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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 2  |  Issue : 4  |  Page : 69-77

The Doctors in ICU Need to Know the Basics of Coagulopathy


Department of Intensive Care Unit, The First Hospital of China Medical University, Shenyang, Liaoning Province, China

Date of Submission18-Dec-2020
Date of Acceptance18-Mar-2021
Date of Web Publication25-Jun-2021

Correspondence Address:
Dr. Renyu Ding
Department of Intensive Care Unit, The First Hospital of China Medical University, Nanjing Bei Street 155, Shenyang 110001, Liaoning Province
China
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DOI: 10.4103/jtccm.jtccm_31_20

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  Abstract 


Coagulopathy is common in critically ill patients. Under pathogenic factors, the homeostasis of coagulation, anticoagulation, and fibrinolytic system is disrupted, causing a series of cascade reactions that ultimately lead to coagulopathy. The pathophysiology of coagulopathy markedly varies according to the etiology. For sepsis-induced coagulopathy, inflammation interacts with coagulation. This process involves various cells, including endothelial cells, neutrophils, and platelets. Thrombocytopenia, as a common coagulopathy disorder among intensive care unit (ICU) patients, is indicative of poor outcome, and its differential diagnosis is crucial. However, the standardized diagnostic criteria for disseminated intravascular coagulation are yet to be established, and the existing ones have limitations. Therefore, we used PubMed to search literature related to “thrombocytopenia,” “sepsis,” “coagulopathy,” “disseminated intravascular coagulation,” and “coagulation biomarkers” and expected ICU doctors to fully understand knowledgeable of the pathophysiology of Coagulopathy. The traditional coagulation indicators can be combined with novel coagulation-related biomarkers for the accurate diagnosis and treatment of coagulopathy.

Keywords: Coagulation biomarkers, coagulopathy, disseminated intravascular coagulation, sepsis, thrombocytopenia


How to cite this article:
Hu Z, Miao H, Ma X, Ding R. The Doctors in ICU Need to Know the Basics of Coagulopathy. J Transl Crit Care Med 2020;2:69-77

How to cite this URL:
Hu Z, Miao H, Ma X, Ding R. The Doctors in ICU Need to Know the Basics of Coagulopathy. J Transl Crit Care Med [serial online] 2020 [cited 2021 Nov 30];2:69-77. Available from: http://www.tccmjournal.com/text.asp?2020/2/4/69/319414

Ziwei Hu and He Miao; These authors contributed equally to this work.





  Introduction Top


Coagulopathy is a common condition among critically ill patients. The most common causes of coagulopathy among critically ill patients are sepsis and trauma bleeding. However, although both are coagulopathies, the pathophysiological mechanisms and therapeutic strategies differ greatly between sepsis-induced coagulopathy (SIC) and trauma-induced coagulopathy (TIC). For SIC, the main pathophysiological mechanisms are inflammatory coagulation interaction, platelet activation, and endothelial cell injury.[1],[2],[3] Meanwhile, TIC is related to the loss of coagulation substrates, early hyperfibrinolysis, and endothelial cell injury. Acidosis, hypothermia, and massive fluid resuscitation are also factors that cause or aggravate TIC.[4],[5]

When treatment is delayed, coagulopathy can progress to disseminated intravascular coagulation (DIC), increasing the risk of mortality. However, the existing diagnostic criteria for DIC do not reflect the difference in pathophysiological mechanisms, according to the etiology of DIC. Intensive care unit (ICU) physicians need to have a deep understanding of coagulation to achieve accurate diagnosis and treatment of severe coagulopathy. Therefore, literature related to “;thrombocytopenia,” “sepsis,” “coagulopathy,” “disseminated intravascular coagulation,” and “coagulation biomarkers” was searched using PubMed. In this review, we summarize the pathophysiological mechanisms of coagulopathy under different etiologies and provide clinicians with more understanding of the diagnosis and treatment of coagulopathy in critically ill patients.


  Basic Knowledge of Severe coagulopathy: Coagulation, Anticoagulation, and the Fibrinolysis System Top


Under the action of pathogenic factors such as infection and trauma, the dynamic balance between the coagulation system, anticoagulant system, and fibrinolysis system is altered.[6] A profound understanding of the coagulation, anticoagulation, and fibrinolysis systems is a prerequisite for accurate diagnosis and treatment of severe coagulopathy [Figure 1].
Figure 1: The coagulation, anticoagulation, and the fibrinolysis system. TF: Tissue factor, AT: Antithrombin, APC: Activated protein C, TPA: Tissue-type plasminogen activator, PAI-1: Plasminogen activator inhibitor-1, D-D: D-dimer, FDP: Fibrin/fibrinogen degradation products, α2-PI: α2-plasmin inhibitor

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The coagulation system is divided into exogenous and endogenous coagulation system. The intrinsic pathway is initiated by contact activation of high molecular weight kininogen (HMWK), prekallikrein and Factor XII. FXII is activated by binding to negatively charged surfaces. Then, FXIIa converts prekallikrein into kallikrein and activates Factor XI to Factor FXIa.[7] Activation of the extrinsic coagulation system begins with the release of tissue factor (TF), forming a TF-Ca2+-VII complex, and activation of FVII to FVIIa. The common coagulation pathway begins with the activation of FX to FXa,[8] which activates coagulation FV to promote the generation of more thrombin. Thrombin is the key to the coagulation system, and it can convert fibrinogen to fibrin monomers. Fibrin monomers adhere to form a soluble complex, that is, the soluble fibrin monomer–fibrinogen complex (SFMC), which is involved in platelet activation and aggregation. The production of SFMC in the plasma is indicative of enhanced thrombin activity and a prothrombotic state.[9],[10] Fragment 1 + 2 (F1 + 2) is released during the activation of prothrombin to thrombin by FXa. F1 + 2 reflects the activity of the FXa complex and is a specific marker of prothrombin activation.[11] The thrombin–antithrombin complex (TAT) is a molecular complex composed of thrombin and antithrombin (AT) in a 1:1 ratio. TAT is a biomarker generated from thrombin, and elevated TAT indicates excessive thrombin production, making TAT a marker reflecting the prothrombotic state.[12]

The main anticoagulant systems are the AT system, the protein C (PC) system, and the tissue factor pathway inhibitor (TFPI).[13] AT is a broad-spectrum serine protease inhibitor that can inhibit contact FXIa and FXIIa and also inhibits the activity of FIXa in the endogenous coagulation system.[14],[15],[16] AT can bind heparin, heparin sulfate, and glycosaminoglycan. Binding to heparin, AT inactivates the TF-VIIa complex in the exogenous coagulation system and increases its activity by more than 1000 times.[17] Activated protein C (APC) is a serine proteinase that is derived from an inactive precursor protein (i.e., PC). The APC system contains thrombomodulin, PC, protein S, and endothelial protein C receptor (EPCR).[18] Thrombin bound to thrombomodulin can activate PC through the EPCR on the surface of endothelial cells.[19] APC exerts an anticoagulant effect by inactivating FVIIIa and FVa under the action of protein cofactor protein S and FV.[20] TFPI is an anticoagulant protein, and endothelial cells and platelets can express different subtypes, TFPIα and TFPIβ.[6] TFPIα is a soluble protein secreted by endothelial cells and activated platelets, while TFPIβ is anchored to the endothelial surface through glycosyl phosphatidylinositol.[21] TFPI relies on FXa to inhibit the TF-FVIIa complex and can also exert its anticoagulant effect by inhibiting prothrombin during the initial phase of coagulation.[22]

The fibrinolysis system mainly includes plasminogen activator (PA), plasminogen, plasmin, and thrombin-activatable fibrinolysis inhibitors. Its main function is to dissolve fibrin clots. After activating the coagulation system, plasmin regulates fibrinolysis. Tissue-type plasminogen activator is only derived from endothelial cells. It is a serine proteinase that can convert plasminogen into active serine proteinase, namely plasmin.[23] Plasmin activity is mainly regulated by PA and plasminogen activator inhibitor-1 (PAI-1).[24],[25] PAI-1 is the main inhibitor of plasminogen activation and plasmin production. Levels of plasma PAI-1 can predict the severity of sepsis and the associated mortality risk.[26],[27] Fibrin and fibrinogen in the blood are decomposed into fibrin/fibrinogen degradation products (FDPs) under the action of plasmin, which is related to the activation of the fibrinolytic system. In hyperfibrinolysis, FDP content is significantly increased.[28] D-dimer (D-D) is a specific fibrin degradation product produced by cross-linked fibrin under the action of plasmin, and its increased level suggests that fibrinolytic activity is enhanced. D-D and FDP are increased in secondary increased fibrinolytic activity.[29],[30] After its generation, plasmin can rapidly bind to α2-plasmin inhibitor into a specific complex in a 1:1 ratio, and it is a physiological inhibitor of late plasmin that regulates fibrinolysis.[24]


  Basic Knowledge of Severe Coagulopathy: Thrombocytopenia Top


The incidence of thrombocytopenia (TCP) in the ICU varies widely; it can be as low as 13.0% but can also be as high as 44.1%.[31] In China, the diagnostic criterion for TCP is a peripheral blood platelet count of <100 × 109/L (<150 × 109/L in European and American races).[32] Platelets play an important role in coagulation, inflammation, and immunity. When the vessel wall is injured, exposed collagen binds and activates platelets directly or through the Von Willebrand factor (VWF). Then, platelet adhesion and aggregation occur at the site of injury, and negatively charged phosphatidylserine is exposed lateral to the platelet plasma membrane bilayer, promoting prothrombin complex formation that in turn leads to coagulation and thrombosis.[32],[33],[34] In addition to participating in the coagulation pathway, platelets play an important role in regulating inflammation and immunity. Platelet activation can upregulate pro-inflammatory and anti-inflammatory factors, and platelet binding to neutrophils induces the formation of neutrophil extracellular traps (NETs).[35],[36] Platelets express Toll-like receptors and are involved in innate immunity and NET formation.[37] Activated platelets also express CD40 L (also known as CD154), which can regulate B and T cell functions and affect innate and adaptive immunity.[38],[39],[40] Moreover, platelets express major histocompatibility complex-I and mediate T cell activation.[41]

There are many causes of TCP in the ICU, including sepsis, DIC, hemodilution, massive blood loss, malignant tumor, hemophagocytic histiocytosis, thrombotic microangiopathy (TMA), drugs (e.g., heparin-induced TCP [HIT]), and extracorporeal circulation. For critically ill patients, TCP is rarely caused by a single factor; therefore, identifying the cause of TCP has become the hotspot and difficulty of clinical work. Sepsis is the most common cause of TCP in the ICU, and the platelet count is closely related to the severity and prognosis of sepsis.[42],[43] TCP due to sepsis is mainly caused by decreased platelet production, hemodilution due to fluid resuscitation, increased platelet consumption, and immune-mediated platelet destruction.[36] Current research supports that increased platelet consumption may be a major cause of TCP in sepsis.[44],[45] In some critically ill patients with TCP and hemophagocytic histiocytosis, specific indicators such as ferritin levels, SCD25, NK cell activity, and myelogram can assist in diagnosis.[46]

TMA is also a common cause of TCP in the ICU and needs to be differentiated from TCP due to DIC in sepsis. TMA includes thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). TTP is associated with ADAMTS13 deficiency or decreased activity. ADAMTS13 is a protease that cleaves VWF to smaller fragments and prevents large VWF aggregation. When TTP occurs, ADAMTS13 deficiency or decreased activity leads to platelet binding to VWF multimers and aggregation into microthrombi.[23],[47] HUS is characterized by intravascular hemolysis, TCP, and acute renal failure. The mechanism of TCP in HUS possibly involves an interaction between endothelial cell injury and platelet activation triggered by Shigella toxin. Further, it is also associated with the dysregulation of the complement system.[48],[49] TMA is characterized by TCP and microvascular hemolytic anemia. DIC is accompanied by significant abnormalities in coagulation indexes such as prothrombin time (PT) and activated partial thromboplastin time. Many patients with TMA are diagnosed with DIC, but only 15% of patients with DIC are diagnosed with TMA.[50] Significantly reduced ADAMTS13 activity can be used to differentiate TTP from DIC.[51] The differential diagnosis of TCP induced by DIC or TMA is shown in [Figure 2].
Figure 2: The differential diagnosis of thrombocytopenia induced by DIC or TMA. DIC: Disseminated intravascular coagulation, TMA: Thrombotic microangiopathy, TTP: Thrombotic thrombocytopenic purpura, HUS: Hemolytic uremic syndrome, PT: Prothrombin time, APTT: Activated partial thromboplastin time, D-D: D-dimer, FDP: Fibrin/fibrinogen degradation products, Fig: Fibrinogen, PLT: platelet

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Drug-related TCP can be divided into two categories: drug-induced nonimmune TCP and drug-induced immune TCP.[52] HIT is most common in the ICU. Patients presenting with a platelet decrease by >50% after 5–10 days of heparin therapy should be assessed for HIT.[53] HIT occurs when the Fc domain of immune complexes, which are generated by IgG antibodies against platelet factor 4-heparin complexes, binds to the platelet FCγRIIa receptor. This leads to platelet aggregation and activation. Eventually, thrombin is formed and platelets are consumed, resulting in TCP.[54],[55] In differential diagnosis, it is necessary to combine the medication history of heparin, laboratory indicators, and HIT-related antibodies.


  Basic Knowledge of SEPSIS-induced Coagulopathy: The Interaction among Endothelial Cells, Neutrophils, and Platelets Top


Various cells are involved in the interaction between inflammation and coagulation in sepsis [Figure 3]. Vascular endothelial cells play a key role in the regulation of the natural anticoagulant pathway, including the PC/protein S system, TFPIs, and AT.[56] In sepsis, endothelial cell injury leads to the inhibition of the anticoagulant system, while the coagulation system is enhanced (increased expression of TF) and the fibrinolysis system is inhibited (increased expression of PAI-1). These pathophysiological changes cause early SIC to manifest as a tendency for thrombosis, which is also the theoretical basis for anticoagulant therapy in SIC.[57],[58] Vascular endothelial cells are coated with polysaccharides, also known as the “glycocalyx.” They are synthesized by vascular endothelial cells and expressed on the surface of endothelial cells. Further, they are involved in regulating thrombosis, vascular permeability, and inflammation[59] and can also prevent unnecessary cell–cell interactions and adhesion.[60] In sepsis, the plasma content of markers of glycocalyx degradation and disruption (e.g., heparan sulfate, hyaluronic acid) is significantly increased. Clinical studies have shown that the blood levels of glycocalyx-related markers are associated with organ dysfunction, disease severity, and mortality.[61]
Figure 3: The interaction among endothelial cells, neutrophils, and platelets in sepsis-induced coagulopathy. ADAMTS-13: A disintegrin and metalloproteinase with thrombospondin type 1 motif, 13, HMGB-1: High-mobility group box 1, NETs: Neutrophil extracellular traps, PECAM-1: Platelet endothelial cell adhesion molecule-1, ROS: Reactive oxygen species, TF: Tissue factor, VWF: Von Willebrand factor

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In sepsis, leukocytes can release granzymes (e.g., cathepsin G/elastase) that activate the coagulation cascade by directly activating coagulation FV, FVIII, and FX[62],[63] or degrading anticoagulants such as AT and TFPI.[64],[65],[66] The binding of leukocytes to endothelial cell surface receptors via adhesion factors (mainly selectins and β2 integrins) triggers intracellular signal transduction, leading to leukocyte migration. Activated neutrophils release reactive oxygen species and cytokines, resulting in disruption of the endothelial cell barrier and increased microvascular permeability.[67] Histones[68] and HMGB-1[69] released by leukocytes can increase TF activity in endothelial cells. Histones and cytokines can stimulate endothelial cells to release VWF and P-selectin.[70] Cytokines and neutrophil oxidants can also weaken the cleavage of VWF by the protease ADAMTS-13 and increase the binding ability of VWF multimers to platelets in the blood.[71]

Under physiological conditions, endothelial cells release nitric oxide and prostacyclin to inhibit platelet adhesion. Meanwhile, under the action of injury factors, endothelial cells express various molecules such as platelet endothelial cell adhesion molecule-1 and P-selectin, resulting in platelet adhesion and aggregation.[72],[73],[74] Platelets can potentiate the multiple biological effects of neutrophils, such as inflammatory response, oxidative burst, phagocytosis, and NET formation.[75],[76] In sepsis, NET formation is increased, contributing to the activation of intravascular coagulation and thrombosis formation in the microvasculature.[66],[77] NETs are composed of histones and a DNA fiber network structure that can induce platelet aggregation[78] and endothelial cell damage.[79] In addition to platelets, endothelial cells also promote NET production of neutrophils.[80]


  Problems in the Disseminated Intravascular Coagulation Diagnostic Criteria Top


There is currently no internationally unified standard for DIC diagnosis. The common DIC scoring criteria include those stipulated by the International Society on Thrombosis and Hemostasis (ISTH),[81] Japanese Ministry of Health and Welfare (JMHW),[82] and Japanese Association of Acute Medicine (JAAM)[83] [Figure 4].
Figure 4: The common DIC scoring criteria. DIC: Disseminated intravascular coagulation, D-D: D dimer, FDP: Fibrin degradation products, PT: Prothrombin time, SF: Soluble fibrin, TAT: Thrombin–antithrombin, PF1 + 2: Prothrombin fragment 1 + 2, ISTH: The International Society of Thrombosis and Hemostasis, JAAM: Japanese Association for Acute Medicine, JMHW: Japanese Ministry of Health and Welfare, JSTH: Japanese Society on Thrombosis and Hemostasis, SIC: Sepsis-induced coagulopathy

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The traditional DIC scoring criteria have many disadvantages. The ISTH criteria have low sensitivity, and the JAAM score cannot be applied to all potential diseases (such as DIC complicated by hematopoietic system abnormalities). The JMHW scoring criteria distinguish the causes of disease and assign scores to basic diseases, bleeding, organ failure, and various coagulation indexes. However, they lack sensitivity for sepsis-induced DIC. The Japanese Society on Thrombosis and Hemostasis score increases AT activity and coagulation-related molecular markers (TAT, soluble fibrin [SF], F1 + 2), which may represent a new trend in the diagnostic criteria of DIC.[84]

DIC caused by sepsis may be “classical” DIC, including hypercoagulable stage, consumed hypocoagulable stage, and secondary fibrinolytic stage. The hypercoagulable stage is characterized by systemic intravascular coagulation activation, impaired anticoagulant function, and microvascular endothelial injury caused by fibrinolysis deficiency, which leads to extensive microvascular thrombosis.[12] Meanwhile, the consumed hypocoagulable stage is characterized by massive microthrombosis, resulting in the consumption of coagulation substances. Patients present with prolonged of clotting time and reduced platelets and fibrinogen. In the fibrinolytic stage, the fibrinolysis system is activated by massive microthrombosis, and the secondary fibrinolysis index D-D is significantly increased. Coagulopathy or DIC from trauma is significantly different from sepsis-induced DIC, with TIC presenting as a hypocoagulable state and hyperfibrinolysis in the early stage. Thus, it is unreasonable to diagnose coagulopathy caused by different etiologies with a standard criterion. Moreover, fibrinogen <1.0 is uncommon in septic coagulopathy or DIC.[85] Some scholars believe that PAI-1 elevation may lead to inhibition of the fibrinolysis system in sepsis. Thus, the SIC criteria established in 2017 include three items:[86] platelet count, PT-international normalized ratio, and the four-item sequential organ failure assessment score. Studies have shown that the SIC score facilitates the early diagnosis of patients with DIC and sepsis.[87]


  Correct Interpretation of Coagulation Indexes Can Achieve Accurate Diagnosis and Treatment of Severe Coagulopathy Top


ICU physicians usually judge the coagulation status of patients based on conventional coagulation indexes and thromboelastography. However, although the coagulation indexes are similar among coagulopathy caused by varying etiologies, the treatment strategy should be specific. Studies have shown that patients with septic coagulopathy who have a prolonged clotting time may benefit from anticoagulant therapy.[88] Similarly, the threshold of platelet transfusion in patients with sepsis TCP is significantly lower than that in patients with trauma bleeding.[89],[90] Therefore, when coagulopathy is caused by different etiologies, correct interpretation of coagulation indexes is the key to achieving accurate treatment of severe coagulation.

There have been several studies on coagulation-related biomarkers that have potential value for the accurate diagnosis and treatment of coagulopathy and DIC. For example, prothrombin F1 + 2 and TAT reflect increased thrombin and thrombin-mediated production of fibrinogen. These markers have high sensitivity for detecting low-grade coagulation activation.[91] Studies have shown that the plasma levels of TAT, SF, and F1 + 2 in the DIC group were significantly higher than those in the non-DIC group.[92],[93] The Japanese Society of Thrombosis and Hemostasis included these markers in the JMHW criteria to increase the sensitivity and specificity of DIC diagnosis.[94] Recently, the SCARLET study found a more obvious reduction in 28-day all-cause mortality after anticoagulation treatment with recombinant human thrombomodulin in patients with higher levels of markers reflecting thrombin generation (F1 + 2 and TAT).[95]


  Conclusion Top


Coagulopathy is highly common in the ICU. The diagnosis and treatment of coagulopathy or DIC should be specific according to its etiology. The international standard diagnostic criteria for DIC are yet to be established. Therefore, ICU physicians need to be knowledgeable of coagulation to interpret coagulation indexes correctly. Biomarkers may help achieve accurate diagnosis and treatment of severe coagulopathy.

Financial support and sponsorship

This work was supported by the Scientific Project of The Educational Department of Liaoning Province (Grant No. ZF2019010) and China Medical University's COVID-19 prevention- and control-related research projects.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med 1999;341:586-92.  Back to cited text no. 1
    
2.
Semeraro N, Ammollo CT, Semeraro F, Colucci M. Sepsis, thrombosis and organ dysfunction. Thromb Res 2012;129:290-5.  Back to cited text no. 2
    
3.
Denning NL, Aziz M, Gurien SD, Wang P. DAMPs and NETs in sepsis. Front Immunol 2019;10:2536.  Back to cited text no. 3
    
4.
Petros S. Trauma-induced coagulopathy. Hamostaseologie 2019;39:20-7.  Back to cited text no. 4
    
5.
Gando S. Disseminated intravascular coagulation in trauma patients. Semin Thromb Hemost 2001;27:585-92.  Back to cited text no. 5
    
6.
Mast AE. Tissue factor pathway inhibitor: Multiple anticoagulant activities for a single protein. Arterioscler Thromb Vasc Biol 2016;36:9-14.  Back to cited text no. 6
    
7.
Grover SP, Mackman N. Intrinsic pathway of coagulation and thrombosis. Arterioscler Thromb Vasc Biol 2019;39:331-8.  Back to cited text no. 7
    
8.
Chaudhry R, Usama SM, Babiker HM. Physiology, coagulation pathways. In: StatPearls. Treasure Island, FL: StatPearls Publishing; 2020.  Back to cited text no. 8
    
9.
Horan JT, Francis CW. Fibrin degradation products, fibrin monomer and soluble fibrin in disseminated intravascular coagulation. Semin Thromb Hemost 2001;27:657-66.  Back to cited text no. 9
    
10.
Koga S. A novel molecular marker for thrombus formation and life prognosis--clinical usefulness of measurement of soluble fibrin monomer-fibrinogen complex (SF). Rinsho Byori 2004;52:355-61.  Back to cited text no. 10
    
11.
Aronson DL, Stevan L, Ball AP, Franza BR Jr, Finlayson JS. Generation of the combined prothrombin activation peptide (F1-2) during the clotting of blood and plasma. J Clin Invest 1977;60:1410-8.  Back to cited text no. 11
    
12.
Koyama K, Madoiwa S, Nunomiya S, Koinuma T, Wada M, Sakata A, et al. Combination of thrombin-antithrombin complex, plasminogen activator inhibitor-1, and protein C activity for early identification of severe coagulopathy in initial phase of sepsis: A prospective observational study. Crit Care 2014;18:R13.  Back to cited text no. 12
    
13.
Iba T, Levy JH, Raj A, Warkentin TE. Advance in the management of sepsis-induced coagulopathy and disseminated intravascular coagulation. J Clin Med 2019;8:728.  Back to cited text no. 13
    
14.
Hsu E, Moosavi L. Biochemistry, antithrombin III. In: StatPearls. Treasure Island, FL: StatPearls Publishing; 2020.  Back to cited text no. 14
    
15.
Hepner M, Karlaftis V. Antithrombin. Methods Mol Biol 2013;992:355-64.  Back to cited text no. 15
    
16.
Bock SC, Harris JF, Balazs I, Trent JM. Assignment of the human antithrombin III structural gene to chromosome 1q23-25. Cytogenet Cell Genet 1985;39:67-9.  Back to cited text no. 16
    
17.
Opal SM, Kessler CM, Roemisch J, Knaub S. Antithrombin, heparin, and heparan sulfate. Crit Care Med 2002;30:S325-31.  Back to cited text no. 17
    
18.
Griffin JH, Zlokovic BV, Mosnier LO. Activated protein C: Biased for translation. Blood 2015;125:2898-907.  Back to cited text no. 18
    
19.
Dahlbäck B, Villoutreix BO. Regulation of blood coagulation by the protein C anticoagulant pathway: Novel insights into structure-function relationships and molecular recognition. Arterioscler Thromb Vasc Biol 2005;25:1311-20.  Back to cited text no. 19
    
20.
Dahlbäck B, Villoutreix BO. The anticoagulant protein C pathway. FEBS Lett 2005;579:3310-6.  Back to cited text no. 20
    
21.
Ellery PE, Adams MJ. Tissue factor pathway inhibitor: Then and now. Semin Thromb Hemost 2014;40:881-6.  Back to cited text no. 21
    
22.
Lockett JM, Mast AE. Contribution of regions distal to glycine-160 to the anticoagulant activity of tissue factor pathway inhibitor. Biochemistry 2002;41:4989-97.  Back to cited text no. 22
    
23.
Guthoff M, Heyne N. Klinik und differenzialdiagnose der thrombotischen mikroangiopathie [Clinical course and differential diagnosis of thrombotic microangiopathy]. Med Klin Intensivmed Notfmed 2018;113:293-8.  Back to cited text no. 23
    
24.
Madoiwa S. Recent advances in disseminated intravascular coagulation: Endothelial cells and fibrinolysis in sepsis-induced DIC. J Intensive Care 2015;3:8.  Back to cited text no. 24
    
25.
Emeis JJ, Kooistra T. Interleukin 1 and lipopolysaccharide induce an inhibitor of tissue-type plasminogen activator in vivo and in cultured endothelial cells. J Exp Med 1986;163:1260-6.  Back to cited text no. 25
    
26.
Wood JP, Bunce MW, Maroney SA, Tracy PB, Camire RM, Mast AE. Tissue factor pathway inhibitor-alpha inhibits prothrombinase during the initiation of blood coagulation. Proc Natl Acad Sci U S A 2013;110:17838-43.  Back to cited text no. 26
    
27.
Lorente L, Martín MM, Borreguero-León JM, Solé-Violán J, Ferreres J, Labarta L, et al. Sustained high plasma plasminogen activator inhibitor-1 levels are associated with severity and mortality in septic patients. Thromb Res 2014;134:182-6.  Back to cited text no. 27
    
28.
Shi D, Xia T, Feng H, Cheng Q. Evaluating the diagnostic value of vWF: Ag, D-D and FDP in patients with acute cerebral infarction using ROC curves. Exp Ther Med 2014;7:1573-7.  Back to cited text no. 28
    
29.
Carr JM, McKinney M, McDonagh J. Diagnosis of disseminated intravascular coagulation. Role of D-dimer. Am J Clin Pathol 1989;91:280-7.  Back to cited text no. 29
    
30.
Righini M, Perrier A, De Moerloose P, Bounameaux H. D-Dimer for venous thromboembolism diagnosis: 20 years later. J Thromb Haemost 2008;6:1059-71.  Back to cited text no. 30
    
31.
Hui P, Cook DJ, Lim W, Fraser GA, Arnold DM. The frequency and clinical significance of thrombocytopenia complicating critical illness: A systematic review. Chest 2011;139:271-8.  Back to cited text no. 31
    
32.
Rondina MT, Garraud O. Emerging evidence for platelets as immune and inflammatory effector cells. Front Immunol 2014;5:653.  Back to cited text no. 32
    
33.
Xu XR, Zhang D, Oswald BE, Carrim N, Wang X, Hou Y, et al. Platelets are versatile cells: New discoveries in hemostasis, thrombosis, immune responses, tumor metastasis and beyond. Crit Rev Clin Lab Sci 2016;53:409-30.  Back to cited text no. 33
    
34.
Lhermusier T, Chap H, Payrastre B. Platelet membrane phospholipid asymmetry: From the characterization of a scramblase activity to the identification of an essential protein mutated in Scott syndrome. J Thromb Haemost 2011;9:1883-91.  Back to cited text no. 34
    
35.
Assinger A. Platelets and infection-An emerging role of platelets in viral infection. Front Immunol 2014;5:649.  Back to cited text no. 35
    
36.
Vardon-Bounes F, Ruiz S, Gratacap MP, Garcia C, Payrastre B, Minville V. Platelets Are Critical Key Players in Sepsis. Int J Mol Sci 2019;20:3494.  Back to cited text no. 36
    
37.
Andonegui G, Kerfoot SM, McNagny K, Ebbert KV, Patel KD, Kubes P. Platelets express functional Toll-like receptor-4. Blood 2005;106:2417-23.  Back to cited text no. 37
    
38.
André P, Nannizzi-Alaimo L, Prasad SK, Phillips DR. Platelet-derived CD40L: The switch-hitting player of cardiovascular disease. Circulation 2002;106:896-9.  Back to cited text no. 38
    
39.
Hamzeh-Cognasse H, Cognasse F, Palle S, Chavarin P, Olivier T, Delézay O, et al. Direct contact of platelets and their released products exert different effects on human dendritic cell maturation. BMC Immunol 2008;9:54.  Back to cited text no. 39
    
40.
Aloui C, Prigent A, Sut C, Tariket S, Hamzeh-Cognasse H, Pozzetto B, et al. The signaling role of CD40 ligand in platelet biology and in platelet component transfusion. Int J Mol Sci 2014;15:22342-64.  Back to cited text no. 40
    
41.
Zufferey A, Speck ER, Machlus KR, Aslam R, Guo L, McVey MJ, et al. Mature murine megakaryocytes present antigen-MHC class I molecules to T cells and transfer them to platelets. Blood Adv 2017;1:1773-85.  Back to cited text no. 41
    
42.
Akca S, Haji-Michael P, de Mendonça A, Suter P, Levi M, Vincent JL. Time course of platelet counts in critically ill patients. Crit Care Med 2002;30:753-6.  Back to cited text no. 42
    
43.
de Stoppelaar SF, van 't Veer C, van der Poll T. The role of platelets in sepsis. Thromb Haemost 2014;112:666-77.  Back to cited text no. 43
    
44.
Bedet A, Razazi K, Boissier F, Surenaud M, Hue S, Giraudier S, et al. Mechanisms of thrombocytopenia during septic shock: A multiplex cluster analysis of endogenous sepsis mediators. Shock 2018;49:641-8.  Back to cited text no. 44
    
45.
Claushuis TA, van Vught LA, Scicluna BP, Wiewel MA, Klein Klouwenberg PM, Hoogendijk AJ, et al. Thrombocytopenia is associated with a dysregulated host response in critically ill sepsis patients. Blood 2016;127:3062-72.  Back to cited text no. 45
    
46.
Tothova Z, Berliner N. Hemophagocytic syndrome and critical illness: New insights into diagnosis and management. J Intensive Care Med 2015;30:401-12.  Back to cited text no. 46
    
47.
Sadler JE, Moake JL, Miyata T, George JN. Recent advances in thrombotic thrombocytopenic purpura. Hematology Am Soc Hematol Educ Program 2004(1):407-23.  Back to cited text no. 47
    
48.
Karpman D, Loos S, Tati R, Arvidsson I. Haemolytic uraemic syndrome. J Intern Med 2017;281:123-48.  Back to cited text no. 48
    
49.
Jokiranta TS. HUS and atypical HUS. Blood 2017;129:2847-56.  Back to cited text no. 49
    
50.
Wada H, Matsumoto T, Suzuki K, Imai H, Katayama N, Iba T, et al. Differences and similarities between disseminated intravascular coagulation and thrombotic microangiopathy. Thromb J 2018;16:14.  Back to cited text no. 50
    
51.
Kobayashi T, Wada H, Nishioka N, Yamamoto M, Matsumoto T, Tamaru T, et al. ADAMTS13 related markers and von Willebrand factor in plasma from patients with thrombotic microangiopathy (TMA). Thromb Res 2008;121:849-54.  Back to cited text no. 51
    
52.
Greinacher A, Selleng S. How I evaluate and treat thrombocytopenia in the intensive care unit patient. Blood 2016;128:3032-42.  Back to cited text no. 52
    
53.
Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med 2001;344:1286-92.  Back to cited text no. 53
    
54.
Greinacher A. Clinical practice. Heparin-induced thrombocytopenia. N Engl J Med 2015;373:252-61.  Back to cited text no. 54
    
55.
Aluru N, Samavedam S. Thrombocytopenia in Intensive Care Unit. Indian J Crit Care Med 2019;23(Suppl 3):S185-8.  Back to cited text no. 55
    
56.
Verhamme P, Hoylaerts MF. The pivotal role of the endothelium in haemostasis and thrombosis. Acta Clin Belg 2006;61:213-9.  Back to cited text no. 56
    
57.
Levi M, de Jonge E, van der Poll T. New treatment strategies for disseminated intravascular coagulation based on current understanding of the pathophysiology. Ann Med 2004;36:41-9.  Back to cited text no. 57
    
58.
Murao S, Yamakawa K. A systematic summary of systematic reviews on anticoagulant therapy in sepsis. J Clin Med 2019;8:1869.  Back to cited text no. 58
    
59.
Van Teeffelen JW, Brands J, Stroes ES, Vink H. Endothelial glycocalyx: Sweet shield of blood vessels. Trends Cardiovasc Med 2007;17:101-5.  Back to cited text no. 59
    
60.
Iba T, Levy JH. Inflammation and thrombosis: Roles of neutrophils, platelets and endothelial cells and their interactions in thrombus formation during sepsis. J Thromb Haemost 2018;16:231-41.  Back to cited text no. 60
    
61.
Uchimido R, Schmidt EP, Shapiro NI. The glycocalyx: A novel diagnostic and therapeutic target in sepsis. Crit Care 2019;23:16.  Back to cited text no. 61
    
62.
Allen DH, Tracy PB. Human coagulation factor V is activated to the functional cofactor by elastase and cathepsin G expressed at the monocyte surface. J Biol Chem 1995;270:1408-15.  Back to cited text no. 62
    
63.
Gale AJ, Rozenshteyn D. Cathepsin G, a leukocyte protease, activates coagulation factor VIII. Thromb Haemost 2008;99:44-51.  Back to cited text no. 63
    
64.
Swystun LL, Liaw PC. The role of leukocytes in thrombosis. Blood 2016;128:753-62.  Back to cited text no. 64
    
65.
Plescia J, Altieri DC. Activation of Mac-1 (CD11b/CD18)-bound factor X by released cathepsin G defines an alternative pathway of leucocyte initiation of coagulation. Biochem J 1996;319(Pt 3):873-9.  Back to cited text no. 65
    
66.
Massberg S, Grahl L, von Bruehl ML, Manukyan D, Pfeiler S, Goosmann C, et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med 2010;16:887-96.  Back to cited text no. 66
    
67.
Yuan SY, Shen Q, Rigor RR, Wu MH. Neutrophil transmigration, focal adhesion kinase and endothelial barrier function. Microvasc Res 2012;83:82-8.  Back to cited text no. 67
    
68.
Semeraro F, Ammollo CT, Esmon NL, Esmon CT. Histones induce phosphatidylserine exposure and a procoagulant phenotype in human red blood cells. J Thromb Haemost 2014;12:1697-702.  Back to cited text no. 68
    
69.
Ito T, Kawahara K, Nakamura T, Yamada S, Nakamura T, Abeyama K, et al. High-mobility group box 1 protein promotes development of microvascular thrombosis in rats. J Thromb Haemost 2007;5:109-16.  Back to cited text no. 69
    
70.
Bernardo A, Ball C, Nolasco L, Moake JF, Dong JF. Effects of inflammatory cytokines on the release and cleavage of the endothelial cell-derived ultralarge von Willebrand factor multimers under flow. Blood 2004;104:100-6.  Back to cited text no. 70
    
71.
Chen J, Fu X, Wang Y, Ling M, McMullen B, Kulman J, et al. Oxidative modification of von Willebrand factor by neutrophil oxidants inhibits its cleavage by ADAMTS13. Blood 2010;115:706-12.  Back to cited text no. 71
    
72.
Meza D, Shanmugavelayudam SK, Mendoza A, Sanchez C, Rubenstein DA, Yin W. Platelets modulate endothelial cell response to dynamic shear stress through PECAM-1. Thromb Res 2017;150:44-50.  Back to cited text no. 72
    
73.
Etulain J, Schattner M. Glycobiology of platelet-endothelial cell interactions. Glycobiology 2014;24:1252-9.  Back to cited text no. 73
    
74.
Chen J, López JA. Interactions of platelets with subendothelium and endothelium. Microcirculation 2005;12:235-46.  Back to cited text no. 74
    
75.
Ribeiro LS, Migliari Branco L, Franklin BS. Regulation of innate immune responses by platelets. Front Immunol 2019;10:1320.  Back to cited text no. 75
    
76.
Schrottmaier WC, Mussbacher M, Salzmann M, Assinger A. Platelet-leukocyte interplay during vascular disease. Atherosclerosis 2020;307:109-20.  Back to cited text no. 76
    
77.
Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol 2013;13:34-45.  Back to cited text no. 77
    
78.
Kapoor S, Opneja A, Nayak L. The role of neutrophils in thrombosis. Thromb Res 2018;170:87-96.  Back to cited text no. 78
    
79.
Saffarzadeh M, Juenemann C, Queisser MA, Lochnit G, Barreto G, Galuska SP, et al. Neutrophil extracellular traps directly induce epithelial and endothelial cell death: A predominant role of histones. PLoS One 2012;7:e32366.  Back to cited text no. 79
    
80.
Kazzaz NM, Sule G, Knight JS. Intercellular interactions as regulators of NETosis. Front Immunol 2016;7:453.  Back to cited text no. 80
    
81.
Aylor FB Jr., Toh CH, Hoots WK, Wada H, Levi M, Scientific Subcommittee on Disseminated Intravascular Coagulation of the International Society on T, et al. Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemos 2001;86:1327-30.  Back to cited text no. 81
    
82.
Kobayashi N, Maekawa T, Takada M, Tanaka H, Gonmori H. Criteria for diagnosis of DIC based on the analysis of clinical and laboratory findings in 345 DIC patients collected by the Research Committee on DIC in Japan. Bibl Haematol 1983;(49):265-75  Back to cited text no. 82
    
83.
Satoshi G TI, Yutaka E. A muticenter, prospective validation of disseminated intravascular coagulation diagnostic criteria for critically ill patients: Comparing current criteria. Crit Care Med 2006;34:625-31.  Back to cited text no. 83
    
84.
Asakura H, Takahashi H, Uchiyama T, Eguchi Y, Okamoto K, Kawasugi K, et al. Proposal for new diagnostic criteria for DIC from the Japanese Society on Thrombosis and Hemostasis. Thromb J 2016;14:42.  Back to cited text no. 84
    
85.
Ding R, Wang Z, Lin Y, Liu B, Zhang Z, Ma X. Comparison of a new criteria for sepsis-induced coagulopathy and International Society on Thrombosis and Haemostasis disseminated intravascular coagulation score in critically ill patients with sepsis 3.0: A retrospective study. Blood Coagul Fibrinolysis 2018;29:551-8.  Back to cited text no. 85
    
86.
Iba T, Levy JH, Warkentin TE, Thachil J, van der Poll T, Levi M, et al. Diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation. J Thromb Haemost 2019;17:1989-94.  Back to cited text no. 86
    
87.
Iba T, Arakawa M, Di Nisio M, Gando S, Anan H, Sato K, et al. Newly proposed sepsis-induced coagulopathy precedes International Society on Thrombosis and Haemostasis overt-disseminated intravascular coagulation and predicts high mortality. J Intensive Care Med 2020;35:643-9.  Back to cited text no. 87
    
88.
Umemura Y, Yamakawa K, Ogura H, Yuhara H, Fujimi S. Efficacy and safety of anticoagulant therapy in three specific populations with sepsis: A meta-analysis of randomized controlled trials. J Thromb Haemost 2016;14:518-30.  Back to cited text no. 88
    
89.
Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving sepsis campaign: International guidelines for management of sepsis and septic shock: 2016. Intensive Care Med 2017;43:304-77.  Back to cited text no. 89
    
90.
Thachil J, Warkentin TE. How do we approach thrombocytopenia in critically ill patients? Br J Haematol 2017;177:27-38.  Back to cited text no. 90
    
91.
Levi M, Meijers JC. DIC: Which laboratory tests are most useful. Blood Rev 2011;25:33-7.  Back to cited text no. 91
    
92.
Kushimoto S, Wada H, Kawasugi K, Okamoto K, Uchiyama T, Seki Y, et al. Increased ratio of soluble fibrin formation/thrombin generation in patients with DIC. Clin Appl Thromb Hemost 2012;18:628-32.  Back to cited text no. 92
    
93.
Wada H, Sase T, Matsumoto T, Kushiya F, Sakakura M, Mori Y, et al. Increased soluble fibrin in plasma of patients with disseminated intravascular coagulation. Clin Appl Thromb Hemost 2003;9:233-40.  Back to cited text no. 93
    
94.
Wada H, Wakita Y, Nakase T, Shimura M, Hiyoyama K, Nagaya S, et al. Diagnosis of pre-disseminated intravascular coagulation stage with hemostatic molecular markers. The Mie DIC Study Group. Pol J Pharmacol 1996;48:225-8.  Back to cited text no. 94
    
95.
Vincent JL, Francois B, Zabolotskikh I, Daga MK, Lascarrou JB, Kirov MY, et al. Effect of a recombinant human soluble thrombomodulin on mortality in patients with sepsis-associated coagulopathy: The SCARLET randomized clinical trial. JAMA 2019;321:1993-2002.  Back to cited text no. 95
    


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