Deep venous thrombosis and previous myocardial infarction in mild factor XII deficiency: a risk factor for both venous and arterial thrombosis

Factor XII deficiency is associated with increased risk for both arterial and venous thrombosis. We describe a case of DVT involving superficial femoral and popliteal vein occurred following total hip replacement and despite prophylaxis with low molecular weight heparin in a subject with previous acute myocardial infarction (AMI). Tests of haemostasis documented a slightly prolonged activated partial thromboplastin time (APTT) (45′′) due to mild factor XII deficiency (clotting activity 32%). A therapeutic dose of enoxaparin was started, together with warfarin therapy. The patient was advised to continue oral anticoagulation indefinitely. Although cases of both venous and arterial thrombosis in carriers of severe factor XII deficiency have been already reported, to our knowledge this is the first case in the literature occurred in a carrier of partial factor XII deficiency. In conclusion, factor XII deficiency should be suspected if a patient presents with recurrent arterial and/or venous thrombosis and prolonged APTT. If this defect is diagnosed, in the presence of a history of thrombotic events, lifelong anticoagulation could be considered.     

von Willebrand factor and factor VIII as risk factors for arterial and venous thrombosis

Since the early 1990s attempts have been made to elucidate whether high concentrations of von Willebrand factor (VWF) and factor VIII (FVIII) in plasma are associated with an increased risk of thrombosis. Several prospective studies on the role of VWF in arterial thrombosis, mainly coronary heart disease, were performed in healthy individuals and patients with previous cardiovascular disease. Although the majority showed an association between high VWF levels and arterial thrombosis, others failed to confirm such findings. A smaller number of studies have evaluated FVIII, mainly for its association with venous thrombosis. Two prospective observations, together with several case-control studies, provided solid evidence of an association between high FVIII levels and a first or recurrent episode of venous thrombosis. On the whole, high levels of VWF and FVIII in plasma confer a moderately high risk of arterial and venous thrombosis, respectively. These findings have no therapeutic implication, but they should be taken into account in the assessment of the individual risk profile.     

Common risk factors for both arterial and venous thrombosis

Arterial and venous thromboses have traditionally been viewed as distinct conditions, with differences in risk factors, pathology and treatment. However, recent epidemiological studies have suggested associations between venous thromboembolism, arterial thromboembolism (myocardial infarction and stroke) and atherosclerosis. While several biological mechanisms might contribute to these associations, common risk factors for both arterial and venous thrombosis probably play the major role. This article summarizes the evidence for shared risk factors (clinical, biochemical and haematological) that supports this conclusion. At a practical level, it is suggested that following routine treatment of venous thromboembolism with a course of anticoagulant drugs, patients should be routinely assessed not only for risk of recurrent venous thromboembolism but also for risk of arterial thromboembolism. Appropriate lifestyle advice and medication (including aspirin) should then be considered.     

Minor injuries as a risk factor for venous thrombosis

BACKGROUND: Injuries increase the risk of venous thrombosis. So far, most research has focused on major injuries that are accompanied by other risk factors for venous thrombosis, such as plaster casts and surgery. We studied the association of venous thrombosis with common minor injuries, such as minor sural muscle ruptures and ankle sprains. METHODS: We performed a large, population-based, case-control study (the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis [MEGA] study), including consecutive patients with a first deep venous thrombosis of the leg or pulmonary embolism and control subjects. Participants with malignant neoplasms, those who underwent surgery, and those who had a plaster cast or extended bed rest were excluded. RESULTS: Of 2471 patients, 289 (11.7%), and of 3534 controls, 154 (4.4%) had a minor injury in the 3 months preceding the venous thrombosis (patients) or completion of the questionnaire (controls). Venous thrombosis was associated with previous minor injury (odds ratio adjusted for sex and age, 3.1; 95% confidence interval, 2.5-3.8). The association was strongest for injuries that occurred in the 4 weeks before thrombosis and was not apparent before 10 weeks. Thrombosis was more strongly associated with minor injuries located in the leg (odds ratio adjusted for sex and age, 5.1; 95% confidence interval, 3.9-6.7), while those located in other body parts were not associated. A 50-fold increased risk was found in factor V Leiden carriers with a leg injury compared with noncarriers without injury (odds ratio, 49.7; 95% confidence interval, 6.8-362.7). CONCLUSIONS: Minor injuries in the leg are associated with greater risk of venous thrombosis. Because minor injuries are common, they could be major contributors to the occurrence of venous thrombosis.     

Posttreatment ultrasound-detected residual venous thrombosis: a risk factor for recurrent venous thromboembolism and mortality

PURPOSE OF REVIEW: The cumulative risk of recurrent venous thrombosis may rise to 30% over 8 years. Extended oral anticoagulation is effective but major bleeding is increased. To balance these risks attention has focused on identifying patients with the highest likelihood of recurrence for whom continued therapy is most beneficial. Another issue of interest has been the increased probability of death after venous thrombosis, due primarily to malignancy but also to vascular disease. RECENT FINDINGS: Unprovoked events and cancer are known to be associated with recurrent thrombosis. Residual posttreatment thrombosis confirmed by compression ultrasound is regarded as another risk for recurrence. Confounders in the published studies are the patient mix and the ultrasound technique employed. Other variables such as gender and D-dimer may also predict risk. Although arterial disease is increased in patients with venous thromboses, the association between idiopathic venous thromboembolism and atherosclerosis remains circumstantial. SUMMARY: There are no validated approaches for predicting recurrent venous events. Ultrasound interrogation for residual thrombosis after primary therapy may improve treatment stratification by defining patients suitable for extended anticoagulation.     

Hyperhomocysteinemia: a novel risk factor for erectile dysfunction

Nitric oxide (NO), the key mediator synthesized by different NO synthase isoenzymes, plays an important role in endothelial function. It was recently shown that hyperhomocysteinemia is an important regulator of NO synthase. We investigated the role of homocysteine (Hcys) in erectile dysfunction (ED), which is associated with the defect in NO generation. Thirty-one nondiabetic patients and 33 control cases were evaluated. Patients with diabetes, coronary artery disease, vitamin B(12), or folate deficiency were excluded in the study. The International Index of Erectile Function questionnaire was used to gauge identified erectile quality. Fasting plasma glucose, total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, vitamin B(12), folic acid, and Hcys levels of patients were measured. Penile color Dupplex ultrasound was used to detect vascular abnormalities in nondiabetic patients with ED. Patients with ED were older than the control subjects (55.6 +/- 8.4 vs 44.5 +/- 4.7 years, respectively; P < .001). Patients with ED had higher fasting plasma glucose, total cholesterol, low-density lipoprotein cholesterol, and Hcys levels. There was a significant negative correlation between mean Hcys level and mean International Index of Erectile Function domain score (P < .001). The penile color Doppler ultrasound findings showed that there was a negative significant correlation between mean Hcys level and the 1st, 5th, and 10th minute's peak-systolic velocity. Logistic regression analysis revealed that age and Hcys levels were the main determinants in ED. Hyperhomocysteinemia, known to be an important risk factor in endothelial dysfunction, seems to be an important determinant in ED. These data suggest that slightly elevated Hcys levels are significantly related with arterial and probably endothelial dysfunction in patients with ED.     

The venous thrombosis risk factor 20210 A allele of the prothrombin gene is not a major risk factor for arterial thrombotic disease

A nucleotide change (G to A transition) at position 20210 has recently been demonstrated to be a risk factor for venous thrombosis. The relevance of this polymorphism to thrombotic disease was investigated by genotypic identification in three prospective case–control studies: 101 case patients with acute coronary heart disease (CHD), 104 patients with acute cerebrovascular disease (CVD), 82 patients with a confirmed diagnosis of deep venous thrombosis (DVT), and one control age- and sex-matched for each patient. The prevalence of the genetic variation was significantly associated with the occurrence of DVT, but did not differ in patients with CHD or CVD from that in controls, suggesting that this allele should not be considered a major risk factor for arterial thrombotic disease.     

Fibrinolysis and the risk of venous and arterial thrombosis

PURPOSE OF REVIEW: The fibrinolytic system is often regarded as just an innocent bystander in the pathogenesis of venous and arterial thrombosis, while (hyper)coagulation as a risk factor has been studied extensively. In this review, we evaluated studies that investigated the association between fibrinolysis and thrombosis. RECENT FINDINGS: There is some evidence for an association between impaired overall fibrinolytic activity and increased risk of venous or arterial thrombosis. Plasminogen levels were found not to be related to thrombosis. Plasma levels of tissue-type plasminogen activator were related to arterial thrombosis in a number of studies but not to venous thrombosis. Thrombin activatable fibrinolysis inhibitor levels appeared to be associated with venous thrombosis. Studies on the association between thrombin activatable fibrinolysis inhibitor or plasminogen activator inhibitor-1 and arterial thrombosis had conflicting results. SUMMARY: Current evidence on an association between fibrinolysis and thrombosis is inconclusive. Although overall assays point to an association, not all individual factors have an association with thrombosis. Most importantly, plasminogen deficiency is not related to thrombosis, which suggests that the fibrinolytic system as a whole is unimportant in the occurrence of thrombosis. Certain components of the fibrinolytic system, however, appear to be involved in processes unrelated to fibrin degradation but related to other processes important in the development of thrombosis.     

Reduced plasma fibrinolytic potential is a risk factor for venous thrombosis

The role of the fibrinolytic system in the development of deep vein thrombosis (DVT) is unclear. We determined the plasma fibrinolytic potential of patients enrolled in the Leiden Thrombophilia Study (LETS), a population-based case-control study on risk factors for DVT. Plasma fibrinolytic potential was determined in 421 patients and 469 control subjects by means of a tissue factor-induced and tissue-type plasminogen activator (tPA)-induced clot lysis assay. Using clot lysis times above the 70th, 80th, 90th, 95th, and 99th percentiles of the values found in control subjects as cut-off levels, we found a dose-dependent increase in risk for DVT in patients with hypofibrinolysis (odds ratios of 1.4, 1.6, 1.9, 2.1, and 2.2, respectively). This indicates a 2-fold increased risk of DVT in subjects with clot lysis times above the 90th percentile. The risk increase was not affected by age or sex (adjusted odds ratio for 90th percentile, 2.0), and after correction for all possible confounders (age, sex, and levels of procoagulant proteins shown to associate with clot lysis times in the control population), the risk estimate was marginally reduced (odds ratio, 1.6 for 90th percentile). Taken together, these results indicate that plasma hypofibrinolysis constitutes a risk factor for venous thrombosis, with a doubling of the risk at clot lysis times that are present in 10% of the population.     

Hypofibrinolysis is a risk factor for arterial thrombosis at young age

The relationship between defective fibrinolysis and arterial thrombosis is uncertain. The evaluation of the plasma fibrinolytic potential might provide stronger evidence linking fibrinolysis to arterial thrombosis than the evaluation of the individual fibrinolytic factors. We determined the plasma fibrinolytic potential of 335 young survivors of a first arterial thrombosis, including coronary artery disease ( n  = 198), ischaemic stroke ( n  = 103) and peripheral artery disease ( n  = 34), enrolled in a population-based case–control study and of 330 healthy individuals. Patients had significantly higher clot lysis times (CLTs) than the controls. Odds ratios (ORs) were calculated as a measure of relative risk. The OR for arterial thrombosis was determined in these subjects who had a CLT above the 60th, 70th, 80th, 90th and 95th percentiles of the values found in the control subjects. We found a progressive increase in risk of arterial thrombosis in subjects with hypofibrinolysis (OR: 1·7, 2·0, 2·3, 2·3 and 2·9, respectively). Relative risk estimates obtained in the whole group were comparable those obtained in the event-subgroups. In conclusion, a low plasma fibrinolytic potential, found in 10% of the population, increases the relative risk of arterial thrombosis twofold. This points to an important contribution of hypofibrinolysis to the burden of arterial thrombosis.     

Pseudohomozygosity for activated protein C resistance is a risk factor for venous thrombosis

Pseudohomozygosity for activated protein C resistance (APC-r) is a rare condition due to the association of heterozygous FV Leiden mutation and partial type I FV deficiency. To assess the risk of venous thromboembolism in these subjects, seven families including 11 pseudohomozygotes and 45 relatives were examined. Among the relatives, 16 were heterozygous FV Leiden carriers, nine showed partial FV deficiency and 20 no abnormalities. Deep vein thrombosis occurred in 4/11 (36.3%) pseudohomozygous patients versus 6/16 (37. 4%) FV Leiden carriers and 1/20 (5%) normal relatives. Pseudohomozygotes and FV Leiden carriers had a significantly increased risk of venous thrombosis in comparison to normal relatives (RR 8.8 and 5.7, respectively). There was no difference between the thrombotic risk of pseudohomozygous subjects and of FV Leiden carriers (RR 1.6, 95% CI 0.43-5.7). Furthermore, there was no difference in thrombosis-free survival between pseudohomozygotes and 45 consecutive FV Leiden heterozygous outpatients, suggesting that a referral bias may explain the apparent younger age of thrombosis in the pseudohomozygotes in comparison to relatives with FV Leiden heterozygosity (27 years v 54 years; P = 0.01). Pseudohomozygosity for APC resistance carries a significantly higher risk for venous thromboembolism in comparison to normal subjects, but probably not in comparison to heterozygous FV Leiden carriers.     

Elevated factor VIII levels and risk of venous thrombosis

Modern thrombophilia testing fails to identify any underlying prothrombotic tendency in a significant number of patients presenting with objectively confirmed venous thromboemboembolism (VTE). This observation has led to a search for other novel inherited or acquired human thrombophilias. Although a number of putative mechanisms have been described, the evidence behind many of these candidates remains weak. In contrast, an increasing body of work supports the hypothesis that increased plasma factor VIII (FVIII) levels may be important in this context. An association between elevated plasma FVIII levels and VTE was first described in the Leiden Thrombophilia Study (LETS). Subsequently, these conclusions have been supported by an increasing number of independent case-control studies. Cumulatively, these studies have clearly demonstrated that high FVIII levels constitute a prevalent, dose-dependent risk factor for VTE. Furthermore, more recent studies have shown that the risk of recurrent venous thrombosis is also significantly increased in patients with high FVIII levels. In this review, we present the evidence supporting the hypothesis that elevated FVIII levels constitute a clinically important thrombophilia. In addition, we examine the biological mechanisms that may underlie persistently elevated FVIII levels, and the pathways through which high FVIII may serve to increase thrombotic risk.     

Aggressive lymphoma subtype is a risk factor for venous thrombosis. Development of lymphoma - specific venous thrombosis prediction models

Venous thromboembolic events (VTE) are a frequent complication of lymphoma. We conducted a retrospective analysis to compare VTE risk in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Subjects were randomly assigned to training and validation sets to identify risk factors of VTE and evaluate risk model performance, including the Khorana score. A group of 790 patients were diagnosed from 2002 to 2014 (DLBCL = 542, FL = 248). Median follow- up was 49 months. We observed 106 VTE, with higher incidence in DLBCL (5-year cumulative incidence = 16.3% vs 3.8% in FL patients). Five-year OS for patients with VTE was 51.4% vs 73.1% in patients without VTE (P < .001). Baseline VTE risk factors identified in the training cohort included lymphoma subtype, previous VTE, ECOG performance status ≥2, decreased albumin, increased calcium, elevated WBC, absolute lymphocyte count or monocyte count, and presence of bulky disease. Addition of new variables to the Khorana score improved its performance measured by Akaike information criterion and Concordance index. A new risk model including lymphoma subtype, albumin, WBC count, and bulky disease was validated in time-based ROC analyses. These findings were confirmed in the validation cohort. Lymphoma subtypes have different VTE risk. The effect of lymphoma subtype was independent from disease burden and the use of systemic therapy. The Khorana risk-score was validated in time to event analyses, and a more robust lymphoma-specific VTE risk score is proposed. These findings suggest lymphoma patients with highest VTE risk can be identified with baseline parameters.