thromboxane-a2 and von-Willebrand-Diseases

Aspirin has a well established role in the prevention of arterial thrombosis. Discussion on the efficacy and safety of aspirin in the treatment and prophylaxis of thrombosis in essential thrombocythemia (ET) has become an important issue. The rationale for its use in ET comes from the observation that arterial thrombosis and platelet-mediated microcirculatory disturbances are the major causes of morbidity and mortality in ET. Experimental data have shown persistently elevated levels of thromboxane A2 (TXA2) in ET patients probably reflecting an enhanced in vivo platelet activation. Increased TXA2 biosynthesis and platelet activation in vivo in ET are selectively suppressed by repeated low doses of aspirin. ET-related symptoms such as erythromelalgia, transient neurologic and ocular disturbances are sensitive to aspirin. However, the benefit of low-dose aspirin is still uncertain in the primary prevention of thrombosis in ET. Furthermore, aspirin may unmask a latent bleeding diathesis frequently present in ET which may result in severe hemorrhagic complications. Thus, aspirin is contraindicated in ET patients with a bleeding history or a very high platelet count (> 1500 x 10(9)/L) leading to the acquisition of von Willebrand factor deficiency. If indicated, aspirin is presently used in the widely accepted low-dose regimen of 100 mg daily. However, an optimal effective dose has not yet been established. To further evaluate the efficacy and safety of aspirin in ET, prospective clinical trials are needed.

Topics: Abortion, Habitual; Aspirin; Cerebrovascular Disorders; Cohort Studies; Contraindications; Erythromelalgia; Female; Fibrinolytic Agents; Forecasting; Hemorrhage; Humans; Incidence; Middle Aged; Myeloproliferative Disorders; Pilot Projects; Platelet Activation; Platelet Aggregation Inhibitors; Pregnancy; Pregnancy Complications, Hematologic; Retrospective Studies; Safety; Thrombocythemia, Essential; Thrombophilia; Thrombosis; Thromboxane A2; Vision Disorders; von Willebrand Diseases

Topics: Blood Coagulation Disorders; Blood Platelet Disorders; Blood Platelets; Heterozygote; Humans; Platelet Aggregation; Syndrome; Thromboxane A2; Thromboxanes; von Willebrand Diseases

Platelet membranes play a key role in all stages of the haemostatic mechanism. Four of these in particular are considered here: adhesion to subendothelium, which involves an interaction between the glycoprotein I complex in the platelet membrane (deficient in the Bernard-Soulier syndrome) and plasma factor VIII; aggregation, involving the membrane glycoprotein IIb/IIIa complex (deficient in thrombasthenia), plasma fibrinogen and divalent cations; platelet factor 3 availability, a function of surface membrane phospholipids; and thromboxane synthesis, a function of the phospholipids of the membrane of the dense tubular system. The glycoprotein I complex also carries binding sites for thrombin and for drug-dependent antibodies, and glycoprotein IIb/IIIa is the site of the P1A1 antigen and of alpha-actinin.

Topics: Blood Platelet Disorders; Blood Platelets; Cell Adhesion; Cell Membrane; Connective Tissue; Hemostasis; Humans; Platelet Aggregation; Platelet Factor 3; Prostaglandin Endoperoxides; Thromboxane A2; von Willebrand Diseases

Incubation at 0 degrees C is known to expose b- N -acetyl-D-glucosamine residues on glycoprotein (GP) Ibalpha inducing receptor clustering and alpha(M)beta(2)-mediated platelet destruction by macrophages. Here we show that incubation at 0/37 degrees C (4 hours at 0 degrees C, followed by 1 hour at 37 degrees C to mimic cold-storage and post-transfusion conditions) triggers a conformational change in the N -terminal flank (NTF, amino acids, aa 1-35) but not in aa 36-282 of GPIbalpha as detected by antibody binding. Addition of the sugar N -acetyl-D-glucosamine (GN) inhibits responses induced by 0/37 degrees C. Incubation at 0 degrees C shifts GPIbalpha from the membrane skeleton to the cytoskeleton. Different GPIbalpha conformations have little effect on VWF/ristocetin-induced aggregation, but arrest of NTF change by GN interferes with agglutination and spreading on a VWF-coated surface under flow. Strikingly, incubation at 0/37 degrees C initiates thromboxane A(2) formation through a von Willebrand factor (VWF)-independent and GPIbalpha-dependent mechanism, as confirmed in VWF- and GPIbalpha-deficient platelets. We conclude that the NTF change induced by 0/37 degrees C incubation reflects clustering of GPIbalpha supports VWF/ristocetin-induced agglutination and spreading and is sufficient to initiate platelet activation in the absence of VWF.

Topics: Acetylglucosamine; Antibodies, Monoclonal; Blood Platelets; Blood Preservation; Cells, Cultured; Cytoskeleton; Humans; Macrophage Activation; Macrophage-1 Antigen; Platelet Activation; Platelet Glycoprotein GPIb-IX Complex; Platelet Transfusion; Protein Binding; Protein Conformation; Protein Transport; Receptor Aggregation; Temperature; Thromboxane A2; von Willebrand Diseases; von Willebrand Factor

Von Willebrand's disease (vWd) and hemophilia are associated with hemorrhagic diathesis and disturbances in platelet aggregation to vessel wall. We compared the time course of thromboxane A2 (TXA2) formation by platelets during spontaneous clotting of blood of patients with von Willebrand syndrome and from patients with hemophilia A or B with that of healthy controls which were matched for sex, age and serum lipid status. In clotting blood of healthy females the TXA2 production rose at 37 degrees C in 60 min up to 228.2 +/- 32.3 ng/ml. In patients with vWd the TXA2 production at 60 min was significantly lower (129.1 +/- 26.7 ng/ml, p < 0/05). In hemophilia type A and B the TXA2 formation after 5-30 min was significantly diminished in comparison to healthy male controls (p < 0.05). From the diminished amount of TXA2 formed during spontaneous clotting of whole blood we conclude that the activation of platelets of patients with von Willebrand syndrome or hemophilia type A and B is diminished as compared to healthy controls possibly caused by reduced formation of thrombin in the blood coagulation process.

Topics: Adolescent; Adult; Aged; Blood Coagulation; Blood Platelets; Female; Hemophilia A; Hemophilia B; Humans; In Vitro Techniques; Kinetics; Male; Middle Aged; Platelet Activation; Thromboxane A2; von Willebrand Diseases