Parameters influencing FVIII pharmacokinetics in patients with severe and moderate haemophilia A.

In haemophilia A patients factor VIII (FVIII) recovery and half-life can vary substantially. There are parameters known to modulate FVIII pharmacokinetics (PK), but they explain only about 34% of the variability. The aim of this study was to identify new parameters that influence FVIII PK and thus to expand the current knowledge. FVIII PK were determined in 42 haemophilia A patients (37 severe, 5 moderate) without inhibitor. Patients' characteristics and laboratory parameters were evaluated for an association with FVIII PK. We analysed plasma levels of low-density lipoprotein receptor-related protein 1 (LRP1) and protein C (PC) activity, which had been hypothesized to influence FVIII activity. Furthermore, four variations in intron 6 of the LRP1 gene, which had been shown to influence LRP1, were investigated. FVIII half-life differed widely from 6.2 to 20.7 h, with a median of 10.0 h. Patients with blood group O had shorter FVIII half-life compared to patients with non-O blood group (median FVIII half-life 9.0 h vs. 10.4 h, P = 0.018). Age was significantly associated with FVIII half-life (r = 0.32, P = 0.035). Besides age, also VWF antigen (r = 0.52, P < 0.001) and blood group (r = -0.37, P = 0.015) was associated with FVIII half-life. No correlation was found with FVIII- or LRP1-genotype, LRP1 or PC concentrations. Our data showed large differences in FVIII PK between individual patients and revealed age, blood group and VWF levels as important determining factors for FVIII half-life. FVIII genotype or levels of LRP1 or PC had no influence on FVIII PK.

The risk of thromboembolism in asymptomatic patients with protein C and protein S deficiency: a prospective cohort study.

BACKGROUND: Prospective studies on the incidence of thrombosis in asymptomatic individuals with hereditary protein C- or protein S deficiency have not been performed so far. OBJECTIVE: We have carried out a prospective cohort study in 44 asymptomatic protein C- and protein S deficient subjects and in 49 asymptomatic non-deficient relatives (age at study entry > 14 years) of symptomatic deficient patients. METHODS: 20 asymptomatic protein C deficient (median age 20 years) and 24 asymptomatic protein S deficient patients (median age 21.5 years) were prospectively followed and compared with 20 asymptomatic non-deficient relatives (median age 25 years) of protein C- and 29 (median age 27 years) of protein S deficient patients. The total observation period was 118.8 patient years for protein C deficient and 92.8 for protein S deficient patients. Patients were not on anticoagulants except for short duration in case of high risk situations. RESULTS: Eight thromboembolic events (1 pulmonary embolism, 1 deep vein thrombosis + pulmonary embolism, 3 deep vein thrombosis, 1 caval vein thrombosis and 2 superficial vein thrombosis) occurred in 6 deficient patients. The incidence of thromboembolism was 2.5% per patient year for protein C deficient and 3.5% per patient year for protein S deficient patients. 4 events occurred spontaneously, in 2 patients thromboembolic events were triggered by high risk situations (caesarean section, minor trauma). In the controls no thromboembolic events occurred. The probability for thromboembolism was significantly higher in protein C and protein S deficient patients compared to the control group (Wilcoxon test, p = 0.002, log rank test, p = 0.001). One major and 5 minor uneventful surgeries were carried out in the deficient patients using heparin prophylaxis. 1/8 pregnancies was complicated by superficial vein thrombosis during the second trimester despite prophylactic heparin administration. The same pregnancy was complicated by pulmonary embolism 5 weeks after delivery after discontinuation of heparin. CONCLUSIONS: Asymptomatic deficient relatives of symptomatic patients with protein C or protein S deficiency are at an increased risk of thrombosis compared to nondeficient individuals. Prophylactic treatment seems to be highly effective in high risk situations.

Thromboxane A2 and prostacyclin generation in the microvasculature of patients with atherosclerosis--effect of low-dose aspirin.

Generation of thromboxane A2 (TxA2) and prostacyclin (PGI2) at the site of platelet-vessel wall interaction, i.e. in blood emerging from a standardized injury of the microvasculature made to determine skin bleeding time was investigated in 7 patients with atherosclerosis (angiographically verified obstructions of the femoral arteries) and in 7 normal control subjects apparently free of atherosclerotic lesions. Similar amounts of TxA2 (measured as thromboxane B2, TxB2) were generated at the site of plug formation in the patients with peripheral vascular disease (PVD) and in the control subjects. Significantly lower levels of PGI2 (measured as 6-keto-prostaglandin F1 alpha, 6-keto-PGF1 alpha) were found in blood from an injury of the microvasculature in the patients compared with the controls. These data do not suggest a major role of the platelet prostaglandin metabolism in the development of atherosclerosis. However, decreased synthesis of PGI2 by endothelial cells might contribute to the development and/or progression of atherosclerotic lesions. In the patients with PVD, low-dose aspirin (50 mg/day for 7 days) resulted in a greater than 90% inhibition of the TxB2 production at the site of plug formation. Following low-dose aspirin 6-keto-PGF1 alpha levels were below 20 pg/ml (limit of sensitivity of our radioimmunoassay procedure) in the majority of the samples. We therefore conclude that in patients with PVD a decreased synthesis of PGI2 by endothelial cells might contribute to the progression of atherosclerosis. Furthermore, low-dose aspirin treatment results in a similar inhibition of the platelet prostaglandin generation as recently observed in healthy subjects.

Pacing-induced myocardial ischemia does not affect the endothelial release of coagulant and fibrinolytic factors into the coronary circulation.

The present study addresses the potential effects of pacing-induced myocardial ischemia on the secretion of coagulant and fibrinolytic factors within the coronary circulation. In 6 patients undergoing programmed ventricular stimulation with repeated induction of clinical ventricular tachycardia, the coronary release of tissue-type plasminogen activator (t-PA) antigen, plasminogen activator inhibitor (PAI) capacity, von Willebrand factor antigen (WF:Ag), and prostacyclin (6-keto-PGF 1a) was measured. Blood samples were collected simultaneously from the ascending aorta and the coronary sinus at baseline and immediately after the induction of ventricular tachycardia. The occurrence of pacing-induced myocardial ischemia was established by myocardial net lactate production. Myocardial ischemia was induced in every patient by repeated pacing trials. Pacing-induced ischemia did not affect the coronary release of any of the above factors. Consequently, there was no alteration of transcardiac gradients of thrombin-antithrombin complexes and D-dimer. The present results indicate that pacing-induced myocardial ischemia does not affect the release of coagulant and fibrinolytic endothelial factors or prostacyclin into the coronary circulation.

Cerebral sinus thrombosis in a patient with hereditary protein S deficiency: case report and review of the literature.

Hereditary protein S deficiency is an established risk factor for venous thrombosis. The common sites of thrombosis are the deep leg and pelvic veins. We report on a 38-year-old female patient with hereditary protein S deficiency and a previous history of deep leg vein thrombosis, who developed thrombosis of the cerebral straight and superior sagittal sinus while taking oral contraceptives. The diagnosis was established by computerized tomography and carotid angiography. Lysis of the thrombus occurred during heparin treatment. The hereditary nature of protein S deficiency was documented by family studies, since nine additional family members deficient in protein S were identified. Nineteen published cases of cerebral vein thrombosis and a deficiency of either anti-thrombin III, protein C, or protein S were reviewed. Compared with patients without a deficiency state, the clinical features of cerebral vein thrombosis were similar except for an earlier onset and a positive medical history of venous thromboembolic events in a considerable number of patients.

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.