Disseminated intravascular coagulation (DIC), also known as consumptive coagulopathy or defibrination syndrome, is an acquired disorder of the hemostatic system that results in the pathologic activation and disequilibria of normal hemostasis and fibrinolysis, leading to potentially fatal consequences. This syndrome is common in critically ill veterinary patients and is always secondary to an underlying disorder that increases systemic thrombin and plasmin activities.1-9
The potential clinical consequences of DIC are systemic microvascular thrombosis with secondary organ damage or failure, hemorrhagic tendencies, shock, and death.1-5,9-11 These consequences make establishing a rapid diagnosis a must, so appropriate therapy can be initiated quickly to optimize a patient's response.
The principal goal of DIC therapy is to remove the primary disorder serving as the procoagulant stimulus. Until the primary disorder is eliminated, DIC will persist. Eliminating the primary disorder is rarely accomplished quickly, so the treatment regimen is initially supportive. To establish a correct diagnosis and rational therapeutic decisions regarding DIC, clinicians must be familiar with the normal hemostatic system and the pathophysiology of DIC.
The hemostatic system controls endothelial damage by generating a platelet plug and fibrin clots (coagulation) to minimize blood loss. The system also uses fibrinolysis to slowly dissolve clots to maintain organ perfusion. Physiologic inhibitors in the plasma maintain balance between coagulation and fibrinolysis by localizing coagulation activity and preventing systemic coagulation. Any hemostatic system disorder can lead to hypocoagulation (hemorrhage), hypercoagulation (thrombosis), or both (DIC).1,6,12
The hemostatic system is traditionally divided into three categories based on the types of disorders encountered in clinical medicine and on in vitro laboratory testing: primary hemostasis, secondary hemostasis, and fibrinolysis.
Platelet adherence and activation initiate hemostasis. Von Willebrand's factor and membrane glycoproteins mediate platelet adherence to damaged endothelium or collagen.6,12-14 Once adhered, the platelets become activated to aggregate, secrete, and contract. Activated platelets secrete serotonin and thromboxane A2, which initiate smooth muscle contraction of the vessel wall.6,12-14 This contraction, plus platelet contraction through cytoplasmic microtubules, forms the platelet plug. However, for hemostasis to continue, secondary hemostasis must follow.13
Secondary hemostasis, or the activation of coagulation factors, begins when blood is exposed to negatively charged surfaces of damaged endothelium (intrinsic coagulation system) or extravascular tissues (extrinsic coagulation system).6,13 The common endpoint of intrinsic and extrinsic coagulation is the conversion of prothrombin to thrombin—the critical step in fibrin clot formation.
When blood is exposed to damaged endothelium, the enzyme kallikrein activates factor XII. Kallikrein is produced from a complex formed by prekallikrein, high-molecular-weight kininogen, and activated factor XII. Once activated, factor XII activates factor XI. Activated factor XI then activates factor IX, and the process continues, involving a total of 10 serum proteins, calcium, and phospholipids (Figure 1).13
When blood is exposed to extravascular tissue, factor VII contacts calcium and a cell membrane factor (factor III, tissue thromboplastin, or tissue factor) and induces coagulation.13 Tissue factor is abundantly present on extravascular tissues and certain neoplastic cells. Endothelial cells, monocytes, and macrophages can express tissue factor in response to cytokines, especially interleukin-1 and tumor necrosis factor alpha (TNF-alpha), and to endotoxin.5,9,15-17 Activation of factor X leads to the common pathway and, ultimately, fibrin clot formation (Figure 1).
Fibrinolysis begins simultaneously with coagulation cascade activation. Endothelial and extravascular tissue damage facilitate the conversion of plasminogen to plasmin through the release of tissue plasminogen activator from the endothelium and urokinase plasminogen activator from the kidneys. Factor XII can facilitate the conversion as well.3,15 Plasmin degrades fibrin and fibrinogen into fibrin degradation products (FDPs) (Figure 1) and degrades activated factors V, VIII, IX, and XI.3 The liver removes FDPS from circulation.12
Physiologic inhibitors of coagulation
Numerous physiologic inhibitors in plasma localize coagulation activity to the injury site and maintain balance between coagulation and fibrinolysis to minimize bleeding and ensure continuous organ perfusion. The most important inhibitor is antithrombin III (antithrombin). Antithrombin is a physiologic inhibitor of blood coagulation in normal animals. Heparin accelerates antithrombin complex formation with thrombin. These antithrombin-thrombin complexes are removed by the liver, which decreases circulating thrombin. It has been suggested that antithrombin also inactivates factors IX, X, XI, and XII and kallikrein and plasmin.3,14,18
In addition, circulating thrombin loses its coagulation activity by binding to an endothelial receptor, thrombomodulin. The thrombin-thrombomodulin complexes activate protein C to activated protein C. Activated protein C, with the assistance of cofactor protein S, inactivates factors V and VIII.5,14,16,17,19,20
The fibrinolytic system is primarily opposed by alpha2-antiplasmin and by plasminogen activator inhibitor. Alpha2-antiplasmin binds and inactivates plasmin. Plasminogen activator inhibitor inactivates tissue plasminogen activator and urokinase plasminogen activator, which regulates the conversion of plasminogen to plasmin.5,16,17
DIC ETIOLOGY AND PATHOPHYSIOLOGY
DIC is a common syndrome, especially in critically ill dogs, and is always secondary to an underlying disorder.1-9 Many clinically diverse disorders can initiate DIC, but they share certain disease mechanisms that result in a common endpoint: excessive systemic circulating activities of thrombin and plasmin. These excessive thrombin and plasmin activities are the primary contributors in the development of DIC.3,5 In addition, many secondary events such as thrombocytopenia or thrombocytopathy, excessive consumption of coagulation or fibrinolysis inhibitors, and complement activation contribute to the DIC syndrome.1-5,12,21
Systemic inflammation produces numerous cytokines; those most important in DIC are interleukin-1 and TNF-alpha.5,15 These cytokines promote the production and expression of tissue factor from monocytes and endothelial cells, which are the primary events that initiate DIC in patients with systemic inflammation.3,5,15-17,22,23 Factor VII binds to tissue factor, serving to activate factor X, which converts prothrombin to thrombin (Figure 1).
In addition to inflammation-associated increased thrombin activity, down-regulation of coagulation and fibrinolysis inhibitors occur.3,16 Initially, total tissue and urokinase plasminogen activator activities increase at a normal ratio to TNF-alpha concentrations.16 This converts plasminogen to plasmin and increases circulating plasmin–alpha2-antiplasmin activities. However, fibrinolytic activity subsequently decreases because of increased plasminogen activator inhibitor activity. This inhibition of plasminogen activation may be the most important factor in inflammation-associated DIC.16,24 It is not clear how, why, and where plasminogen activator inhibitor increases.16 In addition, TNF-alpha causes down-regulation of thrombomodulin,3,16 resulting in the inactivation of the protein C-protein S anticoagulant pathway, which controls microvascular thrombosis.16 The increase in plasminogen activator inhibitor and down-regulation of thrombomodulin in systemic inflammation predispose patients to microvascular thrombosis.3,16
The mechanism of malignancy-induced DIC is poorly understood. DIC is thought to be a result of malignant cell invasion of the endothelium, the production of tissue factor by neoplastic cells, or the production of proteins by neoplastic cells that directly activate factor X.3,8
A severely decreased functional hepatic mass results in decreased production of coagulation and fibrinolysis factors and inhibitors and decreased Kupffer cell activity.3,6,23,25 The Kupffer cells of the liver remove activated clotting factors, FDPs, and absorbed endotoxin (from the gastrointestinal tract) from circulation.3,25,26 So severe hepatic disease can cause imbalance between coagulation and fibrinolysis because of increased circulating activated clotting factors, FDPs, and endotoxin. Increased circulating FDPs contribute to DIC in three ways: making fibrin dysfunctional, altering normal thrombin activity, and binding to platelets to create a thrombocytopathy.1-4
Direct activation of factor X
Snake envenomation, increased circulating trypsin secondary to pancreatitis, and certain neoplasms directly activate factor X.3 This activation increases systemic circulating activity of thrombin (Figure 1).
Regardless of the cause of DIC, these underlying disorders all increase systemic circulating thrombin and plasmin. The increased thrombin causes excessive fibrin clot deposition and systemic microvascular thrombosis. The microvascular thrombosis contributes to poor organ perfusion with possible ischemia-associated cell death or organ failure. The microvascular thrombosis also excessively entraps platelets and exceeds the thrombopoietic capacity of the bone marrow.2-4,7,8,12,21 Therefore, consumptive thrombocytopenia is commonly associated with DIC. The excessive fibrin generated from thrombin deposits on the endothelium, resulting in endothelial damage and red blood cell shearing (schistocytosis).3 The damaged vascular endothelium and red blood cell stroma amplify coagulation by expressing and releasing tissue factor.
The damaged endothelium, damaged extravascular tissues, and activated factor XII convert plasminogen to plasmin through tissue plasminogen activator and urokinase plasminogen activator. Excessive plasmin generation causes rapid dissolution of fibrin clots and the degradation of activated factors V, VIII, IX, and XI. This contributes to the hemorrhagic tendencies of patients with the acute form of DIC.3 Excessive plasmin has also been shown to activate complement, allowing lysis of red blood cells and platelets.3,13
Many of the coagulation and fibrinolysis inhibitors (e.g. antithrombin, alpha2-antiplasmin, activated protein C) that localize coagulation and maintain a balance between coagulation and fibrinolysis are consumed during the process of excessive thrombin and plasmin generation.
Understanding the hemostatic process and how it can be compromised is critical in managing patients with DIC. The next article shows you how to diagnose and treat this common, life-threatening disorder in pets.
Justin D. Thomason, DVM
Clay A. Calvert, DVM, DACVIM
Craig E. Greene, DVM, MS, DACVIM
Department of Small Animal Medicine and Surgery
College of Veterinary Medicine
University of Georgia
Athens, GA 30602
1. Carr AP, Johnson GS. A review of hemostatic abnormalities in dogs and cats. J Am Anim Hosp Assoc 1994;30:475-482.
2. Couto CG. Disseminated intravascular coagulation in dogs and cats. Vet Med 1999;94:547-554.
3. Bateman SW, Matthews KA, Abrams AC. Disseminated intravascular coagulation in dogs: review of the literature. J Vet Emerg Critic Care 1998;8:29-45.
4. Bateman SW, Mathews KA, Abrams-Ogg AC, et al. Diagnosis of disseminated intravascular coagulation in dogs admitted to an intensive care unit. J Am Vet Med Assoc 1999;215:798-804.
5. Mammen EF. Disseminated intravascular coagulation (DIC). Clin Lab Sci 2000;13:239-245.
6. Latimer KS, Mahaffey EA, Prasse KW, et al. Hemostasis. In: Duncan & Prasse's veterinary laboratory medicine: clinical pathology. 4th ed. Ames: Iowa State Press, 2003:99-135.
7. Stokol T, Brooks MB, Erb HN, et al. D-dimer concentrations in healthy dogs and dogs with disseminated intravascular coagulation. Am J Vet Res 2000;61:393-398.
8. Levi M. Cancer and DIC. Haemostasis 2001;31(suppl 1):47-48.
9. Asakura H, Suga Y, Aoshima K, et al. Marked difference in pathophysiology between tissue factor- and lipopolysaccharide-induced disseminated intravascular coagulation models in rats. Crit Care Med 2002;30:161-164.
10. Stokol T, Brooks M, Erb H, et al. Evaluation of kits for the detection of fibrin(ogen) degradation products in dogs. J Vet Intern Med 1999;13:478-484.
11. Greene CE. Disseminated intravascular coagulation in the dog: a review. J Am Anim Hosp Assoc 1975;11:674-687.
12. Hackner SG. Approach to the diagnosing of bleeding disorders. Compend Contin Educ Pract Vet 1995;17:331-349.
13. Breazile JE, College of Veterinary Medicine, Oklahoma State University, Stillwater, Okla: Personal communication, 2004.
14. Triplett DA. Coagulation and bleeding disorders: review and update. Clin Chem 2000;46:1260-1269.
15. Hack CE. Derangements of coagulation and fibrinolysis in infectious diseases. Contrib Microbiol 2003;10:18-37.
16. Levi M. Pathogenesis and treatment of disseminated intravascular coagulation in the septic patient. J Crit Care 2001;16:167-177.
17. ten Cate H. Pathophysiology of disseminated intravascular coagulation in sepsis. Crit Care Med 2000;28(suppl 9):S9-S11.
18. Rozanski EA, Hughes D, Scotti M, et al. The effect of heparin and fresh frozen plasma on plasma antithrombin III activity, prothrombin time and activated partial thromboplastin time in critically ill dogs. J Vet Emerg Critic Care 2001;11:15-21.
19. Aoki Y, Ota M, Katsuura Y, et al. Effect of activated human protein C on disseminated intravascular coagulation induced by lipopolysaccharide in rats. Arzneimittelforschung 2000;50:809-815.
20. Izutani W, Fujita M, Nishizawa K, et al. Urinary protein C inhibitor as a therapeutic agent to disseminated intravascular coagulation (DIC): a comparison with low molecular weight heparin in rats with lipopolysaccharide-induced DIC. Biol Pharm Bull 2000;23:1046-1050.
21. Feldman BF, Madewell BR, O'Neill S. Disseminated intravascular coagulation: antithrombin, plasminogen, and coagulation abnormalities in 41 dogs. J Am Vet Med Assoc 1981;179:151-154.
22. ten Cate H, Schoenmakers SH, Franco R, et al. Microvascular coagulopathy and disseminated intravascular coagulation. Crit Care Med 2001;29(suppl 7):S95-S98.
23. Dhainaut JF, Yan SB, Cariou A, et al. Soluble thrombomodulin, plasma-derived unactivated protein C, and recombinant human activated protein C in sepsis. Crit Care Med 2002;30(suppl 5):S318-S324.
24. Levi M, de Jonge E, van der Poll T, et al. Novel approaches to the management of disseminated intravascular coagulation. Crit Care Med 2000;28(suppl 9):S20-S24.
25. Van Thiel DH, George M, Fareed J. Low levels of thrombin activatable fibrinolysis inhibitor (TAFI) in patients with chronic liver disease. Thromb Haemost 2001;85:667-670.
26. Mueller MM, Bomke B, Seifried E. Fresh frozen plasma in patients with disseminated intravascular coagulation or in patients with liver diseases. Thromb Res 2002;107(suppl 1):S9-S17.