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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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Summary y
Inn this thesis a number of studies are described on the pathogenesis and managementt of coagulation disorders in critical care medicine. The first part of thee thesis (chapters 2-7) consists of studies on the pathogenesis and treatment of disseminatedd intravascular coagulation (DIC), while the second part (chapters
8-11)) addresses the influence of some pharmacological interventions on blood coagulation. .
Chapterr 2 constitutes a review of the pathogenetic mechanisms of disseminated
intravascularr coagulation (DIC) and the currently available treatment strategies. DICC is the result of simultaneously occurring activation of coagulation, depressionn of natural anticoagulant pathways and depression of endogenous fibrinolysis.. The role of plasma- and platelet replacement therapy, anticoagulant strategies,, and antithrombin supplementation is thoroughly discussed. Results of studiess on treatment with protein C concentrate, thrombomodulin, and inhibitors off tissue factor in patients with DIC appear promising.
Chapterr 3 also reviews the pathogenesis of DIC and specifically address the
rolee of natural inhibitors of coagulation like protein C, antithrombin and tissue factorr pathway inhibitor (TFPI). Furthermore, it describes the relations between thee coagulation, fibrinolytic and inflammatory pathways. While cytokines can elicitt a procoagulant response, activated coagulation factors in turn can induce proinflammatoryy responses. Natural inhibitors of coagulation appear also to modulatee inflammatory pathways independent of coagulation.
Inn chapter 4 and chapter 5, studies are presented on the influence of two differentt doses of tissue factor pathway inhibitor (TFPI) on endotoxin-induced coagulant,, fibrinolytic and inflammatory pathways in healthy human subjects. Sixteenn healthy males were studied twice. On one occasion a bolus intravenous injectionn of endotoxin was followed by a bolus injection and 6-hour infusion of TFPI;; on the other occasion the same dose of endotoxin was followed by placebo.. Both experiments were seperated by a 6-weeks interval. Endotoxin injectionn induced activation of coagulation , activation and subsequent inhibitionn of fibrinolysis, and activation of inflammatory pathways. While TFPI 182 2
dose-dependentlyy inhibited the activation of coagulation following endotoxin, it didd not influence fibrinolytic and inflammatory pathways.
Inn chapter 6, we sought to determine whether activation of coagulation per se cann lead to a proinflammatory response in humans in vivo. Six healthy men were studiedd after the injection of 90 ug/kg recombinant factor Vila preceded by eitherr 3.5 ug/kg of the inhibitor of tissue factor NAPc2 or placebo. Administrationn of factor Vila resulted in a marked generation of thrombin that wass partly prevented by the pretreatment with NAPc2. Activation of coagulation resultedd in increased plasma levels of interleukin (IL)-6 and IL-8 without influencee on tumor necrosis factor (TNF). This IL-6 and IL-8 response was absentt when activation of coagulation was inhibited by NAPc2. This study is consistentt with observations in animal and in vitro experiments, also showing thatt coagulation can induce an IL-6 and IL-8 response.
Chapterr 7 describes the in vivo pattern of tissue factor messenger RNA
(TFF mRNA) during human endotoxemia. Ten healthy volunteers were challengedd with endotoxin and total blood RNA was isolated and amplified by nucleicc acid sequence-based amplification (NASBA) followed by meauring TF mRNAA by an electrochemiluminiscence (ECL) assay. TF mRNA expression per monocytee increased 125-fold after administration of endotoxin peaking at 3 to-afterr endotoxin. The activation of coagulation followed TF mRNA expression, withh F1+2 and TAT levels reaching peak values at 4 hr after endotoxin. These findingsfindings add further evidence to the concept that TF plays a critical role in the activationn of coagulation after endotoxin challenge.
Chapterr 8 reviews the effects of different artificial plasma substitutes on blood
coagulation.. The available plasma substitutes, i.e. dextrans, gelatins and hydroxyethyll starches (HES), may all lead to decreased plasma levels of von Willebrandd factor (vWF). Blood coagulation is most impaired by dextran, high molecularr weight HES and by some forms of medium molecular weight HES thatt are slowly degradable. Those forms of medium molecular weight HES that aree rapidly degradable MMW-HES and gelatin-based plasma substitutes appear too have modest vWF lowering effects in healthy volunteers. However, this vWF loweringg effect is compensated for by the acute phase response-induced increase
inn vWF in acutely ill patients. Therefor, rapidly degradable MMW-HES and gelatinss appear not to influence haemostasis and post-operative blood loss in clinicall practice.
Chapterr 9 describes the influence of intravenous administration of 1L
gelatin-basedd plasma substitute on blood coagulation in healthy human subjects. Administrationn of gelatin results in an impairment of haemostasis and thrombin generation.. The defect in primary haemostasis appears to be related to a gelatin-inducedd reduction in vWF, whereas the decreased thrombin generation may be duee to dilution of coagulation factors by the infused fluid. The reduction in vWF mayy be caused by binding of gelatin to the collagen-binding site of vWF, leadingg to increased in vivo clearance of gelatin-vWF complexes.
Inn chapter 10, the effects of the intravenous administration of 1L rapidly degradablee MMW-HES (HES 200/0.5/6) on blood coagulation are presented. Thee infusion of HES resulted in a decrease of vWF that was more than could be explainedd by dilution. This was associated with an impairment of in vitro platelett function as measured by the PFA-100 platelet function analyzer. Thrombinn generation was not altered by the administration of HES.
Chapterr 11 consists of a meta-analysis of all randomised, controlled trials on
treatmentt with either aprotinine, lysine analogues or desmopressin to reduce peri-operativee blood-loss in cardiac surgery. The results of this meta-analysis indicatee that aprotinine and lysine analogues may reduce peri-operative blood losss and reduce mortality, the need for rethoracotomy and the proportion of patientss receiving a blood transfusion. Desmopressin also resulted in a small reductionn in peri-operative blood loss, but was associated with a 2.4 fold increasee in peri-operative myocardial infarction.
