Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomized first human dose trial.

BACKGROUND: Prophylaxis with either intravenous (i.v.) factor VIII (FVIII) or FIX is the gold standard of care for patients with severe hemophilia. A monoclonal antibody (concizumab) targeting tissue factor pathway inhibitor (TFPI) that can be administered subcutaneously (s.c.) has the potential to alter current concepts of prophylaxis in hemophilia. OBJECTIVES: To evaluate the safety and describe the pharmacokinetics and pharmacodynamics of single-dose concizumab in healthy volunteers and patients with hemophilia A or B. METHODS: In this first human dose, phase 1, multicenter, randomized, double-blind, placebo-controlled trial escalating single i.v. (0.5-9000 µg kg(-1) ) or s.c. (50-3000 µg kg(-1) ) doses of concizumab were administered to healthy volunteers (n = 28) and hemophilia patients (n = 24). RESULTS: Concizumab had a favorable safety profile after single i.v. or s.c. administration. There were no serious adverse events and no anti-concizumab antibodies. No clinically relevant changes in platelets, prothrombin time, activated partial thromboplastin time, fibrinogen, or antithrombin were found. A dose-dependent procoagulant effect of concizumab was seen as increased levels of D-dimers and prothrombin fragment 1 + 2. Nonlinear pharmacokinetics of concizumab was observed due to target-mediated clearance. A maximum mean AUC0-∞ of 33 960 h µg mL(-1) and a maximum mean concentration of 247 µg mL(-1) was measured at the highest dose. CONCLUSIONS: Concizumab showed a favorable safety profile after i.v. or s.c. administration and nonlinear pharmacokinetics was observed due to target-mediated clearance. A concentration-dependent procoagulant effect of concizumab was observed, supporting further study into the potential use of s.c. concizumab for hemophilia treatment.

The effect of erythropoietin on platelet function and fibrinolysis in chronic renal failure.

The influence of erythropoietin therapy on platelet function and fibrinolysis was evaluated in 12 anemic hemodialysis patients. Six months of therapy with human erythropoietin (50 to 80 IU/kg initially) raised the hemoglobin level to 10.8 g/dl but did not increase platelet activity in vivo as measured by beta-thromboglobulin or platelet factor 4. There was no change in the platelet aggregation thresholds in vitro for ADP, adrenaline, thrombin or collagen during treatment. Platelet number and volume were also unaffected. Fibrinolytic activity intensified as erythropoietin treatment proceeded, with a fall of euglobulin clot lysis time and rise in the activity of t-PA. PAI-1 levels also showed a downward trend, without reaching significance. Thus erythropoietin treatment in modest doses does not seem to adversely influence the hemostatic system in patients on hemodialysis.

Continuous high-dose factor VIII for the induction of immune tolerance in haemophilia A patients with high responder state: a description of eleven patients treated.

Eleven severely affected haemophilia A patients (aged 6-42 y) with F VIII:C inhibitor (high responders) were treated with high-dose F VIII in order to eliminate the inhibitors. The patients comprise Danish high responder patients treated during the period 1977-1985. In all patients the inhibitors decreased significantly. In six, the inhibitor apparently disappeared (detection limit 0.4 Bethesda Units per ml) (BU/ml), in four patients a low level inhibitor of 0.4-1.4 BU/ml persisted. One patient is still on high-dose schedule. The duration of high-dose treatments ranged from less than one month up to 18 months. In all patients the tendency to spontaneous bleedings vanished when a measurable VIII:C level appeared in the post-infusion sample. The inhibitor suppression has allowed for extensive physical training and rehabilitation orthopaedic surgery. The patients are now able to conduct a normal haemophilic life on self-administered prophylactic doses of F VIII.

Changes in platelet function and blood serotonin level in migraine patients during treatment with femoxetine.

Reports have indicated that patients with migraine have abnormalities in platelet function and in the metabolism of vasoactive monoamines. On the basis of these findings, a number of compounds with a stabilizing effect on the level of free vasoactive monoamines in plasma or with anti-platelet effects have been evaluated with regard to their prophylactic effect in migraine. Femoxetine, a new phenylpiperidine derivative and a potent selective serotonin uptake inhibitor, has been suggested as a useful prophylactic drug in migraine. The present studies were designed to evaluate platelet function and blood serotonin levels in patients with migraine before and during femoxetine treatment. During the treatment of 11 patients with migraine with 300 mg femoxetine daily, blood serotonin decreased from 0.17 +/- 0.06 microgram/ml (mean +/- SD) to 0.06 +/- 0.02 microgram/ml. In 8 patients treated with 300 mg femoxetine daily for 12 weeks, 14C-serotonin uptake into platelets in vitro was reduced significantly. Unlike most drugs used in migraine prophylaxis, femoxetine did not influence platelet aggregation in vitro. The demonstration of a certain prophylactic effect of femoxetine in some patients lends support to theories of a serotonin involvement in the pathogenesis of migraine. It does not, however, exclude the possibility of a platelet abnormality as the primary cause of migraine. A hypothesis combining the 2 theories is put forward.

Changes in platelet function, blood coagulation and fibrinolysis during insulin-induced hypoglycaemia in juvenile diabetics and normal subjects.

Haemostatic parameters were assessed before insulin induced hypoglycaemia and 0, 1 and 2 hr after discontinuation of insulin infusion in 7 non-diabetics, aged 28 (22-31) years (mean and range), and 8 juvenile diabetics, aged 31 (27-35) years, with a mean duration of diabetes of 4 years. The patients were normoglycaemic for at least 10 hr before the study. Platelet aggregation in vitro was induced by lower adenosine diphosphate (ADP) concentrations in the diabetics than in the controls before hypoglycaemia and 0 and 60 min after insulin infusion. Platelet counts decreased significantly in the diabetics after hypoglycaemia, whereas no changes were seen in the control group. The activated partial thromboplastin time (APTT) was reduced in both groups and significantly lower in the diabetics than in the controls 120 min after insulin infusion. Fibrinogen and factor VIII R:Ag increased after insulin infusion; highest values were seen in the diabetics. The euglobulin clot lysis time (ELT) was reduced in both groups during insulin infusion; 120 min after end of insulin infusion ELT was significantly longer in the diabetics than in the control group.

Impaired platelet aggregation and increased bleeding time during general anaesthesia with halothane.

A significant correlation was found between the inhibition produced by 1% halothane with nitrous oxide and oxygen on platelet aggregation in vitro and the increase in bleeding time during anaesthesia with halothane, nitrous oxide and oxygen in 10 patients. It is suggested that halothane in nitrous oxide with oxygen inhibits platelet aggregation in vivo and in vitro. The inhibition is not seen when platelet aggregation is studied in platelet-rich plasma from anaesthetized patients because the agents evaporate during preparation of platelet-rich plasma and during analysis in the aggregometer.

Effect of long-term beta-blockade with alprenolol on platelet function and fibrinolytic activity in patients with coronary heart disease.

In 14 patients with coronary heart disease the effect of long-term treatment (mean 16 months, range 12-33) with alprenolol on platelet function and fibrinolytic activity was studied. While on the beta-blocker and two weeks after gradual withdrawal of it, the patients performed a bicycle-ergometer test and blood samples were obtained before and following exercise. Pre-exercise fibrinolytic activity, assessed by the euglobulin clot lysis time, was 183 +/- 27 min (mean +/- SEM) while on alprenolol as compared to 111 +/- 18 min (p less than 0.01) after its withdrawal. Activation of fibrinolysis following exercise was not significantly influenced by alprenolol. In patients treated with alprenolol, the pre-exercise threshold level of ADP, producing platelet aggregation was 3.3 muM (geometric mean) and 5.1 muM after stopping treatment (p less than or equal to 0.05). In patients receiving the beta-blocker, the ADP- threshold value dropped from 3.3 muM before exercise to 2.3 muM immediately after exercise (not significant). The corresponding values after withdrawal of alprenolol were 5.1 muM and 2.7 muM (p less than or equal to 0.02). Adrenaline - stimulated aggregation was not significantly influenced by alprenolol. Serotonin release from platelets following maximal ADP- and adrenaline stimuli was not significantly changed by exercise in patients on beta-blockade. After stopping treatment, ADP-induced serotonin release was 22 +/- 4.1% before and 15 +/- 4.7% after exercise (p less than 0.02). the corresponding values using the adrenaline stimulus were 29 +/- 5.7% and 17 +/- 4.7% (p less than 0.05). It is suggested that during physical stress alprenolol may protect platelets against aggregatory stimuli.

Effects of halothane on platelet function.

Human platelets in platelet rich plasma (PRP) incubated at 37 degrees C with 0.3-2% halothane for 5-10 min lost the ability to aggregate with ADP, epinephrine and collagen. At the same time uptake and release of 14C-serotonin was inhibited. When halothane supply was removed, platelet functions rapidly returned to normal. However, after high concentrations of halothane, the inhibition of platelet aggregation was irreversible or only partially reversible. The results suggest that halothane anaesthesia produces a transient impairment of platelet function.