Paul A. Kyrle

von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome.

BACKGROUND Thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome are severe microvascular disorders of platelet clumping with similar signs and symptoms. Unusually large multimers of von Willebrand factor, capable of agglutinating circulating platelets under high shear stress, occur in the two conditions. We investigated the prevalence of von Willebrand factor-cleaving protease deficiency in patients with familial and nonfamilial forms of these disorders. METHODS Plasma samples were obtained from 53 patients with thrombotic thrombocytopenic purpura or hemolytic-uremic syndrome. Von Willebrand factor-cleaving protease was assayed in diluted plasma samples with purified normal von Willebrand factor as the substrate. The extent of the degradation of von Willebrand factor was assessed by electrophoresis in sodium dodecyl sulfate-agarose gels and immunoblotting. To determine whether an inhibitor of von Willebrand factor-cleaving protease was present, we measured the protease activity in normal plasma after incubation with plasma from the patients. RESULTS We examined 30 patients with thrombotic thrombocytopenic purpura and 23 patients with the hemolytic-uremic syndrome. Of 24 patients with nonfamilial thrombotic thrombocytopenic purpura, 20 had severe and 4 had moderate protease deficiency during an acute event. An inhibitor found in 20 of these patients was shown to be IgG in five of five tested plasma samples. Of 13 patients with nonfamilial hemolytic-uremic syndrome, 11 had normal levels of activity of von Willebrand factor-cleaving protease during the acute episode, whereas in 2 patients, the activity was slightly decreased. All 6 patients with familial thrombotic thrombocytopenic purpura lacked von Willebrand factor-cleaving protease activity but had no inhibitor, whereas all 10 patients with familial hemolytic-uremic syndrome had normal protease activity. In vitro proteolytic degradation of von Willebrand factor by the protease was studied in 5 patients with familial and 7 patients with nonfamilial hemolytic-uremic syndrome and was normal in all 12 patients. CONCLUSIONS Nonfamilial thrombotic thrombocytopenic purpura is due to an inhibitor of von Willebrand factor-cleaving protease, whereas the familial form seems to be caused by a constitutional deficiency of the protease. Patients with the hemolyticuremic syndrome do not have a deficiency of von Willebrand factor-cleaving protease or a defect in von Willebrand factor that leads to its resistance to protease.

HIGH PLASMA LEVELS OF FACTOR VIII AND THE RISK OF RECURRENT VENOUS THROMBOEMBOLISM

BACKGROUND A high plasma level of factor VIII is a risk factor for venous thromboembolism. We evaluated the risk of a recurrence of thrombosis after an initial episode of spontaneous venous thromboembolism among patients with high plasma levels of factor VIII. METHODS We studied 360 patients for an average follow-up period of 30 months after a first episode of venous thromboembolism and discontinuation of oral anticoagulants. Patients who had recurrent or secondary venous thromboembolism, a congenital deficiency of an anticoagulant, the lupus anticoagulant, hyperhomocysteinemia, cancer, or a requirement for long-term treatment with antithrombotic drugs or who were pregnant were excluded. The end point was objectively documented, symptomatic recurrent venous thromboembolism. RESULTS Recurrent venous thromboembolism developed in 38 of the 360 patients (10.6 percent). Patients with recurrence had higher mean (+/-SD) plasma levels of factor VIII than those without recurrence (182+/-66 vs. 157+/-54 IU per deciliter, P=0.009). The relative risk of recurrent venous thrombosis was 1.08 (95 percent confidence interval, 1.04 to 1.12; P<0.001) for each increase of 10 IU per deciliter in the plasma level of factor VIII. Among patients with a factor VIII level above the 90th percentile of the values in the study population, the likelihood of recurrence at two years was 37 percent, as compared with a 5 percent likelihood among patients with lower levels (P<0.001). Among patients with plasma factor VIII levels above the 90th percentile, as compared with those with lower levels, the overall relative risk of recurrence was 6.7 (95 percent confidence interval, 3.0 to 14.8) after adjustment for age, sex, the presence or absence of factor V Leiden or the G20210A prothrombin mutation, and the duration of oral anticoagulation. CONCLUSIONS Patients with a high plasma level of factor VIII have an increased risk of recurrent venous thromboembolism.

Deep vein thrombosis

Summary Deep vein thrombosis and its sequelae pulmonary embolism and post-thrombotic syndrome are some of the most common disorders. A thrombus either arises spontaneously or is caused by clinical conditions including surgery, trauma, or prolonged bed rest. In these instances, prophylaxis with low-dose anticoagulation is effective. Diagnosis of deep vein thrombosis relies on imaging techniques such as ultrasonography or venography. Only about 25% of symptomatic patients have a thrombus. Thus, clinical risk assessment and D-dimer measurement are used to rule out deep vein thrombosis. Thrombus progression and embolisation can be prevented by low-molecular-weight heparin followed by vitamin K antagonists. Use of these antagonists for 3–6 months is sufficient for many patients. Those with antithrombin deficiency, the lupus anticoagulant, homozygous or combined defects, or with previous deep vein thrombosis can benefit from indefinite anticoagulation. In cancer patients, low-molecular-weight heparin is more effective than and is at least as safe as vitamin K antagonists. Women seem to have a lower thrombosis risk than men, but pregnancy or use of oral contraceptives or hormone replacement therapy represent important risk factors.

Risk Assessment of Recurrence in Patients With Unprovoked Deep Vein Thrombosis or Pulmonary Embolism. The Vienna Prediction Model

Background— Predicting the risk of recurrent venous thromboembolism (VTE) in an individual patient is often not feasible. We aimed to develop a simple risk assessment model that improves prediction of the recurrence risk. Methods and Results— In a prospective cohort study, 929 patients with a first unprovoked VTE were followed up for a median of 43.3 months after discontinuation of anticoagulation. We excluded patients with a strong thrombophilic defect such as a natural inhibitor deficiency, the lupus anticoagulant, and homozygous or combined defects. A total of 176 patients (18.9%) had recurrent VTE. Preselected clinical and laboratory variables (age, sex, location of VTE, body mass index, factor V Leiden, prothrombin G20210A mutation, D-dimer, and in vitro thrombin generation) were analyzed in a Cox proportional hazards model, and those variables that were significantly associated with recurrence were used to compute risk scores. Male sex (hazard ratio versus female sex 1.90, 95% confidence interval 1.31 to 2.75), proximal deep vein thrombosis (hazard ratio versus distal 2.08, 95% confidence interval 1.16 to 3.74), pulmonary embolism (hazard ratio versus distal thrombosis 2.60, 95% confidence interval 1.49 to 4.53), and elevated levels of D-dimer (hazard ratio per doubling 1.27, 95% confidence interval 1.08 to 1.51) were related to a higher recurrence risk. Using these variables, we developed a nomogram that can be used to calculate risk scores and to estimate the cumulative probability of recurrence in an individual patient. The model was cross validated, and patients were assigned to different risk categories based on their risk score. Recurrence rates corresponded well with the different risk categories. Conclusions— By use of a simple scoring system, the assessment of the recurrence risk in patients with a first unprovoked VTE and without strong thrombophilic defects can be improved.

Tissue factor-positive microparticles : Cellular origin and association with coagulation activation in patients with colorectal cancer

The pathogenesis of hypercoagulability in cancer is not entirely understood. We hypothesized that in cancer patients circulating tissue factor-positive microparticles (TF (+) MPs) are increased and associated with hemostatic system activation. In 20 patients with advanced colorectal cancer and in 20 age- and sex-matched controls, number and cellular origin of TF (+) MPs were determined in plasma by flow cytometry. D-dimer was determined as an indicator of hemostatic system activation. Compared to controls, the median (interquartile range) number of TF (+) MPs was two-fold higher in cancer patients: 25.9 (15.4 - 42.0) x 10 (3) /ml plasma versus 13.1 (11.9 - 19.7) x 10 (3) /ml plasma, p = 0.007. This was mainly due to a higher amount of TF (+) MPs from platelets (13.4 [5.0 - 17.4] x 10 (3) /ml plasma vs. 5.8 [4.5 - 7.5] x 10 (3) /ml plasma, p = 0.017). TF (+) MPs correlated with D-dimer ( ? = 0.48, p = 0.002). High levels of TF (+) MPs in cancer patients and their correlation with D-dimer suggest that TF (+) MPs might be involved in hemostasis activation in cancer patients.

The post-thrombotic syndrome: risk factors and impact on the course of thrombotic disease

Summary.  Background: The post‐thrombotic syndrome (PTS) is a frequent complication of deep vein thrombosis (DVT). Patients with recurrent ipsilateral DVT have an increased risk of PTS; other risk factors are unknown. Objectives: To establish risk factors of PTS and its impact on venous thrombotic disease. Patients: We prospectively followed 406 patients after a first symptomatic DVT for a median of 60 months. Patients with recurrent DVT, a natural inhibitor deficiency, the lupus anticoagulant, cancer, long‐term anticoagulation, an observation time < 18 months and DVT‐recurrence prior PTS‐assessment were excluded. Study outcomes were occurrence of PTS and recurrent symptomatic DVT. Results: PTS was assessed after 44 ± 23 months (mean ± SD) using a clinical classification score. PTS developed in 176 of 406 patients (43.3%). Severe PTS was rare (1.4%). Proximal DVT was the strongest risk factor of PTS [odds ratio (OR) 2.1, 95% confidence interval (CI) 1.3–3.7]. Male gender (OR 1.6, 95% CI 1.0–2.8) and elevated D‐dimer levels (OR 1.9, 95% CI 1.0–3.9) were weaker risk factors. Factor V Leiden, factor II G20210A or high factor VIII did not confer an increased risk of PTS. At 4 years, the cumulative probability of recurrence was 7.4% (95% CI 3.2–11.7) among patients with PTS when compared with 1.6% (95% CI 0–3.5; P < 0.02) among patients without PTS. The risk of recurrence was 2.6‐fold (95% CI 1.2–5.9) increased when PTS was present. Conclusions: Proximal DVT, male gender, and high D‐dimer levels are independently associated with the development of PTS in patients with a first DVT. Patients with PTS have an increased risk of recurrent venous thromboembolism.

Medical conditions increasing the risk of chronic thromboembolic pulmonary hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by organized thromboemboli that obstruct the pulmonary vascular bed. Although CTEPH is a serious complication of acute symptomatic pulmonary embolism in 4% of cases, signs, symptoms and classical risk factors for venous thromboembolism are lacking. The aim of the present study was to identify medical conditions conferring an increased risk of CTEPH. We performed a case-control-study comparing 109 consecutive CTEPH patients to 187 patients with acute pulmonary embolism that was confirmed by a high probability lung scan. Splenectomy (odds ratio=13, 95% CI 2.7-127), ventriculo-atrial (VA-) shunt for the treatment of hydrocephalus (odds ratio=13, 95% CI 2.5-129) and chronic inflammatory disorders, such as osteomyelitis and inflammatory bowel disease (IBD, odds ratio=67, 95% CI 7.9-8832) were associated with an increased risk of CTEPH.

Overweight, Obesity, and the Risk of Recurrent Venous Thromboembolism

BACKGROUND Excess body weight is a risk factor for a first venous thromboembolism. The impact of excess body weight on risk of recurrent venous thrombosis is uncertain. METHODS We studied 1107 patients for an average of 46 months after a first unprovoked venous thromboembolism and withdrawal of anticoagulant therapy. Excluded were pregnant patients, those requiring long-term antithrombotic treatment, and those who had a previous or secondary thrombosis, natural coagulation inhibitor deficiency, lupus anticoagulant, or cancer. Our study end point was symptomatic recurrent venous thromboembolism. RESULTS A total of 168 patients had recurrent venous thromboembolism. Mean (SD) body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) was significantly higher among patients with recurrence than among those without recurrence: 28.5 (6.0) vs 26.9 (5.0) (P = .01). The relationship between excess body weight and recurrence was linear; the adjusted hazard ratio for each 1-point increase in BMI was 1.044 (95% confidence interval [CI], 1.013-1.076) (P < .001). Four years after discontinuation of anticoagulant therapy, the probability of recurrence was 9.3% (95% CI, 6.0%-12.7%) among patients of normal weight and 16.7% (95% CI, 11.0%-22.3%) and 17.5% (95% CI, 13.0%-22.0%) among overweight and obese patients, respectively. Compared with patients of normal weight, the hazard ratio of recurrence adjusted for age, sex, factor V Leiden, prothrombin G20210A mutation, high factor VIII levels, and type of initial venous thromboembolic event was 1.3 (95% CI, 0.9-1.9) (P = .20) among overweight patients and 1.6 (95% CI, 1.1-2.4) (P = .02) among obese individuals. The population attributable risk corresponding to excess body weight was 26.8% (95% CI, 5.3%-48.2%). CONCLUSION Excess body weight is a risk factor of recurrent venous thromboembolism.

Risk assessment for recurrent venous thrombosis

Venous thrombosis is a common disease that frequently recurs. Recurrence can be prevented by anticoagulants, albeit at the cost of bleeding. Thus, assessment of the risk of recurrence is important to balance the risks and benefits of anticoagulation treatment. Many clinical and laboratory risk factors for recurrent venous thrombosis have been established. Nevertheless, prediction of recurrence in an individual patient remains a challenge. Detection of some laboratory markers is associated with only a moderate risk of recurrence, and the relevance of others is not known. Many patients have several risk factors and the effect of combined defects is obscure. Routine screening for these laboratory markers should therefore be abandoned. Risk assessment can be improved by measurement of global markers that encompass the effects of clotting and fibrinolytic disorders. Analysis of preliminary data suggests that risk assessment can also be refined through integration of prothrombotic coagulation changes and clinical risk factors.

Risk of pregnancy-associated recurrent venous thromboembolism in women with a history of venous thrombosis

Summary.  Background: Limited data exist on the risk of pregnancy‐associated venous thromboembolism (VTE) in women with a history of VTE. Objective: To evaluate the risk of recurrent pregnancy‐associated thrombosis in women with previous VTE in a large retrospective cohort study. Patients and methods: One hundred and fifty‐nine women with at least one pregnancy (293 pregnancies in total) after a VTE were included into the study. The patients underwent a standardized interview on their history of thrombosis and pregnancy‐associated complications. Results: Eight recurrent events occurred during 197 pregnancies without thrombosis prophylaxis. The probability of VTE during pregnancy without thrombosis prophylaxis was 6.2% (95% confidence interval 1.6–10.9%). The risk was constant over the whole period of pregnancy. Of the eight women with VTE during pregnancy four had heterozygous FV:R506Q, two in combination with hyperhomocysteinemia. No VTE occurred during 87 pregnancies with thrombosis prophylaxis. In the postpartum period 15 VTEs occurred, two of 83 (2.4%) after pregnancy termination, one of 53 (1.9%) after miscarriage, three of 10 (30%) after stillbirth and nine of 138 (6.5%) after live birth. Conclusions: Without thrombosis prophylaxis the risk for recurrent symptomatic VTE is substantial during the whole period of pregnancy in women with previous VTE. The majority of events occurred after delivery, reflecting the very high risk during the postpartum period. Prospective and comparative trials to ascertain efficacy and safety of prophylactic heparin are urgently needed.