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Pathophysiology and management of coagulation disorders in critical care
medicine
de Jonge, E.
Publication date 2000
Link to publication
Citation for published version (APA):
de Jonge, E. (2000). Pathophysiology and management of coagulation disorders in critical care medicine.
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ChapterChapter 1
Generall Introduction
and d
ChapterChapter 1
Generall introduction
Coagulationn disorders, which may present as either localized or systemic thrombosiss or increased bleeding tendency, are problems physicians frequently encounterr when treating intensive care patients. Bleeding may be caused by surgicall or accidental trauma or by a variety of medical conditions. Although hemorrhagee can result from undue stress on a normal hemostatic system, it also mayy result from or be aggravated by acquired coagulation defects. Some of these coagulationn defects are a direct result of medical treatments like anticoagulants, fibrinolyticc drugs, platelet aggregation inhibitors or artificial plasma substitutes. Acquiredd coagulation disorders also may result from conditions like liver failure,, myeloproliferative disorders or hypothermia. Furthermore, a complex hemorrhagicc syndrome has emerged following open heart surgery with extracorporeall circulation.1 It should be noted that all of these conditions associatedd with increased bleeding tendency are likely to be seen in the intensive caree unit. Paradoxically, not only increased bleeding tendency but also hypercoagulabilityy is a frequent complication of critically ill patients, for examplee leading to the clinical syndrome of disseminated intravascular coagulationn (DIC).2
Influencee of coagulation disorders on patient outcome and costs of treatment t
Coagulationn disorders may have a significant impact on outcome and costs of treatmentt of critically ill patients. Abnormal prothrombin time and thrombocytopeniaa have repeatedly been identified as risk factors for death in intensivee care patients.3'5 The precise mechanism by which abnormal coagulationn and thrombocytopenia are related to a poor prognosis is unknown. It mayy be speculated that the associated bleeding tendency may lead to shock and organn failure or that increased blood transfusion is responsible for the higher mortality.66 Alternatively, prolonged coagulation times and thrombocytopenia couldd be present in patients with the worst prognosis due to consumption by DIC.. Indeed, in patients with sepsis, the severity of DIC has been shown to correlatee with poor outcome.7
Knowledgee of the pathophysiology and treatment options of coagulation disorderss is not only important to improve patient outcome, it also may affect thee economics of intensive care medicine. Treatment of coagulation disorders
frequentlyfrequently consists of replacement therapy with plasma, coagulation factors or 10 0
platelets,, all of which are very expensive. Blood and coagulation products have beenn reported to account for more than 16% of total intensive care costs8 and theree are anecdotal reports of treatments with purified coagulation factors at expensess up to € 700,000 for one patient [Wester JP, personal communication]. Evidencee of the benefit of expensive treatments, e.g. antithrombin replacement therapyy in patients with DIC, is frequently not or only partly present.9
Aimm and outline of this thesis
Too improve patient outcome and decrease the costs of treatment more research onn the pathophysiology and treatment of coagulation disorders is necessary. Aim off this thesis is to contribute to this research. Two major subjects are addressed. First,, we present a series of studies on the role of tissue factor (TF) and its major endogenouss inhibitor tissue factor pathway inhibitor (TFPI) in the pathophysiologyy of disseminated intravascular coagulation (DIC). DIC is a frequentfrequent complication of a variety of disease states like sepsis and trauma and mayy have a major impact on patient outcome.2;? In the second part of this thesis
wee focus on the effects of some treatments that are frequently given to intensive caree patients on blood coagulation and post-operative blood loss.
ChapterChapter 2 and 3 give an overview of the pathophysiology of DIC, the relations
betweenn activation of coagulation and inflammatory responses and the treatment strategiess presently available.
Inn Chapter 4 and 5 we studied the influence of a 6-hr infusion of recombinant TFPII on the endotoxin-induced coagulant, fibrinolytic and inflammatory responsee in healthy human subjects. Two different doses of TFPI were investigatedd in a randomized, placebo-controlled, cross-over study.
ChapterChapter 6 addresses the question whether activation of coagulation can induce a
proinflammatoryy response in humans. Six healthy human volunteers received a boluss injection of recombinant factor Vila (rVIIa) preceded by either a subcutaneouss injection of recombinant NAPc2, a specific inhibitor of tissue factor,, or placebo. The study was designed as a randomized, placebo controlled, cross-overr study. We investigated the effects of rVIIa and rNAPc2 on the activationn of coagulation and on the cytokine response.
ChapterChapter 1
Inn Chapter 7 we studied the expression of TF mRNA on human monocytes duringg endotoxemia and correlated the pattern of TF mRNA expression with in
vivovivo thrombin generation.
ChapterChapter 8 presents an overview of the effects of different artificial plasma
substitutess on blood coagulation and peri-operative blood loss.
Inn Chapter 9 and 10 we studied the influence of two plasma substitutes (i.e. a modifiedd gelatin and a rapidly degradable medium molecular weight hydroxyethyll starch) on primary hemostasis and blood coagulation. Both studies weree randomized, controlled cross-over experiments in healthy human subjects.
ChapterChapter 11 provides a meta-analysis of all randomized, controlled trials that
studiedd the effcets of aprotinin, e-aminocaproic acid, tranexamic acid and desmopressinn on blood loss in cardiac surgery. Only trials were included that reportedd at least one of the following outcomes: mortality, re-thoracotomy, proportionn of patients receiving blood transfusion or peri-operative myocardial infarction. .
Thee results of our studies are summarized in Chapter 12.
References s
1.. Mammen EF, Koets MH, Washington BC, et al. Hemostasis changes during cardiopulmonaryy bypass surgery. Semin Thromb Hemost 1985; 11: 281-292.
2.. Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med 1999; 341: 586-592. .
3.. Vincent JL, de Mendonca A, Cantraine F, et al. Use of the SOFA score to assess the incidencee of organ dysfunction/failure in intensive care units: results of a multicenter, prospectivee study. Working group on "sepsis-related problems" of the European Society off Intensive Care Medicine.. Crit Care Med 1998; 26: 1793-1800.
4.. Le Gall JR, Klar J, Lemeshow S, et al. The Logistic Organ Dysfunction system. A new wayy to assess organ dysfunction in the intensive care unit. ICU Scoring Group. JAMA 1996;; 276: 802-810.
5.. Lemeshow S, Teres D, Klar J, Avrunin JS, Gehlbach SH, Rapoport J. Mortality Probabilityy Models (MPM II) based on an international cohort of intensive care unit patients.. JAMA 1993; 270: 2478-2486.
6.. Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical triall of transfusion requirements in critical care. Transfusion Requirements in Critical Caree Investigators, Canadian Critical Care Trials Group. N Engl J Med 1999; 340: 409-417. .
7.. Fourrier F, Chopin C, Goudemand J, et al. Septic shock, multiple organ failure, and disseminatedd intravascular coagulation. Compared patterns of antithrombin III, protein C, andd protein S deficiencies. Chest 1992; 101: 816-823.
8.. Klepzig H, Winten G, Thierolf C, Kiesling G, Usadel KH, Zeiher AM. [Treatment costs inn a medical intensive care unit: a comparison of 1992 and 1997]. Dtsch Med Wochenschrr 1998; 123: 719-725.
9.. Levi M, de Jonge E, van der Poll T, Ten Cate H. Disseminated intravascular coagulation. State-of-the-art.. Thromb Haemost 1999; 82: 695-705.
