Traumatic brain injury-associated coagulopathy

Abstract

Traumatic injury is a common cause of coagulopathy, primarily due to blood loss and hemodilution secondary to fluid resuscitation. Traumatic injury-associated coagulopathy often follows a course of transition from hyper- to hypocoagulable state exemplified in disseminated intravascular coagulation. The incidence of coagulopathy is significantly higher in patients with traumatic brain injury (TBI), especially those with penetrating trauma compared to injury to the trunk and limbs. This occurs despite the fact that patients with isolated TBI bleed less and receive restricted volume load of fluids. TBI-associated coagulopathy is extensively documented to associate with poor clinical outcomes, but its pathophysiology remains poorly understood. Studies in the past have shown that brain tissue is highly enriched in key procoagulant molecules. This review focuses on the biochemical and cellular characteristics of these molecules and pathways that could make brain uniquely procoagulant and prone to coagulopathy. Understanding this unique procoagulant environment will help to identify new therapeutic targets that could reverse a state of coagulopathy with minimal impacts on hemostasis, a critical requirement for neurosurgical treatments of TBI.

Figures

FIG. 1.

Schematic of hemostasis and coagulation. Hemostasis is initiated by an interaction between von Willebrand factor (VWF) in the subendothelium and the GP Ib-IX-V complex on platelets that slows down the movement of platelets to engage other ligand-receptor interactions with slower on-rates. Platelets are rapidly activated and firmly adhere to the subendothelium through an interaction between collagen matrix and GP VI and the integrin α2β1. Activated platelets aggregate by fibrinogen crosslinking the integrin αIIbβ3. They also provide a phosphatidylserine (PS)-rich surface on which tissue factor forms a complex with coagulation factor VIIa to initiate the extrinsic pathway of coagulation. Thrombin generated through this pathway cleaves fibrinogen to fibrin that forms laterally associated fibrils to stabilize platelet aggregation. Several procoagulant molecules are enriched in the brain and key steps of hemostasis and coagulation are uniquely enhanced in TBI.

FIG. 2.

Synthesis and multimerization of von Willebrand factor (VWF). VWF is initially synthesized as a monomeric glycoprotein that then forms a C-terminal disulfide-linked homodimer. VWF dimers subsequently form multimers through N-terminal disulfide linkages after proteolytic removal of a large 714 amino acid propeptide. Once secreted, ULVWF (ultra-large von Willebrand factor) multimers are subjected to cleavage at the A2 domain by ADAMTS-13. The cleaved VWF multimers have variable sizes, with the largest multimers being hemostatically most active.

FIG. 3.

Lipid microdomains in cell membrane. These microdomains (rafts) are cholesterol- and sphingolipid-rich compartmentalized regions of cell membrane where signaling molecules, receptors, and phosphatidylserine (PS) are selectively concentrated. These domains are orderly and tightly packed and can float freely in the membrane bilayer. Upon activation, platelets generate microparticles that are enriched in these lipid microdomains with concentrated adhesion receptors and PS. The latter could carry coagulation factors. Other cells may also produce microparticles that are PS-rich and contain signature molecules from the parental cells that deliver microparticles to target cells.