Complement Activation in Trauma Patients Alters Platelet Function

Abstract

Trauma remains the main cause of death for both civilians and those in uniform. Trauma-associated coagulopathy is a complex process involving inflammation, coagulation, and platelet dysfunction. It is unknown whether activation of complement, which occurs invariably in trauma patients, is involved in the expression of trauma-associated coagulopathy. We designed a prospective study in which we enrolled 40 trauma patients and 30 healthy donors upon arrival to the emergency department of BIDMC. Platelets from healthy individuals were incubated with sera from trauma patients and their responsiveness to a thrombin receptor-activating peptide was measured using aggregometry. Complement deposition on platelets from trauma patients was measured by flow cytometry. Normal platelets displayed hypoactivity after incubation with trauma sera even though exposure to trauma sera resulted in increased agonist-induced calcium flux. Depletion of complement from sera further blocked activation of hypoactive platelets. Conversely, complement activation increased aggregation of platelets. Platelets from trauma patients were found to have significantly higher amounts of C3a and C4d on their surface compared with platelets from controls. Depletion of complement (C4d, C3a) reversed the ability of trauma sera to augment agonist-induced calcium flux in donor platelets. Our data indicate that complement enhances platelet aggregation. Despite its complement content, trauma sera render platelets hypoactive and complement depletion further blocks activation of hypoactive platelets. The defect in platelet activation induced by trauma sera is distal to receptor activation since agonist-induced Ca2+ flux is elevated in the presence of trauma sera owing to complement deposition.

Platelets and Fibrinogen: Emerging Complexity in Trauma-Induced Coagulopathy

“…If the defects are not ultimately found to exist on the platelet surface or the plasma environment, it is possible there is an intracellular defect. This could include abnormal cellular metabolism by mitochondrial dysfunction, 35,36,42 altered calcium signaling, 43,44 and cytoskeletal dysfunction. 19,45 Given the numerous changes known to occur in TIC, it seems likely that more than one of these processes are present.…”

Complement component 5 promotes lethal thrombosis

“…In turn, the coagulation cascade is promoted by activation of the complement system 19 20 22 23 . Recently, it has been shown that complement component 3a (C3a) and complement component 4d (C4d) are deposited on the platelet surface in trauma patients and promote platelet aggregation 24 . Thrombotic microangiopathy, including haemolytic uremic syndrome (HUS), is a systemic syndrome that is characterized by platelet aggregation and promotes liver injury 25 .…”

Does Complement-Mediated Hemostatic Disturbance Occur in Traumatic Brain Injury? A Literature Review and Observational Study Protocol

“…The study found that complement activation increased platelet aggregation, and that platelets from trauma patients had significantly higher amounts of C3a and C4d on their surfaces compared to controls. However, despite this increased complement content, trauma sera rendered platelets hypoactive, with the depletion of complement from the sera further blocking the activation of the hypoactive platelets [80]. This finding is surprising, as one would expect the increased complement deposition in trauma platelets to result in increased platelet activity and aggregation.…”