A Review of the Role of Platelets in Vascular Trauma Patients Compared to Patients With Chronic Vascular Disease

Abstract

Normal platelet count is dynamic, reflecting the bone marrow production of about 150 billion platelets daily and circulating survival time of approximately 10 days under normal conditions. Higher platelet counts decrease transfusion requirements and improve survival in the critically injured patient. Transfusing platelets in a 1:1 ratio to red blood cells is associated with decreased multiple organ failure-related mortality in patients with vascular trauma. Unopposed platelet activation and aggregation in chronic vascular patients leads to plaque formation, resulting in acute myocardial infarction, stroke, or death; however, functional platelets are beneficial in the vascular trauma patient. There is a difference in the role that platelets play when comparing chronic vascular patients with the vascular trauma patient. This review discusses the different roles platelets play in the injured vascular patient vs the chronic vascular patient. 

VASCULAR DISEASE MANAGEMENT 2013:10(11):E240-E243

Key words: platelet function, anticoagulation, hemodynamics

Normal platelet count is dynamic, reflecting the bone marrow production of about 150 billion platelets daily and circulating survival time of approximately 10 days under normal conditions.¹ Higher platelet counts decrease transfusion requirements and improve survival in the critically injured patient.² Transfusing platelets in a 1:1 ratio to red blood cells is associated with improved early and late survival, decreased hemorrhagic death, and a concomitant decrease in multiple organ failure-related mortality in patients with vascular trauma.³ Unopposed platelet activation and aggregation in chronic vascular patients leads to plaque formation, resulting in acute myocardial infarction, stroke, or death; however, functional platelets are beneficial in the vascular trauma patient.⁴ There is a difference in the role that platelets play when comparing chronic vascular patients with the vascular trauma patient.   

Pathophysiology

Chronic Vascular Disease

There is an interplay between inflammation and platelet activation in the development and progression of atherosclerosis.⁴ Persistent in vivo platelet activation is observed in hypercholesterolemia and results in pathophysiological implications in the development and progression of atherosclerotic plaques.⁴

Links between thrombosis and inflammation are seen at the molecular and cellular levels in the endothelium. Von Willebrand factor (vWF) and P-selectin, the primary molecules responsible for the initiation of platelet and leukocyte adhesion, are stored in Weibel-Palade bodies. Both vWF and P-selectin mediate platelet interaction with the endothelial surface.^5,6 The release of these molecules occurs during inflammation and induces leukocytes, endothelial cells, and platelets; this response is attenuated in models that lack P-selectin.^5,6 

P-selectin mediates monocytes and neutrophils with circulating activated platelets, which is an interaction that increases monocyte adhesion to endothelial cells, facilitating macrophage accumulation in the vessel wall. Platelets adherent to subendothelial matrix also support leukocyte rolling and adhesion. During endothelial adhesion, activated platelets release proinflammatory cytokines that stimulate the endothelium. Platelets, once recruited to atherosclerotic lesions, release molecules that can promote chemoattraction of leukocytes and stimulate while promoting collagen synthesis. Overall, in the chronic vascular disease patient, platelets can be detrimental, increasing the plaque burden and resulting in devastating complications including stroke or myocardial infarction (MI).^5,6 As a result, therapies such as statins and antiplatelet medications are the mainstay of medical management and have been shown to reduce negative outcomes in patients with vascular disease. 

Vascular Trauma

Platelets serve two purposes after vascular trauma: hemostatic control and inflammation mediation.² During vascular injury, platelets cover the exposed subendothelial matrix and mediate additional platelet and leukocyte recruitment. Immediately following vascular injury, platelets adhere to the damaged endothelium, where they become activated. Activated platelets release prothrombotic factors such as thromboxane A2 and adenosine diphosphate that recruit more platelets to the site of injury, forming a hemostatic plug that seals the injury. Platelets provide the surface for the binding of leukocyte-derived microparticles containing tissue factor for a localized induction of the coagulation cascade. Platelets also release microparticles that mediate leukocyte-leukocyte and leukocyte-endothelial cell interactions. Activated platelets increase leukocyte adhesion to the endothelium and promote leukocyte activation through deposition of chemokines on the endothelium. This enables leukocytes to firmly attach to the vessel wall and finally to transmigrate into the subendothelial tissue.^2,5,6

Data demonstrate a clear survival benefit and overall lower amount of hemorrhage in massively bleeding patients treated aggressively with platelets and fresh frozen plasma.^7-9 However, the role of continued platelet administration or endogenous stimulation of platelets in relation to patient outcome once admitted to the ICU has not been described. Thrombocytopenia (<100,000 platelets/µL) is a strong negative prognostic factor and can exist even with a normal platelet count (PC), as those circulating platelets may be dysfunctional. The prevalence of thrombocytopenia ranges between 20% and 30% and thrombocytopenia is reported overall in 41% of critically injured patients.^1,10 Surgical ICU patients have a higher incidence of severe thrombocytopenia compared with medical ICU patients. 

Higher levels of platelet count have been correlated with a decrease in mortality.² However, most trauma patients present with a platelet count within normal range reportedly falling between 140 and 274.4 x 10³/µL.^11,12 After the initial platelet decrease in a trauma patient, however, in survivors, platelet production increases, sometimes to thrombocytosis levels, by day 7 post injury.^11,12 Furthermore, reactive thrombocytosis is associated with a better survival than predicted by severity of illness score and patients with thrombocytosis were more likely to survive their injury.¹⁴ Nonsurvivors are more likely to develop a consumptive coagulopathy and remain thrombocytopenic. Thrombocytopenia, as a result, in ICU patients has been correlated with poor survival.

Platelet dysfunction is independently linked to detrimental effects in trauma patients both within the first 24-hour period after injury and during ICU stay. Why platelets become dysfunctional and require days to recover has not been confirmed. While further studies are needed to determine why platelets become dysfunctional, there is mounting evidence that such dysfunction can have devastating effects in critically ill patients.

Gando reviewed 136 trauma patients admitted to the ICU who developed systemic inflammatory response syndrome (SIRS) in order to define an early detection system for multiple organ dysfunction syndrome (MODS) to determine the accuracy of disseminated intravascular coagulation (DIC) and sustained SIRS in predicting post-trauma MODS and to find a simple laboratory test for detecting MODS.¹⁴ Platelets were measured on the day of admission and on days 1 through 4 after admission. Platelet counts (80 x 10⁹/µL) on day 1 had a sensitivity of 83.3% and a specificity of 100% for predicting MODS and platelet counts showed significant differences among groups. Disseminated intravascular coagulation, acute respiratory distress syndrome, and MODS were significantly higher in patients with SIRS for 3 or more days compared with those in the other groups, leading to a poor outcome. The authors concluded the likely cause of thrombocytopenia in the group with SIRS for 3 or more days was likely consumptive coagulopathy given that although these patients were given massive platelet transfusions, counts remained low.

Other studies have concluded that postinjury thrombocytopenia is an independent risk factor for MODS, death, and other complications. Following platelet count trends over the first several days post injury can help predict which high-risk patient will develop these adverse outcomes.¹⁵ An increasing proportion of trauma patients are on anticoagulation or antiplatelet therapy. Unlike warfarin, where measuring international normalized ratio can help direct management, measuring platelet inhibition from clopidogrel (Plavix) is not standardized. P2Y12, a point-of-care assay (VerifyNow; Accumetrics), is designed to determine the magnitude of platelet inhibition in trauma patients using clopidogrel. Bansal et al, utilizing this point-of-care assay, reported that a large percentage of their trauma patients had low platelet inhibition despite being on clopidogrel therapy.¹⁶ The study concluded that these patients may be clopidogrel “nonresponders” hence clopidogrel reversal therapies, such as platelet transfusions, would not be beneficial in this group.¹⁶ This is an important point as current strategies to curtail bleeding rely heavily on the administration of platelets in ratios with plasma and red blood cells. Another study by Taylor et al noted that in trauma patients on clopidogrel, platelet transfusion did not restore platelet function; however, these transfusions were efficient for patients taking aspirin.¹⁷ The authors concluded that emergency platelet transfusion may only be indicated in aspirin users who are “responders” and not in all patients under antiplatelet therapy as is currently recommended.^17,18

Few studies have examined the effects of platelets on healing in an attempt to describe their role. Anastomotic healing in rats was examined when exposed to varying levels of platelet-rich plasma (PRP) and PRP concentration was found to play a crucial role in a dose-dependent manner with the PRP action driven by the platelets themselves.¹⁹  

Overall, multiple studies have described a direct correlation between increased platelet function and survival.^1-7 Platelet count itself is not a good indicator of platelet function; platelet assays may take time to complete and hence are not ideal for the actively hemorrhaging patient but resuscitative therapy can be guided at the bedside through the use of thromboelastograms, which provide information on platelet function, thrombin generation, fibrinolysis, and clot strength.^2,20 

Conclusion

In general, platelets are associated with atherosclerosis leading to stroke and myocardial infarction in vascular patients. However, their role cannot be underestimated in the critically ill vascular trauma patient. Aggressive platelet transfusion early in the course of critical care management has been associated with positive outcomes but it remains unclear whether platelet function directly impacts outcome or if declining platelet function is a marker of advanced disease or injury. Further studies are required to delineate this phenomenon. 

Editor’s Note: Disclosure:  The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no disclosures related to the content of this manuscript.

 Manuscript received June 10, 2013; provisional acceptance given June 25, 2013; final version accepted June 26, 2013.  

Address for correspondence: Anahita Dua, MD, University of Texas-Houston, Center for Translational Injury Research, Department of Surgery, MSB 5.030, 6413 Fannin Street, Houston, TX 77034, USA. Email: anahita.dua@uth.tmc.edu

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