It is well documented that alterations in the coagulation system have a significant impact on the morbidity and mortality in sepsis. In addition, data has emerged suggesting that platelets and platelet function play a key role in the sepsis response. The goal of this talk is to provide new insight into the important role platelets play in the septic and inflammatory response.
Platelets are unique in many aspects. They are the smallest blood cells in the body and they have no nucleus. Platelet production occurs through the development of megakaryocytes and then a subsequent endomitotic process. This fragmentation of megakaryocytes occurs secondary to shear forces of circulating blood. Thrombopoietin in a hormone synthesized in numerous organs and released by several cells types. Although thrombopoietin is the primary hormone controlling platelet development, numerous other cytokines and hormones are also involved, including interleukins 3, 6 and 11. The elimination of thrombopoietin is accomplished by circulating platelets. Therefore, as the number of circulating platelets decrease, thrombopoietin levels in the blood increase. The lifespan of platelets in quite short - the average platelet only survives an average of 10 days, and younger platelets have superior functional abilities.
Platelet function has been divided into 4 phases: activation, adhesion, aggregation, and secretion. During these phases numerous substances are released which have subsequent effects on inflammation, vascular tone, endothelial membrane integrity/stabilization, and stimulation of the coagulation cascade.
Systemic effects: Another important function of platelets is the regulation of vascular tone. Platelets secrete numerous substances responsible for both vasodilation as well as vasoconstriction. The platelet-induced changes in vascular tone may play a role in progressive organ dysfunction in the critically ill patient. However, platelets also play a pivotal role in stabilizing endothelial membranes and attenuating tissue injury related to ischemia-reperfusion.
The interactions between platelets and white blood cells are of paramount importance in the inflammatory response. Platelets are capable of activating leukocytes and macrophages in multiple ways, including direct cell-to-cell interactions and though the release of various substances such as cytokines.
Platelet Function in Sepsis - Too Much or Too Little?
Experimental work: Experimental studies evaluating the effects of bacteria and bacterial products on platelet function have yielded extremely conflicting results. The effects seem to vary depending on numerous factors, including the species studied, the study design, the severity and pathogenesis of the septic insult, and the timing of platelet function analysis as it relates to the septic insult. In numerous animal models utilizing rats and rabbits, lipolysaccharide was shown to increase platelet aggregation. However, in another study utilizing a rat model, endotoxin decreased the platelet response to both ADP and collagen. Interestingly, this decreased responsiveness only occurred in the presence of plasma, which led the authors to suggest that the effects were not due to the endotoxin itself, but rather other mediators present in plasma. In vitro human studies have documented decreased platelet responsiveness secondary to both gram-positive and gram-negative bacteria. Experiments have also shown that incubation of human plasma with endotoxin did not cause platelet aggregation, but incubation of whole blood with endotoxin does cause platelet aggregation, again suggesting the role of another mediator present in plasma that is affecting platelet aggregation.
Clinical studies: Clinical studies in critically ill human patients have investigated both platelet function as well as platelet numbers in critical illness. Although determination of the particular mechanisms and consequences of changes in platelet function and numbers will require further studies, it is clear that platelets play an integral role in the septic and inflammatory response. Similar to the experimental studies, clinical trials have also yielded somewhat conflicting results. In a study of trauma patients, platelet aggregation was initially increased. However, in the patients that developed sepsis, platelet aggregation decreased during the course of hospitalization. Similarly, in a study of 34 patients with severe sepsis, decreased platelet aggregation was documented by aggregometry. The decreased aggregation in these patients was significantly different when compared to healthy control subjects. Utilizing flow cytometry, the authors were able to determine that the number of membrane receptors was unchanged, but the receptors involved in the activation of GP IIb/IIIa were abnormal. The authors theorized that the decreased aggregation in these cases was due to an abnormality within the platelet, but further studies are needed to fully elucidate this abnormality.
In contrast to the previous studies that found decreased platelet function in sepsis, a study looking at 41 patients admitted to a medical ICU found increased activation and adhesiveness of platelets obtained from septic patients. In addition, plasma taken from septic patients was then introduced into a culture medium containing normal platelets. The addition of the plasma from the septic patients resulted in an increase in both the adhesiveness and aggregation of the normal platelets, again suggesting the role of another mediator present in plasma. Increased platelet activation was also documented in another study evaluating global coagulation in sepsis. This increase in platelet activation occurred irrespective of the causative microbial agent.
After recovery from a significant inflammatory event, thrombocytosis occurs and some authors suggest this is a late part of the acute phase response. The reason for this classification is the fact that this rise in platelet numbers is cytokine mediated. Numerous studies in human medicine have documented the presence of thrombocytopenia in critically ill patients and both the initial platelet count as well as the lack of an increase in platelet count has been related to outcome. More recent studies have further investigated the time course of platelet counts in critically ill patients as well as the association between thrombocytopenia, prognosis, and outcome.
The etiology of thrombocytopenia in these patients is clearly multifactorial. Numerous etiologies have been proposed, including platelet destruction (possibly mediated by increased concentrations of macrophage colony-stimulating factor, drug effects), decreased platelet production, hemodilution, ongoing platelet consumption (disseminated intravascular coagulation) and abnormal sequestration. In a prospective study of 329 patients admitted to a medical intensive care unit, thrombocytopenia was present in 41.3% of patients (platelet count < 150 x 109/L). Thrombocytopenic patients had a significantly higher MODS, SAPS, and APACHE II scores at admission, significantly longer ICU hospitalization, and significantly higher mortality. In addition, patients that experienced a decrease of ≥ 50% of the admission platelet count had a significantly higher mortality. In a logistic regression analysis, the presence of thrombocytopenia had more explanatory power than any of the admission disease severity scores. To further investigate thrombocytopenia in critically ill patients, a prospective study of 1415 patients in a surgical ICU not only confirmed the presence of thrombocytopenia in critically ill patients, it also documented an increased mortality in patients that had a decreased or absent rise in platelet count after the initial decrease. In an attempt to further describe the time course of changes in platelet counts in the critically ill and the relation to survival, 1449 critically ill patients from 40 different ICUs were evaluated. The mean platelet count was significantly higher in survivors throughout the study. In both survivors and non-survivors, the platelet counts decreased during the first days, reaching a nadir at day 4. In survivors, the platelet count returned to the admission value by the end of the week and then continued to increase to become significantly higher than the admission platelet count by day 9. In the non-survivors, the platelet count also returned to the admission value by the end of the week, but the platelet counts in these patients did not continue to rise. Therefore, patients who did not have a relative increase in platelet count on day 14 had a significantly increased mortality rate.
These studies document that in human critical care patients, a decreased platelet count or a precipitous drop in platelet numbers is a poor prognostic indicator - particularly in patients who do not respond with a subsequent improvement in their platelet count.
Platelet inhibition? It has been suggested that increased platelet activation, adhesiveness, aggregation and secretion in sepsis may contribute to organ dysfunction, impairment of microvascular flow and triggering of the coagulation system. Platelet activation plays a central role in coagulation, and may also contribute to endothelial disruption and injury. It is clear that dysfunction of both the vascular endothelium and the coagulation system occurs in septic patients. What is not clear is whether these are 2 independent processes, or whether one is responsible for the other.
It is clear that platelets have an integral role in the systemic inflammation that accompanies sepsis. In addition, the relationship between platelet activation and the coagulation system illustrates the diverse effects platelets can have in disease states. The relationship between mortality and platelet counts in critically ill human patients is well documented. Further studies to investigate the relationship between platelet parameters and outcome, as well as the potential use of platelet inhibitors in sepsis are warranted.
References are available upon request.