Introduction

Rather than a disease itself, DIC is the pathological consequent to many different disorders characterized by an acute widespread activation of coagulation, resulting in thromboembolic complications due to intravascular formation of fibrin, as well as diffuse hemorrhage, due to the consumption of platelets and coagulation factors.¹ The clinical presentation can range from sub-clinical prolongation of clotting times to widespread and simultaneous microvascular thrombosis and bleeding. In small animals, DIC appears to be characterized predominantly by bleeding tendencies rather than thromboembolic tendencies, however this requires further investigation.

The key issues with the management of patients with DIC revolve around resolution of primary cause, proper diagnosis, recognizing patients at risk for developing DIC, and consideration of rational treatment. Recent developments in therapy in people with DIC centre on reducing development of thromboembolic complications. In small animals, the focus of DIC therapy is geared towards reversing life-threatening bleeding as our ability to detect thromboembolic events is quite limited.

Pathogenesis

As DIC is always secondary to an underlying disorder, rational therapy should always be targeted at reversing the primary disease. Common diseases associated with DIC in dogs include sepsis, IMHA, pancreatitis, severe trauma, heat-stroke, and malignancy. While treatment of the underlying disease remains the cornerstone of DIC management, supportive therapies designed to modulate the coagulation system may be necessary to restore normal hemostasis. Pathophysiological processes that play a role in the development of DIC include tissue factor-dependent activation of coagulation, defective physiological anticoagulant pathways (e.g., antithrombin), and impaired fibrinolysis.^1-3 A generalized inflammatory response characterized by the elevation of cytokines is responsible for the derangement of the coagulation system.^1-3 Tissue factor, which is exposed following injury to the endothelium, triggers the initiation of the coagulation cascade. Local generation of thrombin leads to the formation of thrombi. In this process of self-perpetuating coagulation, clotting factors are consumed. Once the fibrinolytic system is activated, inactivation of clotting factors, and impaired platelet function follows. FDPs, produced by clot lysis, are strong inhibitors of platelet function. This is then followed by antithrombin, proteins C and S depletion, highlighting the consumptive nature of this haemostatic disorder.

In people, the hypercoagulable aspects of DIC appear to predominate and much of the morbidity and mortality associated with DIC centre on thromboembolic events. In contrast, it appears that mortality in dogs with DIC is significantly higher in individuals with pronounced hypocoagulable states.⁴

Diagnosis

Definitive diagnosis of DIC remains controversial both in people and animals. Since no single laboratory test or set of tests have been shown to be sensitive or specific enough to make a definitive diagnosis (i.e., there is no true "gold-standard"), a sensible approach for the diagnosis should be based on the combination of various clinical and laboratory findings in a patient predisposed to DIC. Based on our current understanding of DIC, a proper diagnosis requires identification of on-going coagulation disturbances (prolongation of clotting times, fibrinogen consumption), on-going fibrinolysis (usually via detection of FDPs or D-dimers), endogenous anticoagulant depletion (AT deficiency) and clinical manifestations of these abnormalities--this is to say that DIC should not be diagnosed if only laboratory abnormalities are identified.^1,2 Recent developments in the study of DIC in dogs revolve on the use thromboelastography (TEG)⁴; however, the greatest potential of this modality lies in further characterization of the hemostatic disturbances rather than as a diagnostic tool.

Recently, a scoring system for DIC has been developed in dogs, which was developed in a similar fashion to the International Society of Thrombosis and Haemostasis' DIC scoring system.⁵ This scoring scheme is reliant on APTT, PT, d-dimers, and fibrinogen concentration. The reported sensitivity and specificity of this new scoring scheme is 83.3% and 77.3%, respectively.⁵

Update on Therapy

Given the heterogenicity of the underlying disorders that predispose patients to DIC, a standard therapy for DIC is unlikely to be effective in all cases. Therefore, success is largely dependent on treating the underlying disease. However, therapies designed to modulate coagulation processes (e.g., replenishment of depleted clotting factors, anticoagulants) may yet have a role in the management of patients with DIC. With replacement therapy, the aim is to restore consumed platelets and clotting factors responsible for overt bleeding.

In regards to specific therapies, results remain controversial. Heparin (both unfractionated and low-weight molecular heparin therapy for example), has been evaluated in multiple studies for efficacy against DIC and results remain inconclusive. Physiologically, heparin serves to activate antithrombin and therefore would seem beneficial in DIC. However, clinical trials have not been convincing in supporting the universal use of heparin in DIC. In syndromes where thrombosis dominates, such as "chronic" or "compensated" DIC, heparin may have a more important role. Based on a very recent consensus statement from the British Committee on Haematology Standards, the following recommendations were made⁶:

1.  Transfusion of platelets or plasma in patients with DIC are not recommended if the decisions are solely based on laboratory results. Such interventions are generally reserved for patients who present with bleeding tendencies.

2.  In people with DIC that are bleeding or at high risk of bleeding (e.g., postoperative patients or patients due to undergo an invasive procedure) and have significant thrombocytopenia (platelet count of <50 x 10⁹/l), transfusions of platelets are considered. In non-bleeding human patients with DIC, prophylactic platelet transfusions are not administered unless it is perceived that there is a high risk of bleeding.

3.  In bleeding human patients with DIC and prolonged PT and aPTT, administration of FFP may be useful. There is no evidence that infusion of plasma stimulates the ongoing activation of coagulation.

4.  In people with severe hypofibrinogenemia (<1 g/l) that persists despite FFP replacement, they may be treated with fibrinogen concentrate or cryoprecipitate.

5.  In cases of DIC where thrombosis predominates, such as arterial or venous thromboembolism, therapeutic doses of heparin should be considered. In patients where there is a perceived high risk of bleeding, there may be benefits in using continuous infusion of unfractionated heparin due to its short half-life and reversibility.

6.  In critically ill, non-bleeding patients with DIC, prophylaxis for venous thromboembolism with prophylactic doses of heparin or low molecular weight heparin is recommended in people.

7.  Patients at high risk of bleeding are not treated with recombinant human activated protein C, although there is a great deal of research evaluating the utility of treating patients with severe sepsis and DIC with recombinant human activated protein C.

8.  There is no good evidence supporting the use of antithrombin concentrate in patients with DIC.

9.  In general, patients with DIC are not treated with antifibrinolytic agents.

Prospects for Companion Animals

Despite the recent developments in therapeutics for DIC in people, the veterinary literature is almost devoid of any trials evaluating therapies for dogs or cats with DIC. Veterinary treatment recommendations are largely derived from physiological rationale and experimental animal models rather than any clinical study. As in people, FFP is often recommended and justified for treatment of overt coagulopathic DIC to replenish consumed clotting factors.

The addition of heparin (as a means to activate AT) to FFP therapy has also not been shown to be particularly beneficial in clinically affected animals, yet this recommendation permeates the veterinary literature. AT activity has been shown not to significantly increase in dogs following transfusion with FFP or FFP and heparin.⁷ One study proposed that low weight molecular heparin may be useful in limiting the consumptive aspect of DIC.⁸ What little information there is in the veterinary literature only allows us to conclude that the dose, type, and clinical conditions best suited for treatment with heparin are still unknown.^7-9

In regards to possibly using drugs such as human recombinant aPC in animals with sepsis and DIC, the prospect is highly unlikely. The main issues are cost, antigenicity, and feasibility. From limited studies in dogs (experimental model), the dose of human recombinant aPC is 15-20 times higher in dogs than in people to achieve the same degree of anticoagulation making this an untenable therapy for dogs.¹⁰

Conclusions

Recent advances in coagulation and diagnostic techniques will improve our ability to rapidly diagnose and better understand the pathogenesis of DIC in animals. Promising therapies used in people with DIC are unlikely to be employed in veterinary patients in the foreseeable future. Greater experience with low molecular weight heparins may reveal a potential role for this drug, although this strategy is not necessarily associated with improved clinical outcome in people.

References

1.  Levi M, et al. N Engl J Med 1999;341: 586.

2.  Franchini M. Clin Lab 2005;51:633.

3.  Levi M, et al. Ann Med 2004;36:41.

4.  Wiinberg B, et al. J Vet Intern Med. 2008; 22:357.

5.  Wiinberg B, et al. Vet J. 2010 (in press).

6.  Levi M, et al. Br J Haematol. 2009;145:24.

7.  Rozanski EA, et al. J Vet Emerg Crit Care 2001;11:15.

8.  Mischke R, et al. Res Vet Sci. 2005;79:69.

9.  Scott KC, et al. J Vet Emerg Crit Care 2009;19:74.

10. Jackson CV, et al. J Pharmacol Exp Ther 2000;295:967.