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
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
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
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.
