Deficiency of factor Xa-factor Va binding sites on the platelets of a patient with a bleeding disorder

Abstract

Factor V (Va) is essential for binding of factor Xa to the surface of platelets. After thrombin treatment, normal platelets release at least five times more factor Va activity than is required for maximal factor Xa binding. The concentration of factor V activity obtained after thrombin stimulation of 10(7) normal platelets is sufficient to allow half-maximal factor Xa binding to 10(8) platelets (10% normal, 90% factor-V deficient). Therefore, factor Va activity is not limiting in platelet-surface factor Xa binding and prothrombin activation in normal platelets; some other components limit the number of binding sites. We report studies of a patient (M.S.) with a moderate to severe bleeding abnormality whose platelets are deficient in the platelet-surface component required for the factor Va-factor Xa binding. The patient's platelet factor Va activity released after thrombin treatment is normal, but factor Xa binding is 20%-25% of control values at saturation. Abnormal prothrombin consumption in a patient with normal plasma coagulation factors and platelet function suggests a disorder in platelet-surface thrombin formation.

Characterization of a novel bleeding disorder with isolated prolonged bleeding time and deficiency of platelet microvesicle generation

“…In addition to the assembly of prothrombinase complex, PPA also includes the assembly of tenase complex, the activation of factor X and the release of intrinsic platelet procoagulant proteins, including the release of platelet factor V. This latter phenomenon is particularly important also for the expression of PPA (Rosing et al, 1991;Miletich et al, 1979;Ahmad et al, 1989;Walsh & Griffin, 1981;Miletich et al, 1978b), since it can express at least 5 times more FVa activity as necessary for maximal factor Xa binding (Ahmad et al, 1989). Platelet factor V is an essential component in maintaining stable and prolonged haemostasis after trauma and also plays a role in early steps of haemostasis (Osterud et al, 1977;Miletich et al, 1978b).…”

“…Weiss et al (1979) reported a patient with life-long bleeding diathesis in whom reduced PF3 availability and PCT was observed. The disorder, now referred to as Scott syndrome, has since then been characterized as an isolated deficiency of platelet procoagulant activity (PPA), and reduced prothrombinase activity and MV generation were subsequently demonstrated (Sims et al, 1989;Rosing et al, 1985;Miletich et al, 1979;Ahmad et al, 1989). An additional family displaying the same abnormality has been recently reported (Toti et al, 1996).…”

“…In this case, prothrombin consumption test (PCT) and platelet factor 3 availability (PF3a), which reflects PPA, are impaired. Upon activation, these platelets have considerably decreased binding sites for FVa and a marked deficiency in their ability to support both tenase and prothrombinase complex, decreased surface exposure of plasma membrane phosphatidylserine, and impaired capacity to generate microvesicles (MV) (Sims et al, 1989;Rosing et al, 1985;Miletich et al, 1979;Ahmad et al, 1989). Even though three other similar cases have been reported in the literature (Girolami et al, 1973;Sultan et al, 1976;Minkoff et al, 1980), only recently has an additional family been characterized in detail with the demonstration of the recessive inheritance pattern of the disorder (Toti et al, 1996).…”

Impaired Platelet Procoagulant Mechanisms in Patients with Bleeding Disorders

“…The only abnormal screening tests were a markedly shortened serum prothrombin time (13 seconds) that was corrected by addition of either platelets or phospholipid, and an impaired platelet PCA activity in PF3a tests using either the recalcification or Russell viper venom assays (see previous section ''Clinical Tests''). 19 A molecular basis for her PCA defect was provided initially by the observations that her platelets developed less prothrombinase activity when stimulated by thrombin, 22 calcium plus thrombin, 23 or the calcium ionophore A23187. 23 Further studies demonstrated that the prothrombinase defect in Scott platelets was due to an impairment in the binding of factor Xa, a defect not corrected by factor Va. 22 Because the latter is a component of the binding site for factor Xa, these findings suggested impaired factor Va binding as the basis for the platelet PCA defect in Scott syndrome.…”

Impaired redistribution of aminophospholipids with distinctive cell shape change during Ca2+‐induced activation of platelets from a patient with Scott syndrome

“…Scott syndrome, first described by Weiss et al (1979 ), is a rare bleeding disorder associated with an isolated deficiency of platelet procoagulant activity. After activation, these Scott syndrome platelets show decreased exposure of PS ( Rosing et al , 1985 ), impaired capacity to generate plasma membrane vesicles ( Sims et al , 1989 ), and a decreased number of binding sites for factors Va and VIIIa ( Miletich et al , 1979 ; Ahmad et al , 1989 ). In normal platelets the vesicles stemming from the plasma membrane are highly enriched in factor Va‐binding sites ( Sims et al , 1988 ) and are intimately associated with PS exposure and cytoskeleton proteolysis during platelet activation ( Bassé et al , 1994, 1993; Dachary‐Prigent et al , 1995 ).…”