Disseminated Intravascular Coagulation: The Past, Present, and Future Considerations

Abstract

Disseminated intravascular coagulation (DIC) has been understood as a consumptive coagulopathy. However, impaired hemostasis is a component of DIC that occurs in a progressive manner. The critical concept of DIC is systemic activation of coagulation with vascular endothelial damage. DIC is the dynamic coagulation/fibrinolysis disorder that can proceed from compensated to decompensated phases, and is not simply impaired hemostasis, a misunderstanding that continues to evoke confusion among clinicians. DIC is a critical step of disease progression that is important to monitor over time. Impaired microcirculation and subsequent organ failure due to pathologic microthrombi formation are the pathophysiologies in sepsis-associated DIC. Impaired hemostasis due to coagulation factor depletion from hemodilution, shock, and hyperfibrinolysis occurs in trauma-associated DIC. Overt-DIC diagnostic criteria have been used clinically for more than 20 years but may not be adequate to detect the compensated phase of DIC, and due to different underlying causes, there is no “one-size-fits-all criteria.” Individualized criteria for heterogeneous conditions continue to be proposed to facilitate the diagnosis. We believe that future research will provide therapeutics using new diagnostic criteria. Finally, DIC is also classified as either acute or chronic, and acute DIC results from progressive coagulation activation over a short time and requires urgent management. In this review, we examine the advances in research for DIC.

Keywords

disseminated intravascular coagulation - thrombus - hemostasis - fibrinolysis - endothelial cell

In the 1950s, the term “disseminated intravascular coagulation (DIC)” indicated a mysterious thrombo-hemorrhagic syndrome.[1] Initially, DIC was understood as pathologic findings on postmortem of diffuse microvascular thrombosis, and did not consistently include clinical manifestation of hemorrhage. As its name suggests, systemic fibrin clot formation in the vasculature was the critical manifestation of DIC.[2] However, DIC has attracted interest as a clinical entity because of its unique presentation where bleeding and thrombosis coexist,[3] [4] especially with a paradox of two contrasting states due to activated coagulation followed by consumptive coagulopathy. The international diagnostic criteria were reported based on this concept.[5] Nevertheless, understanding DIC is still confusing for clinicians and investigators.[6] DIC is not a disease by itself but a pathophysiologic process due to a specific underlying disorder. However, DIC is commonly used when patients present with hemostatic disorders secondary to underlying critical conditions.[3] For more than 50 years, discussion regarding the diagnosis of DIC appears to have influenced research; however, there has not been any agents developed for treating DIC. Heparin as a therapeutic agent has been discussed since the 1960s, and the debate is still ongoing.[7] [8] Recently, Umemura et al[9] suggested the awareness of DIC development could improve outcomes, and we should consider the history of DIC to facilitate future studies.

DIC management depends on treating the underlying diseases, the specific thrombotic or bleeding-predominant coagulopathy, and the acute or chronic onset. Acute DIC is triggered by life-threatening disorders such as infection/sepsis, trauma, and obstetrical complications where the clinical conditions change rapidly. Chronic DIC refers to a gradual activation of coagulation, a finding commonly seen in solid cancers,[10] that causes chronic consumption of coagulation factors. In this review, we will focus on acute DIC.

Disseminated Intravascular Coagulation in the Past

Underlying Conditions and Classification

DIC is a secondary complication that arises from various underlying diseases.[5] Common causative diseases include severe infection, solid tumor, hematological neoplasia, pregnancy complication, vascular disease, neonatal pathologies, tissue damage due to internal or external insult, and chemical and biological agents.[11] However, according to specific DIC definitions, not all are considered to cause DIC. For example, aortic aneurysm or Kasabach-Merritt syndrome can cause consumptive coagulopathy characterized by thrombocytopenia with elevated D-dimer and prolonged prothrombin time. Patients may present with bleeding tendency, and the clinical presentation and laboratory findings can mimic DIC. However, the platelets and coagulation factors are consumed at the local site, and systemic endothelial damage is absent. Therefore, it may not be proper to apply the DIC diagnosis based only on the clinical feature and laboratory findings.

DIC can also be divided into two phenotypes that include thrombosis and/or bleeding manifestations. Both types can progress to a consumptive coagulopathy and are recognized as decompensated DIC[12] ([Fig. 1]). From the viewpoint of fibrinolysis, DIC can develop as an “enhanced fibrinolysis” type or a “suppressed fibrinolysis” type, with clinical manifestations as bleeding and thrombosis, respectively.[13] Fibrinolysis seems to be secondary to coagulation activation, but in the suppressed fibrinolysis type, disorganized endothelial production of plasminogen activator inhibitor 1 (PAI-1) and thrombin-mediated activation of thrombin-activatable fibrinolysis inhibitor suppress the fibrinolytic function, sometimes termed “fibrinolytic shutdown.”[14]

Fig. 1 The dual aspects of disseminated intravascular coagulation (DIC) and representative underlying diseases. DIC can be classified into the thrombotic type and the bleeding type; however, the clinical symptoms are often a mixture of thrombotic and bleeding phenotypes. Intravital microscopic views of the mesenteric microcirculation in the sepsis model of rats are shown. The left panel demonstrates the thrombus formation and the right panel showed extravasation of red blood cells after lipopolysaccharide injection. The characteristics of DIC are roughly divided into either thrombotic type or bleeding type based on the underlying diseases. The representative diseases of thrombosis-type DIC and bleeding-type DIC are listed.

DIC determination by biomarkers depends on specific biomarkers examined. Sensitive molecular markers such as thrombin–antithrombin complex, soluble fibrin, and plasmin–antiplasmin complex have been proposed, but still optimal hemostatic markers are lacking.[15] There are no established biomarkers for the evaluation of endothelial damage, although glycocalyx components, endothelial adhesion molecules, and extracellular vesicles are potential candidates considered.[16] [17] The relevance of activated coagulation on thrombus formation varies among the underlying diseases. For example, readily available coagulation tests, including D-dimer and prothrombin time, represent critical components of sepsis-associated DIC, but are only mild to moderately altered in COVID-19-associated coagulopathy, likely due to specific activation in the lung microcirculation and systemic coagulation activation being less significant.[18] Despite distinctly different pathogenesis, both diseases can progress to microthrombosis. The question often asked is COVID-19-associated coagulopathy DIC. Of note is that it does not initially fulfill the criteria of overt-DIC, but has some similarities.[19] We suggest that DIC should not be based on whether the condition fulfills overt DIC criteria. Finally, although all DIC scoring systems include platelet count/thrombocytopenia, the platelet count is only a quantitative number and not a direct indicator of coagulation systems. Although decreased platelet counts can represent activated coagulation, endothelial injury, and consumption, platelets are critical for clotting, and facilitate inflammatory responses. Neutrophils and platelets are the first lines of host defense, activated platelets trigger neutrophil extracellular traps (NETs) release, and platelets–leukocytes aggregates provide the platforms for the microthrombosis.[20] Therefore, the platelet count is also affected by inflammation, and the count can be influenced by both infectious and noninfectious diseases.

Definition and Diagnosis

For many years, DIC was recognized as a consumptive coagulopathy because the diagnosis was suggested by the clinical manifestation (i.e., unusual bleeding and/or organ dysfunction). Furthermore, a definitive diagnosis was developed using the overt-DIC diagnostic criteria released by the International Society on Thrombosis and Haemostasias (ISTH[5]; [Table 1]). The overt-DIC criteria were designed to categorize a definitive DIC associated with a critical hemostatic disorder, and organ dysfunction. However, over time, early detection was suggested because coagulopathy was recognized as an important cause of organ dysfunction.[21] Recent research supports the concept that the preceding coagulopathy contributes to progression in various diseases,[22] with diagnostic criteria to determine early phase of acute DIC.[23] As a result, the Japanese Association for Acute Medicine (JAAM) criteria were specially designed for acute DIC, mainly sepsis-associated DIC, and are widely used in Japan.[24] However, the JAAM criteria were not adopted by others because anticoagulation for early-phase DIC was not routinely followed outside Japan. Based on the pathophysiology and the critical role of immunothrombosis in organ dysfunction,[25] [26] the Scientific Standardization Committee (SSC) of the ISTH released a new category of early-phase DIC arising from sepsis as the sepsis-induced coagulopathy (SIC) in 2019.[27]

Table 1 ISTH overt DIC, JAAM DIC, and SIC scoring systems

		ISTH overt DIC	JAAM DIC	SIC
Item	Score	Range	Range	Range
Platelet count (×109/L)	3	−	<80 ≧50% decrease within 24 h	−
	2	<50	−	< 100
	1	≧50, <100	>120, ≦80 ≧30% decrease within 24 h	≧100, <150
FDP (D-dimer)	3	Strong increase	≧25 μg/mL (use convert chart)	−
	2	Moderate increase	−	−
	1	−	≧10, <25 μg/mL (use convert chart)	−
PT ratio	2	≧6 s	−	>1.4
	1	≧3 s, <6 s	≧1.2 (PT ratio)	>1.2, ≦1.4 (PT ratio)
Fibrinogen (g/mL)	1	<100	−	−
SIRS score	1	−	>3	−
SOFA score	2	−	−	≧2
	1	−	−	1
Total score for DIC or SIC		≧5	≧4	≧4

Abbreviations: DIC, disseminated intravascular coagulation; ISTH, International Society on Thrombosis and Haemostasis; JAAM, Japanese Society on Acute Medicine; PT, prothrombin time; SIC, sepsis-induced coagulopathy; SIRS, systemic inflammatory response syndrome; SOFA, sequential organ failure assessment.

Note: Total SOFA score is the sum of four items (respiratory SOFA, cardiovascular SOFA, hepatic SOFA, and renal SOFA).

As a reminder, the consensus definition of DIC by the ISTH in 2001 reported, “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.”[5] The original concept of DIC established at that time was the systemic activation of coagulation and not a consumptive coagulopathy. Therefore, criteria that can determine the preceding compensated phase of DIC were needed. The JAAM DIC criteria and SIC can cover the thrombosis type of DIC but are not suitable for detecting early stages of bleeding (enhanced fibrinolysis)-type DIC in trauma and obstetric emergency. For the early and accurate detection of bleeding-type coagulopathy, measurement of platelet counts and fibrinogen are helpful.[28] In addition, viscoelastic testing for this type of coagulopathy has been useful.[29] Therefore, we propose to build an individualized scoring system that can capture the dynamic status of coagulopathy.

Thrombosis-Type Disseminated Intravascular Coagulation

Sepsis-Associated DIC

Sepsis is the most common underlying disease causing DIC. The systemic activation in coagulation and microthrombus formation is understood as essential host responses to infection. The systemic infection induces (1) sequential responses that activate coagulation, (2) disrupted in antithrombotic mechanisms, and (3) suppressed fibrinolysis. Since these changes are natural host defenses, a high incidence of associated DIC is not surprising.[30] Coagulation is activated by various mechanisms. Monocytes, platelets, and endothelial cells are stimulated by pathogen-associated molecular patterns as well as damage-associated molecular patterns (DAMPs) released from host cells via pattern-recognizing receptors and express procoagulant factors on their surface.[31] [32] Tissue factor–initiated extrinsic pathway and phosphatidyl serine–initiated intrinsic pathway upregulate the prothrombotic responses in collaboration with platelets, and these mechanisms are further facilitated by the release of microvesicles that express or contain the same procoagulant factors.[33] [34] Physiologic anticoagulation systems that include the antithrombin–heparan sulfate system and thrombomodulin–protein C system prevent unfavorable thrombosis; however, these systems are readily impaired during sepsis.[35] Also, vascular endothelial cells provide antithrombotic effects but can shift to prothrombotic state following injury, with decreased production of nitric oxide, prostaglandin I2, shedding glycocalyx, expressing adhesion molecules, and releasing von Willebrand factor. This acquired endotheliopathy is a major factor of thrombogenicity in sepsis.[36] Finally, suppressed fibrinolytic system via increased production of PAI-1 leads to decreased circulation during sepsis, and this impaired fibrinolysis is critical for thrombosis-type DIC development[37] ([Fig. 2]). As a result of these sequential events, disseminated microthrombi, namely immunothrombosis, are formed leading to detrimental organ dysfunction. The epoch-making event in this field was the discovery of NETs in 2004 and the subsequent report on immunothrombus formation. The major components of NETs are DNA, histones, and cytotoxic proteases which are all highly procoagulant and proinflammatory.[38] Immunothrombus is the hallmark of SIC that takes the position of the crossroad between host defense and tissue microcirculation.[39] Since SIC is most common with a high mortality, further research in this field is warranted.

Fig. 2 The time course of thrombosis-type disseminated intravascular coagulation (DIC) and bleeding-type DIC. The predominant phenotype changes dynamically usually from thrombotic to bleeding predominant. Activated coagulation, suppressed fibrinolysis, endothelial damage, decreased anticoagulant activity, and increased platelet activity are the positive factors that increase thrombotic property. By contrast, loss of coagulation, increased fibrinolysis, and impaired platelet function are the negative factors and facilitate bleeding. Both types of DIC finally lead to the consumptive coagulopathy.

COVID-19-Associated Coagulopathy

COVID-19 is associated with macro- and microthrombosis.[40] In the early phase of the disease, the thrombosis is primarily localized in the lung microvasculature and contributes to the ventilation–perfusion mismatch and results in hypoxemia.[41] However, it can spread systemically as the disease progresses, and patients may develop secondary bacterial infections and systemic coagulopathy.[41] There is still a debate on whether COVID-19-associated coagulopathy (CAC) is DIC or different from DIC because CAC rarely fulfills overt-DIC criteria.[42] Apart from the argument, we have proposed the diagnostic criteria of CAC as proven COVID-19 and two or more of the following criteria: (1) decrease in platelet count (less than 150 × 10⁹/L); (2) increase in D-dimer (more than two times the upper limit of normal); (3) more than 1 second prolonged prothrombin time or international normalized ratio (INR) greater than 1.2; (4) decrease in fibrinogen level; and (5) the presence of thrombosis (macrothrombosis including deep vein thrombosis/venous thromboembolism, thrombotic stroke, acute coronary syndrome, etc.).[19] The enigma of COVID-19 is the coagulation test abnormalities leading to the frequent thrombosis recognized in severe cases. Although D-dimer levels are moderately elevated, platelet count and prothrombin time are usually within a normal range, and fibrinogen levels are elevated.[43] However, platelet α-granule components are increased, including large von Willebrand factor macromolecules, platelet factor 4, and P-selectin,[44] and the presence of autoimmune antibodies such as antiphospholipid antibodies indicates the relevance of activated platelets and adaptive immunity to thromboinflammation.[45] [46] SARS-CoV-2 can modify the platelet function and antithrombotic property of vascular endothelium to prothrombotic by binding to angiotensin-converting enzyme 2 (ACE2) on the cellular surface, and these changes can be the predominant causes of thrombosis in COVID-19.[18] Endotheliopathy is induced via the binding of SARS-CoV-2 to ACE2 on endothelial cells. Suppressed regulation of type I interferon and the decreased major histocompatibility complex class II–related activity due to the explosive replication of causative viruses in dendritic cells and macrophages are reported.[47] CAC is a new type of coagulopathy that we have never experienced. From the viewpoint of definition, since CAC is associated with systemic activation in coagulation and the derangement of endothelial cells, it can be recognized as DIC. Currently, the effects of anticoagulants are actively being examined, and the results will be feedback to other types of coagulopathies.[48]

Obstetrical Disseminated Intravascular Coagulation

Although the clinical phenotype is primarily bleeding, some obstetrical emergencies, such as placental abruption, amniotic fluid embolism, and preeclampsia, can be complicated with thrombosis.[49] For example, in preeclampsia, incomplete endovascular trophoblast invasion with the reduced remodeling of uterine arteries leads to placental hypoperfusion and cytokine production, and increased nucleosome and cell-free DNA in plasma activate coagulation.[50] [51] Different from other thrombotic DIC, the clinical characteristics of non–bleeding-caused obstetrical DIC are often organ dysfunction associated with bleeding.[52] The consumption of coagulation factors following activated coagulation, especially the depletion of fibrinogen, is the crucial point in the development of impaired hemostasis.[53] However, to detect the subclinical phase of obstetrical DIC, not only identifying the decrease in coagulation factors but the monitoring of activated coagulation system is necessary, and placental abruption, amniotic fluid embolism, and HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome are the causes. Many of the cases can be managed by rapid delivery of the baby together with coagulation factor supplementation, including anticoagulation in some cases.[54] For such DIC, the diagnostic score should be capable of detecting the compensated phase. Kobayashi[55] designed diagnostic criteria by weighing higher scores for clinical parameters rather than the laboratory parameters, and the score is calculated as the sum of (1) the underlying diseases, (2) the clinical symptoms, and (3) the laboratory findings. As for the coagulation tests, Erez et al[56] reported fibrinogen concentrations with a cutoff point of ≤3.9 g/L had a sensitivity of 87% and a specificity of 92% for the development of DIC. Building the pregnancy-specific criteria with this approach is reasonable because the laboratory tests may not be sensitive enough, and the delayed diagnosis can lead to fatal outcomes or serious maternal adverse events such as massive transfusion and aggressive surgery. In 2019, the ISTH introduced a pregnancy-modified DIC score composed of platelet count, prothrombin time, and fibrinogen level.[57] The evaluation of the new scoring system is currently underway.[58]

Heatstroke-Associated DIC

Heatstroke has been known to be frequently complicated by DIC. A cross-sectional survey in Japan reported that among 763 heatstroke patients, 11.6% were diagnosed as having DIC.[59] Hyperthermia directly affects coagulation and fibrinolysis; however, activated inflammation and cellular damage seem to be the major causes of heatstroke-induced coagulopathy. The primate model of heatstroke demonstrated the increased expression of tissue factor and von Willebrand factor on damaged endothelial cells.[60] Huisse et al[61] reported increased levels of inflammation and stress mediators such as IL-6, IL-8, and heat shock protein 60 and 70 in critically ill patients. They also reported the leukocyte activation represented by the upregulation of adhesion molecules and intensified production of reactive oxygen species. More recently, Hirose et al[62] reported an increase in NETs formation and elevated citrullinated histone H3 levels in heatstroke patients. The hallmark of heatstroke-induced coagulopathy is the clot formation induced by leukocyte and endothelial cell damage ([Fig. 3]), although the exact mechanism remains to be determined. Since the incidence is anticipated to rise drastically along with the rapid climate change, the research in this field is extremely important.

Fig. 3 Blood smear findings in heatstroke model of rats. Rats were subjected to a body temperature of 42 degrees centigrade for 120 min. Blood films are observed under the microscope with May-Grunwald–Giemsa stain. Neutrophils and platelets aggregate and form a hybrid thrombus (left). The cytoplasmic membrane of the leukocytes was ruptured and the cellular contents were expelled (right). These changes activate coagulation and facilitate microthrombi formation.

Bleeding-Type Disseminated Intravascular Coagulation

Trauma-Associated Disseminated Intravascular Coagulation

There has been a long-time debate between DIC and trauma researchers on the understanding of trauma-induced coagulopathy (TIC).[63] [64] The critical issue was whether TIC was identical to the bleeding type of DIC. The trauma researchers advocated that pathophysiology is significantly different and more complex. Meanwhile, DIC researchers considered that TIC is understood as a bleeding type of DIC. In 2019, an agreement was made between the groups in a consensus document released by several SSCs of the ISTH.[65] Both groups reported thrombin generation triggers coagulation disorders in TIC; the chronological change in fibrinolysis is recognized in TIC; and, if severe, TIC can progress to a procoagulant status that resembles coagulopathy seen in thrombotic type DIC and/or a consumptive coagulopathy ([Fig. 4]). Thus, the term “coagulopathy” is used to refer to the hemostatic impairment of trauma.[66] By contrast, it implies hypercoagulability and microthrombosis when used in sepsis.[67] In severe cases of trauma, patients initially die due to bleeding, while in sepsis, the major cause of death is multiorgan failure. The published concordance document emphasizes that the pathophysiology of TIC partially overlaps with that of SIC in the late phase.[65]

Fig. 4 Microcirculation in the trauma model of rats. Rats were subjected to multiple traumas. Thirty minutes later, a microthrombus in the mesenteric venule was observed under the intravital microscope (arrowheads); 180 minutes later, the thrombus was dissolved but extravasation of leukocytes (black arrows) and red blood cells (micro bleeding) increased.

Beyond the discussion of whether TIC is a type of DIC, impaired hemostasis is the most critical issue in the early phase of trauma, and damage control surgery together with blood product administration is the primary therapy.[66] [68] Massive blood loss followed by volume resuscitation must play important roles in the pathogenesis of TIC, and other factors such as shock, acidosis, hypothermia, increased plasmin activity, and possibly physiological anticoagulants may accelerate the uncontrolled bleeding.[69] The principle of damage control resuscitation includes minimized use of crystalloid, permissive hypotension, balanced transfusion of red blood cells and plasma, and goal-directed correction of coagulopathy.[70] After all, the pathophysiologic mechanisms are partially overlapped, but the therapeutic approaches are completely different from those for thrombotic type DIC, as the term “DIC” is not appropriate. Thereby we propose to use cause-specific terms such as TIC, SIC, and heatstroke-induced coagulopathy rather than DIC to avoid further arguments.

Obstetrical Bleeding-Type DIC

In contrast to the thrombotic type of obstetrical DIC, consumption of platelets and coagulation factors due to peripartum bleeding can cause life-threatening hemorrhage. Atonic uterus with continuous bleeding, vaginal/cervical lacerations, and uterine rupture with massive bleeding are the representative causes of postpartum hemorrhage.[71] The preexisting conditions such as hemodilution and decreased coagulation factor production in the liver in addition to consumptive coagulopathy may relate to the acute unexpected bleeding.[72] Discriminating abnormal obstetric coagulopathy from normal bleeding can be difficult. Together with the treatment for underlying conditions, timely blood transfusion is needed. The aforementioned modified ISTH DIC score[56] [57] adopted three laboratory tests, which are platelet count, prothrombin time difference, and fibrinogen level, and fibrin degradation products were eliminated. The cutoffs were modified, and the weights of prothrombin time and fibrinogen were increased. Since these markers are useful to evaluate the bleeding risks,[73] [74] we think this modification is rational; however, clinical manifestation of coagulopathy should be more important for the correct diagnosis. Similar to TIC, the fundamental treatment for the bleeding type obstetric DIC is the fixation of the causative problem with balanced blood transfusion following the massive transfusion protocol.[75] Although TIC and obstetric coagulopathy are triggered by tissue injury and coagulation activation, massive hemorrhage is significant, and the clinical symptoms and therapeutic approach are considerably different from those in thrombotic type DIC. We understand that these two contrastive phenotypes of coagulopathies are the different phases of the sequential process; however, a separate approach should be emphasized.

Other Bleeding Types

Acute leukemia is frequently complicated with DIC, with up to 100% prevalence in acute promyelocytic leukemia (APL) and between 8.5 and 25% in acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).[76] In APL, high levels of annexin II on leukemic cells are responsible for the upregulation of the fibrinolytic system.[77] Annexin II has a high affinity for both plasminogen and its activator tissue-type plasminogen activator (t-PA), and facilitates plasminogen activation leading to increased fibrinolysis.[78] Concurrent with hyperfibrinolysis, leukemic cells express tissue factor and activate coagulation. Besides, leukemic cells release microvesicles containing tissue factors, t-PA, PAI-1, and annexin II. The relevance of endothelial damage in APL may not be significant, but it is reported that adherent leukemic cells onto endothelial cells damage the endothelium and increase the hemorrhage.[79] The pathogeneses are complex and can vary among the types of leukemia. The clinical feature is primarily bleeding predominant in APL, while thrombosis is also commonly seen in ALL and AML.

Viral hemorrhagic fevers such as Ebola hemorrhagic fever and Marburg hemorrhagic fever are commonly associated with severe hemostasis impairment in the advanced stages.[80] The increased capillary permeability due to endothelial injury, shock, and coagulation defect are the major causes of death, and the pathological examination revealed focal coagulative necrosis and hemorrhage with widespread vascular damage in a variety of organs.[81] The viral infection induces significant suppression in the host immune system with abrupt activation in inflammation and coagulation which subsequently turns to the depletion of coagulation factors. Inhibition of the dendritic cell maturation and the expression and major histocompatibility complex class II lead to impaired T-cell proliferation and antibody production of B-lymphocytes. In addition, the induction of cytokines such as interleukin (IL)-6, IL-12, tumor necrosis factor-α, and interferon-α and -β induced by the explosive replication of causative viruses in dendritic cells/macrophages was reported.[82] Other than the aforementioned filovirus diseases, Aedes-borne viral diseases such as dengue hemorrhagic fever and tick-borne viral diseases such as severe fever with thrombocytopenia syndrome should be cautioned because of the widespread due to climate change.[83]

Venom toxin is a historical biologic substance that still poses problems, namely, venom-induced consumptive coagulopathy worldwide.[84] Toxins vary among snakes but in some snake bites, venom toxins promote consumptive coagulopathy.[85] The most relevant procoagulant toxins are metalloproteinases that activate prothrombin, factor V, factor X, or thrombin-like enzymes.[86] Other than that, hyaluronidase, collagenase, proteinases, and phospholipases cause a variety of clinical toxin syndromes that includes venom-induced consumptive coagulopathy associated with continuous hemorrhage.[87] As for the laboratory tests, decreased platelet count, prolonged prothrombin time, and a decrease in fibrinogen are observed. Notably, since the targets of venom toxins are the clotting factors, venom toxins can cause thrombosis and thrombotic microangiopathy.[84] In such cases, hemotoxic venoms can be classified as thrombotic categories.[88]

Disseminated Intravascular Coagulation in the Future

Recent research has significantly contributed to our understanding of DIC pathogenesis. With respect to coagulation markers, waveform analysis of the global coagulation tests, such as activated partial thromboplastin time and prothrombin time, were proposed to provide more useful information.[89] In addition, molecular markers are more sensitive to monitoring the coagulation/fibrinolysis status.[90] By using these new modalities, we expect more specific and adequate management of DIC can be possible.

Other than the activated coagulation, cell-mediated thrombus formation has been realized to actively participate in the pathogenesis of DIC. For example, platelet aggregation has been thought to occur as the secondary reaction to the activated coagulation in infection. Although platelets are activated via the thrombin-protease activated receptor binding, platelets also actively participate in the activation coagulation and thrombus formation. For effective hemostasis, the efficient sequential activation of factors XI, IX, and X and prothrombin, followed by the fibrin generation on the activated platelet surface, is necessary.[91] Platelet-derived procoagulant microvesicles play significant roles in DIC, and the platelet-derived microvesicles can be the new biomarker of DIC.[92] Platelets can also trigger the NETs release from neutrophils through the interaction between P-selection and P-selectin glycoprotein ligand-1.[93]

Besides platelets, the critical roles of neutrophils are important. NETs-induced immunothrombosis are extremely important in various conditions, and the approach to detect NETs is likely to be useful.[94] Derangement of endothelium is another factor that facilitates coagulation, and glycocalyx damage is a current topic of research.[16] The regulation of fibrinolytic function by t-PA, PAI-1, and thrombin-activatable fibrinolysis inhibitor has actively been studied. The relevance of endothelial cell–derived procoagulant substances such as von Willebrand factor and angiopoietin 2 should be examined in the future.[95] Other important factors that can induce DIC, such as DAMPs from the injured cells, are the target of research.[96]

Along with the advances of the aforementioned research, the understanding of the detailed differences in pathophysiology between the underlying conditions progresses, and the diagnostic criteria specially designed for each disease are important for future development.[6]

Summary and Conclusion

DIC diagnosis is often first made when the patients demonstrate unusual bleeding, and may be predictive of adverse outcomes. DIC is a continuing process from systemic activated coagulation with endothelial damage to decompensated coagulopathy and organ dysfunction with high mortality. Following this consensus, the coagulation/fibrinolysis status should be monitored among patients with high-risk underlying diseases. Diagnosis should be made using the best suitable diagnostic criteria for each underlying condition. Thereafter, international collaborative studies are necessary to develop databases based on the unified diagnosis with new biomarkers, and therapeutics should be developed based on this integrated database. DIC is a living category, and diseases such as COVID-19 can be added as a new underlying condition. By contrast, classically considered DIC caused by an aneurysm or large hemangioma can be eliminated from the DIC category. It is necessary to keep updating the latest knowledge and renew the management protocol.

Conflict of Interest

T.I. participated in advisory boards of Japan Blood Products Organization, Asahi Kasei Pharmaceuticals, and Toray Medical. J.H.L. serves on the Steering or Advisory Committees for Instrumentation Laboratories, Merck, Octapharma. The other authors have no conflict of interest.

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Publication History

Article published online:
13 September 2022