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Perhaps it's not the platelet

Ristocetin uncovers the potential role of von Willebrand factor in impaired platelet aggregation following traumatic brain injury

Kornblith, Lucy Z., MD; Robles, Anamaria J., MD; Conroy, Amanda S.; Hendrickson, Carolyn M., MD, MPH; Calfee, Carolyn S., MD, MAS; Fields, Alexander T., PhD; Callcut, Rachael A., MD, MSPH; Cohen, Mitchell J., MD

Journal of Trauma and Acute Care Surgery: November 2018 - Volume 85 - Issue 5 - p 873–880
doi: 10.1097/TA.0000000000002025

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 that 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 with 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 was 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). Patients with TBI 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 (odds ratio, 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 Prognostic study, level II.

From the Department of Surgery (L.Z.K, A.J.R., A.S.C., A.T.F., R.A.C.,), Zuckerberg San Francisco General Hospital and the University of California, San Francisco, San Francisco, California; Department of Medicine (C.M.H., C.S.C.), San Francisco General Hospital and the University of California, San Francisco, San Francisco, California; and Department of Surgery (M.J.C.), Denver Health Medical Center and the University of Colorado; Denver, Colorado.

Submitted: January 16, 2018, Revised: June 7, 2018, Accepted: June 23, 2018, Published online: July 6, 2018.

M.J.C. is supported by DoD W911QY-15-C-0044 and NIH UM1HL120877. R.A.C. is supported by NIH K01ES026834 and DoD W911QY-15-C-0044. C.S.C. is supported by NIH HL110969. C.M.H. is supported by K23 HL133495.

This study was presented during the Earl G. Young Resident Paper Competition at the 48th annual meeting of the Western Trauma Association; February 25 to March 2, 2018; Whistler, British Columbia, Canada.

Address for reprints: Lucy Z. Kornblith, MD Department of Surgery, Ward 3A, San Francisco General Hospital, 1001 Potrero Ave, San Francisco, CA 94110; email:

© 2018 Lippincott Williams & Wilkins, Inc.