Perhaps It’s Not the Platelet: Ristocetin Uncovers the Potential Role of von Willebrand Factor in Impaired Platelet Aggregation Following Traumatic Brain Injury

Background Injury to the blood brain barrier exposes endothelium rich in von Willebrand factor (vWF) which may play a role in altered platelet aggregation following traumatic brain injury (TBI). Ristocetin is an antimicrobial substance which induces vWF-mediated aggregation of platelets. We examined these mechanisms in injured patients by measuring the aggregation response of platelets to stimulating agonists (including ristocetin) via whole blood multiple electrode platelet aggregometry. We hypothesized that patients with TBI have an altered platelet aggregation response to ristocetin stimulation compared to patients without TBI. Methods Blood was collected from 233 trauma patients without thrombocytopenia. Platelet aggregation was assessed using multiple electrode platelet aggregometry (Multiplate®). Platelet aggregation response to stimulating agonists collagen, thrombin receptor-activating peptide-6, adenosine diphosphate, arachidonic acid, and ristocetin were measured. Factor activity was measured. Results Of the 233 patients, 23% had TBI. There were no differences in platelet aggregation responses to any agonists between TBI and non-TBI patients except ristocetin. Platelet aggregation response to ristocetin stimulation was significantly lower in TBI patients (p=0.03). TBI patients also had higher factor VIII activity (215% vs. 156%, p=0.01). In multivariate analysis, there was a significant independent association of impaired platelet aggregation response to ristocetin stimulation with TBI (OR 3.05, p=0.04). Conclusions Given the importance of platelets in hemostasis, understanding the mechanisms of impaired platelet aggregation following injury is critical. The impaired platelet aggregation response to ristocetin stimulation and corresponding increase in factor VIII activity in TBI patients may be secondary to a TBI-induced effect on vWF quantity (due to injury driven consumption of vWF) or vWF function with resultant increase in circulating factor VIII activity (due to impaired carrying capacity of vWF). Given there are multiple known therapies for vWF deficits including Desmopressin, purified and recombinant vWF, and estrogens, these lines of investigation are particularly compelling in patients with TBI and hemorrhage. Level of Evidence IV Study Type Prognostic Submitted: January 16, 2018, Revised: June 7, 2018, Accepted: June 23, 2018, Published online: Month DD, YYYY. Disclosure Information: Dr. Cohen is supported by DoD W911QY-15-C-0044 and NIH UM1HL120877, Dr. Callcut is supported by NIH K01ES026834 and DoD W911QY-15-C-0044, Dr. Calfee is supported by NIH HL110969, Dr. Hendrickson is supported by K23 HL133495. Disclosure outside the scope of this work: none. Meeting presentation: To be presented during the Earl G. Young Resident Paper Competition at the 48th annual meeting of the Western Trauma Association; February 25–March 2, 2018; in Whistler, British Columbia. Corresponding author: Lucy Z Kornblith, MD, Department of Surgery, Ward 3A, San Francisco General Hospital, 1001 Potrero Avenue, San Francisco, CA 94110. Email: lucy.kornblith@ucsf.edu. Phone: (415) 206-6649. Fax: (415) 206-5484 © 2018 Lippincott Williams & Wilkins, Inc.

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