Pathogenesis and diagnosis of disseminated intravascular coagulation

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1 Received: 31 December 2017 Accepted: 07 February 2018 DOI: /ijlh REVIEW ARTICLE Pathogenesis and diagnosis of disseminated intravascular coagulation M. Levi 1,2 1 Department of Medicine, University College London Hospitals NHS Foundation Trust, London, UK 2 Cardiometabolic Programme-NIHR UCLH/ UCL BRC, London, UK Correspondence Marcel Levi, Department of Medicine, University College London Hospitals, London, UK. marcel.levi@nhs.net Abstract Several clinical conditions, in particular those associated with a systemic inflammatory response, can cause some degree of activation of coagulation but when the procoagulant stimulus is sufficiently severe and overcomes the natural anticoagulant mechanisms of coagulation, disseminated intravascular coagulation (DIC) may occur. The clinical manifestations of DIC encompass multiorgan dysfunction caused by fibrin- platelet clots in the microcirculation, and bleeding caused by consumption of platelets and coagulation factors. Molecular mechanisms that play a role in inflammation- induced effects on coagulation have been recognized in much detail. Exposure of blood to tissue factor is the most common trigger, whereas the intravascular coagulation is propagated due to loss of function of physiological anticoagulants and impaired fibrinolysis. In patients with DIC, various abnormalities in routine coagulation parameters may be observed, including thrombocytopenia, prolonged global coagulation assays, or high levels of fibrin split products. In addition, more sophisticated tests for activation of individual factors or pathways of coagulation may point to specific involvement of these components in the pathogenesis of the disorder. A combination of readily available tests is usually sufficient in establishing the diagnosis of DIC, and for this purpose, several scoring algorithms have been developed. Some specific clinical situations may elicit coagulation responses that can be distinguished from DIC or may occur in combination with DIC, including dilutional coagulopathy, liver failure- related coagulation derangement, and thrombotic microangiopathies. KEYWORDS anticoagulants, coagulation, coagulation factors, disseminated intravascular coagulation, fibrin degradation products, fibrinolysis, platelets 1 INTRODUCTION Many disorders, including severe infections or sepsis, cancer, or trauma, may generate some degree of coagulation activation. Usually, this hemostatic activation will not lead to clinically relevant effects and may not even be detected by routine laboratory surveillance, but can only be identified employing sensitive assays for coagulation activation, such as tests for activation peptides or complexes between activated proteases and their inhibitors. 1 However, when the coagulation activation is more robust, consumption of clotting factors and platelets and coagulation proteins may become noticeable through elongation of routine clotting assays (such as prothrombin time and activated partial thromboplastin time) and a low or decreasing platelet count. An even stronger activation of coagulation may manifest as disseminated intravascular coagulation (DIC). DIC is typically characterized by the concurrent presence of widespread thrombotic Int J Lab Hem. 2018;40(Suppl. 1): wileyonlinelibrary.com/journal/ijlh 2018 John Wiley & Sons Ltd 15

2 16 LEVI deposition in the microvasculature and an increased bleeding tendency. The ongoing thrombotic process impedes adequate oxygen delivery to many organs and may thereby be a significant factor in the development of multiple organ dysfunction. 2-4 The bleeding tendency is caused by ongoing activation of the hemostatic system, causing consumption and subsequent exhaustion of clotting factors and platelets, accompanied by reduced synthesis and enhanced degradation of these factors and their inhibitors. As a result, a hemorrhagic tendency may occur, sometimes resulting in spontaneous profuse bleeding from various sites. Many dysfunctional organs in patients affected by DIC display intravascular fibrin deposition at microscopic examination. 5 Experimental studies in animals with DIC have demonstrated intraand extravascular fibrin formation in almost all organs and mitigation of the coagulopathy by various interventions ameliorates organ dysfunction and other clinically relevant outcomes. Clinical studies have demonstrated that DIC is an independent and powerful predictor of organ failure and mortality. 6,7 2 CLINICAL CONDITIONS KNOWN TO BE ASSOCIATED WITH DIC It should be stressed that DIC is not an independent clinical condition but is always a complication of another disease that results in the activation of coagulation. 8 The clinical settings most commonly underlying DIC are listed in Table 1. DIC may complicate the clinical course of about one- third of patients with severe sepsis The incidence of DIC in patients with gram- negative of gram- positive bacterial infections is more or less equal, and systemic infections with viruses, fungi, or parasites may result in DIC as well. 9 Microbial membrane structures, including lipopolysaccharide or lipoteichoic acid, or exotoxins (eg, staphylococcal ɑ- toxin) may elicit a strong immunological response and release of inflammatory mediators. Severe trauma is another clinical setting known to be associated with DIC. 2 DIC is part of a more wider definition of trauma- induced coagulopathy (TIC) that encompasses the dilutional coagulopathy that may occur upon major blood loss and resuscitation with plasma expanders and trauma- induced endothelial dysfunction. Systemic levels of inflammatory mediators in severe trauma patients were demonstrated to be indistinguishable from those of patients with sepsis. 10 In addition, release of tissue material (such as tissue thromboplastin, in particular in patients with head trauma) and disintegrity of the endothelium may aggravate the systemic coagulation activation. Cancer can cause DIC as a result of expression of procoagulant factors by tumor cells. 11 In some series, in particular, in patients with metastasized adenocarcinoma or lymphoproliferative disease, an incidence of up to 20% of patients with DIC complicating the cancer was observed. The clinical manifestation of DIC in patients with malignant disease has commonly a less fulminant presentation than DIC that may be due to other underlying conditions, such as sepsis and trauma. In cancer, a more insidious, but also more protracted, diffuse activation of coagulation can proceed without any symptom. Ultimately, this may lead to deficiency of platelets and clotting factors and hemorrhage (often at the site of the tumor) may be the first clinical symptom indicating the presence of DIC. Obstetric catastrophes, such as placental abruption and amniotic fluid emboli, may be complicated by instantaneous and severe DIC. 12 The extent of placental separation in solutio placentae is related to the severity of DIC, suggesting that release of placental or amniotic material (containing abundant tissue factor) into the maternal blood is initiating coagulation activation and DIC. Disorder Sepsis or severe infections Cancer Severe trauma Obstetrical catastrophes Vascular abnormalities Severe immunologic reactions Heat stroke Examples Gram- positive or gram- negative bacteria, malaria, fungi, viral hemorrhagic fevers Lymphoproliferative disease Acute promyelocytic leukemia or monocytic leukemia Solid tumors, eg, adenocarcinomas (prostate, pancreas, stomach) Multitrauma Brain injury Extensive burns Amniotic fluid embolism Abruptio placentae Intrauterine fetal death Giant hemangiomas Kasabach- Merrit syndrome Other vascular malformations Large aortic aneurysms Severe anaphylaxis Hemolytic transfusion reaction TABLE 1 Clinical disorders commonly associated with DIC

3 LEVI 17 The DIC accompanying vascular malformations is due to localized intravascular clotting and excessive fibrinolysis and fibrinogenolysis due to release of large amounts of plasminogen activators by the abnormal endothelium lining the tumor vessels. 13 In addition, in patients with giant hemangiomas, thrombotic microangiopathy may occur due to excessive release of large multimeric von Willebrand factor. For other underlying conditions (Table 1), DIC is a relatively uncommon consequence. In the majority of settings, the intensity of the associated systemic inflammatory reaction in combination with specific conditions, such as concomitant infections, will determine whether DIC will occur. 3 PATHOGENESIS OF DIC A variety of relevant mechanisms contributing to the derangement of coagulation in DIC have been elucidated. Initiation and propagation of coagulation with concurrent impairment of physiological anticoagulant pathways and a deficit of endogenous fibrinolysis, all as a result of systemic inflammatory activation, are resulting in platelet activation and fibrin deposition. 5 Important inflammatory mediators that govern these processes include tumor necrosis factor (TNF)- ɑ and interleukin (IL)- 1 and IL- 6. In addition, recent work indicates that intravascular webs ( neutrophil extracellular traps ) composed of denatured DNA from destructed cells and entangling neutrophils, platelets, fibrin, and cationic proteins, such as histones, may play a crucial role in the development of thrombus deposition. 14 Thrombin production in DIC originates through activation of the tissue factor/factor VII(a) pathway that will subsequently cause factor Xa and IXa generation. 15 Tissue factor may be exposed by activated mononuclear cells but also by endothelial cells or malignant cells. In DIC, all natural anticoagulant pathways are functionally defective. 5 A significant imbalance of tissue factor pathway inhibitor (TFPI) function compared to the increased tissue factor- dependent coagulation activation has been reported. 16 In addition, a serious deficiency of the protein C system may further impede adequate inhibition of thrombin generation. The impairment in the protein C pathway is caused by a downregulation of thrombomodulin expression on endothelial cells in combination with decreased synthesis and enhanced degradation of protein C. 17 Also, plasma levels of antithrombin, the principal inhibitor of thrombin, are significantly decreased in DIC, due to concurrent consumption, impaired synthesis, and degradation by elastase from activated neutrophils. 5 On top of that, endogenous fibrinolysis is largely inactive due to a sustained rise in plasminogen activator inhibitor- 1 (PAI- 1), the most important regulator of plasminogen activation and plasmin generation. 2 4 DIFFERENTIAL LABORATORY DIAGNOSIS OF DIC The typical laboratory signature of DIC is a coagulopathy characterized by a low (or decreasing) platelet count, prolonged global coagulation assays, and increased fibrin degradation products (such as D- dimer). These laboratory abnormalities may be compatible with DIC; however, some differential diagnostic considerations needs to be taken into account. 18 It may be challenging to differentiate DIC from the coagulation defect due to excessive blood loss and the dilutional coagulopathy caused by massive infusion of large volumes of plasma expanders that may take place in the first hours after major trauma. Sepsis per se can cause thrombocytopenia and the severity of sepsis correlates with the reduction in platelet count. 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. Also, in a significant number of patients with sepsis hemophagocytosis, consisting of active phagocytosis of megakaryocytes and other hematopoietic cells by monocytes and macrophages, can take place. 19 Measurement of isolated coagulation factors in DIC is of limited relevance. Coagulation proteins with a marked acute phase behavior, such as factor VIII or fibrinogen, are usually not decreased or may even increase. One of the often advocated laboratory tests for the diagnosis of DIC, fibrinogen, is therefore not a very sensitive marker for DIC, except in severe cases. Dynamic changes in coagulation factors and platelets may add important information. A significant drop in platelet count, a lengthening duration of clotting assays, or increase in fibrin split products, even still within the normal range, can indicate an early stage of developing DIC. 7 There is no single laboratory test with sufficient accuracy for the diagnosis of DIC. For the diagnosis of DIC, a simple algorithm has been developed by the International Society on Thrombosis and Hemostasis (ISTH). 20,21 The score can be calculated with readily available laboratory parameters, that is, platelet count, prothrombin time, a fibrin- related marker (usually D- dimer), and fibrinogen. Prospective studies have demonstrated that the sensitivity of the DIC algorithm is 93%, with a specificity of 98%. 6 Similar scoring algorithms have been developed and extensively evaluated in various countries. Point- of- care tests are increasingly employed in patients with a coagulopathy related to critical illness, including DIC. 22 Thromboelastography (TEG) is a whole blood coagulation assay in which a small sample of blood is rotated in a cuvette and the strength, elasticity, and dissolution of the forming clot are measured by a torsion wire or by optical means. A variation to this test is rotational thromboelastometry (ROTEM) in which a spinning pin is positioned in a cuvette with whole blood and clotting is detected by reduced rotation of the pin. DIC as measured with thromboelastography was demonstrated to have a good correlation with clinically important organ dysfunction and survival, although its superiority over more common coagulation tests has not yet been established. In a systematic review of 2 randomized controlled trials and 16 observational studies in sepsis, thromboelastography was shown to correctly identify relevant coagulation changes. 23 There was also a relationship

4 18 LEVI between abnormalities in thromboelastography (in particular parameters reflecting speed of clot formation and clot strength) and reduced survival. The use of thromboelastography for the diagnosis of DIC has not been systematically studied although some authors believe that the test may be useful for appraising coagulopathies in critically ill patients. 24 Another test to assess hypercoagulability in critically ill patients is the activated partial thromboplastin (aptt) biphasic waveform analysis that can be detected on some optical coagulation analyzers. The biphasic waveform is related to the occurrence of complexes of very- low- density lipoprotein and C- reactive protein, and its presence was shown to have more than 90% accuracy for development of DIC and an adverse outcome DIC OR LIVER FAILURE? In patients with severe hepatic failure, a myriad of changes in coagulation can be observed. More than 75% of patients with cirrhosis have thrombocytopenia (platelets < /L), and in more than 10% of patients, this is < /L. The reduction in platelet count is due to sequestration of platelets in the enlarged spleen, reduced levels of thrombopoietin, and consumption. 26 In addition, plasma concentrations of almost all coagulation proteins (except factor VIII and von Willebrand factor) are reduced, as the liver is the most important site of coagulation factor synthesis. The combination of thrombocytopenia and low levels of coagulation factors was traditionally interpreted as a hypocoagulable state and associated with a high risk of bleeding. However, recent insights point to a rebalanced hemostatic system in patients with chronic liver failure as low levels of physiological coagulation inhibitors may balance low levels of coagulation factors and thrombocytopenia may be offset by increased levels of von Willebrand factor. 27 The differential diagnosis between the coagulopathy of liver disease and DIC is challenging as many laboratory abnormalities point in the same direction. 8 Even more complex situations may occur when the coagulopathy of liver disease is complicated by DIC, as patients with severe liver disease may present with infectious complications (such as bacterial peritonitis) or leakage of endotoxin from the intestinal compartment that may elicit DIC. However, in most cases, the coagulopathy of liver disease can eventually be distinguished from the presence of DIC. Useful clues may be that in contrast to patients with DIC, in severe liver disease, the (low) platelet count is usually stable and fibrin degradation markers (such as D- dimer) are only mildly increased. 28,29 As the alpha subunit of factor XIII is produced in magakaryocytes and white blood cells, levels of factor XIII may remain relatively stable in patients with impaired liver function despite decreased production of the beta subunit in the liver, whereas in DIC, factor XIII levels are usually low. In addition, clinical signs, such as the presence of splenomegaly and ascites, may indicate that liver disease rather than DIC is the cause of the coagulopathy. 6 THROMBOTIC MICROANGIOPATHY AND DIC The presence of thrombocytopenia and schistocytes in the blood film may point in the direction of a thrombotic microangiopathy, such as thrombotic thrombocytopenic purpura or hemolytic- uremic syndrome. However, these syndromes are typically accompanied by normal clotting times and normal or only slightly elevated D- dimer. Schistocytes may also be seen in patients with DIC as a result of enhanced platelet- vessel wall interaction and formation of microvascular thrombotic obstruction, causing mechanical damage to erythrocytes. Similar to other types of thrombotic microangiopathy, that associated with DIC is caused by an enhanced platelet- vessel wall interaction. A crucial factor in the pathogenesis of this enhanced platelet- vessel wall interaction is thought to be the release of (ultralarge) von Willebrand factor multimers as a result of inflammation- induced endothelial cell perturbations. von Willebrand factor is an acute phase protein that is markedly upregulated and released during systemic inflammation. 30 In addition to very high levels of von Willebrand factor antigen and von Willebrand factor propeptide (indicating substantial release of the protein), ultralarge von Willebrand factor multimers are found in the blood of septic patients and correlate with disease severity. 31 Apart from playing a role as a ligand between platelets and the (sub) endothelium, ultralarge von Willebrand factor may also play a role in further attracting leukocytes to the injured endothelium, facilitating complement activation, and promoting adhesion of microorganisms to the surface of the vessel wall. The concentration of (ultralarge) von Willebrand factor multimers in patients with DIC was inversely correlated with the plasma level of ADAMTS13. Several studies have also confirmed the association between low ADAMTS13 levels and sepsis severity. 30,31 Hypothetically, the inflammation- mediated massive release of von Willebrand factor from the endothelium consumes and depletes the available concentration of ADAMTS13, leading to insufficient cleavage capacity and control of von Willebrand factor multimeric size. 32 Other factors that may contribute to the reduction in plasma activity of ADAMTS13 in patients with sepsis are proteolytic cleavage by neutrophil elastase, thrombin, or plasmin (which are all being generated during sepsis), and inhibition of the metalloprotease by pro- inflammatory cytokines, such as interleukin (IL) Furthermore, competitive inhibition of ADAMTS13 binding to von Willebrand factor caused by high levels of thrombospondin- 1 during severe inflammatory states (during which secretion of thrombospondin as a result of platelet activation may generate a 100- fold increase in its plasma concentration) may (theoretically) contribute to the failure to adequately regulate cleavage of ultralarge von Willebrand factor multimers. 34 Several studies have focused on ADAMTS13 levels in patients with sepsis. Up to one- third of patients with sepsis have ADAMTS13 levels that are <50% of normal. 30,32 One study reported that about 15% of patients had severely reduced (<10%) ADAMTS13 levels; however, it should be noted that this study was carried out in Japanese

5 LEVI 19 patients who have a relatively high frequency of the ADAMTS13 p.p475s polymorphism (allele frequency approximately 10%), which is urea- sensitive. As ADAMTS13 levels in this study were measured with a urea- based assay, these much reduced levels may have been spuriously low. 32 Studies in septic children also report decreased ADAMTS13 levels in the majority of cases, with the deficiency strongly correlating to a more severe coagulopathy. 35,36 Low levels of ADAMTS13 in sepsis are associated with reduced concentrations of cleaved von Willebrand factor. 37 Low levels of ADAMTS13 are also seen more frequently in patients with overt DIC and are strongly correlated with more severe renal insufficiency. 32,38 The decrease in ADAMTS13 levels appears to be clearly associated with severity and increasing organ failure scores. Interestingly, plasma levels of ADAMTS13 were significantly lower (mean levels 31%) in patients with sepsis compared to patients with other systemic inflammatory conditions with a non- infective etiology (mean levels 56%). 39 A strong association is reported between the magnitude of decrease in ADAMTS13 levels in patients with sepsis and an adverse outcome. Significantly lower ADAMTS13 levels are seen at the time of intensive care admission in eventual non- survivors. 40 Patients with ADAMTS13 plasma concentrations 50% had an approximate 10% higher risk of death compared with patients who present with no or only mild reduction in ADAMTS13 levels. 35 One recent study demonstrated an approximate 50% lower survival rate in patients (mortality 59%) with septic shock and ADAMTS13 levels <30%, compared with patients having higher levels of ADAMTS13 (mortality 28%). 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