Phenotypes of Disseminated Intravascular Coagulation

Abstract

Two phenotypes of disseminated intravascular coagulation (DIC) are systematically reviewed. DIC is classified into thrombotic and fibrinolytic phenotypes characterized by thrombosis and hemorrhage, respectively. Major pathology of DIC with thrombotic phenotype is the activation of coagulation, insufficient anticoagulation with endothelial injury, and plasminogen activator inhibitor-1-mediated inhibition of fibrinolysis, leading to microvascular fibrin thrombosis and organ dysfunction. DIC with fibrinolytic phenotype is defined as massive thrombin generation commonly observed in any type of DIC, combined with systemic pathologic hyperfibrinogenolysis caused by underlying disorder that results in severe bleeding due to excessive plasmin formation. Three major pathomechanisms of systemic hyperfibrinogenolysis have been considered: (1) acceleration of tissue-type plasminogen activator (t-PA) release from hypoxic endothelial cells and t-PA-rich storage pools, (2) enhancement of the conversion of plasminogen to plasmin due to specific proteins and receptors that are expressed on cancer cells and endothelial cells, and (3) alternative pathways of fibrinolysis. DIC with fibrinolytic phenotype can be diagnosed by DIC diagnosis followed by the recognition of systemic pathologic hyperfibrin(ogen)olysis. Low fibrinogen levels, high fibrinogen and fibrin degradation products (FDPs), and the FDP/D-dimer ratio are important for the diagnosis of systemic pathologic hyperfibrin(ogen)olysis. Currently, evidence-based treatment strategies for DIC with fibrinolytic phenotypes are lacking. Tranexamic acid appears to be one of the few methods to be effective in the treatment of systemic pathologic hyperfibrin(ogen)olysis. International cooperation for the elucidation of pathomechanisms, establishment of diagnostic criteria, and treatment strategies for DIC with fibrinolytic phenotype are urgent issues in the field of thrombosis and hemostasis.

Fig. 1

Brief summary of fibrinolytic system. Primary stimulators of secondary fibrinolysis are thrombin and hypoxia of endothelial cells under fibrin thrombus. Plasminogen and t-PA released from endothelial cells due to these stimulations meet on the fibrin thrombus, and subsequently degrade fibrin. Three major inhibitors of fibrinolysis are PAI-1, α2-antiplasmin, and TAFI. Fibrin degradation by plasmin forms D-dimer, while excessive plasmin escaped from α2-antiplasmin degrades fibrinogen in the circulation. α2AP, α2-antiplasmin; FDP, fibrinogen/fibrin degradation products; FgDP, fibrinogen degradation products: LBS, lysine binding site; PAI-1, plasminogen activator inhibitor-1; Plg, plasminogen, TAFI, thrombin activatable fibrinolysis inhibitor; t-PA, tissue-type plasminogen activators.

Fig. 2

Factor XIIa and KKS in fibrinolysis. Factor XIIa and KKS are involved in the fibrinolytic system through plasmin formation by factor XIIa and kallikrein, and bradykinin-induced t-PA release from endothelial cells via kinin B2 receptor. Major inhibitor in these fibrinolytic systems is C1-INH. ACE, angiotensin converting enzyme; C1-INH, C1-(esterase) inhibitor; DABK, des-Arg9-bradykinin; KB1R, kinin B1 receptor; KB2R, kinin B2 receptor; PAI-1, plasminogen activator inhibitor-1; t-PA, tissue-type plasminogen activator.

Fig. 3

Two phenotypes of DIC. Basic principle of DIC is a thrombotic phenotype characterized by activation of coagulation, insufficient anticoagulation with endothelial injury, and inhibition of fibrinolysis by PAI-1. Thrombotic phenotype gives rise to organ dysfunction due to microvascular fibrin thrombosis. DIC with fibrinolytic phenotype is defined as simultaneous development of both DIC and systemic pathologic hyperfibrin(ogen)olysis under one insult, which shows typical oozing-type bleeding. Thrombin generation due to activation of coagulation and insufficient anticoagulation always underlies both phenotypes of DIC. DIC, disseminated intravascular coagulation.

Fig. 4

Pathomechanisms of systemic pathologic hyperfibrin(ogen)olysis and underlying disorders. Three major pathomechanisms are acceleration of t-PA release from hypoxic endothelial cells and t-PA rich storage pools and enhancement of conversion of plasminogen to plasmin due to specific protein and receptor. Plg, plasminogen; t-PA, tissue-type plasminogen activator; u-PA, urokinase (urinary)-type plasminogen activator.