Elevated Prothrombin Promotes Venous, but Not Arterial, Thrombosis in Mice

Abstract

Objective Individuals with elevated prothrombin, including those with the prothrombin G20210A mutation, have increased risk of venous thrombosis. Although these individuals do not have increased circulating prothrombotic biomarkers, their plasma demonstrates increased tissue factor-dependent thrombin generation in vitro. The objectives of this study were to determine the pathologic role of elevated prothrombin in venous and arterial thrombosis in vivo, and distinguish thrombogenic mechanisms in these vessels. Approach and results Prothrombin was infused into mice to raise circulating levels. Venous thrombosis was induced by electrolytic stimulus to the femoral vein or inferior vena cava ligation. Arterial thrombosis was induced by electrolytic stimulus or ferric chloride application to the carotid artery. Mice infused with prothrombin demonstrated increased tissue factor-triggered thrombin generation measured ex vivo, but did not have increased circulating prothrombotic biomarkers in the absence of vessel injury. Following venous injury, elevated prothrombin increased thrombin generation and the fibrin accumulation rate and total amount of fibrin ~3-fold, producing extended thrombi with increased mass. However, elevated prothrombin did not accelerate platelet accumulation, increase the fibrin accumulation rate, or shorten the vessel occlusion time following arterial injury. Conclusions These findings reconcile previously discordant findings regarding thrombin generation in hyperprothrombinemic individuals measured ex vivo and in vitro, and show elevated prothrombin promotes venous, but not arterial, thrombosis in vivo.

Factor XIIIa-dependent retention of red blood cells in clots is mediated by fibrin α-chain crosslinking

“…[38][39][40][41][42][43] It is tempting to speculate that these dense networks trap more RBCs, resulting in large, occlusive venous thrombi. Indeed, we previously observed that hyperprothrombinemia leads to the formation of clots with increased network density 44 and that mice with elevated prothrombin produce significantly larger venous thrombi 38 that have higher RBC content (M. M. Aleman and A.S.W., unpublished observations, October 31, 2012). Together, these findings suggest an abnormally high density of crosslinked fibrin promotes venous occlusion by increasing RBC retention in the thrombus, and therefore, thrombus size.…”

Factor XIII activity mediates red blood cell retention in venous thrombi

“…+/+ mice as described (58,59). Briefly, anesthetized mice were subject to sterile laparotomy and exposure of the IVC.…”

A systems approach to hemostasis: 2. Computational analysis of molecular transport in the thrombus microenvironment

“…1 Artificially increasing the plasma prothrombin concentration does not increase total platelet accumulation in an arterial injury model, 18 suggesting that increasing the concentration of thrombin precursor does not lead to increased thrombin production or increased platelet recruitment. Finally, our model predicts that changing the dynamics of transport changes the effective concentration of agonists and thus thrombus architecture.…”