Megakaryocytes endocytose and subsequently modify human factor V in vivo to form the entire pool of a unique platelet-derived cofactor

Abstract

To cite this article: Gould WR, Simioni P, Silveira JR, Tormene D, Kalafatis M, Tracy PB. Megakaryocytes endocytose and subsequently modify human factor V in vivo to form the entire pool of a unique platelet-derived cofactor. J Thromb Haemost 2005; 3: 450-6.See also Hoffman M. One more way that mice and men are different. This issue, pp 448-9.Summary. Factor Va (FVa), derived from plasma or released from stimulated platelets, is the essential cofactor in thrombin production catalyzed by the prothrombinase complex. Plasma-derived factor V (FV) is synthesized in the liver. The source(s) of the platelet-derived cofactor remains in question. We identified a patient homozygous for the FV Leiden mutation, who received a liver transplant from a homozygous wildtype FV donor. Eighteen days post-transplant, phenotypic analysis of the patient's platelet-derived FV indicated that the platelets were acquiring wild-type FV, consistent with the temporal differentiation of megakaryocytes and subsequent platelet production. Nine months post-transplant, the plateletderived FV pool consisted entirely of wild-type FV. Consequently, megakaryocyte endocytosis of plasma-derived FV must account for the entire platelet-derived pool, because blood-borne platelets cannot bind or endocytose FV. Subsequent to this endocytic process, the patient's platelet-derived FV was cleaved to a partially active cofactor, and rendered resistant to phosphorylation catalyzed by a platelet-associated kinase, and hence less susceptible to activated protein C-catalyzed inactivation. These data provide the first in vivo demonstration of an endocytosed plasma protein undergoing intracellular modifications that alter its function. This process results in the sequestration of active FVa within the platelet compartment, poised for immediate action subsequent to release from platelets at a site of injury.

Polyphosphate modulates blood coagulation and fibrinolysis

“…Platelet factor V is more active in supporting clotting than is plasma factor V, and in particular, platelet factor V is activated by factor Xa at an accelerated rate relative to plasma factor V (9). Platelet factor V is structurally modified compared to the plasma protein, which may help explain its enhanced activity (8,10). We propose that an additional factor enhancing the procoagulant function of platelet factor V is the concomitant secretion of polyP upon platelet activation, and that polyP serves as a cofactor to enhance the rate of factor V activation by both thrombin and factor Xa.…”

“…Platelet alpha granules contain factor V, which is secreted upon platelet activation (8). Platelet factor V is more active in supporting clotting than is plasma factor V, and in particular, platelet factor V is activated by factor Xa at an accelerated rate relative to plasma factor V (9).…”

Genotype-phenotype correlation in combined deficiency of factor V and factor VIII

“…The platelet FV pool has been shown to originate from endocytosis of plasma FV in humans 18,32 ; although in mice, platelet FV is derived exclusively from biosynthesis within the megakaryocytes. 33,34 To address the question of whether LMAN1 and MCFD2 mutations exert differential effects between these 2 pools, we measured platelet FV antigen levels in 4 patients with LMAN1 mutations and 3 patients with MCFD2 mutations, as well as 15 healthy controls.…”

An acquired factor V inhibitor associated with defective factor V function, storage and binding to multimerin 1

“…In humans, 80% of FV is found in plasma, and the remainder is stored in platelets, complexed to multimerin 1 (MMRN1), after FV is endocytosed from plasma [2][3][4]. Acquired FV inhibitors, although rare, can cause serious bleeding [5][6][7][8][9].…”