Thrombosis in the intensive care unit: protein C and a whole lot more!

Hemostasis is a dynamic process wherein the balance between clot formation and inhibition of coagulation are tightly controlled to stop unwanted bleeding and prevent unwanted thrombosis. Although hemorrhage has long been recognized as a major factor contributing to the morbidity and mortality of critically ill patients, pathologic thrombosis, other than that which occurs in acute coronary syndromes, pulmonary emboli, and postoperative deep venous thrombosis, has only recently received the attention it deserves in this patient population. This may be, in part, attributable to the fact that only recently has medical evaluation been able to identify gene and protein abnormalities that provide insight into the pathophysiology of thrombi formation in those patients who display a thrombophilic phenotype. However, we cannot discount the possibility that this lack of attention is also attributable in part to the fact that thrombosis, especially thrombosis at the microvascular level, is often silent. In contrast to bleeding, the clinician cannot directly see or measure thrombi formation until it has progressed to the point that organ or limb function has been compromised. By that time, the patient’s prognosis is often compromised as well. Over the years, a subset of intensivists and hematologists have put forth the hypothesis that multiorgan failure is a consequence of microvascular thrombosis; consequently, there has been a steady stream of bench and clinical progress in this area. The Margaux conference of 2001 addressed this issue in the context of sepsis/septic shock (1–4). Whereas many trials of novel proteins have failed to show clinical benefit (5, 6), the “high water” mark in this regard came with the publication of the results of the PROWESS and ENHANCE US trials by Barnard et al (7–9). The fact that activated protein C was chosen as a target therapy for microvascular thrombosis in sepsis is not surprising given the large body of laboratory data indicating the central role activated protein C plays in the interaction between inflammation and coagulation (10–12). One of this issue’s contributions is an insightful review of the role the protein C system plays in the regulation of hemostasis. Although recombinant human-activated protein C has been shown to be beneficial in selected patients, the initial enthusiasm after the publication of the PROWESS data has not been universally sustained because of side effects (bleeding), cost, efficacy, and difficulty in identifying appropriate patients who would best benefit from this therapy (13–16). What may have been lost in all of the discussion and controversy surrounding the use of recombinant activated protein C in sepsis is the fact that over the past several years, our knowledge of how hemostasis is regulated has improved and other clinically relevant risk factors for thrombosis have been described. These factors include gene mutations/polymorphisms, abnormalities in the blood levels of specific proteins (too high or too low), and acquired abnormalities (17–23). Although the R506Q mutation in the factor V gene (factor V Leiden) identified by the Dutch group (in Leiden) may be the most widely known of these risk factors, it is only one of several such risk factors. For many of these factors, the strength of the venous thromboembolism risk is marginal or only putative. A listing of some of these risk factors along with a suggested priority for testing in intensive care unit (ICU) patients is shown in the Table 1. There is no consensus regarding the appropriate hematologic workup of a patient who presents with a pathologic thrombus or in whom a pathologic thrombus develops, and “experts” can disagree as to just what an initial evaluation should include when looking for underlying risk factors. In general, it is always prudent to tailor one’s evaluation to the specific clinical picture presented by the patient. However, it is anticipated that a better understanding of the basis for pathologic thrombus formation will translate to better decisions in this regard. Although much has been written concerning the value, or lack thereof, of testing patients who experience an “unprovoked venous thromboembolism, and their relatives” (22–26), even in the presence of consensus guidelines for thrombophilia testing, studies have shown that appropriate patients are frequently not tested whereas others are inappropriately tested for the presence of thrombotic risk factors (27, 28). When confronted with a critically ill patient who manifests a clinically significant thrombotic event or process, testing at a minimum should include those elements that we can “fix,” i.e., the replacement of deficient anticoagulant proteins that will damp-down the coagulation process (e.g., protein C, protein S, antithrombin III). The finding of a genetic risk (e.g., factor V Leiden) will not change one’s initial management but may affect therapy after the resolution of the acute illness (29). Application of the findings and recommendations derived from population studies to patients in the ICU should be attempted with caution. One could argue that any patient in the ICU has an increased risk for thrombosis because that patient is in the ICU. This risk accrues from both the condition that From Pediatric Hematology/Oncology, Stony Brook University Cancer Center, SUNY at Stony Brook, Stony Brook, NY. The author has not disclosed any potential conflicts of interest. For information regarding this article, E-mail: robert.parker@stonybrook.edu Copyright © 2010 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins