High proportion of patients with bleeding of unknown cause in persons with a mild-to-moderate bleeding tendency: Results from the Vienna Bleeding Biobank (VIBB).

INTRODUCTION: Data on clinical characteristics and the prevalence of underlying coagulopathies in patients with mild-to-moderate bleeding disorders (MBDs) are scarce. AIM: We established the Vienna Bleeding Biobank (VIBB) to characterize and thoroughly investigate Austrian patients with MBDs. RESULTS: Four hundred eighteen patients (female = 345, 82.5%) were included. A platelet function defect (PFD) was diagnosed in 26 (6.2%) and a possible PFD in 30 (7.2%) patients. Eight patients (1.9%) were diagnosed with von Willebrand disease (VWD) (type 1 n = 6; type 2 n = 2), and 29 patients had low VWF (30-50 IU/dL). Deficiencies in factor VIII, IX, XI or XIII were found in 11 (2.6%), 3 (0.7%), 3 (0.7%) and 1 patient(s), 2 patients had dysfibrinogenaemia, and further 2 had possible PFD and FXI deficiency. Probable causal mutations were detected in 8 of 11 patients with FVIII deficiency, 2 of 3 patients with FIX deficiency and 2 of 8 patients with VWD. Three hundred three patients (72.5%) had normal results in the coagulation assays and were categorized as patients with bleeding of unknown cause (BUC). The bleeding score did not differ between patients with and without established diagnosis. A diagnosis of a bleeding disorder was more frequently made in men than in women (49.3% vs 22.9%). Male sex (OR 3.55, 95% CI: 2.02-6.22; P < .001) and blood group 0 (OR 1.86, 95% CI: 1.17-2.94; P = .008) were independently associated with diagnosis of a bleeding disorder. CONCLUSION: The high rate of patients with BUC despite in-depth haemostatic assessment underlines the incompleteness of available routine laboratory tests. Males with MBDs were more likely to be diagnosed with an established bleeding disorder than females.

Natural antibodies to oxidation-specific epitopes: innate immune response and venous thromboembolic disease.

Essentials Natural antibodies to oxidation-specific epitopes have antithrombotic properties. We evaluated the relation between natural IgM and IgG antibodies and the venous thrombosis risk. Risk of recurrent thrombosis was higher in patients with low natural IgM antibody levels. The protective effect of high IgM levels suggests a role of innate immune response in thrombosis. SUMMARY: Background and objectives Natural antibodies to oxidation-specific epitopes protect from atherothrombotic events. Whether mechanisms of innate immunity are relevant in the pathogenesis of venous thromboembolism (VTE) is unknown. Patients/Methods We measured plasma levels of immunoglobulin M (IgM) antibodies to oxidized low-density lipoproteins (OxLDL) and phosphocholine (PC) by enzyme linked immune assay in 663 patients with unprovoked VTE, who were prospectively followed after discontinuation of anticoagulation for a median of 8.8 years. The study endpoint was recurrent VTE. Results IgM antibody levels to OxLDL and PC were higher in patients without compared to those with recurrent VTE (n = 174, 26.2%). For each doubling of OxLDL-IgM or PC-IgM the hazard ratio (HR) of recurrence was 0.88 (95% confidence interval [CI], 0.77-1.01) and 0.82 (95% CI, 0.71-0.94), respectively. After 5 years the probability of recurrence in patients with PC-IgM levels in the highest tertile (> 19.6 RLU/100 ms) was 13.0% (95% CI, 8.1-17.6%), compared with 21.1% (95% CI, 14.9-26.9%) in the middle tertile and 20.6% (95% CI, 14.7-26.0%) in the lowest tertile. The corresponding HR was 0.56 (0.39-0.82) for PC-IgM levels in the highest compared with the lowest tertile. Neither immunoglobulin G IgG antibody levels to OxLDL nor those to PC were associated with risk of VTE. Conclusion Levels of natural IgM antibodies to oxidation-specific epitopes are inversely related to the risk of VTE.

Risk of cancer after anticoagulation in patients with unprovoked venous thromboembolism: an observational cohort study.

Essentials Data on long-term cancer risk are controversial in patients with venous thromboembolism (VTE). We assessed long-term rates and risk factors of cancer in patients with VTE. Cancer risk after anticoagulation is not higher in VTE patients than in the general population. VTE recurrence is not predictive of a future cancer diagnosis. SUMMARY: Background Patients with venous thromboembolism (VTE) are at risk of having a subsequent cancer diagnosis. The risk is highest during the first 6 months. Reports on cancer rates thereafter are controversial. We aimed to assess long-term rates and risk factors of cancer in patients with VTE. Methods and Results We followed patients with a first unprovoked VTE after discontinuation of anticoagulation, and excluded those receiving long-term antithrombotic therapy or with major thrombophilia. The study endpoint was the occurrence of cancer. Sixty-two (5.2%) of 1188 patients developed cancer during a median follow-up of 98 months. The cumulative incidence rates of cancer were 0.7% (95% confidence interval [CI] 0.2-1.2%), 3.1% (95% CI 2.0-4.1%) and 9% (95% CI 6.5-11.5) after 1, 5 and 15 years; these were not significantly different from those in the matched general population (0.6%, 3.4%, and 12.2%, respectively). The corresponding standardized incidence ratios (ratio of the observed cancer cases and the number of cases based on national cancer incidence rates) of 1.1 (95% CI 0.5-2.5), 1.0 (95% CI 0.6-1.4) and 0.9 (95% CI 0.7-1.2) did not indicate a difference in cancer incidence between our cohort and the general population. Advancing age (hazard ratio [HR] per decade 1.5, 95% CI 1.2-2.0) and shorter duration of anticoagulation (HR per 1-month decrease 1.3, 95% CI 1.1-1.6) were associated with an increased cancer risk, whereas VTE recurrence was not (HR 1.17, 95% CI 0.66-2.07). Conclusions Asymptomatic patients with unprovoked VTE who have completed anticoagulation therapy do not have a higher cancer risk. The inverse association between the duration of anticoagulation and the incidence of cancer warrants further investigation.

The long-term recurrence risk of patients with unprovoked venous thromboembolism: an observational cohort study.

Essentials Long-term recurrence risk of venous thromboembolism (VTE) is uncertain. We performed a prospective cohort study of 839 patients with first unprovoked VTE. VTE recurrence risk is high, particularly in men with proximal thrombosis or pulmonary embolism. Sex and VTE site determine the recurrence risk and should be considered for patient counseling. SUMMARY: Background The long-term recurrence risk (ltRR) of venous thromboembolism (VTE) is uncertain. Objective To assess the ltRR of patients with first unprovoked VTE. Patients/methods Patients were classified into three categories: distal deep vein thrombosis (DVT), proximal DVT or pulmonary embolism (PE), that is, PE associated with DVT or isolated PE. Patients with major thrombophilia or antithrombotic therapy were excluded. The endpoint was recurrent symptomatic VTE. Results A total of 839 patients were followed for a median of 7.7 years. VTE recurred in 263 patients (31%). After 10 and 20 years, the cumulative ltRR was 32% (95% confidence interval [CI], 29-36) and 44% (95% CI, 38-49) with 3.9 (95% CI, 3.3-4.6) and 3.3 (95% CI, 2.7-4.0) events per 100 patient-years, respectively. The adjusted hazard ratio was 2.1 (95% CI, 1.4-3.2) and 2.1 (95% CI, 1.4-3.2) for patients with proximal DVT or PE compared with patients with distal DVT and was 2.1 (95% CI, 1.6-2.9) for men compared with women. At 10 years, 4.7 (95% CI, 3.8-5.8) events per 100 patient-years occurred in men with proximal DVT or PE, 2.4 (95% CI, 1.2-4.4) in men with distal DVT, 1.9 (95% CI, 1.2-2.8) in women with proximal DVT or PE and 0.9 (95% CI, 0.2-1.9) in women with distal DVT. Conclusion The ltRR of patients with first unprovoked VTE is high and dependent upon sex and VTE site.

The risk of recurrence in women with venous thromboembolism while using estrogens: a prospective cohort study.

BACKGROUND: The optimal duration of anticoagulation for women who had venous thromboembolism (VTE) associated with estrogen use is unknown. OBJECTIVES: To test the hypothesis that women who had a first VTE while using estrogens have a low risk of recurrence. METHODS: A Prospective cohort study of 630 women (333 estrogen users, 297 non-users) with a first VTE, who were followed for an average of 69 months after anticoagulation withdrawal. Women with a previous or secondary VTE, coagulation inhibitor deficiency, lupus anticoagulant, cancer, pregnancy, requirement of long-term antithrombotic therapy or homozygosity or double heterozygosity for factor V Leiden and/or the G20210A prothrombin mutation were excluded. The endpoint was objectively documented symptomatic recurrent VTE. RESULTS: VTE recurred in 22 (7%) estrogen users and in 49 (17%) non-users. After 1, 2 and 5 years, the cumulative probability of recurrence was 1% (95% confidence interval [CI], 0-2), 1% (95% CI, 0-2) and 6% (95% CI, 3-9) among estrogen users and 5% (95% CI, 2-7), 9% (95% CI, 6-13) and 17% (95% CI, 12-22) among non-users. Compared with non-users, estrogen users had an adjusted relative risk (RR) of recurrent VTE of 0.4 (95% CI, 0.2-0.8). Compared with non-users in the respective age groups, the RR of recurrence was 0.4 (95% CI, 0.2-0.8) among estrogen-containing-contraceptive users and 0.7 (95% CI, 0.3-1.5) among women using estrogen-containing menopausal hormone therapy. CONCLUSIONS: Women who had their first VTE while using estrogens have a low risk of recurrent VTE. These women might not benefit from extended anticoagulant therapy.

Predicting the risk of recurrent venous thromboembolism. The Austrian study on recurrent venous thromboembolism (AUREC).

Venous thromboembolism (VTE) is a disease, which often recurs. The recurrence risk is highest in patients with unprovoked proximal deep-vein thrombosis (VT) or pulmonary embolism. Men have a higher risk than women. The risk is low in patients with VTE related to a temporary risk factor such as surgery or estrogen use. Other risk factors include overweight, post-thrombotic syndrome, history of VTE, residual VT or a vena cava filter. Both factor V Leiden and the prothrombin mutation confer a negligible increase in recurrence risk. High clotting factor levels, deficiency of a natural coagulation inhibitor, or hyperhomocysteinaemia are also associated with an increased risk. Reasons why routine laboratory thrombophilia screening however is no longer warranted are addressed in this article. Prediction rules combining clinical characteristics and coagulation assays have recently been developed. One such model, the Vienna Prediction Model, allows predicting recurrent VTE on the basis of VTE location, sex and D-dimer. This article describes strategies to distinguish between patients with high risk of recurrent VTE from those with a lower risk, who might not benefit from long-term antithrombotic therapy.

6 versus 30 months anticoagulation for recurrent venous thrombosis in patients with high factor VIII.

Patients with first venous thromboembolism (VTE) and high factor VIII (FVIII) are at increased risk of recurrence. It is unknown whether these patients benefit from prolonged secondary thrombophrophylaxis. In a prospective trial patients with first spontaneous VTE and FVIII levels >230 IU/dl were randomized to discontinue vitamin K Antagonist (VKA) after 6 months or to continue VKA for additional 24 months. Patients were excluded if they had a natural inhibitor deficiency, lupus anticoagulant, cancer, were pregnant, required long-term antithrombotic therapy or had acute-phase reaction. Primary study endpoints were symptomatic recurrent VTE or major bleeding within 2 years. Follow-up was continued beyond 2 years. Of 3,219 screened patients 34 met the inclusion criteria. Mean observation time was 37 months. Two of 17 patients allocated to discontinue VKA and two of 17 patients randomized to prolonged anticoagulation had recurrent VTE within 2 years. In the prolonged treatment group, one patient had recurrence during VKA therapy and one patient 4 weeks after voluntary discontinuation of VKA. One major nonfatal bleeding (severe epistaxis) after 10 months of VKA occurred in the prolonged treatment group. Five patients allocated to prolonged anticoagulation had recurrent VTE after discontinuation of VKA. The probability of recurrence at 2 years after discontinuation of VKA was 30% (95% CI 13-46%). Patients with high FVIII are at increased risk of recurrence. Our findings in a small number of patients indicate that prolonged anticoagulation seems to be effective but that the benefit is not maintained after discontinuation of anticoagulation.

Comparison between idiopathic deep vein thrombosis of the upper and lower extremity regarding risk factors and recurrence.

BACKGROUND: The pathogenesis and natural course of idiopathic upper extremity deep vein thrombosis (UEDVT) are unclear. OBJECTIVE: To compare patients with UEDVT and with idiopathic lower extremity deep vein thrombosis (LEDVT) regarding risk factors and recurrence. METHODS: We followed 50 patients with first idiopathic UEDVT and 841 patients with first idiopathic LEDVT for an average of 59 and 46 months, respectively. We excluded patients with natural inhibitor deficiency, lupus anticoagulant, cancer, pregnancy, isolated pulmonary embolism (PE), or long-term antithrombotic treatment. The endpoint was recurrent venous thromboembolism (VTE). RESULTS: In comparison to LEDVT patients, UEDVT patients were younger (38 +/- 13 years vs. 49 +/- 16 years, P < 0.001), slimmer (body mass index: 24 +/- 4 vs. 27 +/- 5, P < 0.001), less frequently had a family history of VTE (18% vs. 31%, P = 0.06) or concomitant PE (8% vs. 31%, P =0.001), were less frequently carriers of factor V Leiden (12% vs. 30%, P = 0.009), and had lower thrombin generation marker levels (D-dimer, 283 +/- 361 ng mL(-1) vs. 456 +/- 446 ng mL(-1), P < 0.001; peak thrombin, 298 +/- 101 nm vs. 363 +/- 111 nm, P = 0.001). Recurrence occurred in two of 50 patients with UEDVT (4%) and in 129 of 841 patients with LEDVT (15%). After 5 years, the likelihood of recurrence was 2% [95% confidence interval (CI) 0-6] among UEDVT patients and 19% (95% CI 16-22; P = 0.02) among LEDVT patients. As compared to LEDVT patients, the adjusted risk of recurrence was 0.26 (95% CI 0.06-1.05; P = 0.059) in UEDVT patients. CONCLUSION: The pathogenesis and natural course of the disease differ between patients with idiopathic UEDVT and LEDVT.