TEE. Immediately after TEE, CV was attempted and warfarin was initiated. All patients received warfarin for one month after CV. In the LMWH group, 89 of 90 patients (98.9%) were successfully cardioverted. CV was successful in 97.5% of the patients in the UFH group. None of the patients experienced thromboembolic events during the four weeks after CV. TEE guided early CV in conjunction with short-term LMWH treatment is as safe as UFH for the prevention of thromboembolic events after CV.

Durée du traitement anticoagulant oral dans la TVP des membres inférieurs

The optimal duration of oral anticoagulant therapy is a matter of debate. It is essential to balance the desired effect of the anticoagulants in reducing recurrences against the risk of major bleeding. Recent data suggest that it is necessary to tailor the duration of anticoagulation individually according to the topography of deep vein thrombosis (DVT) and the presence of risk factors. A six-week treatment for patients with isolated calf DVT is sufficient. For proximal DVT and/or pulmonary embolism, a short anticoagulant course seems sufficient in patients with temporary risk factors (three months) and a longer anticoagulant course (six months at least) is recommended for cases with permanent risk factors or idiopathic DVT. The inherited or acquired hypercoagulable states can be divides into those that are common and associated with a modest risk of recurrence (i.e. isolated factor V Leiden or G20210A prothrombin gene) and those are uncommon but associated with a high risk of recurrence (i.e. antithrombin, protein C or S deficiencies and anticardiolipin antibodies). Thus, the presence of one of these last abnormalities favours more prolonged anticoagulant therapy. For the high-risk of recurrence patients, there is a paucity of evidence based medicine particularly for patients with biological thrombophilia, and randomised controlled trials in this population are required. An assessment of low- or fixed-dose oral anticoagulation is also necessary in order to reduce the bleeding risk.

Durée du traitement anticoagulant oral dans la maladie thromboembolique veineuse

Purpose. – The optimal duration of oral anticoagulant therapy after a first episode of venous thromboembolism is still a matter of debate. It is essential to balance the desired effect of the anticoagulants in reducing recurrences against the risk of major bleeding. The aims of this paper are to describe the current concepts in this field. Current knowledge and key points. – Recent data, based on randomised controlled trials, suggest that it is necessary to tailor the duration of anticoagulation individually according to the topography of venous thromboembolism and the presence of risk factors. A 6-week treatment for patients with isolated calf vein thrombosis is sufficient. For proximal thrombosis and/or pulmonary embolism, a short anticoagulant course seems sufficient in patients with temporary risk factors (3 months) and a longer anticoagulant course (6 months at least) is recommended for cases with permanent risk factors or idiopathic venous thromboembolism. The inherited or acquired hypercoagulable states can be divided into those that are common and associated with a modest risk of recurrence (i.e., isolated factor V Leiden or G20210A prothrombin gene) and those that are uncommon but associated with a high risk of recurrence (i.e., antithrombin, protein C or S deficiencies and anticardiolipin antibodies). Thus, the presence of one of these last abnormalities favours more prolonged anticoagulant therapy. Future prospects and projects. – 1) For patients at high risk of recurrence, there is a paucity of evidence-based medicine, particularly for patients with biological thrombophilia, and randomised controlled trials in this population are required. An assessment of low- or fixed-dose oral anticoagulation is also necessary in order to reduce the bleeding risk. 2) It is not always possible to precisely determine the optimal duration with the available data. We have performed a meta-analysis on summary data which suggests that a long course of oral anticoagulant therapy is superior to a short course. An individual meta-analytic approach is needed to draw more precise conclusions on an interesting and important clinical topic and we propose to perform this analysis in a international collaborative group.

Warfarin-associated intracapsular hemorrhage causing an acutely painful total hip arthroplasty: A rare complication of prolonged anticoagulant therapy

Hemorrhage is the most prevalent adverse effect of oral anticoagulant therapy. The incidence of bleeding complications is related to the duration and range of therapy. A patient on long-term warfarin anticoagulation developed a spontaneous intracapsular bleed into a total hip arthroplasty that had been implanted 11 years before. Joint aspiration allowed early recognition with immediate resolution of symptoms. Diagnosis and treatment of this rare complication are discussed with a review of the literature.

Management of patients with hereditary hypercoagulable disorders.

The inherited hypercoagulable states can be divided into those that are common and associated with a modest risk of thrombosis (i.e. factor V Leiden and G20210A prothrombin gene) and those that are uncommon but associated with a high risk of thrombosis. There is no convincing evidence that, independent of other clinical factors, the presence of factor V Leiden or the prothrombin gene mutation should influence the use of primary prophylaxis or the duration of anticoagulant therapy following an episode of thrombosis. Indirect evidence suggests that the presence of antithrombin, protein C deficiency, or protein S deficiency justifies avoiding additional risk factors for thrombosis, such as estrogen therapy, and justifies use of more aggressive primary prophylaxis when additional risk factors cannot readily be avoided (e.g. pregnancy). The presence of one of these three abnormalities also favors more prolonged anticoagulant therapy following venous thrombosis. However, their presence or absence appears to have less influence on the risk of recurrent venous thromboembolism than whether thrombosis was provoked by a major reversible risk factor, such as surgery.