Impaired Platelet Procoagulant Mechanisms in Patients with Bleeding Disorders

Abstract

Activated platelets contribute to the arrest of bleeding by forming aggregates at sites of vascular injury and by providing a surface for assembling enzyme complexes involved in fibrin formation (platelet procoagulant activity; PCA). Impairment in the latter property of platelets has been observed in some disorders of hemostasis. In Scott syndrome, there is a defect in membrane vesiculation and in the surface expression of phosphatidylserine (PS), the phospholipid that is necessary for assembling the factor VIIIa/IXa (tenase) and factor Va/Xa (prothrombinase) complexes involved in thrombin formation. A family with an isolated defect in vesiculation, but normal prothrombinase activity, has also been reported. In the Quebec platelet disorder, overexpression of the fibrinolytic enzyme urokinase-type plasminogen activator results in the degradation of alpha-granule proteins, including factor V, and a specific abnormality in platelet factor V is the basis for the prothrombinase defect in platelet factor V-New York. The impaired prothrombinase activity in patients with delta-storage pool deficiency may be due to a failure to provide sufficient amounts of secreted adenine nucleotides which, when bound to P2 purinergic receptors, are necessary to maintain the intracellular Ca (2+) levels that are required for the surface expression of PS. Platelet prothrombinase activity and thrombin potential in patients with Glanzmann thrombasthenia (GPIIb-IIIa deficiency) may be decreased, normal, or increased, depending on the experimental conditions, for reasons that are not currently clear. The most consistent platelet PCA abnormality in the Bernard-Soulier syndrome (GPIb-complex deficiency) is an abnormally short serum prothrombin time, associated with a defect in the process by which an interaction between fibrin, von Willebrand factor, and GPIb promotes PCA.

A central role of GPIb-IX in the procoagulant function of platelets that is independent of the 45-kDa GPIbα N-terminal extracellular domain

“…13 A contribution of GPIb-V-IX has long been postulated on the grounds of the decreased prothrombin consumption observed in Bernard-Soulier patients. [14][15][16][17] The evaluation of procoagulant activity in Bernard-Soulier platelets initially led to divergent conclusions. 16,[18][19][20][21][22][23] Whereas decreased thrombin generation was reported by some authors, 18,23 increased thrombin generation 19 and PS exposure was observed by others in activated and resting platelets.…”

Inherited platelet disorders: a clinical approach to diagnosis and management

“…In Scott syndrome, abnormal platelet procoagulant activity can be measured using the serum prothrombin time or with the serum prothrombin consumption index [108,109]. The diagnosis of Scott syndrome can also be made using flow cytometry.…”

Update: Thrombozytopathie/Thrombocytopathy: an update

“…Pathophysiologisch ist bei diesen Sekretionsstörungen insbesondere die Amplifikationsphase der thrombozytären Gerinnung gestört, weiterhin sind plasmatische Störungen durch verminderte Faktorenfreisetzung (z.B. Faktor V) oder gesteigerte Freisetzung von fibrinolytischen Faktoren (Quebec-Thrombozytopathie) beschrieben [4,5,7]. Sekretionsstörungen repräsentieren zahlenmäßig die wahrscheinlich bedeutendste Gruppe thrombozytopathischer Störungen, aufgrund der großen interindividuellen Variabilität und der diagnostischen Limitierungen ist die Prävalenz jedoch weitgehend unklar.…”