Effect of conjugated estrogens on platelet function and prostacyclin generation in CRF

In a double-blind, randomized, placebo-controlled cross-over study, we investigated in seven patients with chronic renal failure the effect of conjugated estrogens (0.6 mg/kg/day for 5 days) on template bleeding time and on thromboxane A2 (TxA2), beta-thromboglobulin (beta-TG) and prostacyclin (PGI2) concentrations in blood emerging from the template bleeding time incisions. Administration of conjugated estrogens resulted in a significant shortening of the bleeding time in six out of seven patients with a maximum effect 7 and/or 14 days following treatment. Both TxA2 (measured as thromboxane B2, TxB2) and beta-TG release in bleeding time blood were significantly higher following administration of conjugated estrogens as compared to placebo administration. No difference was seen in endothelial PGI2 (measured as 6-keto-prostaglandin F1 alpha) formation when patients were treated with conjugated estrogens as compared to placebo administration over the 28 day observation period. We conclude that in patients with chronic renal failure, infusion of conjugated estrogens results in a significant shortening of the bleeding time together with an increase in platelet reactivity, as indicated by an increase of TxA2 and beta-TG concentration in the microvasculature. No effect was seen on PGI2 production, thereby excluding a major effect on vascular prostaglandin metabolism.     

Hereditary deficiency of antithrombin III, protein C and protein S: prevalence in patients with a history of venous thrombosis and criteria for rational patient screening.

Data in the literature on the prevalence of hereditary deficiency of the natural coagulation inhibitors are conflicting. We conducted a prospective study on 680 consecutive patients with a history of venous thrombosis to determine the prevalence of hereditary deficiency of antithrombin III (AT III), protein C(PC) and protein S(PS) and to establish selection criteria for rational patient screening. The mean age of the patients at investigation was 44.3 +/- 15.4 years, while that at the first thrombotic event was 38.5 +/- 14.8 years. The total prevalence of inhibitor deficiency states was 48/680 (7.1%). 19/680 patients (2.8%) had AT III-deficiency, 17 (2.5%) PC-deficiency, nine (1.3%) PS-deficiency and three (0.4%) a combined deficiency. In 37/48 deficient patients family studies were performed and the hereditary nature was established in 19 cases (2.8% of total patient population, six with AT III-deficiency, eight with PC-deficiency, four with PS-deficiency and one with a combined deficiency). Family studies in these 19 patients revealed 46 additional individual patients with a hereditary deficiency state. A positive family history was found in 15/19 (79%) with a proven hereditary deficiency state, in 153/619 (25%) of non-deficient patients and in 11/29 (38%) of deficient patients without established hereditary nature. The mean age at the first thrombotic event was significantly lower in patients with a hereditary deficiency state (26.8 years) compared with the other two groups (39.0 and 39.7 years, respectively). In all patients with a hereditary deficiency the first thrombotic event occurred before the age of 45 years.(ABSTRACT TRUNCATED AT 250 WORDS)     

Factor VIII concentrates in HIV-1-positive hemophiliacs--is pure better?

39 human immunodeficiency-virus-1 (HIV-1)-positive hemophiliacs who had been regularly treated with non-virus-inactivated intermediate-purity factor VIII concentrates were divided into two groups. Group A consisted of 21 patients with a CD4/CD8 cell ratio of less than 1.0 and group B of 18 patients with a CD4/CD8 cell ratio of greater than 1.0. All patients of group A were switched to a high-purity virus-inactivated factor VIII concentrate, whereas patients of group B continued to receive the intermediate-purity concentrate. There was no significant difference in the average decline of CD4 cells between the two groups during the observation period. 9 patients of group A and 4 patients of group B developed AIDS. 5 patients of group A but 11 patients of group B remained clinically asymptomatic. We conclude that the 15-fold increase in purity of the factor VIII concentrate had no apparent beneficial effect on the CD4 cell counts in this patient group.     

The Factor V (Leiden) test: evaluation of an assay based on dilute Russell Viper Venom Time for the detection of the Factor V Leiden mutation

In the present study a new clotting assay for the detection of an increased resistance of coagulation factor V against degradation by activated protein C (Factor V Leiden mutation, FVLM) was evaluated. The Factor V (Leiden) Test (Gradipore, North Ryde NSW, Australia) is based on the dilute Russell Viper Venom Time (DRVVT), which is prolonged when the plasma sample is preincubated with dilute whole Agkistrodon contortrix contortrix venom for activation of protein C (PC). In contrast to the DRVVT based global assay, Protein C Pathway Test (Gradipore, North Ryde NSW, Australia) this new assay is expected to be more specific for FVLM because of optimized amounts of the venom. The test result is expressed as the ratio between the DRVVT with and without addition of the venom. The following precision values were found: intraassay coefficient of variation (CV): 5.53% (n=20) in the normal range, 4.30% (n=20) in the pathological range; interassay CV: 6.90% (n=10) and 7.64% (n=10), respectively. A normal range (5th to 95th percentile) of 2.12 to 3.08 was calculated from 50 healthy controls. A ratio below 2.12 was found in all samples from patients with FVLM (n=21), in 9 of 12 patients with PC, in 0 of 6 with protein S (PS), and in 0 of 4 with antithrombin (AT) deficiency. There was, however, a good discrimination between carriers of the FVLM (highest ratio 1.44) and patients deficient in PC (lowest ratio 1.59), in particular when samples were prediluted with factor V deficient plasma FVDP (1.16 vs. 1.96, respectively). Predilution of samples with FVDP caused a clear discrimination between controls and patients deficient in PC, PS, AT, and FVLM-positive individuals and also in patients on oral anticoagulant treatment. Our data show that the Factor V (Leiden) Test discriminates well between carriers of the FVLM and healthy controls or patients deficient in PC, PS, and AT. Individuals presenting values between the lower cutoff of controls and the range in which FVLM-positive individuals are found are highly suspicious for protein C deficiency.     

Symptomatic pulmonary embolism and the risk of recurrent venous thromboembolism

BACKGROUND: In patients with a first symptomatic pulmonary embolism (PE), the risk of recurrence is unknown. We therefore investigated the risk of recurrence among patients with spontaneous symptomatic PE and among those with deep vein thrombosis (DVT) without symptoms of PE. METHODS: After discontinuation of secondary thromboprophylaxis for a first venous thromboembolism (VTE), we prospectively observed 436 patients for an average of 30 months. Patients with secondary VTE, natural inhibitor deficiencies, lupus anticoagulant, cancer, long-term antithrombotic therapy, vena cava filters, or pregnancy were excluded. The study outcome was objectively documented recurrent symptomatic VTE. RESULTS: Recurrent VTE was seen among 28 (17.3%) of 162 patients with symptomatic PE and among 26 (9.5%) of 274 patients with DVT without symptoms of PE. Compared with patients with DVT, the relative risk of recurrent VTE among patients with symptomatic PE was 2.2 (95% confidence interval, 1.3-3.7; P =.005). The relative risk was not affected by age, sex, presence of factor V Leiden or prothrombin G20210A, hyperhomocysteinemia, or high factor VIII levels. Compared with patients with DVT without symptoms of PE, patients with symptomatic PE had an adjusted relative risk of PE at recurrence of 4.0 (95% confidence interval, 1.3-12.3; P =.03). CONCLUSION: Patients with a first symptomatic PE not only have a higher risk of recurrent VTE than those with DVT without symptoms of PE, but are also at high risk of symptomatic PE at recurrence.     

The risk of recurrent venous thromboembolism

Venous thromboembolism (VTE) is a chronic rather than acute disease. After withdrawal of secondary thromboprophylaxis, many patients will experience a subsequent episode of thrombosis. Of these patients, approximately 5% will die from pulmonary embolism. The risk of recurrent VTE depends on the number of risk factors and their severity. High-risk patients, i.e. those with a natural coagulation inhibitor deficiency, recurrent thrombosis, active cancer, the lupus anticoagulant or compound clotting defects most probably benefit from indefinite oral anticoagulation. In these patients the risk of bleeding due to anticoagulant treatment seems to be outweighed by the risk of VTE. Patients with hyperhomocysteinemia or high factor (F) VIII plasma levels are also at an increased risk of recurrence. The optimal duration of secondary thromboprophylaxis in these patients is currently under investigation. Patients with the heterozygous F V Leiden mutation or the G20210A mutation in the F II gene do not require extended anticoagulation since their risk of recurrence is similar as in patients without the aforementioned mutations. Patients with VTE secondary to surgery or trauma have a relatively low risk of recurrence. In these patients short-term secondary thromboprophylaxis (6 to 12 weeks) is justified whereas patients with a first episode of spontaneous VTE should be treated with oral anticoagulants for a longer period of time (3 to 6 months).     

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.     

Über die Behandlungserfolge bei der «akuten Pankreatitis» mit intravenös verabreichten Lokalanaestheticis

Ohne Zusammenfassung Mit 4 Textabbildungen.