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Holzheimer RG, Mannick JA, editors. Surgical Treatment: Evidence-Based and Problem-Oriented. Munich: Zuckschwerdt; 2001.

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Surgical Treatment: Evidence-Based and Problem-Oriented.

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Assessment of coagulation in surgical critical care patients

, M.D. and , M.D.

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Abnormalities of coagulation are commonplace in the critically ill surgical patient. The causes of these changes are multifactorial including nutritional, drug interactions, liver dysfunction and underlying disease processes. In particular, infection and inflammation interact with the immune coagulation system to induce a net procoagulant state characterized by increased cellular tissue factor and plasminogen activator inhibitor and reduced fibrinolysis. This article overviews the coagulation cascade, measurement of coagulation and abnormalities observed in the critically ill surgical patient. An understanding of the role of the immune coagulation system in the pathogenesis of disease in these patients may suggest approaches to therapy.


In addition to its traditional role in hemostasis, the initiation of the coagulation cascade serves as a sign of underlying inflammation and contributes to its pathogenesis through its interaction with the immune system. Nowhere is this pleotropism of function more relevant than in the surgical critical care patient, who may have an urgent need for postoperative hemostasis but who may also suffer from a systemic inflammatory response. Assessment of the coagulation cascade in these patients requires a careful evaluation of the patient from both points of view, recognizing that alterations in coagulation parameters will impact on the patient's tendency to bleed, prognosis and immediate therapy. This review briefly summarizes the activation of the coagulation cascade and the tests commonly available for its assessment, discusses coagulation issues relevant to the critical care patient, and suggests an approach for coagulation assessment in the critically ill surgical patient.

The coagulation cascade

For hemostasis to occur, there must be activation of coagulation cascade culminating in fibrin deposition through the action of thrombin on fibrinogen. The chief inducer of coagulation in vivo is Tissue Factor (TF), a 47 kDa glycoprotein. TF binds to factor VIIa, initiating a cascade of protease activation in which zymogen precursors are cleaved to their active form (denoted by the suffix “a”) and resulting in the construction of prothombinase complexes (factors Xa/Va) on cell surfaces which activate thrombin (factor IIa). The only cells capable of expressing TF in the bloodstream are endothelial cells and monocytes. By contrast, many cells outside the bloodstream, including adventitial fibroblasts, constitutively express TF and thus form an “extravascular envelope” capable of initiating coagulation in the event of a disruption in vascular integrity. The recognition of the central role of TF in the coagulation cascade has supplanted the classical notion of the extrinsic (or contact) and intrinsic pathways. Nevertheless, these are useful tools for conceptualizing coagulation tests and are presented in schematic form in figure 1.

Figure 1. Intrinsic and Extrinsic pathway of coagulation.

Figure 1

Intrinsic and Extrinsic pathway of coagulation.

In addition to TF, platelets are critical both for the induction and formation of an adequate blood clot. Platelets act as a phospholipid surface upon which prothrombinase complexes are formed and act as a physical scaffold for the developing clot.

Counter-regulation of coagulation

The net procoagulant response represents a balance between processes initiating coagulation and those which inhibit coagulation or induce degradation of fibrin. There are three major anticoagulant and fibrinolytic mechanisms:


antithrombin III (ATIII), a serine protease inhibitor that covalenty binds and inactivates active coagulation factors;


protein C, which is activated by endothelial thrombomodulin/Xa complexes and degrade factors Va and VIIIa; and


plasmin, a direct fibrinolytic which is generated from its plasminogen precursor by secreted or cell-associated plasminogen activators.

Contribution of the coagulation cascade to the local and systemic inflammatory response

Both the activation and function of the coagulation cascade play key roles in inflammatory responses. For example, the classical extrinsic pathway, induced by bacterial endotoxin and proteinases, acts primarily as part of the kallikrein-kinin axis and activates the C1-esterase-dependent complement cascade (1). The major procoagulant molecule, TF, is induced on monocytes/macrophages and endothelial cells both in vitro and in vivo by a wide variety of inflammatory mediators, including complement, cytokines, and endotoxin (1, 2, 3). Many of the byproducts of coagulation, including factor Xa, thrombin, and fibrinopeptides, can also directly lead to inflammatory cell activation or contribute to leukocyte chemotaxis (1). Independent of coagulation per se, fibrinogen may also contribute to local organ inflammation by acting as a tether between activated endothelial cells and circulating neutrophils (4). The anticoagulant molecules may also influence the inflammatory response. For example, plasmin is known to activate complement, upregulate endothelial cell adhesion molecules and generate chemoattractant fibrin degradation products, while activated protein C has direct anti-inflammatory properties (5). In addition to these direct effects, the microvascular thrombosis associated with activation of the coagulation cascade is clearly a hallmark of the pathological changes associated with organ dysfunction during sepsis.

The surgical critically ill patient: a procoagulant condition

Critically ill surgical patients are often prone to bleeding, with marked alterations in laboratory parameters of coagulation. The cause of these alterations is usually multifactorial including the presence of liver dysfunction, the effect of various drugs on the coagulation process especially platelets, altered nutritional status and an overexuberant systemic activation of the coagulation cascade as part of the systemic inflammatory response syndrome (SIRS). Both experimentally and in humans, sepsis is associated with a net procoagulant state resulting from the induction of the cellular procoagulant response manifested by increased tissue factor and plasminogen activator inhibitor activity, as well as inactivation of the fibrinolytic mechanisms especially plasminogen activator (reviewed in 6). With continued systemic inflammation, there is ongoing activation of the coagulation cascade with consumption of coagulation factors as well as the anticoagulant proteins ATIII and protein C. This consumptive process may lead to disseminated intravascular coagulation (DIC), characterized by the seemingly paradoxical combination of vascular thrombosis and bleeding diathesis. Indeed, inflammation and coagulation appear to be intimately linked: alterations in indices of coagulation become more marked as SIRS progresses, with over 70% of patients in septic shock exhibiting DIC. Further, decreased ATIII and protein C levels are prognostic of poor outcome (reviewed in 1, 3).

Diagnostic tests of coagulation

The common coagulation tests have been summarized in table I. Several points warrant highlighting. Platelets counts greater than 50,000/μl provide adequate hemostasis unless the patient is challenged by stressful situations such as trauma or surgery. Counts < 10,000/μl may lead to spontaneous bleeding, while counts > 500,000 predispose to thrombosis (5). Bleeding times are an excellent test of platelet function, but should be adjusted in reference to the platelet count itself. TAT complexes and D-dimers are direct indices of activation of the coagulation and fibrinolytic cascades respectively, and deserve a more widespread application in clinical scenarios, while protein C and ATII levels are prognostic of outcome and may help direct coagulation factor substitution therapy. Finally, it is noteworthy that all of these tests are sensitive to liver disease, either as a result of decreased factor production (II, VII, IX, X, protein C, ATIII) or decreased clearance (TAT, α2MXIIa, D-dimers, FDP).

Table I. Commonly used coagulation tests.

Table I

Commonly used coagulation tests.

Coagulation issues in critical care patients

Vitamin K

Vitamin K is a necessary cofactor for the synthesis of factors II, VII, IX and X. While it is normally provided in the diet (vitamin K1) or synthesized by small intestinal flora (vitamin K2), it may be deficient in critically ill patients receiving non-supplemented parenteral nutrition and broad-spectrum antibiotics (7). In addition, second generation cephalosporins can act as vitamin K antagonists and thus, Vitamin K supplement should be considered. In liver disease, cholestasis will reduce vitamin K absorption. An elevated PT in the malnourished critically ill patient on antibiotic therapy should prompt consideration of vitamin K supplementation.

Liver disease

Liver disease is a serious confounding issue in interpreting coagulation tests. Not only is the liver the principal source of most coagulation factors, but the reticuloendothelial system clears the products of anticoagulation and fibrin degradation (7). Patients with liver disease prior to admission to the intensive care or those in whom the liver is involved as part of multiple organ dysfunction syndrome are particularly sensitive to abnormalities of the coagulation system resulting from systemic inflammation and should be monitored closely.

Sepsis and the systemic inflammatory response

As noted above, SIRS results in a hypercoagulable state. In the critically ill patient, alterations in the coagulation cascade should be understood within this context. Thus, DIC is not generally an isolated derangement of coagulation, but frequently a measure of a profound inflammatory response. Its treatment should involve not only judicious replacement of consumed coagulation factors but a search for and treatment of an underlying inflammatory focus (1, 7, 8).

Massive transfusions and hypothermia

Massive transfusions may lead to a dilutional thrombocytopenia, provide an excess of citrate anticoagulant, and lead to lowered body temperature. Blood will tend not to clot in the hypothermic patient: body temperature is a crucial concern in the bleeding critically ill patient, particularly in those undergoing massive fluid replacement.

Medications and illnesses which depress platelet function

Many medications can depress platelet function, particularly the nonsteroidal anti-inflammatory agents, but also beta-lactam antibiotics (penicillins, cephalosporins), calcium channel blockers, and nitrates (8). Equally, renal failure and uremia can disturb platelet function. Platelet function can be assessed by bleeding times, and should be considered as a factor in the bleeding ICU patient.

Cardiopulmonary bypass

Special note should be made of patients who have undergone cardiopulmonary bypass. During bypass, there is activation of coagulation, conventionally by contact (intrinsic) pathway activation but also via extrinsic pathway induction of tissue factor on circulating monocytes. PT and PTT values should be monitored post operatively, and do appear to discriminate “bleeders” from “non-bleeders” (9). As a rule such activation is transient, and PT and PTT values return to normal by 12 hours post operatively (9).

Overview: Assessment of coagulation in the critically ill surgical patient


All critically ill surgical patients should be monitored by routine PT, aPTT and platelet counts. In contrast to the non-critical surgical patient, where routine coagulation tests have little value in predicting bleeding, PT does appear to predict the potential for bleeding in ICU patients (10). The value of these standard tests is also illustrated by a recent retrospective study in trauma patients, which found that low platelet counts (< 80,000/μl) alone were useful in predicting outcome (11). In addition, a careful history should be taken outlining abnormal bleeding prior to admission to the ICU, risks for or evidence of liver disease, and the presence of malnutrition possibly contributing to vitamin K deficiency. Medications should always be considered as potentially affecting platelet function, as should renal disease. General disturbances in patient homeostasis will also directly impact on the coagulation system, particularly hypothermia. In all critically ill patients, alterations in parameters of coagulation should be considered as a potential index of a systemic inflammatory response.



The diagnosis of DIC should be made as early as possible, so that coagulation factor replacement and a search for inflammatory foci can be initiated. The diagnosis can generally be made by the combination of clinical context and evidence of increased coagulation (increased TAT complexes, decreased factors I, VIII, VIII) with increased fibrinolysis (increased FDP, D-dimers).


Alterations in parameters of coagulation have clearly been demonstrated to predict prognosis. In particular, decreased ATIII and protein C levels may identify patients with a poor outcome (1). However, there is no data to suggest that these indices are any better than standard APACHE II predictions.

Coagulation factor substitution

Given the association of abnormal coagulation with systemic inflammation, substitution of coagulation products such as ATIII and protein C has been attempted clinically. However, while there are promising results, there is no clear definition of which population of critically ill patient might benefit from such therapy (1, 2).


Critically ill patients differ from the general population in that coagulation disorders are usually acquired and are quite common. Coagulation and inflammation are closely intertwined, and should be considered together. Every effort should be made to diagnose a tendency to bleed early in the course of care of the critically ill surgical patient: a careful assessment of coagulation may reveal current inflammatory problems and avoid future surgical pitfalls.


This work was supported by the Medical Research Council of Canada. Dr. McGilvray is a fellow of the Medical Research Council of Canada.


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Copyright © 2001, W. Zuckschwerdt Verlag GmbH.
Bookshelf ID: NBK6959


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