Factor V (Va)1 is a critical component of the prothrombinase complex, increasing the activity of factor Xa by more than 5 orders of magnitude. Factor V also has anticoagulant cofactor activity, acting in concert with protein S and activated protein C in the inactivation of factor VIIIa. In humans, 80% of the circulating pool of factor V is located in the plasma, with the remainder stored in the α granules of platelets in complex with its carrier protein, multimerin. Factor V is released on platelet activation, after which multimerin dissociates. In humans, the major site of factor V synthesis is in the liver. α-Granule factor V appears to derive primarily from uptake of plasma factor V into the α granule during megakaryocytopoiesis,2 although a small amount may derive from synthesis in the megakaryocyte. In contrast, in other species, α-granule factor V appears to derive primarily from synthesis in the megakaryocyte. The complete absence of factor V in mice is lethal, with about half the animals dying in utero and the remaining half dying at birth. In this issue of Blood, back-to-back papers from Sun and colleagues (page 2856) and Yang and colleagues (page 2851) use different approaches with factor V null mice to address the biosynthetic origin of murine platelet factor V and the issue of whether the individual plasma or platelet pools of factor V alone are sufficient to maintain normal hemostasis.
Yang et al address the biosynthetic origin of murine factor V by transplanting factor V null fetal liver cells in lethally irradiated wild-type mice. The resultant mice, after bone marrow compartment recovery, have similar plasma factor V levels but less than 1% platelet factor V, indicating the megakaryocytic origin of platelet α-granule factor V in mice. The mice had no hemorrhagic defect, suggesting that an intact platelet factor V pool is not required for normal hemostasis.
In the companion paper, Sun et al address the biosynthetic origin of factor V in mice by generating transgenic mice in which factor V expression is limited to either the liver or to the megakaryocyte lineage using bacterial artificial chromosome transgene constructs in a factor V null mouse background. With liver-directed expression, factor V was detected in plasma at 6% to 45% of wild-type levels in 6 different transgenic lines, with no detectable platelet factor V. Conversely, in 1 of 3 assessable transgenic mice with confirmed megakaryocyte-directed factor V expression, factor V was restricted to the platelet pool. Expression from either biosynthetic origin was sufficient to rescue the neonatal lethal hemorrhagic phenotype associated with factor V deficiency, with no evidence of spontaneous bleeding in any of the transgenic mice and near-normal tail bleeding times, suggesting that minimal factor V expression in either the plasma or platelet compartment is suffi-cient for normal hemostasis.
These results confirm the megakaryocytic biosynthetic origin of α-granule factor V in mice but raise the intriguing question as to why this is so different from human platelets where α-granule factor V derives from uptake of plasma factor V, presumptively in megakaryocytes. In human and mouse platelets, α-granule fibrinogen derives from plasma fibrinogen and the uptake is functionally dependent on the platelet arganine-glycine-aspartic acid (RGD)–binding integrin, glycoprotein IIb-IIIa (GP IIb-IIIa). It is interesting to speculate that the factor V carrier protein, multimerin, may be involved in the uptake of human factor V. In this regard, human multimerin contains an RGD motif, whereas mouse multimerin does not. It will therefore be of interest to see whether patients with Glanzmann thrombasthenia whose platelets have absent or functionally deficient GP IIb-IIIa have normal levels of multimerin and factor V.
