Anticoagulant therapy for the thrombotic complications of the antiphospholipid antibody syndrome

Patients with antiphospholipid antibodies (APLA) are at risk of arterial thromboembolism (ATE) or venous thromboembolism (VTE). The true strength of the association between APLA and first TE is unknown as there are no prospective studies of a large, well-characterized inception cohort of matched patients with and without APLA. Thus, evidence-based treatment recommendations for primary prophylaxis of TE in such patients cannot be made. Optimal therapy of patients with recent TE and APLA remains controversial; although there is no doubt that some such patients have a malignant hypercoagulable state characterized by resistance to “usual intensity” anticoagulation; recent evidence suggests that most such patients are adequately treated with “usual therapy”. After warfarin discontinuation, such patients appear to be at increased risk of recurrent TE, as demonstrated in a series of studies of discontinuation of secondary TE prophylaxis in patients with APLA and venous TE (VTE). Because of this increased risk of recurrent TE, after anticoagulants are discontinued, most “experts” recommend extended duration therapeutic dose warfarin for such patients. This paper will briefly review this evidence.     

Use of anticoagulants in elderly patients

Thromboembolic disorders are a major cause of morbidity and mortality, and the risk of thromboembolism increases with age. Anticoagulants are recommended for indications including the prevention of venous thromboembolism in surgical and medical patients, treatment of venous thromboembolism and stroke prevention in patients with atrial fibrillation. Traditional anticoagulants that have been used include unfractionated heparin, low molecular weight heparin, fondaparinux and vitamin K antagonists. However, these agents are all associated with drawbacks (i.e. parenteral administration or frequent coagulation monitoring/dose titration), and it has been particularly challenging to treat elderly patients with anticoagulants. Some specific characteristics of elderly patients may influence the safety of anticoagulant therapy, such as decreased renal function, co-morbidities and the use of multiple medications. The complexity of anticoagulation therapy and the increased risk of bleeding complications in elderly patients may prevent some physicians from prescribing anticoagulants to these patients, which leaves them at risk of thromboembolic events. Thus, safer and more convenient anticoagulants are needed, particularly for elderly patients. New oral anticoagulants have been developed in recent years and have shown promise in clinical studies that included elderly patients. These agents could simplify the management of thromboembolic disorders and improve the safety of anticoagulation.     

Whole blood gene expression analyses in patients with single versus recurrent venous thromboembolism

Introduction

Venous thromboembolism may recur in up to 30% of patients with a spontaneous venous thromboembolism after a standard course of anticoagulation. Identification of patients at risk for recurrent venous thromboembolism would facilitate decisions concerning the duration of anticoagulant therapy.

Objectives

In this exploratory study, we investigated whether whole blood gene expression data could distinguish subjects with single venous thromboembolism from subjects with recurrent venous thromboembolism.

Methods

40 adults with venous thromboembolism (23 with single event and 17 with recurrent events) on warfarin were recruited. Individuals with antiphospholipid syndrome or cancer were excluded. Plasma and serum samples were collected for biomarker testing, and PAXgene tubes were used to collect whole blood RNA samples.

Results

D-dimer levels were significantly higher in patients with recurrent venous thromboembolism, but P-selectin and thrombin-antithrombin complex levels were similar in the two groups. Comparison of gene expression data from the two groups provided us with a 50 gene probe model that distinguished these two groups with good receiver operating curve characteristics (AUC 0.75). This model includes genes involved in mRNA splicing and platelet aggregation. Pathway analysis between subjects with single and recurrent venous thromboembolism revealed that the Akt pathway was up-regulated in the recurrent venous thromboembolism group compared to the single venous thromboembolism group.

Conclusions

In this exploratory study, gene expression profiles of whole blood appear to be a useful strategy to distinguish subjects with single venous thromboembolism from those with recurrent venous thromboembolism. Prospective studies with additional patients are needed to validate these results.     

Antiphospholipid antibodies and thrombosis

Antiphospholipid syndrome is an autoimmune disease which combines vascular thrombosis and/or pregnancy complications with the presence of antiphospholipid antibodies. It could be a devastating and sometimes life-threatening condition. As vascular thrombosis presents as typical venous or arterial thromboembolism diagnosis is based on laboratory data. Therefore proper performance and interpretation of laboratory tests is crucial. Broader knowledge about clinical and laboratory aspects of the syndrome and their associations are essential for proper evaluation and management of the patients.     

Symptomatic venous thromboembolism in acute leukemia. Incidence, risk factors, and impact on prognosis

The association between malignant disorders and occurrence of venous thromboembolism is well established. Patients with cancer and venous thromboembolism have adverse prognosis. No systematic study on the incidence and prognostic impact of venous thromboembolism in acute leukemia has been performed as yet. We retrospectively evaluated the incidence of symptomatic venous thromboembolism before chemotherapy in 719 patients (371 males and 348 females, median age of 57.4 years), diagnosed with acute leukemia [534 with acute myelogenous leukemia, 185 with acute lymphoblastic leukemia]. Furthermore, the relationship of venous thromboembolism to clinical and laboratory parameters and its impact on prognosis was assessed. Fifteen patients (2.09%) had venous thromboembolism (objectively confirmed in 13 patients) in close temporal relationship to the onset of acute leukemia. The incidence of venous thromboembolism was the same in acute myelogenous and lymphoblastic leukemia. In five patients, pulmonary embolism was documented. Venous thromboembolism occurred in all subtypes of acute leukemia, but was most common in promyelocytic leukemia. All but one patient were treated with anticoagulants. No patient died from treatment-related bleedings or venous thromboembolism. Overall, survival, disease-free survival, and remission duration did not differ between the patient groups with and without venous thromboembolism. In contrast to solid tumors, venous thromboembolism before or at diagnosis of acute leukemia is not associated with poor prognosis.     

Thrombophilic abnormalities and recurrence of venous thromboembolism in patients treated with standardized anticoagulant treatment

INTRODUCTION: Whether patients with hereditary or acquired thrombophilia have an increased risk for recurrence of venous thromboembolism (deep vein thrombosis and/or pulmonary embolism) is still controversial. The aim of this study was to evaluate the incidence of recurrence of venous thromboembolism in patients with and without thrombophilic abnormalities treated with standardized anticoagulant treatment. MATERIAL AND METHODS: Database was from a prospective multicenter randomized study aimed at evaluating the long-term clinical benefit of extending to 1 year the 3-month oral anticoagulant treatment after a first episode of idiopathic proximal deep vein thrombosis. The screening for thrombophilia included antithrombin, protein C, protein S deficiencies, resistance to activated protein C and/or factor V R506Q mutation, the mutation 20210GA of the prothrombin gene, hyperhomocysteinemia and antiphospholipid antibodies. The diagnosis of venous thromboembolism recurrence was done by objective tests and adjudicated by a panel unaware of the results of the thrombophilia screening. RESULTS: A screening for thrombophilic abnormalities was performed in 195 patients. Twenty of 57 (35.1%) thrombophilic patients experienced a recurrence of venous thromboembolism as compared with 29 of 138 (21.0%) patients without thrombophilia (HR=1.78, 95% CI 1.002-3.140, p=0.046). The difference in VTE recurrence between patients with and without thrombophilia was accounted for by those who received 3 months of oral anticoagulation (HR=3.21, 95% CI 1.349-7.616, p=0.008). No difference between thrombophilic and non-thrombophilic patients was observed in the time interval from the index episode to recurrent venous thromboembolism (29.1+/-23.9 and 30.6+/-19.8 months, respectively). CONCLUSIONS: Thrombophilic abnormalities are associated with an increased risk of venous thromboembolism recurrence. The role of thrombophilia in the long-term management of venous thromboembolism should be addressed in prospective management studies.     

Hematologic disorders associated with ischemic stroke

Hematological disorders underlie a small proportion of all ischemic strokes. The association of these coagulation abnormalities with ischemic stroke is not always clear. The etiology of stroke still remains uncertain in a large number of cases and proper screening for coagulation abnormalities and the discovery of new coagulation disorders will probably increase the rate of strokes attributable to these causes. Since large case-control studies with unselected and consecutive stroke patients from different ethnic origins have not yet been performed to determine the role of coagulation abnormalities in ischemic stroke, our knowledge is dependent on case reports and small series of mostly younger patients. Extensive hematologic evaluation of unselected stroke patients will likely yield little useful information and be too expensive. Every stroke patient needs a careful evaluation, and in selected cases, this should include coagulation parameters. Patients with unexplained strokes after a careful evaluation, previous thrombotic episodes, or a positive family history for thrombosis, are good candidates for further coagulation studies. As long as the hypercoagulable state persists, both arterial and venous thromboembolic recurrences can be expected. Many of these patients may benefit from anticoagulants. In patients with hereditary coagulation disorders, studies should be extended to close relatives. Since some coagulation tests are fairly expensive, provide only equivocal data, and are not widely available, we advise a step-by-step approach starting with the patient and family history.     

Cerebral venous thrombosis in an adolescent with ulcerative colitis

We describe a 17-year-old Caucasian adolescent with ulcerative colitis who presented with cerebral venous sinus thrombosis. Laboratory investigation revealed low protein S levels. With successful management the patient remained without neurologic sequalae. Although there may be an association between ulcerative colitis and cerebral venous sinus thrombosis, the exact pathophysiologic mechanism remains unknown.     

Prevention of venous thromboembolism

Venous thromboembolism is the most common cause of preventable death among hospitalised patients. Systematic prophylaxis with antithrombotic agents in patients at risk for venous thromboembolism is the most effective approach to reduce morbidity and mortality. Despite this evidence, antithrombotic prophylaxis is still underused, due to the underestimation of incidence of venous thromboembolism and to the unjustified fear of bleeding complications. Both the characteristics of the individual patient and the clinical setting contribute to the definition of the risk for venous thromboembolism. Patient-related risk factors include clinical and molecular abnormalities. The grade of risk for venous thromboembolism is defined better by the clinical setting than by the patient characteristics. Prophylactic studies have been extensively carried out in surgical patients and, only more recently, in medical patients. Prophylactic methods include pharmacological agents, such as heparin, low molecular weight heparins, warfarin, and hirudin, as well as mechanical methods such as compression stockings and intermittent pneumatic compression.     

Old and new oral anticoagulants for venous thromboembolism and atrial fibrillation: a review of the literature

Heparin, fondaparinux and vitamin K antagonists (VKAs) are effective for the prevention and treatment of venous thromboembolism. VKAs reduce by almost 60% the rate of cardioembolic complications in patients with atrial fibrillation. The risk for bleeding and the inconvenience for laboratory monitoring, dose adjustment and drug or food interactions are the main limits for VKAs while parenteral administration is the main limit for heparin and fondaparinux. New oral anticoagulants with more predictable anticoagulant response and no need for laboratory monitoring have been shown to be effective for the prevention and treatment of venous thromboembolism and for the prevention of stroke and systemic embolism in patients with atrial fibrillation. The pharmacokinetic and pharmacodynamic profile of the new agents differ for mechanisms of action - mainly anti Xa and one antithrombin agent- bioavailability, half life, renal or live clearance. Drug interactions have been described with the new agents and inhibitors or inducers of P-gp or CYP3A4. Overall, in the prevention of venous thromboembolism after major elective orthopaedic surgery dabigatran was shown to be non-inferior, rivaroxaban and apixaban to be superior to enoxaparin. Both, rivaroxaban and dabigatran were shown to be non-inferior to low-molecular weight heparin and VKAs for the treatment of venous thromboembolism. Dabigatran 150 mg twice daily reduced the incidence of both ischemic and hemorrhagic stroke in patients with atrial fibrillation respect to warfarin. In these patients rivaroxaban and apixaban reduced the incidence of hemorrhagic stroke with a similar incidence of ischemic stroke. No bleeding concern emerged with the new anticoagulant agents in this indication.     

Treatment of venous thromboembolism in cancer patients

The management of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with cancer can be a clinical dilemma. Comorbid conditions, warfarin failure, difficult venous access, and a high bleeding risk are some of the factors that often complicate anticoagulant therapy in these patients. In addition, the use of central venous access devices is increasing but the optimal treatment of catheter-related thrombosis remains controversial. Unfractionated heparin (UFH) is the traditional standard for the initial treatment of venous thromboembolism (VTE) but low molecular weight heparins (LMWHs) have been shown to be equally safe and effective in hemodynamically stable patients. For long-term treatment or secondary prophylaxis, vitamin K antagonists remain the mainstay treatment. However, the inconvenience and narrow therapeutic window of oral anticoagulants make extended therapy unattractive and problematic. As a result, LMWHs are being evaluated as an alternative for long-term therapy. New antithrombotic agents are being tested in clinical trials and may have the potential to replace conventional treatment. The role of inferior vena cava filters in cancer patients remains ill defined but these devices remain the treatment of choice in patients with contraindications for anticoagulant therapy.     

Risk of thromboembolism after cerebral venous thrombosis

The outcome of cerebral venous thrombosis (CVT) has been studied infrequently. We assessed the frequency of recurrence of cerebral or systemic thromboembolism and factors influencing recurrence. We performed a retrospective study of consecutive patients with CVT in the period 1985-2002 who were admitted to the University Hospital Gasthuisberg. We performed a chart review and a semi-standardized telephone interview that focused on recurrent CVT or systemic thromboembolism. Fifty-four CVT patients with a mean age of 42 years were followed up for a mean of 3.5 years. Eighty percent were women. Coagulation disorders were found in 17 patients (31%). One patient (1.9%) had recurrent CVT and seven patients (12.9%) suffered systemic thromboembolism after a median of 2.5 months. Patients with recurrent thromboembolism more often had coagulopathies (P = 0.04) or a history of deep venous thrombosis (P = 0.007). Patients with early recurrent venous thromboembolism often were not treated with oral anticoagulants (P < 0.001). It was evident from the above study that a substantial number of patients suffer recurrent thromboembolism after CVT.     

Venous thromboembolism among United States soldiers deployed to Southwest Asia

INTRODUCTION: Military operations may represent a high-risk environment for venous thromboembolism (VTE). We sought to identify and describe cases of venous thromboembolism among US military personnel serving in Southwest Asia, and estimate relative disease rates compared to non-deployed personnel. MATERIALS AND METHODS: Retrospective review of imaging archives, hospital discharge codes, case logs and autopsy records for the diagnosis of deep vein thrombosis or pulmonary embolism occurring from 1 March 2003 through 29 February 2004 among U.S. military personnel deployed to Southwest Asia. Rates of disease in deployed and non-deployed active-duty soldiers were estimated using personnel data and deployment experience obtained from automated rosters. RESULTS: Forty cases of venous thromboembolism were identified. The case-fatality rate was 16% (3/19) among those with pulmonary embolism. Antecedent trauma followed by prolonged air evacuation was present in 55% (22/40). Compared to trauma-associated cases, non-trauma cases were more commonly over 40 years old (44% vs. 5%; p<0.05), assigned to a transportation or quartermaster company (56% vs. 14%; p<0.05), or had a history of remote venous thromboembolism (31% vs. 0%; p<0.05). The overall incidence among deployed active-duty soldiers was 22.1/100,000 person-years. Compared to non-deployed active-duty soldiers, the age-adjusted incidence rate ratio was 1.06 (CI(0.95) 0.68-1.67). CONCLUSIONS: VTE rates among deployed soldiers are relatively low compared to the general population, and are comparable to non-deployed soldiers. Fatalities from PE are not uncommon, and vigilance among clinicians remains warranted. Trauma followed by prolonged air evacuation or ground transport during military operations may represent unique interactive risk factors for venous thromboembolism.     

Comparison of outcomes after hospitalization for deep venous thrombosis or pulmonary embolism

Venous thrombosis and pulmonary embolism are commonly viewed as different manifestations of a single disease process, venous thromboembolism. Recent evidence suggests that there may be important differences between patients who manifest these two conditions. Using linked hospital discharge records we analyzed 71,250 patients hospitalized with a principal diagnosis of venous thrombosis alone or pulmonary embolism and analyzed predictors of rehospitalization within 6 months for venous thrombosis or pulmonary embolism. There were 51233 patients diagnosed with venous thrombosis alone and 21,625 diagnosed with pulmonary embolism. Comparing patients initially diagnosed with venous thrombosis alone to patients with pulmonary embolism, the relative risk of being rehospitalized with venous thrombosis within 6 months for venous thrombosis was 2.7. Conversely, when patients with pulmonary embolism were compared to patients with venous thrombosis alone, the relative risk of rehospitalization within 6 months with a diagnosis of pulmonary embolism was 4.2. In multivariate models the strongest predictor of recurrent thromboembolism manifest as pulmonary embolism was an initial diagnosis of pulmonary embolism and the strongest predictor of recurrence as venous thrombosis was an initial diagnosis of venous thrombosis. We conclude that the initial clinical manifestation of thromboembolism strongly predicts the manifestation of a recurrence. Venous thrombosis and pulmonary embolism appear to be distinct, albeit overlapping, clinical entities with different natural histories.     

Low-molecular-weight heparins for the treatment of acute coronary syndrome and venous thromboembolism in patients with chronic renal insufficiency

The clinical management of patients with renal insufficiency who develop an acute coronary syndrome or venous thromboembolism is a common clinical scenario that is problematic because of the lack of well-designed randomized trials assessing management strategies in such patients. Impaired renal function is common in patients who develop thromboembolic disorders, particularly in elderly patients in whom renal insufficiency is under-recognized. Low-molecular-weight heparins (LMWHs), which are the most widely used anticoagulant for the treatment of patients with an acute coronary syndrome or venous thromboembolism, are eliminated primarily by the kidney and, therefore, pose treatment challenges in patients with impaired renal function. However, there is emerging evidence regarding the use of LMWHs in patients with impaired renal function suggesting that some preparations may be safe in such patients. The objective of this review is to discuss the clinical management of patients with renal insufficiency who develop an acute coronary syndrome or venous thromboembolism, and to explore similarities and differences of LMWHs when used in this clinical setting.     

Can causes of false-normal D-dimer test [SimpliRED] results be identified?

BACKGROUND: To simplify the diagnostic strategy of patients suspected for venous thromboembolism, the use of D-dimer tests has been advocated. Very important for the safety of such diagnostic strategies would be the capacity to recognise false-normal D-dimer results, in order to prevent inadequately withholding anticoagulant treatment in patients who actually have the disease. Insight in the causes of false-normal D-dimer results would therefore be necessary. We hypothesised that certain patient characteristics are associated with relatively low plasma D-dimer levels and, therefore, could increase the risk of false-normal results. METHODS: Consecutive patients with an objectively confirmed venous thromboembolic event and an independently obtained false-normal SimpliRED D-dimer test result were included in the study. For each patient, two controls with objectively confirmed venous thromboembolism and an adequate abnormal D-dimer result were selected. Baseline patient characteristics, obtained by standardised questionnaires, were compared between the two groups of patients. RESULTS: In total, 686 patients had a venous thromboembolic event and 47 of these patients had a false-normal SimpliRED result. Therefore, the overall sensitivity of the SimpliRED test for venous thromboembolism was 94% (95% CI: 92-95%). Although the prevalence of certain clinical characteristics was significantly higher in patients with a false-normal D-dimer result than in the controls [odds ratios for (LMW)heparin treatment and symptoms lasting more than 10 days: 5.1 (95% CI: 1.5-18.7) and 3.2 (95% CI:1.4-7.4), respectively], the prevalence of these characteristics was also high in the control group with an adequate abnormal D-dimer. Combining two or more of these characteristics had a low prevalence and did not further improve the ability to identify those patients with a false-normal D-dimer test at presentation. CONCLUSIONS: Although these findings clearly indicate an association between certain baseline clinical characteristics and the occurrence of a false-normal SimpliRED test, the clinical utility for these characteristics is limited.     

Thrombin generation and D-dimer concentrations in a patient cohort investigated for venous thromboembolism. Relations to venous thrombosis,factor V Leiden and prothrombin G20210A. The LIST study

IntroductionThe present study evaluated possible relations between various markers of thrombin generation, D-dimer and venous thromboembolism in outpatients with and without the FV Leiden and the protrombin mutations.Patients and methodsOur cohort consisted of 98 patients with the FV Leiden and 15 with the prothrombin mutation and an equal number of age- and gender-matched controls. All subjects were investigated due to suspicion of venous thromboembolism and the diagnosis was objectively confirmed or refuted.ResultsWe compared the D-dimer values and the thrombin generation markers among different patient groups (with/without thromboembolism, with/without genetic factors, gender-linked). The only statistically significant difference noted was prolonged time both for the initiation and termination of thrombin generation in patients with thrombosis. This applied to controls and to patients heterozygous for the FV Leiden. Additionally, the D-dimer values were elevated in patients with the FV Leiden. No difference was found among the patients with prothrombin mutation and their controls.DiscussionMulti-variant analysis indicated that the difference in D-dimer between FV Leiden patients and controls was due to the greater number of patients with confirmed thrombosis in the former group, a finding supported by an independent prospective study on postoperative thrombosis. Neither D-dimer concentration nor thrombin generation depend on FV Leiden. The total amount of thrombin generated was not related to diagnosis. The prolonged thrombin generation noted in controls and FV Leiden heterozygotes with thrombosis may point out different thrombin generation profiles in different patient populations and requires further studies.     

Prospective assessment of the natural history of positive D-dimer results in persons with acute venous thromboembolism (DVT or PE)

The natural history of initially positive D-dimers for venous thromboembolism is not known. If it returns to negative in the majority of patients, it would be potentially helpful to diagnose a recurrence. In this study, we prospectively measured D-dimer levels in outpatients with a diagnosis of venous thromboembolism. There were a total of 152 patients with an average age of 57. D-dimer results were performed at baseline and repeated at one week, one month and three months. At baseline 120 of 152 (79%) had a positive D-dimer result. Of those with an initially positive result, 80% were still positive at one week and 39% were still positive at one month. Finally at three months, 13% remained positive. Seven patients had recurrent events and all had persistently elevated D-dimers at one month. This study suggests that a persistently positive D-dimer result after one month of treatment may indicate a higher risk of recurrent venous thromboembolism. D-dimer testing for the diagnosis of recurrence of venous thromboembolism deserves further study.     

Enhanced platelet aggregation with TRAP-6 and collagen in platelet aggregometry in patients with venous thromboembolism

The role of platelet hyperaggregability as a possible risk factor for venous thromboembolism is not well defined. Some authors described enhanced maximal platelet aggregation in platelet aggregometry as a contributing factor for arterial and venous thrombosis. This syndrome has been termed “sticky-platelet syndrome” (SPS). The diagnosis of SPS is based on the demonstration of platelet hyperaggregability in aggregometry after stimulation with epinephrine (EPI) and/or adenosine diphosphate (ADP).

We investigated platelet hyperaggregability in platelet-rich plasma (PRP) of patients (n=34) with unexplained venous thromboembolism in comparison to healthy individuals (n=53). For analysis, platelet aggregometry was performed and the influence of epinephrine, adenosine diphosphate, collagen (Coll) and thrombin receptor-activated peptide (TRAP-6) as agonist were determined. Compared to the control group, patients with venous thromboembolism showed an enhanced maximal platelet aggregation with low concentrations of TRAP-6 (2 μM) and collagen (0.05 μM). In contrast, we could not detect an increased platelet aggregation with EPI or ADP.

Our results indicate that platelet hyperaggregability may represent an independent risk factor in patients with otherwise unexplained venous thromboembolism. In our study, low concentrations of TRAP-6 and collagen are superior to EPI and ADP to define platelet hyperreactivity in platelet aggregometry.