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Differences and similarities between disseminated intravascular coagulation and thrombotic microangiopathy
Thrombosis Journal volume 16, Article number: 14 (2018)
Both disseminated intravascular coagulation (DIC) and thrombotic microangiopathy (TMA) cause microvascular thrombosis associated with thrombocytopenia, bleeding tendency and organ failure.
Reports and discussion
The frequency of DIC is higher than that of thrombotic thrombocytopenic purpura (TTP). Many patients with TMA are diagnosed with DIC, but only about 15% of DIC patients are diagnosed with TMA. Hyperfibrinolysis is observed in most patients with DIC, and microangiopathic hemolytic anemia is observed in most patients with TMA. Markedly decreased ADAMTS13 activity, the presence of Shiga-toxin-producing Escherichia coli (STEC) and abnormality of the complement system are useful for the diagnosis of TTP, STEC-hemolytic uremic syndrome (HUS)and atypical HUS, respectively. However, there are no specific biomarkers for the diagnosis of DIC.
Although DIC and TMA are similar appearances, all coagulation, fibrinolysis and platelet systems are activated in DIC, and only platelets are markedly activated in TMA.
Disseminated intravascular coagulation (DIC) [1, 2] is a serious disease that causes microvascular thrombosis associated with thrombocytopenia, a bleeding tendency and organ failure. These symptoms and laboratory data are similar to those of thrombotic microangiopathy (TMA)  which includes thrombotic thrombocytopenic purpura (TTP) [4, 5], Shiga-toxin-producing Escherichia coli (STEC) - hemolytic uremic syndrome (HUS) [6, 7], complement-mediated TMA (also called atypical HUS; aHUS) [7, 8] and secondary TMA [3, 9]. DIC also has several clinical subtypes, including asymptomatic type, marked bleeding type, organ failure type and complication types such as TTP or heparin-induced thrombocytopenia . As the treatment of DIC  differs from that of TMA [4, 12], it is important to perform a differential diagnosis of DIC and TMA. The differences and similarities between DIC and TMA are reviewed in this study.
Differences in the definition and concept of DIC and TMA
The frequency of pneumonia associated DIC was reported to be about 10,000 cases per year according to the Japanese Diagnosis Procedure Combination (DPC) database , suggesting that DIC due to pneumonia occurs in about 70/106 populations. With the addition of other types of DIC, the frequency of all DIC is about 300/106 populations. In contrast, the frequency of TTP was reported to be 2.0/106 populations . These reports suggest that the frequency of DIC in Japan is 150-fold higher than that of TTP (Fig. 1). According to the International Society of Thrombosis and Haemostasis (ISTH), DIC is an acquired syndrome characterized by the intravascular activation of coagulation with the 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. DIC is characterized by the generation of fibrin related markers (FRMs; soluble fibrin monomers, fibrinogen and fibrin degradation products [FDPs], D-dimers, etc.) and reflects an acquired (inflammatory) or non-inflammatory disorder of the microvasculature . Regarding the definition of TMA, TMA presents with microangiopathic hemolytic anemia (MHA), including hemolytic anemia, thrombocytopenia and organ failure in the kidney, central nervous system, and other organs [3, 4]. These findings suggest that marked elevation of FRMs is required in DIC while MHA is required in TMA; the diagnosis of TTP among TMA requires a markedly decreased ADAMTS13 level , that of STEC-HUS requires the detection of a STEC infection  and that of aHUS requires the detection of abnormalities in the complement system .
However, DIC has no specific marker for its diagnosis and is instead diagnosed by a scoring system using global coagulation tests. Furthermore, DIC is often associated with TMA, and TMA is often associated with DIC , suggesting that a differential diagnosis between DIC and TMA may be difficult.
DIC associated with TMA was observed in patients with bone marrow metastasis of solid cancer as gastric cancer, those with liver failure and those with group A streptococcal infection. In patients with DIC, bone marrow metastasis mainly causes MHA, liver failure mainly causes an increase in the von Willebrand factor/ADAMTS13 ratio, and group A streptococcal infection mainly cause massive hemolysis. However, it would be much more important to find TMA associated with DIC.
Differences and similarities in the mechanism of onset for DIC and TMA
The basic mechanism of onset for DIC is the marked activation and consumption of coagulation system followed by the activation of secondary fibrinolysis . In contrast, the basic mechanism of onset for TMA is the marked activation and consumption of platelets due to several factors followed by the activation and injury of vascular endothelial cells [19, 20] (Fig. 2). Triggers of the activation of coagulation system are reported to include tissue factor (TF) [21, 22], inflammatory cytokines [23, 24] and lipopolysaccharide (LPS) , the activation leukocytes  and abnormal delivery among others. Trigger of platelet and vascular endothelial cells activation are reported to be a marked decrease in the ADAMTS13 levels in TTP , the detection of STEC in STEC-HUS  and the detection of abnormalities in the complement system in aHUS , along with other factors, such as transplantation, pregnancy, drugs and immune diseases, in secondary TMA . Particularly marked decreases in the ADAMS13 level result in an inability to cleave ultra-large multimers of von Willebrand factor [29, 30], thereby causing platelet aggregation. Markedly fibrinolysis is frequently observed in most patients with DIC, except for some septic DIC cases , while markedly fibrinolysis is not observed in patients with TMA.
Both DIC and TMA cause microvascular thrombosis, which is caused mainly by the activation of the coagulation system in DIC and by the activation of platelets and vascular endothelial cells in TMA. Several cases of TMA have been reported to be complicated with hemophilia patients treated with activated prothrombin complex concentrates (APCCs) in the clinical trial for Emicizumab . As APCCs usually causes DIC but not TMA, the differential diagnosis is important in these cases . Although DIC is an acquired disease, Upshaw-Schulman syndrome as familial TTP  and many patients with aHUS are examples of congenital TMA.
Difference in the diagnosis between DIC and TMA
As there is no gold standard for diagnosing DIC and no specific biomarker that clearly diagnoses DIC, the differential diagnosis between DIC and TMA is difficult. Four diagnostic criteria for DIC has been established by the Japanese Ministry of Health, Labor and Welfare , ISTH , Japanese Association for Acute Medicine  and the Japanese Society on Thrombosis and Hemostasis (JSTH) [37, 38]. These diagnostic criteria use a similar scoring system based on global coagulation tests (GLTs) such as the platelet count, prothrombin time (PT), FRMs (Table 1). Therefore, there are no significant differences in the usefulness among various diagnostic criteria for DIC . The diagnosis of TMA is based on the presence of hemolytic anemia (hemoglobin < 10 g/dl), thrombocytopenia (12 × 109/ml) and organ failure. TMA patients with ADAMTS13 < 10%, those with STEC and those with abnormalities in the complement system can be easily diagnosed with TTP, STEC-HUS and aHUS, respectively (Table 2) [4, 40, 41]. However, markedly decreased ADAMTS13 levels have been reported in severe sepsis patients without TTP [42, 43], suggesting that platelet activation due to decreased ADAMTS13 might be observed in DIC patients with severe sepsis. The diagnosis of other TMA aside from DIC with hemolysis is difficult. Most patients with TMA can be diagnosed using several DIC diagnostic criteria to have DIC, but only 10%–15% of DIC patients can be diagnosed to have TMA (Fig. 2).
Differences and similarities between DIC and TMA
The differences and similarities between DIC and TMA are described in Table 3. Among clinical symptoms, bleeding and organ failure are frequently observed in patients with DIC as well as those with TMA, but lung or cardiovascular failures is more frequently observed only in patients with DIC , while renal or central nervous system failure is more frequently observed in patients with TMA . Hypotension as organ failure is observed in many patients with DIC, while hypertension tend to be observed in patients with TMA . Hypertension may be caused by acute kidney injury or arterial occlusion. Anemia is also more frequently observed in patients with TMA [20, 46] than in those with DIC. Red blood cell fragmentation may be caused by microvascular thrombosis on the arterial side which has a high blood pressure, but not on the venous side (Fig. 3). Among laboratory data, thrombocytopenia is observed in both DIC and TMA. A decreased hemoglobin level and increased levels of creatinine, total bilirubin and LDH are observed in most patients with TMA, but these abnormalities are observed in only 15% of patients with DIC. A prolonged PT and decreased AT and albumin levels are frequently (but not always) observed in patients with DIC. Markedly elevated FRMs are observed in most patients with DIC. As markedly fibrinolysis may dissolve microthromboses in patients with DIC but not in those with TMA, thrombosis of DIC is not usually detected on autopsy. Therefore, elevated FRMs and decreased platelet counts are the most useful markers for DIC .
In Japan, regarding the treatment of DIC and TMA, platelet transfusion is contraindicated for TMA , while anticoagulant therapy for DIC, but not for TMA, is recommended [10, 11]. Anti-fibrinolytic therapy is recommended for DIC patients with hyperfibrinolysis. Plasma exchange is recommended in most some cases of TMA such as TTP , but not for DIC. Antithrombin concentrate  and recombinant thrombomodulin  for DIC are frequently used in Japan, while eculizumab  has proven effective for compliment mediated TMA, such as aHUS, and rituximab  is effective for TTP in patients with a high titer of inhibitor for ADAMTS13.
DIC and TMA are similar appearances, however, all coagulation, fibrinolysis and platelet systems are activated in DIC, and only platelets are markedly activated in TMA. As treatment is different between DIC and TMA, differential diagnosis between DIC and TMA is important.
Disseminated intravascular coagulation
Diagnosis Procedure Combination
fibrinogen and fibrin degradation products
fibrin related markers
global coagulation tests
Hemolytic uremic syndrome
International Society of Thrombosis and Haemostasis
Japanese Society on Thrombosis and Hemostasis
microangiopathic hemolytic anemia
Shiga- toxin-producing Escherichia coli
thrombotic thrombocytopenic purpura
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This work was supported in part by a Grant-in-Aid from the Ministry of Health, Labour and Welfare of Japan and the Ministry of Education, Culture, Sports, Science and Technology of Japan.
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