Ludwig Traby

Prediction of recurrent venous thromboembolism by clot lysis time: a prospective cohort study.

Venous thromboembolism (VTE) is a chronic disease, which tends to recur. Whether an abnormal fibrinolytic system is associated with an increased risk of VTE is unclear. We assessed the relationship between fibrinolytic capacity (reflected by clot lysis time [CLT]) and risk of recurrent VTE. We followed 704 patients (378 women; mean age 48 yrs) with a first unprovoked VTE for an average of 46 months after anticoagulation withdrawal. Patients with natural coagulation inhibitor deficiency, lupus anticoagulant, cancer, homozygosity for factor V Leiden or prothrombin mutation, or requirement for indefinite anticoagulation were excluded. Study endpoint was symptomatic recurrent VTE. For measurement of CLT, a tissue factor-induced clot was lysed by adding tissue-type plasminogen activator. Time between clot formation and lysis was determined by measuring the turbidity.135 (19%) patients had recurrent VTE. For each increase in CLT of 10 minutes, the crude relative risk (RR) of recurrence was 1.13 (95% CI 1.02–1.25; p = 0.02) and was 1.08 (95% CI 0.98–1.20; p = 0.13) after adjustment for age and sex. For women only, the adjusted RR was 1.14 (95% CI, 0.91–1.42, p = 0.22) for each increase in CLT of 10 minutes. CLT values in the 4th quartile of the female patient population, as compared to values in the 1st quartile, conferred a risk of recurrence of 3.28 (95% CI, 1.07–10.05; p = 0.04). No association between CLT and recurrence risk was found in men. Hypofibrinolysis as assessed by CLT confers a moderate increase in the risk of recurrent VTE. A weak association between CLT and risk of recurrence was found in women only.

Hematocrit and the risk of recurrent venous thrombosis: a prospective cohort study.

Background Venous thromboembolism (VTE) is a multicausal disease which recurs. Hematocrit is associated with a thrombotic risk. We aimed to investigate if hematocrit is associated with the recurrence risk. Methods Patients with a first VTE were followed after anticoagulation. Patients with VTE provoked by a transient risk factor, natural inhibitor deficiency, lupus anticoagulant, homozygous or double heterozygous defects, cancer, or long-term antithrombotic treatment were excluded. The study endpoint was recurrent VTE. Results 150 (23%) of 653 patients had recurrence. Only high hematocrit was significantly associated with recurrence risk [hazard ratio (HR) for 1% hematocrit increase with the third tertile 1.08; 95% CI 1.01–1.15]. No or only a weak association for hematocrits within the first and second tertile was seen (HR 1.03; 95% CI 0.97–1.09, and 1.07; 95% CI 1.00–1.13). Hematocrit was associated with recurrence risk only among women. After five years, the probability of recurrence was 9.9% (95% CI 3.7%–15.7%), 15.6% (95% CI 9.7%–21.2%) and 25.5% (95% CI 15.1%–34.6%) in women, and was 29.2% (95% CI 21.1%–36.5%), 30.1% (95% CI 24.1%–35.7%) and 30.8% (95% CI 22.0%–38.7%) in men for hematocrits in the first, second and third tertile, respectively. Men had a higher recurrence risk (1.9; 95% CI 1.1–2.7; p = 0.03), which dropped by 23.5% after adjustment for hematocrit. Hematocrit was not a significant mediator of the sex-difference in recurrence risk (p = 0.223). Conclusions High hematocrit is associated with the recurrence only in women. The different recurrence risk between men and women is possibly partly explained by hematocrit.

The effects of low-molecular-weight heparin at two different dosages on thrombin generation in cancer patients. A randomised controlled trial.

Non-surgical cancer patients are at high thrombotic risk. We hypothesised that the prothrombotic state is reflected by elevated thrombin generation and can be mitigated by increasing the low-molecular-weight heparin (LMWH) dose. Non-surgical cancer patients were randomised to enoxaparin 40 or 80 mg. D-dimer, prothrombin fragment F1+2 (F1+2) and peak thrombin (PT) were measured 2, 4, 6 hours (h) after LMWH (day 1) and daily for 4 days. A total of 22 and 27 patients received enoxaparin 40 and 80 mg, respectively. D-dimer and F1+2 moderately decreased after 6 h in both groups. After enoxaparin 80 mg, D-dimer baseline levels [median (quartiles)] decreased from day 1 to 4 [1054.9 (549.5, 2714.0) vs. 613.0 (441.1, 1793.5) ng/ml] (p<0.0001), while no difference was seen after 40 mg. Baseline PT levels [median (quartiles)] were 426.2 nM (347.3, 542.3) (40 mg) and 394.0 nM (357.1, 448.8) (80 mg). After 80 mg, PT significantly decreased to 112.4 nM (68.5, 202.4), 57.1 nM (38.0, 101.2) and 43.6 nM (23.4, 112.8) after 2, 4 and 6 h, which was lower than after 40 mg (p=0.003). After 80 mg, PT decreased from day 1 to 4 [358.6 nM (194.2, 436.6); p=0.06] while no difference was seen after 40 mg. In conclusion, in cancer patients coagulation activation and thrombin generation is substantially increased. Peak thrombin levels are sensitive to the anticoagulant effects of LMWH at different dosages. The prothrombotic state is substantially attenuated by higher LMWH doses.

Thrombin generation in haemophilia A patients with factor VIII inhibitors after infusion of recombinant factor VIIa

Background  Development of factor VIII inhibitors is a serious complication in haemophilia A patients. Recombinant factor VIIa (rVIIa) is clinically effective, but its effects on haemostatic system need still to be fully elucidated.

Effects of P2Y12 receptor inhibition with or without aspirin on hemostatic system activation: a randomized trial in healthy subjects.

Essentials In acute coronary syndromes, dual antiplatelet therapy inhibits platelets but confers a bleeding risk. Healthy male volunteers received clopidogrel or ticagrelor plus aspirin or clopidogrel or ticagrelor alone. The decrease in β‐thromboglobulin in shed blood was comparable after single and dual antiplatelet therapy. We hypothesize that patients with acute coronary syndromes may not require dual antiplatelet therapy.

Effects of clopidogrel with or without aspirin on the generation of extracellular vesicles in the microcirculation and in venous blood: A randomized placebo controlled trial

BACKGROUND Dual-antiplatelet therapy (DAPT) is a standard strategy in acute coronary heart disease; however, it confers a considerable bleeding risk. Single-antiplatelet therapy (SAPT) inhibits haemostatic system activation ex vivo to a similar extent as DAPT. Extracellular vesicles (EV) are procoagulant and contribute to haemostatic system activation. We aimed to investigate the effect of DAPT compared with SAPT on EV. METHODS In a randomized, double-blind, placebo-controlled trial, 44 healthy volunteers received DAPT (clopidogrel + aspirin) or SAPT (clopidogrel + placebo) for 7 days. Blood was obtained from a standardized microvascular injury and through venipuncture at baseline (BL) and at 2 h, 24 h, and 8 days after treatment initiation. The number, origin, and surface expression of EV were assessed using flow cytometry. Data are given as median (quartiles). Non-parametric tests were used to evaluate the short-term (BL vs 2 h) and long-term differences (2 h to 8 days), as well as the differences between treatment groups. RESULTS There was no difference either in the short-term effects on the number (×103 mL-1) of EV in microvascular blood between DAPT [BL: 1433 (653; 3184) vs 2 h: 862 (545; 2026), p = 0.39] and SAPT [(BL: 614 (552; 1402) vs 2 h: 1079 (781; 1538), p = 0.75)] or in the long-term effects. DAPT and SAPT did not exhibit differential short-term effects on the number and proportion (36% and 27% vs 55% and 36%) of platelet-derived EV. DAPT and SAPT resulted in a significant short-term increase in phosphatidylserine expression in microvascular blood. The effects of DAPT and SAPT on EV in venous blood were similar to those in microvascular blood. CONCLUSION DAPT and SAPT have comparable effects on the amount, origin, and surface characteristics of EV.

Risk of venous thromboembolism during rehabilitation of patients with spinal cord injury

Background Patients with spinal cord injury (SCI) are at risk of thrombosis and bleeding. Data on the risks during rehabilitation are inconsistent, and thromboprophylactic strategies are heterogeneous. We aimed to evaluate the thrombotic risk and bleeding events of SCI patients during rehabilitation. Methods We retrospectively collected hospital record data of 263 consecutive SCI patients admitted at a rehabilitation clinic. 78 patients with acute venous thromboembolism (VTE) at the primary center, without acute trauma or lower extremity paresis, less than one month rehabilitation, or reasons for long-term therapeutic anticoagulation, were excluded. All patients received pharmacologic thromboprophylaxis throughout rehabilitation. Primary endpoint was objectively diagnosed VTE; secondary endpoint was bleeding. Results Of 185 patients, 162 (88%) were men; mean age was 47.8 years. 94 patients were tetraplegic, 91 paraplegic. During a mean (±SD) time of 5.1±2.1 months, VTE was diagnosed in 8 patients. After excluding five patients with VTE detected within 2 days after admission, the probability of developing VTE after 6 months of rehabilitation was 2% (95% CI 0–4.4%). Only high D-Dimer upon admission was associated with risk of VTE (adjusted HR 2.3, 95% CI 1.4–4.1). Of 24 bleedings, 14 (64%) occurred at the heparin injection site. Two patients had major bleeding and five had clinically relevant non major bleeding. Conclusion SCI patients are at risk of VTE and bleeding during rehabilitation. Strategies need to be developed to identify these patients in order to initiate adequate anticoagulation. Direct oral anticoagulants, which have a favourable risk-benefit profile and are convenient, should be explored.

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.