Extensive studies have detailed the molecular regulation of individual components of the hemostatic system, including platelets, coagulation factors, and regulatory proteins. Questions remain, however, about how these elements are integrated at the systems level within a rapidly changing physical environment. To answer some of these questions, we developed a puncture injury model in mouse jugular veins that combines high-resolution, multimodal imaging with functional readouts in vivo. The results reveal striking spatial regulation of platelet activation and fibrin formation that could not be inferred from studies performed ex vivo. As in the microcirculation, where previous studies have been performed, gradients of platelet activation are readily apparent, as is an asymmetrical distribution of fibrin deposition and thrombin activity. Both are oriented from the outer to the inner surface of the damaged vessel wall, with a greater extent of platelet activation and fibrin accumulation on the outside than the inside. Further, we show that the importance of P2Y12signaling in establishing a competent hemostatic plug is related to the size of the injury, thus limiting its contribution to hemostasis to specific physiologic contexts. Taken together, these studies offer insights into the organization of hemostatic plugs, provide a detailed understanding of the adverse bleeding associated with a widely prescribed class of antiplatelet agents, and highlight differences between hemostasis and thrombosis that may suggest alternative therapeutic approaches.

Key Points• Coordinated thromboxane A 2 and ADP/P2Y 12 signaling is required for platelet accumulation in the outer shell region of hemostatic plugs.• Platelet activation within the hemostatic plug core region is predominantly mediated by thrombin.The local microenvironment within an evolving hemostatic plug shapes the distribution of soluble platelet agonists, resulting in a gradient of platelet activation. We previously showed that thrombin activity at a site of vascular injury is spatially restricted, resulting in robust activation of a subpopulation of platelets in the hemostatic plug core. In contrast, adenosine 59-diphosphate (ADP)/P2Y 12 signaling contributes to the accumulation of partially activated, loosely packed platelets in a shell overlying the core. The contribution of the additional platelet agonists thromboxane A 2 (TxA 2 ) and epinephrine to this hierarchical organization was not previously shown. Using a combination of genetic and pharmacologic approaches coupled with real-time intravital imaging, we show that TxA 2 signaling is critical and nonredundant with ADP/P2Y 12 for platelet accumulation in the shell region but not required for full platelet activation in the hemostatic plug core, where thrombin activity is highest. In contrast, epinephrine signaling is dispensable even in the presence of a P2Y 12 antagonist. Finally, dual P2Y 12 and thrombin inhibition does not substantially inhibit hemostatic plug core formation any more than thrombin inhibition alone, providing further evidence that thrombin is the primary driver of platelet activation in this region. Taken together, these studies show for the first time how thrombin, P2Y 12 , and TxA 2 signaling are coordinated during development of a hierarchical organization of hemostatic plugs in vivo and provide novel insights into the impact of dual antiplatelet therapy on hemostasis and thrombosis.

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Background: Avulsion injuries of the lesser trochanter apophysis are relatively uncommon injuries and there have been no peer-reviewed case series dedicated to the evaluation and treatment of this injury. The purpose of this study is to characterize avulsion injuries of the lesser trochanter apophysis, review treatment protocols, and time to return to sport.Methods: We reviewed 30 confirmed avulsion fractures of the lesser trochanter. Clinical data were reviewed to evaluate treatment protocols, duration, and time to return to sport. Radiographs were reviewed to confirm lesser trochanter avulsion and fracture displacement.Results: There were 26 males and 4 females, with the average age at the time of injury being 14.2 years. Treatment modalities consisted of protective weight-bearing, discontinuation of the patient's sport in all cases, and formal physical therapy in 18 cases. The average treatment duration was 30.7 days. The mean follow-up time was 102 days. The radiographic assessment demonstrated an average fracture displacement of 5.1 mm. The average return to sport was 11 weeks.Conclusion: This is the first large case series studying avulsion injuries of the lesser trochanter. We have shown that these athletes can be managed non-surgically and can successfully return back to sport within three months.

Background Guidelines support aspirin thromboprophylaxis for primary total hip and knee arthroplasty (THA and TKA) but supporting evidence has come from high volume centers and the practice remains controversial. Methods We studied 4562 Medicare patients who underwent elective primary THA (1736, 38.1%) or TKA (2826, 61.9%) at 9 diverse hospitals. Thirty-day claims data were combined with data from the health system’s electronic medical records to compare rates of venous thromboembolism (VTE) between patients who received prophylaxis with: (1) aspirin alone (47.3%), (2) a single, potent anticoagulant (29%), (3) antiplatelet agents other than aspirin or multiple anticoagulants (21.5%), or (4) low-dose subcutaneous unfractionated heparin or no anticoagulation (2.2%). Sub-analyses separately evaluating THA, TKA and cases from lower volume hospitals (n = 975) were performed. Results The 30-day VTE incidence was 0.6% (29/4562). VTE rates were equal in patients receiving aspirin and those receiving a single potent anticoagulant (0.5% in both groups). Patients with VTE were significantly older than patients without VTE (mean 76.5 vs. 73.1 years, P = 0.04). VTE rate did not associate with sex or hospital case volume. On bivariate analysis considering age, aspirin did not associate with greater VTE risk compared to a single potent anticoagulant (OR = 2.1, CI = 0.7–6.3) with the numbers available. Odds of VTE were increased with use of subcutaneous heparin or no anticoagulant (OR = 6.4, CI = 1.2–35.6) and with multiple anticoagulants (OR = 3.6, CI = 1.1–11.2). THA and TKA demonstrated similar rates of VTE (0.5% vs. 0.7%, respectively, P = 0.43). Of 975 cases done at lower volume hospitals, 387 received aspirin, none of whom developed VTE. Conclusions This study provides further support for aspirin as an effective form of pharmacological VTE prophylaxis after total joint arthroplasty in the setting of a multi-modal regimen using 30-day outcomes. VTE occurred in 0.7% of primary joint arthroplasties. Aspirin prophylaxis did not associate with greater VTE risk compared to potent anticoagulants in the total population or at lower volume hospitals.