Current understanding of disseminated intravascular coagulation (2004)

Disseminated intravascular coagulation (DIC) is a syndrome characterized by systemic intravascular activation of coagulation, leading to widespread fibrin deposition in the circulation. There is compelling evidence from clinical and experimental studies that DIC is involved in the pathogenesis of microvascular dysfunction and contributes to organ failure. In addition, the massive, ongoing activation of coagulation may result in depletion of platelets and coagulation factors, which may cause bleeding. Recent insights in important pathogenetic mechanisms that may lead to DIC have resulted in novel preventive and therapeutic approaches for patients with sepsis and deranged coagulation. Thrombin generation proceeds via the (extrinsic) tissue factor/factor VIIa route and simultaneously occurring depression of inhibitory mechanisms, such as antithrombin III and the protein C system. Also, impaired fibrin degradation, because of high circulating levels of plasminogen activator inhibitor, type 1 (PAI-1), contributes to an enhanced intravascular fibrin deposition. Supportive strategies aimed at the inhibition of coagulation activation may theoretically be justified and were beneficial in experimental and initial clinical studies. These strategies comprise inhibition of tissue factor-mediated activation of coagulation or restoration of physiological anticoagulant pathways, for example by means of the administration of recombinant human activated protein C. Systemic activation of coagulation may occur in the context of a variety of disorders. This coagulation activation may only be detectable by measuring sensitive molecular markers for activation of coagulation factors and pathways, but can become clinically manifest as changes in routine coagulation tests may occur (Bauer & Rosenberg, 1987). The spectrum of clinically manifest coagulation activation ranges from a small decrease in platelet count and sub-clinical prolongation of global clotting times to fulminant DIC, characterized by simultaneous widespread microvascular thrombosis and profuse bleeding from various sites (Levi & ten Cate, 1999). In fact, different specialists may view the syndrome in different ways. Surgeons, for example, may consider DIC as a severe bleeding disorder, whereas intensive care specialists may focus on the role of disseminated fibrin deposition in multiple organ failure. This variable appreciation is also reflected by the many names for the syndrome, ranging from disseminated intravascular fibrin formation to consumptive haemorraghic coagulopathy. The reason for this confusion is not because DIC is a new syndrome. Even in the 1950s, precise patient descriptions suffering from what we would now call DIC appeared in the literature (Ratnoff et al, 1955). Centuries before, Celsus already described diffuse haemorrhage from several sites after a snake bite and in 1834, Dupuy noted that the injection of brain material resulted in a widespread intravascular clotting in dogs. DIC is also not a syndrome that has altogether been ignored in the medical literature. The MedLine database contains about 10 000 articles on DIC that were published between 1966 and 2003. Most of the published literature concerns case reports and studies regarding the pathophysiology of DIC. However, less than 1% of the articles report on clinical studies that may be helpful in guiding the clinician to proper and ‘evidence-based’ management strategies in patients with DIC. This lack of useful literature can probably be explained by the fact that DIC has long been a poorly defined syndrome with a widely variable intensity, often complicating a diversity of severe disorders, which are in themselves related to extensive morbidity and mortality (Marder et al, 1994; Levi et al, 1999). Recently, however, the pathogenesis of DIC has largely been clarified and these novel insights may lead to more adequate management strategies. Some of these strategies are currently being tested in clinical trials. In addition, the improved knowledge on the pathogenesis of DIC may facilitate the development of more accurate diagnostic tests to ascertain or reject the diagnosis of DIC. This article briefly discusses the definition, clinical setting and relevance of DIC, and current insights in the pathogenesis of the syndrome. Subsequently, currently available knowledge regarding the clinical management of patients with DIC will be discussed. Disseminated intravascular coagulation is not a disease or a symptom but a syndrome, which is always secondary to an underlying disorder. The syndrome is characterized by a systemic activation of the blood coagulation system, which results in the generation and deposition of fibrin, leading to microvascular thrombi in various organs and contributing to the development of multi-organ failure. Consumption and subsequent exhaustion of coagulation proteins and platelets, because of the ongoing activation of the coagulation system, may induce severe bleeding complications, although microclot formation may occur in the absence of severe clotting factor depletion and bleeding (Levi et al, 1999). Hence, a patient with DIC can present with a simultaneously occurring thrombotic and bleeding problem (Fig 1), which complicates the proper treatment. The subcommittee on DIC of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis (ISTH) has recently proposed the following definition of DIC: ‘DIC is an acquired syndrome characterized by the intravascular activation of coagulation with loss of localization arising from different causes. It can originate from and cause damage to the microvasculature, which if sufficiently severe, can produce organ dysfunction’ (Taylor et al, 2000). The clinical picture of disseminated intravascular coagulation. Obviously, the clinical importance of a severe depletion of platelets and coagulation factors in patients with diffuse, widespread bleeding or in patients that need to undergo an invasive procedure is indisputable. There is some debate as to what extent the intravascular deposition of fibrin, as a result of the systemic activation of coagulation, contributes to organ failure and mortality. There is, however, ample evidence to indicate that DIC indeed contributes to multiple organ failure (Wheeler & Bernard, 1999). Histological studies in patients with DIC show the presence of ischaemia and necrosis, caused by fibrin deposition in small and mid-size vessels of various organs (Coalson, 1986). The presence of these intravascular thrombi appears to be clearly and specifically related to the clinical dysfunction of the organ. Secondly, experimental animal studies of DIC show fibrin deposition in various organs: amelioration of DIC by various interventions appears to improve organ failure and, in some but not all cases, mortality (Creasey et al, 1993; Kessler et al, 1997). Lastly, DIC has shown to be an independent predictor of mortality in patients with sepsis and severe trauma (Fourrier et al, 1992). Taking this data together, there appears to be sufficient evidence for a pathogenetic role of DIC in organ failure and related mortality. Several disease states may lead to the development of DIC. In general, there are two major pathways that may cause DIC (Levi et al, 1997): (i) a systemic inflammatory response, leading to activation of the cytokine network and subsequent activation of coagulation (such as in sepsis or major trauma) and/or (ii) release or exposure of procoagulant material (in)to the bloodstream (such as in cancer or in obstetrical cases). A list of diseases that are known to be potentially complicated by DIC is given in Table I. Bacterial infection, in particular septicaemia, is commonly associated with DIC (Wheeler & Bernard, 1999). There is no difference in the incidence of DIC in patients with Gram negative or Gram positive sepsis (Bone, 1994). In addition, systemic infections with other microorganisms, such as viruses and parasites, may also lead to DIC. Factors involved in the development of DIC in patients with infections may be specific cell membrane components of the microorganism (lipopolysaccharide or endotoxin) or bacterial exotoxins (e.g. staphylococcal alpha toxin). These components cause a generalized inflammatory response, characterized by the systemic occurrence of pro-inflammatory cytokines (van der Poll et al, 1991; Levi et al, 1997). Severe trauma is another clinical condition frequently associated with DIC (Gando, 2001). A combination of mechanisms including release of tissue material (fat, phospholipids) into the circulation, haemolysis and endothelial damage may contribute to the systemic activation of coagulation. In addition, there is solid evidence that cytokines also play a pivotal role in the occurrence of DIC in trauma patients (Roumen et al, 1993; Gando et al, 1997). In fact, systemic cytokine patterns have been shown to be virtually identical in trauma patients and septic patients. Both solid tumours and haematological malignancies may be complicated by DIC (Colman & Rubin, 1990; Levi, 2001) The mechanism of the derangement of the coagulation system in this situation is poorly understood. Solid tumour cells can express different procoagulant molecules, including tissue factor and a cancer procoagulant, a cysteine protease with factor X (FX) activating properties (Rickles & Falanga, 2001). Cancer procoagulant is found in extracts of neoplastic cells and in the plasma of patients with solid tumours (Donati & Falanga, 2001). Some tumours are associated with a form of DIC that is characterized by severe hyperfibrinolysis on top of an activated coagulation system. This is, for example, the case in acute promyelocytic leukaemia and some forms of prostatic cancer (Barbui & Falanga, 2001). Although clinically bleeding predominates in this situation, disseminated thrombosis is found in a considerable number of patients at autopsy. Acute DIC occurs in obstetrical calamities such as placental abruption and amniotic fluid emboli (Weiner, 1986). Amniotic fluid has been shown to be able to activate coagulation in vitro, and the degree of placental separation correlates with the extent of DIC, suggesting that leakage of thromboplastin-like material from the placental system is responsible for the occurrence of DIC. Although the coagulation system may be activated in patients with pre-eclampsia, and HELLP (haemolysis, elevated liver enzymes, and low platelets) syndrome, clinically significant DIC only occurs in a small percentage of patients, usually with secondary complications. Vascular disorders, such as large aortic aneurysms or giant haemangiomas (Kasabach-Merritt syndrome), may result in the local activation of coagulation (Aboulafia & Aboulafia, 1996; Szlachetka, 1998). Activated coagulation factors can ultimately ‘overflow’ to the systemic circulation and cause DIC, but the systemic depletion of coagulation factors and platelets as a result of local consumption is more common. Although some characteristics of microangiopathic haemolytic anaemia and the resulting thrombotic occlusion of small and midsize vessels leading to organ failure may mimic the clinical picture of DIC, these disorders in fact represent a distinct group of diseases. Microangiopathic haemolytic anaemia represents a group of disorders comprising thrombocytopenic thrombotic purpura (TTP), haemolytic uremic syndrome, chemotherapy-induced microangiopathic haemolytic anaemia, and malignant hypertension (Ruggenenti et al, 2000). global clotting such as the and the activated are helpful in microangiopathic haemolytic anaemia from DIC. Several simultaneously occurring mechanisms play a role in the pathogenesis of DIC (Fig deposition is a result of tissue factor-mediated generation that is by anticoagulant mechanisms, such as the antithrombin system and the protein C system. In to enhanced fibrin fibrin is impaired as a result of depression of the system. This of is caused by high circulating levels of a before, in forms of DIC, may be and contribute to bleeding. In more the following are of pathogenetic pathways in disseminated intravascular coagulation. systemic inflammatory endothelial cells and activated cells may produce cytokines that coagulation of coagulation is by tissue factor on activated cells and endothelial In addition, of physiological anticoagulant mechanisms and inhibition of by endothelial cells will intravascular fibrin deposition. plasminogen activator inhibitor, type Thrombin generation is detectable at after the occurrence of or (van der Poll et al, There is ample evidence for a pivotal role of the tissue system in the of of human or in with the tumour factor not show in markers for activation of the system (van et al, 1990; der Poll et al, In with this inhibition of the system not activation of coagulation in et al, of the tissue by specifically tissue resulted in a inhibition of generation in and the occurrence of DIC and mortality in that were with (Taylor et al, 1991; Levi et al, 1994; et al, tissue factor is detectable in the plasma of patients with DIC et al, 1997). Hence, the activation of coagulation in DIC is tissue whereas the of coagulation not to play an important concerns the of the tissue factor may be on cells in and tissue factor on circulating of patients with severe has been & In addition, tissue factor may be on endothelial cells (Levi et al, although the importance of endothelial cell tissue factor in and role in the pathogenesis of DIC is of tissue factor may be localization on cells and other cell et al, although is that these cells tissue factor in et al, 2000). on the of the of tissue factor from to activated platelets on a in an system, is that this tissue factor is between cells from activated cells et al, 2000). impaired of various pathways of coagulation activation may the generation and contribute to fibrin formation 1987). levels of the important of antithrombin are usually in septic patients. This is caused by a combination of as a result of ongoing by which is from activated and impaired antithrombin III levels in DIC are associated with mortality (Fourrier et al, et al, The fact that low levels of antithrombin the clinical of sepsis in studies that antithrombin is indeed involved in the pathogenesis of this disease and associated organ dysfunction et al, In to the decrease in antithrombin a significant depression of the protein C system may This impaired of the protein C is caused by of on endothelial cells by pro-inflammatory such as and & Rosenberg, Levi et al, 2001). The of has been in studies of patients with sepsis et al, 2001). in combination with low levels of protein C of mechanisms as described for results in protein C which will the procoagulant of severe coagulation activation show that the protein C system results in morbidity and whereas an adequate of activated protein C and organ failure (Taylor et al, in with a of the protein C in protein C have more severe DIC and organ dysfunction and a mortality than type (Levi et al, being in the physiological of activated protein C has probably also important which may be of relevance in the pathogenesis of DIC 2001). The significant of coagulation is tissue factor The role of in the pathogenesis of DIC is not that the administration of recombinant than physiological plasma of generation in and the that of are of mortality systemic and that high of are of tissue factor-mediated coagulation (Creasey et al, 1993; et al, 2000). However, the of is of coagulation activation and systemic et al, indicate that at the of activation of coagulation, the system is largely and results in a occurring in probably because of the release of plasminogen from endothelial cells (Levi et al, 1994). However, this is by a of caused by a in plasma levels of et al, et al, has been shown that a in the the not only the plasma levels of but also to clinical of et al, 1999). strategies that are able to the such as factor or recombinant no on the activation and subsequent inhibition of suggesting an independent of these two activation that not only with coagulation protein but also with specific cell to induce pathways that inflammatory (Fig such as and fibrin, can activate endothelial the of pro-inflammatory cytokines and factors (van der Poll et al, 2001). The important mechanisms by which coagulation is by to protease activated or of which have been all to the of 2000). and are whereas but can be activated by the tissue and 1 can also as a of the tissue and are in the on endothelial platelets, and cells 2000). In evidence for a role of of from that the administration of recombinant to human a small but significant to in plasma levels of and et al, In addition, all physiological anticoagulant pathways are of inflammatory This is shown for the protein C activated protein C has been found to of and by et al, 1994; et al, of activated protein C inflammatory and organ and in an experimental sepsis in (Taylor et al, It is that the of activated protein C on are by the endothelial protein C The between coagulation, and pathways and a diagnosis of DIC, is of important to the clinical into the clinical condition of the the and all available available is sufficiently sensitive or specific to a diagnosis of DIC. In a molecular markers for activation of coagulation or fibrin formation may be the sensitive A number of clinical studies show that the presence of fibrin in plasma has a for the diagnosis of DIC but the is low & 2001). problem is that a for fibrin in plasma is not available and a a various et al, 1999). The of DIC can also be by measuring activation markers that are the of a coagulation factor to an such as activation (Bauer & Rosenberg, et al, these markers are elevated in patients with DIC but the is a In to these of the sensitive and tests described are not available to Although these tests may be helpful in clinical or other often be in a routine A new development is the of the that an measuring global clotting such as the et al, It has been shown that a is a specific and sensitive for DIC. the to this will not be available at Most will have an for fibrin may be by specific or by and in However, some of the available for with the which may cause high results 1996; Levi et al, The of high levels of is and many other such as or are associated with elevated recently tests are specifically aimed at the of on fibrin, such as levels are high in patients with DIC but poorly patients with DIC from patients with trauma or et al, However, in clinical a diagnosis of DIC can often be by a combination of platelet of global clotting times and of or two clotting factors and (such as and a for It be that coagulation tests are usually more helpful than results in the diagnosis of DIC. A in the platelet count or a at subsequent is a sensitive not of DIC et al, The prolongation of global clotting times may the consumption and depletion of various coagulation factors, which may be by the of coagulation factors, such as and of coagulation factors may also be helpful for the of example, caused by has been widely as a useful for the diagnosis of DIC but in fact is not as an and is for example, also in and, ongoing plasma levels can the for a long In a of patients, the of a low for the diagnosis of DIC only and in a small number of severe of DIC only (Levi et al, 1999). of be more useful and diagnostic for or may be helpful to from other that may be associated with a low platelet count and clotting such as liver However, as before, of these tests are not and high levels may be in various clinical A system that tests that are available in all has recently been by the subcommittee on DIC of the (Taylor et al, 2000). The presence of an underlying known to be associated with DIC, as in Table is a for the of the on a a of or more is to be with DIC. studies show a high of this system for the diagnosis of DIC. The of the DIC for a diagnosis of DIC is and the is show that the DIC system is a independent predictor of a in intensive care patients. These studies show that patients with sepsis and DIC, to the system, have a mortality of as with in patients DIC. ‘DIC in the system, the for mortality is in for and the for mortality is The of DIC is the specific and of the underlying disorder. In some cases, the DIC will and after of the underlying condition example, in of DIC by However, in other cases, such as in patients with sepsis and a systemic inflammatory syndrome, DIC may after proper has been In cases, to the DIC can be and may morbidity and mortality. The in the into the various mechanisms that play a role in DIC has indeed been in the development of management as levels of platelets and coagulation factors the of bleeding. However, plasma or platelet not be on the of results is only in patients with bleeding and in an invasive procedure or at for bleeding et al, 1998). The that administration of blood components to the has been in clinical or experimental studies. The of with or platelets is not on but appears to be in bleeding patients or in patients at for bleeding with a significant depletion of these It may be to large of plasma to the coagulation factor such as will this but these lack factors, such as in is with the of in DIC, as may the caused by small of activated factors in the It is, however, not this is for the that are currently in in coagulation factors, such as can be by the administration of coagulation factor studies have shown that can at the activation of coagulation in sepsis and other of DIC et al, case in patients with DIC have to be However, a beneficial of on clinically important in patients with DIC has been in clinical Also, the of is in DIC patients are to bleeding. of are in patients with clinically or extensive fibrin such as purpura or with DIC may from to which will not be with et al, the anticoagulant to in DIC is tissue factor recombinant tissue factor inhibitor, and recombinant anticoagulant protein a and specific of the between tissue and of recombinant in patients with sepsis results but a recently III not show an in patients that were with et al, et al, in an a defined of patients with an International of associated with a more antithrombin is of the important physiological of coagulation, on the of antithrombin III in patients with DIC has been and Most of the patients with septic or show some beneficial in of of of the of DIC, or in organ (Levi et al, 1999). In the more clinical high of antithrombin were to plasma A of small a in mortality in patients (Fourrier et al, 1993; et al, et al, however, no a significant A to this no significant in the mortality of patients with sepsis were with antithrombin et al, 2001). some in patients not but this on the that depression of the protein C system may contribute to the pathophysiology of DIC, of activated protein C be A III of activated protein C in patients with sepsis because of the in mortality in these patients et al, 2001). mortality at after in the activated protein C group in the group Some were regarding this regarding the of on however, these no significant on the of this The administration of activated protein C to cause an amelioration of coagulation and activated protein patients less organ failure et al, In view of the that activated protein C has on of the may have been caused by a beneficial on inflammatory a of this that patients were as DIC, to the DIC system of the a of activated protein C than patients not have DIC The in mortality of patients with sepsis and DIC that activated protein C in with a of in patients with sepsis not have DIC. This to the importance of the coagulation derangement in the pathogenesis of sepsis and the of that restoration of microvascular anticoagulant pathways may in the of DIC. protein C has been in for the of patients with severe sepsis and two or more organ studies focus on the of in patients activated protein C and the of activated protein C in patients with less severe Disseminated intravascular coagulation is a syndrome characterized by systemic intravascular activation of coagulation in the circulation, which contributes to organ failure. the consumption of platelets and coagulation factors may lead to bleeding. Recent knowledge on important pathogenetic mechanisms that may lead to DIC has resulted in clinical management strategies. The important pathways are tissue factor-mediated of physiological anticoagulant such as the antithrombin and protein C and inhibition of a system on the clinical of the patient in combination with a number of an accurate diagnosis of DIC can be The of the management of DIC is the specific and of the underlying disorder. In addition, strategies that with the coagulation system, such as activated protein were found to be beneficial in experimental and clinical studies.