Intern Emerg Med DOI 10.1007/s11739-014-1176-2
IM - REVIEW
Hemostatic abnormalities in critically ill patients Marcel Levi • Suthesh Sivapalaratnam
Received: 22 November 2014 / Accepted: 9 December 2014 Ó SIMI 2014
Abstract Hemostatic abnormalities frequently occur in critically ill patients and may vary from prolonged global clotting tests or isolated thrombocytopenia, to composite defects, such as consumption coagulopathies. There are many reasons for a disturbed coagulation in intensive care patients, and each of these underlying syndromes may require specific therapeutic intervention. Hence, an adequate differential diagnosis and initiation of proper (supportive) therapeutic strategies are critical to decrease morbidity and mortality in critically ill patients with hemostatic abnormalities. Keywords Coagulation Platelets Intensive care Disseminated intravascular coagulation Thrombotic microangiopathy Heparin-induced thrombocytopenia Bleeding Antifibrinolytic agents Recombinant factor VIIa
Introduction Hemostatic abnormalities in critically ill patients require swift and appropriate identification of their primary cause, since many of these disorders may require dissimilar therapeutic management strategies that may have a major impact on outcome [1–3]. A prolongation of global clotting M. Levi S. Sivapalaratnam Department of Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands M. Levi (&) Department of Vascular Medicine/Internal Medicine, Academic Medical Centre F-4, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands e-mail: [email protected]
times [such as the prothrombin time (PT) or the activated partial thromboplastin time (aPTT)], occurs in 14–28 % of critically ill patients [3]. The incidence of a low platelet count (platelet count \150 9 109/l), in an intensive care population is 35–44 % [4]. An even lower platelet count of \100 9 109/l is observed in another 30–50 % of patients (Fig. 1). The low platelet count is likely to be the result of increased platelet turnover due to thrombin generation, and subsequent platelet activation and enhanced platelet-vessel wall interaction [5]. Intensive care unit (ICU) patients with hemostatic defects have a 4 to 5-fold higher risk for bleeding compared to patients with normal coagulation [4]. The risk of intracranial hemorrhage in critically ill patients during ICU admission is relatively low (0.3–0.5 %), but almost 90 % of patients with this complication have platelet counts below 100 9 109/l. Moreover, a decrease in platelet count may indicate ongoing coagulation activation, which plays a role in microvascular thrombosis and subsequent multiple organ failure. Rapid identification of these patients is important to provide adequate supportive therapeutic strategies [6, 7]. Irrespective of the cause, a low platelet count is an independent predictor of ICU mortality in multivariate analyses with an odds ratio of 1.9–4.2 in various studies (Fig. 1) [4, 8]. Other coagulation assay abnormalities regularly observed in critically ill patients encompass increased fibrin degradation products and low concentrations of physiological coagulation inhibitors. Fibrin split products, such as D-dimer, are detectable in about 40 % in consecutive series of ICU patients, in 80 % of trauma patients, and in virtually all patients with severe sepsis [9, 10]. Reduced levels of coagulation inhibitors, such as antithrombin and protein C, are observed in 40–60 % of trauma patients and 90 % of sepsis patients [10].
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Intern Emerg Med Table 1 Causes of prolongation of global coagulation times Test result
Cause
PT prolonged, aPTT normal
Factor VII deficiency Mild vitamin K deficiency Mild liver insufficiency Low doses of vitamin K antagonists
PT normal, aPTT prolonged
Factor VIII, IX, or XI deficiency Use of unfractionated heparin Inhibiting antibody and/or anti-phospholipid antibody Factor XII or prekallikrein deficiency (no relevance for in vivo coagulation)
Fig. 1 Distribution of nadir platelet count (black bars) and survival (striped bars) in a pooled analysis of four clinical studies of consecutive groups of patients admitted to the ICU [1, 3, 4, 6]
Both PT and aPTT prolonged
Factor X, V, II or fibrinogen deficiency Severe vitamin K deficiency Use of vitamin K antagonists
In recent years, comprehensive point of care diagnostic techniques to assess the coagulation status have become widely used. Thrombelastography (TEG) is a method that was developed decades ago, and provides an overall picture of ex vivo coagulation. Modern techniques, such as rotational thrombelastography (ROTEM), enable bedside performance of this test, and it is frequently used in acute care settings [11]. The theoretical advantage of TEG over conventional coagulation assays is that it provides an idea of platelet function as well as fibrinolytic activity. Hyperand hypocoagulability as demonstrated with TEG correlate with clinically relevant morbidity and mortality in several studies [12, 13], although its superiority over conventional tests has not been established unequivocally [14].
Causes of prolonged global coagulation times Global coagulation tests, such as the prothrombin time (PT) and the activated partial thromboplastin time (aPTT), do not reflect in vivo hemostasis very well. However, these tests are useful, and there is a rapid screening method to assess the concentration of one or at times multiple coagulation factors for which each or both tests are sensitive (Table 1) [15]. In general, global clotting tests will be abnormal when the level of coagulation factors are below 50 %. This is pertinent since the levels of clotting factors, which are required for adequate coagulation, are somewhere between 25 and 50 % [16]. Abnormal global coagulation assays may be caused by a deficiency of one or more coagulation factors. In addition, but less frequently, the occurrence of an inhibiting antibody, which can have major in vivo relevance (such as in acquired hemophilia), but can also produce a clinically insignificant laboratory phenomenon, should be taken into account. The presence of antiphospholipid antibodies may
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Global clotting factor deficiency Synthesis: liver failure Loss: massive bleeding Consumption: DIC
cause a prolongation of the aPTT, and can be associated with a low platelet count as well. Paradoxically, these antibodies may enhance the risk of thrombosis dramatically. The presence of an inhibiting antibody can be confirmed by a simple mixing experiment. As a general rule, if a prolongation of a global coagulation test cannot be corrected by mixing 50 % of patient plasma with 50 % of normal plasma, an inhibiting antibody is likely to be present. In the vast majority of critically ill patients, deficiencies of coagulation factors are acquired. In most cases, deficiencies in coagulation factors may be caused by impaired synthesis, massive loss, or increased turnover (consumption). Impaired synthesis is mostly due to liver failure or vitamin K deficiency. A vitamin K deficit may be due to poor nutrition in combination with interventions (e.g. antibiotics), which influence intestinal flora and thereby microbial vitamin K synthesis. The prothrombin time is most sensitive to both conditions, since this test is highly dependent on the plasma levels of factor VII (a vitamin K-dependent coagulation factor with the shortest half-life of the clotting factors). Liver failure may be differentiated from vitamin K deficiency by measuring factor V, which is not vitamin K dependent. In fact, factor V levels are crucial in various scoring systems for severe acute liver failure [17]. Uncompensated losses of coagulation factors can occur after massive hemorrhage in patients undergoing major surgery or in trauma patients. Frequently in these situations, a coagulopathy is specifically encountered in patients with major blood loss and rapid intravascular volume replacement with crystalloids, colloids and red
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cells without simultaneous administration of coagulation factors in plasma preparations. The resulting dilutional form of coagulation defect may persist and aggravate the bleeding condition. In addition, transfusion in these patients may lead to systemic activation of inflammation, and may exacerbate the coagulation derangement [18]. In hypothermic and acidotic patients (e.g. in case of trauma), coagulation assays may underestimate the function of coagulation in vivo, since in the laboratory test-tube assays are standardized, performed in the presence of acidosisdisguising buffers, and performed at 37 °C to mimic normal body temperature. Consumption of coagulation factors may occur in the framework of disseminated intravascular coagulation (see further). In complex cases, different causes for an abnormal global coagulation time may be present at the same time, and the cause may also change over time. For example, multi-trauma patients can initially present with a loss of coagulation factors due to severe hemorrhage that later can evolve to a consumption coagulopathy due to DIC as a result of a systemic inflammatory response. Further derangement of coagulation can subsequently develop from trauma-induced liver injury and acute hepatic failure associated with impaired coagulation factor synthesis. Various anticoagulant agents will also prolong global coagulation times. Unfractionated heparin prolongs the aPTT, but confusingly low molecular weight heparins do not, (or only very modestly). Vitamin K antagonists cause low levels of vitamin K dependent coagulation factors, resulting in an initial prolongation of the PT followed by prolongation of both the PT and aPTT.
Table 2 Differential diagnosis of thrombocytopenia in the ICU
Differential diagnosis of thrombocytopenia
Seven major causes of thrombocytopenia (platelet count\150 9 109/ l) are listed. Relative incidences are based on two studies in consecutive ICU patients [1, 6]. Patients with hematological malignancies were excluded
There are many reasons for a low platelet count in ICU patients. Table 2 summarizes the most common diagnoses. Sepsis is clearly associated with thrombocytopenia in critically ill patients, and the severity of sepsis correlates with the reduction in platelet count [5, 19]. The principal factors that contribute to thrombocytopenia in patients with sepsis are: impaired platelet production, increased consumption or destruction, or sequestration of platelets in the spleen or along the endothelial surface [20, 21]. Decreased production of platelets from the bone marrow may seem inconsistent with the high levels of platelet productionstimulating pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-a and interleukin (IL)-6, and high concentration of circulating thrombopoietin in septic patients. These growth factors and cytokines should theoretically promote megakaryopoiesis in the bone marrow [22]. However, in a large number of patients with sepsis, marked hemophagocytosis may occur. This pathologic
Differential diagnosis
Relative incidence (%)
Additional diagnostic clues
Sepsis
52.4
Positive (blood) cultures, positive sepsis criteria, hematophagocytosis in bone marrow aspirate
DICa
25.3
Prolonged aPTT and PT, increased fibrin split products, low levels of physiological anticoagulant factors (antithrombin, protein C)
Massive blood loss
7.5
Major bleeding, low hemoglobin, prolonged aPTT and PT
Thrombotic microangiopathy
0.7
Schistocytes in blood smear, Coombs-negative hemolysis, fever, neurologic symptoms, renal insufficiency
Heparin-induced thrombocytopenia
1.2
Use of heparin, venous or arterial thrombosis, positive HIT test (usually ELISA for heparin– platelet factor IV antibodies), rebound of platelets after cessation of heparin
Immune thrombocytopenia
3.4
Anti-platelet antibodies, normal or increased number of megakaryocytes in bone marrow aspirate, thrombopoeitin (TPO) decreased
Drug-induced thrombocytopenia
9.5
Decreased number of megakaryocytes in bone marrow aspirate or detection of drug-induced anti-platelet antibodies, rebound of platelet count after cessation of drug
a
Patients with sepsis and DIC are classified as DIC
process consists of active phagocytosis of megakaryocytes and other hematopoietic cells by monocytes and macrophages, hypothetically due to stimulation with high levels of macrophage colony stimulating factor (M-CSF) in sepsis [23]. Consumption of platelets probably also plays a considerable role in patients with sepsis, due to constant generation of thrombin, (which is the most potent activator of platelets in vivo), in its most extreme form presenting as disseminated intravascular coagulation (see further). Platelet activation, consumption, and destruction may also occur at the vascular surface as a result of extensive endothelial cell-platelet interaction in sepsis, which may differentially occur in vascular beds of various organs [5, 24, 25].
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The group of thrombotic microangiopathies includes syndromes such as thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome, chemotherapy-induced microangiopathic hemolytic anemia, severe malignant hypertension, and the HELLP syndrome of pregnancy [26]. A shared pathogenetic pathway of these clinical syndromes is endothelial injury, causing platelet adhesion and aggregation, thrombin generation, and inhibition of fibrinolysis. Clinical consequences of this extensive endothelial dysfunction include thrombocytopenia, mechanical fragmentation of red cells with hemolytic anemia, and obstruction of the microvasculature of various organs, such as the kidney and the brain (leading to renal failure and neurologic dysfunction, respectively). Despite this common final pathway, the various thrombotic microangiopathies have different underlying etiologies. Thrombotic thrombocytopenic purpura is caused by congenital or acquired (auto-immune) deficiency of von Willebrand factor cleaving protease (ADAMTS-13), resulting in endothelial cell-attached ultralarge von Willebrand multimers, that readily bind to platelet surface glycoprotein Ib, and cause platelet adhesion and aggregation [27]. In hemolytic uremic syndrome, a cytotoxin released upon infection with a specific serogroup of Gram-negative microorganisms (usually E. coli serotype O157:H7), is responsible for endothelial cell and platelet activation. In case of malignant hypertension or chemotherapy-induced thrombotic microangiopathy, presumably direct mechanical or chemical damage to the endothelium is responsible for the enhanced endothelial cell-platelet interaction. A diagnosis of thrombotic microangiopathy relies upon the combination of thrombocytopenia, Coombsnegative hemolytic anemia, and the presence of schistocytes in the blood smear. Additional information can be achieved by measurement of ADAMTS-13, however, in all forms of thrombotic microangiopathy, low levels of ADAMTS13 may occur [28]. It has been speculated that recombinant ADAMTS13 might be an interesting new therapeutic agent to target enhanced platelet vessel wall interaction [25]. Drug-induced thrombocytopenia is another frequent cause of thrombocytopenia in the ICU setting [29]. Thrombocytopenia may be caused by drug-induced myelosuppression, such as caused by cytostatic agents, or by immune-mediated mechanisms. Drug-induced thrombocytopenia is a difficult diagnosis to make in the ICU setting, since these patients are often exposed to multiple agents, and have numerous other potential reasons for platelet depletion. Drug-induced thrombocytopenia is often diagnosed based upon the timing of initiation of a new agent in relationship to the development of thrombocytopenia, and after exclusion of other causes of thrombocytopenia. The observation of rapid restoration of the platelet count after discontinuation of the suspected agent is highly suggestive of drug-induced thrombocytopenia.
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A specific form of drug-induced thrombocytopenia is heparin-induced thrombocytopenia (HIT). HIT is triggered by a heparin-induced antibody that binds to the heparin– platelet factor IV complex on the surface of platelets [30]. This may cause substantial platelet activation, and as a result, there occurs a consumptive thrombocytopenia and arterial and venous thrombosis. A consecutive series of critically ill ICU patients who receive heparin show an incidence of 1 % in this setting [31]. Unfractionated heparin carries a higher risk of HIT than low molecular weight (LMW) heparin. Thrombosis may occur in 25–50 % of patients with HIT, (with fatal thrombosis in 4–5 %) [32]. The diagnosis of HIT is based on the detection of HIT antibodies in combination with the occurrence of thrombocytopenia in a patient receiving heparin, with or without concomitant arterial or venous thrombosis. The commonly used ELISA for HIT antibodies is sensitive but non-specific, resulting in a high negative predictive value (100 %) but a very low positive predictive value (10 %) [31]. The gold standard for the diagnosis of HIT is a sensitive platelet activation assay, however, this test is usually not routinely available. Scoring systems for HIT combining clinical and laboratory features may facilitate the diagnostic work-up [32]. Normalization in the number of platelets in 1–3 days after discontinuation of heparin, further supports the diagnosis of HIT. Of note, patients should always receive an alternative anticoagulant agent (such as hirudin, danaparoid, or argatroban) when heparin is discontinued.
Inflammation and coagulation in ICU patients The concurrent and mutually dependent activation of inflammation and coagulation is crucial in the pathogenesis of various systemic inflammatory states that are present in critically ill patients. Vascular wall cells and physiological anticoagulant pathways have a pivotal role at the crossroad of coagulation and inflammation, and therefore the repletion of impaired natural anticoagulant pathways in patients with severe sepsis has been subject of significant consideration (Fig. 2) [33]. There is ample evidence that an elaborate cross-talk between inflammation and coagulation occurs, whereby inflammation not only produces activation of coagulation, but coagulation also markedly influences inflammatory activity [34]. Prohemostatic activity is regulated by three chief anticoagulant conduits: antithrombin, the activated protein C pathway, and tissue factor pathway inhibitor (TFPI). Especially activated protein C (APC), seems to play a central role in the pathogenesis of sepsis and associated organ dysfunction [35]. There is sufficient proof that an inadequate functioning of the protein C pathway plays a role in the hemostatic imbalance in patients with sepsis [36, 37]. The circulating zymogen
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Fig. 2 Schematic representation of pathogenetic pathways involved in the activation of coagulation in critically ill patients. During systemic inflammation, both perturbed endothelial cells and activated mononuclear cells may produce proinflammatory cytokines that mediate coagulation activation. Activation of coagulation is initiated
by tissue factor expression on activated mononuclear cells and endothelial cells. In addition, downregulation of physiological anticoagulant mechanisms and inhibition of fibrinolysis by endothelial cells will further promote intravascular fibrin deposition. PAI-1 plasminogen activator inhibitor, type 1
protein C is activated by the endothelial cell-bound thrombomodulin once this is activated by thrombin [38]. APC acts in concert with its co-factor protein S, and is able to proteolytically degrade the coagulation essential activated co-factors V (FVa) and VIII (FVIIIa); hence, it is an effective anticoagulant. The endothelial protein C receptor (EPCR), not only accelerates the activation of protein C several-fold, but also serves as a receptor for APC, and binding of APC to this receptor may amplify its anticoagulant and anti-inflammatory effects [39]. In patients with sepsis, plasma levels of the zymogen protein C are low or very low, due to impaired synthesis, consumption, and degradation by proteolytic enzymes, such as neutrophil elastase [40–42]. Furthermore, there is a significant downregulation of thrombomodulin, caused by pro-inflammatory cytokines such as tumor necrosis factor-a and interleukin-1 resulting in diminished protein C activation [43, 44]. Lastly, but importantly, the EPCR has shown to be down-regulated in sepsis, and this may further affect the function of the protein C system negatively [45]. Of note, all three anticoagulant systems are in principal located at the endothelial surface, where they can direct both anticoagulant and anti-inflammatory functions. During inflammation-induced activation of coagulation, the function of all three pathways can be impaired [46]. Proinflammatory cytokines and chemokines as well as endothelial cell perturbation affect all physiological anticoagulant mechanisms, and, vice versa, activated coagulation proteases and physiological anticoagulants can modulate inflammation by specific cell receptors.
Neutrophil extracellular traps (NETs), have recently been identified as important contributors to vascular thrombosis and inflammation [47]. These NETs consist of extracellular DNA fibres that are present in inflammatory conditions as a result of programmed cell death of inflammatory cells and endothelial cells [20, 48]. NETs seem to be produced to allow inflammatory cells to trap and deactivate microorganisms in the extracellular environment by forming scaffolds of intact chromatin fibres with antimicrobial proteins. However, NETs may also induce endothelial cell death and detrimental inflammatory activity an effect likely mediated by NET-associated proteases or cationic proteins, including histones [47, 49]. Importantly, it has been demonstrated that activated protein C is a significant inhibitor of histone-mediated detrimental effects in sepsis. Since there is ample interaction between heparin and activated protein C, it is likely that part of the heparin effect on histones is due to modulation of this activated protein C effect, which is in line with very recent observations in mice [50–52].
Disseminated intravascular coagulation Disseminated intravascular coagulation (DIC) occurs in a substantial proportion of consecutive intensive care patients [53]. DIC is due to systemic intravascular activation of coagulation, which may be secondary to a myriad of underlying conditions, including sepsis, severe trauma, malignant disease, or obstetrical calamities such as
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placental abruption or amniotic fluid embolism [54–57]. It is thought that activation of coagulation and fibrin formation may be instrumental in many cases of inflammation that serves to contain the spread of infectious or deleterious cells and proteins. However, in case of DIC, the response may be exaggerated and harmful instead of beneficial. Formation of microvascular thrombi, in concert with inflammatory activation, may cause failure of the microvasculature and thereby contribute to organ dysfunction [58]. Ongoing and insufficiently compensated consumption of platelets and coagulation factors may result in thrombocytopenia and low levels of factors, thereby causing a risk for hemorrhagic complication, especially in perioperative patients or patients who need to undergo invasive procedures. Thrombin generation is initiated via the (extrinsic) tissue factor/factor VIIa pathway, and propagated through an impaired function of inhibitory mechanisms of thrombin generation, such as the natural anticoagulants antithrombin and activated protein C [59]. A dysfunctional fibrin degradation, due to elevated circulating levels of PAI-1, further promotes intravascular fibrin deposition. Patients with DIC have a low or rapidly decreasing platelet count, prolonged global coagulation tests, low plasma levels of coagulation factors and inhibitors, and increased markers of fibrin formation or degradation, such as D-dimer or fibrin degradation products (FDP’s) [60]. Coagulation proteins with a marked acute phase behavior, such as factor VIII or fibrinogen, are usually not decreased, and may even increase. One of the often advocated laboratory tests for the diagnosis of DIC, fibrinogen, is therefore not a very good marker for DIC, except in very severe cases, and although sequential measurements can give some insight. There is no single laboratory test with sufficient accuracy for the diagnosis of DIC. However, a diagnosis of DIC may be made using a simple scoring system based on a combination of routinely available coagulation tests [61]. In a number of prospective validation studies, the sensitivity and specificity of this DIC score is greater than 95 %. Furthermore, this DIC score is a strong and independent predictor of mortality patients with severe sepsis [62]. Combining predictive intensive care measurement systems such as Acute Physiology and Chronic Health Evaluation (APACHE-II), with the DIC score seems to be a potent method to predict the prognosis in DIC. Similar composite scores have been designed and studied in Japan [63–65]. The most important discrepancy between the ISTH and Japanese scores is a higher proportion of patients with haemato-oncological diseases who are diagnosed with DIC by the Japanese systems. Thrombelastography (TEG) is a technique that has been around for many years, but which has gained considerable renewed attention recently due to automation and
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commercial employment [66]. Contemporary versions, e.g. rotational thrombelastography (ROTEM), are increasingly employed in critically ill patients, including those with DIC [11, 67]. The benefit of TEG compared to the usual coagulation parameters is that it includes an assessment of platelet function and of clot-dissolving potential. Procoagulant as well as anticoagulant states as indicated with TEG have a good correlation with clinically important organ dysfunction and survival [12, 13], although its advantage over the usual coagulation assays has not yet been confirmed [14, 68].
Management of coagulation abnormalities in critically ill patients It is obvious that the primary focus of attention in the management of a clinically relevant coagulopathy should be directed towards the adequate treatment of the underlying disorder. This underscores the critical importance of making a correct diagnosis for the condition that has caused the acquired coagulopathy. Despite adequate treatment for the underlying disorder, however, further supportive management of the hemostatic defect is often required [69]. Fresh or frozen plasma contains all coagulation factors, and may be used to replenish congenital or acquired deficiencies of these clotting factors. Current practice guidelines in most centers use solvent or detergent-treated plasma (SDP or ESDP), which may provide better protection against transmission of blood-borne infections, but may also have a lower recovery of coagulation factors [70]. Most consensus guidelines indicate that plasma should only be transfused in case of bleeding or in a situation with a high-risk of bleeding, and not based on laboratory abnormalities alone. For more specific therapy, or if the transfusion of large volumes of plasma is not desirable, fractionated plasma of purified coagulation factor concentrate is available. Prothrombin complex concentrates (PCC’s), contain the vitamin K-dependent coagulation factors II, VII, IX and X. Hence, these concentrates may be used if immediate reversal of vitamin K antagonist treatment is required. Also, PCC’s may be used if global replenishment of coagulation factors is necessary, and large volumes of plasma may not be tolerated. In some cases, administration of purified coagulation factor concentrates, such as fibrinogen concentrate, may be helpful. Most guidelines advocate a platelet transfusion in patients with a platelet count of \30–50 9 109/l accompanied with bleeding or at high risk for bleeding, and in patients with a platelet count\10 9 109/l, regardless of the presence or absence of bleeding. Platelet concentrates usually contain a mixture of the platelets from a blood
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donation from 5 to 6 donors (equals 5–6 units), although in some parts of the world (notably in the US), single donor transfusion has become the usual practice due to a presumed decrease in side effects and less potential antibody formation. Platelet transfusion is particularly effective in patients with a thrombocytopenia due to impaired platelet production or increased consumption, whereas disorders of enhanced platelet destruction (for example immune thrombocytopenia), may necessitate alternative therapies, such as steroids or human immunoglobulin. Some causes of thrombocytopenia may require specific measures. Thrombocytopenia due to HIT (or suspected HIT), requires immediate cessation of heparin and institution of alternative anticoagulant treatment, e.g. with danaparoid, thrombin inhibitors, or fondaparinux [71]. Vitamin K antagonists should be avoided in the initial treatment of HIT, since these agents may cause skin necrosis. In patients with a thrombotic microangiopathy due to antibody-induced low levels of von Willebrand cleaving protease (ADAMTS-13), plasma exchange and immunosuppressive treatment should be initiated, whereas in the case of congenital ADAMTS13 deficiency, plasma infusion suffices [26]. Pro-hemostatic treatment can be used as adjunctive treatment in patients with major blood loss [72, 73]. Deamino D-arginine vasopressin (DDAVP, desmopressin), is a vasopressin analogue that induces release of the contents of the endothelial cell associated Weibel Palade bodies, including von Willebrand factor. Hence, the administration of DDAVP results in a marked increase in the plasma concentration of von Willebrand factor (and associated coagulation factor VIII), and, by as yet unexplained additional mechanisms, a potentiation of primary hemostasis. DDAVP has proven to be effective in the management of patients with von Willebrand’s disease and mild hemophilia A, but also in patients with uremic thrombocytopathy and other defects in primary hemostasis [74]. Anti-fibrinolytic agents, such as lysine analogues (eaminocaproic acid or tranexamic acid), may also be helpful in the prevention or management of bleeding, in particular if hyper-fibrinolysis is thought to be the major contributor to the hemostatic defect. Anti-fibrinolysis therapies may also compensate for other coagulation defects. Anti-fibrinolytic agents have been found effective in the prevention of blood loss and transfusion in patients undergoing major surgical procedures, and are relatively safe [75, 76]. In patients with severe trauma, tranexamic acid is effective in reducing excessive blood loss and reduced mortality [77, 78]. Recombinant factor VIIa is a pro-hemostatic agent that has been licensed for the treatment of patients with hemophilia and inhibiting antibodies towards factor VIII or IX. There is a very large number of case series reporting successful use of recombinant factor VIIa in patients with other types of coagulation defects, or patients with major bleeding due to
surgery or trauma, however, the number of successful controlled clinical trials is still limited. In addition, the safety of recombinant factor VIIa (in terms of thrombotic adverse events), may be an issue [79]. Therefore, until ongoing clinical trials and further safety data in critically ill patients becomes available, off-label use of recombinant factor VIIa can only be justified in the case of life threatening bleeding, when all other conventional treatments have failed [72]. Supportive treatment of the coagulopathy associated with DIC is a complex issue [60]. Administration of anticoagulants may theoretically be beneficial, but their efficacy have never been proven in clinical trials. Restoration of dysfunctional physiological anticoagulant pathways by administration of antithrombin concentrate or (activated) protein C has beneficial effects on laboratory parameters. A large multicenter, randomized controlled trial with antithrombin concentrate shows no significant reduction in mortality of patients with sepsis who are treated with antithrombin concentrate [80]. Interestingly, post hoc subgroup analyses indicate some benefit in patients who do not receive concomitant heparin and in those patients with the most severe coagulopathy, but this observation needs prospective validation [81]. Recent retrospective analyses of large nationwide patient databases from Japan demonstrate that patients treated with antithrombin have a better outcome compared to propensity matched patients who do not receive antithrombin [82–84]. A beneficial effect of recombinant human activated protein C is demonstrated in a randomized controlled phase III trial of recombinant human activated protein C (APC) in patients with severe sepsis [10]. Interestingly, patients who had DIC according to international criteria, benefit more from the therapy with APC than patients who do not have overt DIC [62]. However, meta-analyses of published literature conclude that the basis for treatment with APC, even in patients with a high disease severity, is not very strong. A recently completed placebo-controlled trial in patients with severe sepsis and septic shock was stopped prematurely due to the lack of any significant benefit of APC [85]. Subsequently, the manufacturer of APC has decided to withdraw the product from the market. In a phase III randomized double-blind clinical trial in patients with DIC, administration of soluble thrombomodulin has a significantly better effect on bleeding manifestations and coagulation parameters than heparin, yet the mortality rate at 28 days was similar in the two study groups [86]. When limiting these results to patients with severe infection and sepsis, DIC resolution rates are 67.5 % in thrombomodulin-treated patients and 55.6 % in the control group, and 28-day mortality rates are 21.4 and 31.6 %, respectively. Mortality rates of patients who recover from DIC are 3.7 % in the thrombomodulin group and 15 % in the heparin group [87]. More recent trials and
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observational studies from Japan also point to a potential benefit of this intervention [88, 89].
Conclusions Hemostatic abnormalities are common in critically ill patients, and may significantly affect morbidity and mortality. An adequate diagnosis for the underlying cause of the coagulation abnormality is important, since many of these conditions may necessitate specific treatment. Management of hemostatic abnormalities in critically ill patients should primarily be directed at the underlying cause, but supportive treatment may be required. Deficiencies in platelets and coagulation factors in bleeding patients or patients at risk for hemorrhage can be achieved by transfusion of platelet concentrate or plasma products, respectively. In addition, pro-hemostatic treatment may be beneficial in case of severe bleeding, whereas restoring physiological anticoagulant pathways may theoretically be helpful in patients with sepsis and DIC. Conflict of interest
None.
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58. Wheeler AP, Bernard GR (1999) Treating patients with severe sepsis. N Engl J Med 340:207–214 59. Levi M, Schouten M, van der Poll T (2008) Sepsis, coagulation, and antithrombin: old lessons and new insights. Semin Thromb Hemost 34:742–746 60. Levi M, Toh CH, Thachil J, Watson HG (2009) Guidelines for the management of disseminated intravascular coagulation. Br J Haematol 145:24–33 61. Taylor FBJ, Toh CH, Hoots WK, Wada H, Levi M (2001) Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost 86:1327–1330 62. Dhainaut JF, Yan SB, Joyce DE et al (2004) Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation. J Thromb Haemost 2:1924–1933 63. Wada H, Gabazza EC, Asakura H et al (2003) Comparison of diagnostic criteria for disseminated intravascular coagulation (DIC): diagnostic criteria of the International Society of Thrombosis and Hemostasis and of the Japanese Ministry of Health and Welfare for overt DIC. Am J Hematol 74:17–22 64. Gando S, Saitoh D, Ogura H et al (2013) A multicenter, prospective validation study of the Japanese Association for Acute Medicine disseminated intravascular coagulation scoring system in patients with severe sepsis. Crit Care 17:R111 65. Levi M (2013) Another step in improving the diagnosis of disseminated intravascular coagulation in sepsis. Crit Care 17:448 66. Chitlur M, Rivard GE, Lillicrap D et al (2014) Recommendations for performing thromboelastography/thromboelastometry in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost 12:103–106 67. Haase N, Ostrowski SR, Wetterslev J et al (2014) Thromboelastography in patients with severe sepsis: a prospective cohort study. Intensive Care Med (in press) 68. Ranucci M, Baryshnikova E, Colella D (2012) Monitoring prohemostatic treatment in bleeding patients. Semin Thromb Hemost 38:282–291 69. Spahn DR, Bouillon B, Cerny V et al (2013) Management of bleeding and coagulopathy following major trauma: an updated European guideline. Crit Care 17:R76 70. Hellstern P, Muntean W, Schramm W, Seifried E, Solheim B (2002) Practical guidelines for the clinical use of plasma. Thromb Res 107(Suppl 1):S53 71. Hirsh J, Heddle N, Kelton JG (2004) Treatment of heparininduced thrombocytopenia: a critical review. Arch Intern Med 164:361–369 72. Mannucci PM, Levi M (2007) Prevention and treatment of major blood loss. N Engl J Med 356:2301–2311 73. Henry DA, Carless PA, Moxey AJ et al (2011) Anti-fibrinolytic use for minimising perioperative blood transfusion. Cochrane Database Syst Rev 3:CD1886 74. Mannucci PM (1997) Desmopressin (DDAVP) in the treatment of bleeding disorders: the first 20 years. Blood 90:2515–2521 75. Levi M, Cromheecke ME, de Jonge E et al (1999) Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints. Lancet 354:1940–1947 76. Porte RJ, Molenaar IQ, Begliomini B et al (2000) Aprotinin and transfusion requirements in orthotopic liver transplantation: a multicentre randomised double-blind study. EMSALT Study Group. Lancet 355(9212):1303–1309 77. Shakur H, Roberts I, Bautista R et al (2010) Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet 376:23–32
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IM - REVIEW
Hemostatic abnormalities in critically ill patients Marcel Levi • Suthesh Sivapalaratnam
Received: 22 November 2014 / Accepted: 9 December 2014 Ó SIMI 2014
Abstract Hemostatic abnormalities frequently occur in critically ill patients and may vary from prolonged global clotting tests or isolated thrombocytopenia, to composite defects, such as consumption coagulopathies. There are many reasons for a disturbed coagulation in intensive care patients, and each of these underlying syndromes may require specific therapeutic intervention. Hence, an adequate differential diagnosis and initiation of proper (supportive) therapeutic strategies are critical to decrease morbidity and mortality in critically ill patients with hemostatic abnormalities. Keywords Coagulation Platelets Intensive care Disseminated intravascular coagulation Thrombotic microangiopathy Heparin-induced thrombocytopenia Bleeding Antifibrinolytic agents Recombinant factor VIIa
Introduction Hemostatic abnormalities in critically ill patients require swift and appropriate identification of their primary cause, since many of these disorders may require dissimilar therapeutic management strategies that may have a major impact on outcome [1–3]. A prolongation of global clotting M. Levi S. Sivapalaratnam Department of Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands M. Levi (&) Department of Vascular Medicine/Internal Medicine, Academic Medical Centre F-4, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands e-mail: [email protected]
times [such as the prothrombin time (PT) or the activated partial thromboplastin time (aPTT)], occurs in 14–28 % of critically ill patients [3]. The incidence of a low platelet count (platelet count \150 9 109/l), in an intensive care population is 35–44 % [4]. An even lower platelet count of \100 9 109/l is observed in another 30–50 % of patients (Fig. 1). The low platelet count is likely to be the result of increased platelet turnover due to thrombin generation, and subsequent platelet activation and enhanced platelet-vessel wall interaction [5]. Intensive care unit (ICU) patients with hemostatic defects have a 4 to 5-fold higher risk for bleeding compared to patients with normal coagulation [4]. The risk of intracranial hemorrhage in critically ill patients during ICU admission is relatively low (0.3–0.5 %), but almost 90 % of patients with this complication have platelet counts below 100 9 109/l. Moreover, a decrease in platelet count may indicate ongoing coagulation activation, which plays a role in microvascular thrombosis and subsequent multiple organ failure. Rapid identification of these patients is important to provide adequate supportive therapeutic strategies [6, 7]. Irrespective of the cause, a low platelet count is an independent predictor of ICU mortality in multivariate analyses with an odds ratio of 1.9–4.2 in various studies (Fig. 1) [4, 8]. Other coagulation assay abnormalities regularly observed in critically ill patients encompass increased fibrin degradation products and low concentrations of physiological coagulation inhibitors. Fibrin split products, such as D-dimer, are detectable in about 40 % in consecutive series of ICU patients, in 80 % of trauma patients, and in virtually all patients with severe sepsis [9, 10]. Reduced levels of coagulation inhibitors, such as antithrombin and protein C, are observed in 40–60 % of trauma patients and 90 % of sepsis patients [10].
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Intern Emerg Med Table 1 Causes of prolongation of global coagulation times Test result
Cause
PT prolonged, aPTT normal
Factor VII deficiency Mild vitamin K deficiency Mild liver insufficiency Low doses of vitamin K antagonists
PT normal, aPTT prolonged
Factor VIII, IX, or XI deficiency Use of unfractionated heparin Inhibiting antibody and/or anti-phospholipid antibody Factor XII or prekallikrein deficiency (no relevance for in vivo coagulation)
Fig. 1 Distribution of nadir platelet count (black bars) and survival (striped bars) in a pooled analysis of four clinical studies of consecutive groups of patients admitted to the ICU [1, 3, 4, 6]
Both PT and aPTT prolonged
Factor X, V, II or fibrinogen deficiency Severe vitamin K deficiency Use of vitamin K antagonists
In recent years, comprehensive point of care diagnostic techniques to assess the coagulation status have become widely used. Thrombelastography (TEG) is a method that was developed decades ago, and provides an overall picture of ex vivo coagulation. Modern techniques, such as rotational thrombelastography (ROTEM), enable bedside performance of this test, and it is frequently used in acute care settings [11]. The theoretical advantage of TEG over conventional coagulation assays is that it provides an idea of platelet function as well as fibrinolytic activity. Hyperand hypocoagulability as demonstrated with TEG correlate with clinically relevant morbidity and mortality in several studies [12, 13], although its superiority over conventional tests has not been established unequivocally [14].
Causes of prolonged global coagulation times Global coagulation tests, such as the prothrombin time (PT) and the activated partial thromboplastin time (aPTT), do not reflect in vivo hemostasis very well. However, these tests are useful, and there is a rapid screening method to assess the concentration of one or at times multiple coagulation factors for which each or both tests are sensitive (Table 1) [15]. In general, global clotting tests will be abnormal when the level of coagulation factors are below 50 %. This is pertinent since the levels of clotting factors, which are required for adequate coagulation, are somewhere between 25 and 50 % [16]. Abnormal global coagulation assays may be caused by a deficiency of one or more coagulation factors. In addition, but less frequently, the occurrence of an inhibiting antibody, which can have major in vivo relevance (such as in acquired hemophilia), but can also produce a clinically insignificant laboratory phenomenon, should be taken into account. The presence of antiphospholipid antibodies may
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Global clotting factor deficiency Synthesis: liver failure Loss: massive bleeding Consumption: DIC
cause a prolongation of the aPTT, and can be associated with a low platelet count as well. Paradoxically, these antibodies may enhance the risk of thrombosis dramatically. The presence of an inhibiting antibody can be confirmed by a simple mixing experiment. As a general rule, if a prolongation of a global coagulation test cannot be corrected by mixing 50 % of patient plasma with 50 % of normal plasma, an inhibiting antibody is likely to be present. In the vast majority of critically ill patients, deficiencies of coagulation factors are acquired. In most cases, deficiencies in coagulation factors may be caused by impaired synthesis, massive loss, or increased turnover (consumption). Impaired synthesis is mostly due to liver failure or vitamin K deficiency. A vitamin K deficit may be due to poor nutrition in combination with interventions (e.g. antibiotics), which influence intestinal flora and thereby microbial vitamin K synthesis. The prothrombin time is most sensitive to both conditions, since this test is highly dependent on the plasma levels of factor VII (a vitamin K-dependent coagulation factor with the shortest half-life of the clotting factors). Liver failure may be differentiated from vitamin K deficiency by measuring factor V, which is not vitamin K dependent. In fact, factor V levels are crucial in various scoring systems for severe acute liver failure [17]. Uncompensated losses of coagulation factors can occur after massive hemorrhage in patients undergoing major surgery or in trauma patients. Frequently in these situations, a coagulopathy is specifically encountered in patients with major blood loss and rapid intravascular volume replacement with crystalloids, colloids and red
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cells without simultaneous administration of coagulation factors in plasma preparations. The resulting dilutional form of coagulation defect may persist and aggravate the bleeding condition. In addition, transfusion in these patients may lead to systemic activation of inflammation, and may exacerbate the coagulation derangement [18]. In hypothermic and acidotic patients (e.g. in case of trauma), coagulation assays may underestimate the function of coagulation in vivo, since in the laboratory test-tube assays are standardized, performed in the presence of acidosisdisguising buffers, and performed at 37 °C to mimic normal body temperature. Consumption of coagulation factors may occur in the framework of disseminated intravascular coagulation (see further). In complex cases, different causes for an abnormal global coagulation time may be present at the same time, and the cause may also change over time. For example, multi-trauma patients can initially present with a loss of coagulation factors due to severe hemorrhage that later can evolve to a consumption coagulopathy due to DIC as a result of a systemic inflammatory response. Further derangement of coagulation can subsequently develop from trauma-induced liver injury and acute hepatic failure associated with impaired coagulation factor synthesis. Various anticoagulant agents will also prolong global coagulation times. Unfractionated heparin prolongs the aPTT, but confusingly low molecular weight heparins do not, (or only very modestly). Vitamin K antagonists cause low levels of vitamin K dependent coagulation factors, resulting in an initial prolongation of the PT followed by prolongation of both the PT and aPTT.
Table 2 Differential diagnosis of thrombocytopenia in the ICU
Differential diagnosis of thrombocytopenia
Seven major causes of thrombocytopenia (platelet count\150 9 109/ l) are listed. Relative incidences are based on two studies in consecutive ICU patients [1, 6]. Patients with hematological malignancies were excluded
There are many reasons for a low platelet count in ICU patients. Table 2 summarizes the most common diagnoses. Sepsis is clearly associated with thrombocytopenia in critically ill patients, and the severity of sepsis correlates with the reduction in platelet count [5, 19]. The principal factors that contribute to thrombocytopenia in patients with sepsis are: impaired platelet production, increased consumption or destruction, or sequestration of platelets in the spleen or along the endothelial surface [20, 21]. Decreased production of platelets from the bone marrow may seem inconsistent with the high levels of platelet productionstimulating pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-a and interleukin (IL)-6, and high concentration of circulating thrombopoietin in septic patients. These growth factors and cytokines should theoretically promote megakaryopoiesis in the bone marrow [22]. However, in a large number of patients with sepsis, marked hemophagocytosis may occur. This pathologic
Differential diagnosis
Relative incidence (%)
Additional diagnostic clues
Sepsis
52.4
Positive (blood) cultures, positive sepsis criteria, hematophagocytosis in bone marrow aspirate
DICa
25.3
Prolonged aPTT and PT, increased fibrin split products, low levels of physiological anticoagulant factors (antithrombin, protein C)
Massive blood loss
7.5
Major bleeding, low hemoglobin, prolonged aPTT and PT
Thrombotic microangiopathy
0.7
Schistocytes in blood smear, Coombs-negative hemolysis, fever, neurologic symptoms, renal insufficiency
Heparin-induced thrombocytopenia
1.2
Use of heparin, venous or arterial thrombosis, positive HIT test (usually ELISA for heparin– platelet factor IV antibodies), rebound of platelets after cessation of heparin
Immune thrombocytopenia
3.4
Anti-platelet antibodies, normal or increased number of megakaryocytes in bone marrow aspirate, thrombopoeitin (TPO) decreased
Drug-induced thrombocytopenia
9.5
Decreased number of megakaryocytes in bone marrow aspirate or detection of drug-induced anti-platelet antibodies, rebound of platelet count after cessation of drug
a
Patients with sepsis and DIC are classified as DIC
process consists of active phagocytosis of megakaryocytes and other hematopoietic cells by monocytes and macrophages, hypothetically due to stimulation with high levels of macrophage colony stimulating factor (M-CSF) in sepsis [23]. Consumption of platelets probably also plays a considerable role in patients with sepsis, due to constant generation of thrombin, (which is the most potent activator of platelets in vivo), in its most extreme form presenting as disseminated intravascular coagulation (see further). Platelet activation, consumption, and destruction may also occur at the vascular surface as a result of extensive endothelial cell-platelet interaction in sepsis, which may differentially occur in vascular beds of various organs [5, 24, 25].
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The group of thrombotic microangiopathies includes syndromes such as thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome, chemotherapy-induced microangiopathic hemolytic anemia, severe malignant hypertension, and the HELLP syndrome of pregnancy [26]. A shared pathogenetic pathway of these clinical syndromes is endothelial injury, causing platelet adhesion and aggregation, thrombin generation, and inhibition of fibrinolysis. Clinical consequences of this extensive endothelial dysfunction include thrombocytopenia, mechanical fragmentation of red cells with hemolytic anemia, and obstruction of the microvasculature of various organs, such as the kidney and the brain (leading to renal failure and neurologic dysfunction, respectively). Despite this common final pathway, the various thrombotic microangiopathies have different underlying etiologies. Thrombotic thrombocytopenic purpura is caused by congenital or acquired (auto-immune) deficiency of von Willebrand factor cleaving protease (ADAMTS-13), resulting in endothelial cell-attached ultralarge von Willebrand multimers, that readily bind to platelet surface glycoprotein Ib, and cause platelet adhesion and aggregation [27]. In hemolytic uremic syndrome, a cytotoxin released upon infection with a specific serogroup of Gram-negative microorganisms (usually E. coli serotype O157:H7), is responsible for endothelial cell and platelet activation. In case of malignant hypertension or chemotherapy-induced thrombotic microangiopathy, presumably direct mechanical or chemical damage to the endothelium is responsible for the enhanced endothelial cell-platelet interaction. A diagnosis of thrombotic microangiopathy relies upon the combination of thrombocytopenia, Coombsnegative hemolytic anemia, and the presence of schistocytes in the blood smear. Additional information can be achieved by measurement of ADAMTS-13, however, in all forms of thrombotic microangiopathy, low levels of ADAMTS13 may occur [28]. It has been speculated that recombinant ADAMTS13 might be an interesting new therapeutic agent to target enhanced platelet vessel wall interaction [25]. Drug-induced thrombocytopenia is another frequent cause of thrombocytopenia in the ICU setting [29]. Thrombocytopenia may be caused by drug-induced myelosuppression, such as caused by cytostatic agents, or by immune-mediated mechanisms. Drug-induced thrombocytopenia is a difficult diagnosis to make in the ICU setting, since these patients are often exposed to multiple agents, and have numerous other potential reasons for platelet depletion. Drug-induced thrombocytopenia is often diagnosed based upon the timing of initiation of a new agent in relationship to the development of thrombocytopenia, and after exclusion of other causes of thrombocytopenia. The observation of rapid restoration of the platelet count after discontinuation of the suspected agent is highly suggestive of drug-induced thrombocytopenia.
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A specific form of drug-induced thrombocytopenia is heparin-induced thrombocytopenia (HIT). HIT is triggered by a heparin-induced antibody that binds to the heparin– platelet factor IV complex on the surface of platelets [30]. This may cause substantial platelet activation, and as a result, there occurs a consumptive thrombocytopenia and arterial and venous thrombosis. A consecutive series of critically ill ICU patients who receive heparin show an incidence of 1 % in this setting [31]. Unfractionated heparin carries a higher risk of HIT than low molecular weight (LMW) heparin. Thrombosis may occur in 25–50 % of patients with HIT, (with fatal thrombosis in 4–5 %) [32]. The diagnosis of HIT is based on the detection of HIT antibodies in combination with the occurrence of thrombocytopenia in a patient receiving heparin, with or without concomitant arterial or venous thrombosis. The commonly used ELISA for HIT antibodies is sensitive but non-specific, resulting in a high negative predictive value (100 %) but a very low positive predictive value (10 %) [31]. The gold standard for the diagnosis of HIT is a sensitive platelet activation assay, however, this test is usually not routinely available. Scoring systems for HIT combining clinical and laboratory features may facilitate the diagnostic work-up [32]. Normalization in the number of platelets in 1–3 days after discontinuation of heparin, further supports the diagnosis of HIT. Of note, patients should always receive an alternative anticoagulant agent (such as hirudin, danaparoid, or argatroban) when heparin is discontinued.
Inflammation and coagulation in ICU patients The concurrent and mutually dependent activation of inflammation and coagulation is crucial in the pathogenesis of various systemic inflammatory states that are present in critically ill patients. Vascular wall cells and physiological anticoagulant pathways have a pivotal role at the crossroad of coagulation and inflammation, and therefore the repletion of impaired natural anticoagulant pathways in patients with severe sepsis has been subject of significant consideration (Fig. 2) [33]. There is ample evidence that an elaborate cross-talk between inflammation and coagulation occurs, whereby inflammation not only produces activation of coagulation, but coagulation also markedly influences inflammatory activity [34]. Prohemostatic activity is regulated by three chief anticoagulant conduits: antithrombin, the activated protein C pathway, and tissue factor pathway inhibitor (TFPI). Especially activated protein C (APC), seems to play a central role in the pathogenesis of sepsis and associated organ dysfunction [35]. There is sufficient proof that an inadequate functioning of the protein C pathway plays a role in the hemostatic imbalance in patients with sepsis [36, 37]. The circulating zymogen
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Fig. 2 Schematic representation of pathogenetic pathways involved in the activation of coagulation in critically ill patients. During systemic inflammation, both perturbed endothelial cells and activated mononuclear cells may produce proinflammatory cytokines that mediate coagulation activation. Activation of coagulation is initiated
by tissue factor expression on activated mononuclear cells and endothelial cells. In addition, downregulation of physiological anticoagulant mechanisms and inhibition of fibrinolysis by endothelial cells will further promote intravascular fibrin deposition. PAI-1 plasminogen activator inhibitor, type 1
protein C is activated by the endothelial cell-bound thrombomodulin once this is activated by thrombin [38]. APC acts in concert with its co-factor protein S, and is able to proteolytically degrade the coagulation essential activated co-factors V (FVa) and VIII (FVIIIa); hence, it is an effective anticoagulant. The endothelial protein C receptor (EPCR), not only accelerates the activation of protein C several-fold, but also serves as a receptor for APC, and binding of APC to this receptor may amplify its anticoagulant and anti-inflammatory effects [39]. In patients with sepsis, plasma levels of the zymogen protein C are low or very low, due to impaired synthesis, consumption, and degradation by proteolytic enzymes, such as neutrophil elastase [40–42]. Furthermore, there is a significant downregulation of thrombomodulin, caused by pro-inflammatory cytokines such as tumor necrosis factor-a and interleukin-1 resulting in diminished protein C activation [43, 44]. Lastly, but importantly, the EPCR has shown to be down-regulated in sepsis, and this may further affect the function of the protein C system negatively [45]. Of note, all three anticoagulant systems are in principal located at the endothelial surface, where they can direct both anticoagulant and anti-inflammatory functions. During inflammation-induced activation of coagulation, the function of all three pathways can be impaired [46]. Proinflammatory cytokines and chemokines as well as endothelial cell perturbation affect all physiological anticoagulant mechanisms, and, vice versa, activated coagulation proteases and physiological anticoagulants can modulate inflammation by specific cell receptors.
Neutrophil extracellular traps (NETs), have recently been identified as important contributors to vascular thrombosis and inflammation [47]. These NETs consist of extracellular DNA fibres that are present in inflammatory conditions as a result of programmed cell death of inflammatory cells and endothelial cells [20, 48]. NETs seem to be produced to allow inflammatory cells to trap and deactivate microorganisms in the extracellular environment by forming scaffolds of intact chromatin fibres with antimicrobial proteins. However, NETs may also induce endothelial cell death and detrimental inflammatory activity an effect likely mediated by NET-associated proteases or cationic proteins, including histones [47, 49]. Importantly, it has been demonstrated that activated protein C is a significant inhibitor of histone-mediated detrimental effects in sepsis. Since there is ample interaction between heparin and activated protein C, it is likely that part of the heparin effect on histones is due to modulation of this activated protein C effect, which is in line with very recent observations in mice [50–52].
Disseminated intravascular coagulation Disseminated intravascular coagulation (DIC) occurs in a substantial proportion of consecutive intensive care patients [53]. DIC is due to systemic intravascular activation of coagulation, which may be secondary to a myriad of underlying conditions, including sepsis, severe trauma, malignant disease, or obstetrical calamities such as
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placental abruption or amniotic fluid embolism [54–57]. It is thought that activation of coagulation and fibrin formation may be instrumental in many cases of inflammation that serves to contain the spread of infectious or deleterious cells and proteins. However, in case of DIC, the response may be exaggerated and harmful instead of beneficial. Formation of microvascular thrombi, in concert with inflammatory activation, may cause failure of the microvasculature and thereby contribute to organ dysfunction [58]. Ongoing and insufficiently compensated consumption of platelets and coagulation factors may result in thrombocytopenia and low levels of factors, thereby causing a risk for hemorrhagic complication, especially in perioperative patients or patients who need to undergo invasive procedures. Thrombin generation is initiated via the (extrinsic) tissue factor/factor VIIa pathway, and propagated through an impaired function of inhibitory mechanisms of thrombin generation, such as the natural anticoagulants antithrombin and activated protein C [59]. A dysfunctional fibrin degradation, due to elevated circulating levels of PAI-1, further promotes intravascular fibrin deposition. Patients with DIC have a low or rapidly decreasing platelet count, prolonged global coagulation tests, low plasma levels of coagulation factors and inhibitors, and increased markers of fibrin formation or degradation, such as D-dimer or fibrin degradation products (FDP’s) [60]. Coagulation proteins with a marked acute phase behavior, such as factor VIII or fibrinogen, are usually not decreased, and may even increase. One of the often advocated laboratory tests for the diagnosis of DIC, fibrinogen, is therefore not a very good marker for DIC, except in very severe cases, and although sequential measurements can give some insight. There is no single laboratory test with sufficient accuracy for the diagnosis of DIC. However, a diagnosis of DIC may be made using a simple scoring system based on a combination of routinely available coagulation tests [61]. In a number of prospective validation studies, the sensitivity and specificity of this DIC score is greater than 95 %. Furthermore, this DIC score is a strong and independent predictor of mortality patients with severe sepsis [62]. Combining predictive intensive care measurement systems such as Acute Physiology and Chronic Health Evaluation (APACHE-II), with the DIC score seems to be a potent method to predict the prognosis in DIC. Similar composite scores have been designed and studied in Japan [63–65]. The most important discrepancy between the ISTH and Japanese scores is a higher proportion of patients with haemato-oncological diseases who are diagnosed with DIC by the Japanese systems. Thrombelastography (TEG) is a technique that has been around for many years, but which has gained considerable renewed attention recently due to automation and
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commercial employment [66]. Contemporary versions, e.g. rotational thrombelastography (ROTEM), are increasingly employed in critically ill patients, including those with DIC [11, 67]. The benefit of TEG compared to the usual coagulation parameters is that it includes an assessment of platelet function and of clot-dissolving potential. Procoagulant as well as anticoagulant states as indicated with TEG have a good correlation with clinically important organ dysfunction and survival [12, 13], although its advantage over the usual coagulation assays has not yet been confirmed [14, 68].
Management of coagulation abnormalities in critically ill patients It is obvious that the primary focus of attention in the management of a clinically relevant coagulopathy should be directed towards the adequate treatment of the underlying disorder. This underscores the critical importance of making a correct diagnosis for the condition that has caused the acquired coagulopathy. Despite adequate treatment for the underlying disorder, however, further supportive management of the hemostatic defect is often required [69]. Fresh or frozen plasma contains all coagulation factors, and may be used to replenish congenital or acquired deficiencies of these clotting factors. Current practice guidelines in most centers use solvent or detergent-treated plasma (SDP or ESDP), which may provide better protection against transmission of blood-borne infections, but may also have a lower recovery of coagulation factors [70]. Most consensus guidelines indicate that plasma should only be transfused in case of bleeding or in a situation with a high-risk of bleeding, and not based on laboratory abnormalities alone. For more specific therapy, or if the transfusion of large volumes of plasma is not desirable, fractionated plasma of purified coagulation factor concentrate is available. Prothrombin complex concentrates (PCC’s), contain the vitamin K-dependent coagulation factors II, VII, IX and X. Hence, these concentrates may be used if immediate reversal of vitamin K antagonist treatment is required. Also, PCC’s may be used if global replenishment of coagulation factors is necessary, and large volumes of plasma may not be tolerated. In some cases, administration of purified coagulation factor concentrates, such as fibrinogen concentrate, may be helpful. Most guidelines advocate a platelet transfusion in patients with a platelet count of \30–50 9 109/l accompanied with bleeding or at high risk for bleeding, and in patients with a platelet count\10 9 109/l, regardless of the presence or absence of bleeding. Platelet concentrates usually contain a mixture of the platelets from a blood
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donation from 5 to 6 donors (equals 5–6 units), although in some parts of the world (notably in the US), single donor transfusion has become the usual practice due to a presumed decrease in side effects and less potential antibody formation. Platelet transfusion is particularly effective in patients with a thrombocytopenia due to impaired platelet production or increased consumption, whereas disorders of enhanced platelet destruction (for example immune thrombocytopenia), may necessitate alternative therapies, such as steroids or human immunoglobulin. Some causes of thrombocytopenia may require specific measures. Thrombocytopenia due to HIT (or suspected HIT), requires immediate cessation of heparin and institution of alternative anticoagulant treatment, e.g. with danaparoid, thrombin inhibitors, or fondaparinux [71]. Vitamin K antagonists should be avoided in the initial treatment of HIT, since these agents may cause skin necrosis. In patients with a thrombotic microangiopathy due to antibody-induced low levels of von Willebrand cleaving protease (ADAMTS-13), plasma exchange and immunosuppressive treatment should be initiated, whereas in the case of congenital ADAMTS13 deficiency, plasma infusion suffices [26]. Pro-hemostatic treatment can be used as adjunctive treatment in patients with major blood loss [72, 73]. Deamino D-arginine vasopressin (DDAVP, desmopressin), is a vasopressin analogue that induces release of the contents of the endothelial cell associated Weibel Palade bodies, including von Willebrand factor. Hence, the administration of DDAVP results in a marked increase in the plasma concentration of von Willebrand factor (and associated coagulation factor VIII), and, by as yet unexplained additional mechanisms, a potentiation of primary hemostasis. DDAVP has proven to be effective in the management of patients with von Willebrand’s disease and mild hemophilia A, but also in patients with uremic thrombocytopathy and other defects in primary hemostasis [74]. Anti-fibrinolytic agents, such as lysine analogues (eaminocaproic acid or tranexamic acid), may also be helpful in the prevention or management of bleeding, in particular if hyper-fibrinolysis is thought to be the major contributor to the hemostatic defect. Anti-fibrinolysis therapies may also compensate for other coagulation defects. Anti-fibrinolytic agents have been found effective in the prevention of blood loss and transfusion in patients undergoing major surgical procedures, and are relatively safe [75, 76]. In patients with severe trauma, tranexamic acid is effective in reducing excessive blood loss and reduced mortality [77, 78]. Recombinant factor VIIa is a pro-hemostatic agent that has been licensed for the treatment of patients with hemophilia and inhibiting antibodies towards factor VIII or IX. There is a very large number of case series reporting successful use of recombinant factor VIIa in patients with other types of coagulation defects, or patients with major bleeding due to
surgery or trauma, however, the number of successful controlled clinical trials is still limited. In addition, the safety of recombinant factor VIIa (in terms of thrombotic adverse events), may be an issue [79]. Therefore, until ongoing clinical trials and further safety data in critically ill patients becomes available, off-label use of recombinant factor VIIa can only be justified in the case of life threatening bleeding, when all other conventional treatments have failed [72]. Supportive treatment of the coagulopathy associated with DIC is a complex issue [60]. Administration of anticoagulants may theoretically be beneficial, but their efficacy have never been proven in clinical trials. Restoration of dysfunctional physiological anticoagulant pathways by administration of antithrombin concentrate or (activated) protein C has beneficial effects on laboratory parameters. A large multicenter, randomized controlled trial with antithrombin concentrate shows no significant reduction in mortality of patients with sepsis who are treated with antithrombin concentrate [80]. Interestingly, post hoc subgroup analyses indicate some benefit in patients who do not receive concomitant heparin and in those patients with the most severe coagulopathy, but this observation needs prospective validation [81]. Recent retrospective analyses of large nationwide patient databases from Japan demonstrate that patients treated with antithrombin have a better outcome compared to propensity matched patients who do not receive antithrombin [82–84]. A beneficial effect of recombinant human activated protein C is demonstrated in a randomized controlled phase III trial of recombinant human activated protein C (APC) in patients with severe sepsis [10]. Interestingly, patients who had DIC according to international criteria, benefit more from the therapy with APC than patients who do not have overt DIC [62]. However, meta-analyses of published literature conclude that the basis for treatment with APC, even in patients with a high disease severity, is not very strong. A recently completed placebo-controlled trial in patients with severe sepsis and septic shock was stopped prematurely due to the lack of any significant benefit of APC [85]. Subsequently, the manufacturer of APC has decided to withdraw the product from the market. In a phase III randomized double-blind clinical trial in patients with DIC, administration of soluble thrombomodulin has a significantly better effect on bleeding manifestations and coagulation parameters than heparin, yet the mortality rate at 28 days was similar in the two study groups [86]. When limiting these results to patients with severe infection and sepsis, DIC resolution rates are 67.5 % in thrombomodulin-treated patients and 55.6 % in the control group, and 28-day mortality rates are 21.4 and 31.6 %, respectively. Mortality rates of patients who recover from DIC are 3.7 % in the thrombomodulin group and 15 % in the heparin group [87]. More recent trials and
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observational studies from Japan also point to a potential benefit of this intervention [88, 89].
Conclusions Hemostatic abnormalities are common in critically ill patients, and may significantly affect morbidity and mortality. An adequate diagnosis for the underlying cause of the coagulation abnormality is important, since many of these conditions may necessitate specific treatment. Management of hemostatic abnormalities in critically ill patients should primarily be directed at the underlying cause, but supportive treatment may be required. Deficiencies in platelets and coagulation factors in bleeding patients or patients at risk for hemorrhage can be achieved by transfusion of platelet concentrate or plasma products, respectively. In addition, pro-hemostatic treatment may be beneficial in case of severe bleeding, whereas restoring physiological anticoagulant pathways may theoretically be helpful in patients with sepsis and DIC. Conflict of interest
None.
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