DIC: Diagnosing and treating a complex disorder

September 1, 2005

In this article, we provide guidance to help you identify and effectively treat patients with DIC early, improving their outcome.

Many diseases or disorders can lead to disseminated intravascular coagulation (DIC), as discussed in the previous article. DIC can manifest in a variety of forms depending on the severity and duration of the procoagulant stimulus, so patients with DIC can have a variety of signs. In addition, a gold standard test for establishing a definitive diagnosis is lacking, so clinicians rely heavily on evaluating patients and appropriately interpreting available laboratory test results.

Treatment is challenging as well, because the primary disorder stimulating coagulation must be identified and eliminated for a complete recovery. Supportive treatment of DIC consists of controlling excessive intravascular coagulation, maintaining organ perfusion, and replacing coagulation components, if necessary. Supportive treatment is continued until the primary disease can be eliminated. In this article, we provide guidance to help you identify and effectively treat patients with DIC early, improving their outcome.

CLINICAL FEATURES

Because of its pathophysiology, DIC can manifest as massive thrombosis, hemorrhage, or both. Most often thrombosis and hemorrhage occur simultaneously. Adding to this complexity, three clinical forms exist: peracute, acute (fulminant or end-stage), and chronic (subclinical or low-grade).1-7 The varying forms seem to be related to the intensity of the procoagulant stimulus. For example, acute DIC may be a true acute process or, more commonly, an acute decompensation of peracute DIC. Chronic DIC tends to be common with malignancies and other localized or chronic, low-intensity hypercoagulable disorders (e.g. pulmonary thromboembolism).

Peracute DIC

Patients with peracute DIC most often demonstrate organ thrombosis with a mild consumptive thrombocytopenia. Thrombosis is evidenced by clinical and clinicopathologic abnormalities indicative of organ dysfunction (Table 1). The most common organs or systems to thrombose are the kidneys, lungs, heart, central nervous system, and gastrointestinal tract.2,6 These patients may present with a primary hemostatic abnormality; however, typically thrombocytopenia is mild, and no hemostatic abnormalities are evident. Clotting times may be faster than normal and may be indicative of hypercoagulation.8 However, assessing D-dimer concentration is a more sensitive test for acute thromboembolism.9 The severity of organ failure determines these patients' outcomes.

Table 1. Common Sites of Thrombosis and the Respective Clinical Signs and Clinicopathologic Findings

Acute DIC

Patients with acute DIC typically present with both thrombosis and hemorrhage. Acute DIC is typically an acute decompensation of peracute DIC.8 The decompensation is secondary to ongoing damaged endothelium, damaged extravascular tissues, and increases in factor XII with secondary excessive plasmin generation. Excessive plasmin causes rapid dissolution of fibrin clots and degradation of factors V, VIII, IX, and XI. Primary (petechiation, ecchymosis, mucosal bleeding) and secondary (body cavity hemorrhage) hemostatic abnormalities are present.1,2,4 Acute DIC is rapidly fatal, usually because of severe hypotension and irreversible shock.1,2,4

Chronic DIC

Clinical signs are less obvious and slow to develop in patients with chronic DIC. As a result, the body can compensate with increased production of clotting factors, platelets, and inhibitors.1-4 Platelets tend to be decreased while coagulation factors are normal because bone marrow production (platelets) is more limited than hepatic production (coagulation factors).7 This compensation prevents the spontaneous hemorrhage evident with acute DIC. However, if hemorrhage is evident, it is generally due to primary hemostatic dysfunction. If recognized early, chronic DIC tends to have a better prognosis because multiple organ dysfunction and severe shock are usually not present.

DIAGNOSIS

The diversity and complexity of DIC make establishing a diagnosis difficult. Always consider DIC in patients with an unexplained sudden onset of hemorrhage, thrombosis of one or more organ systems, or a disease commonly associated with DIC. It is impossible to differentiate between a patient with an early platelet consumptive process that will soon develop acute DIC and a patient with chronic DIC. So it is important to screen patients that present with disease associated with DIC before signs of organ failure or overt hemorrhage occur. Early recognition facilitates early therapeutic intervention and possibly prevents acute DIC.

Clinical signs and laboratory tests

The clinical features of DIC are nonspecific and depend on the degree of coagulation and organ systems affected. Most patients present for evaluation of the primary disease and are rarely bleeding spontaneously.1 For patients with evidence of hemorrhage, consider other acquired bleeding disorders. Even if you suspect DIC, a definitive diagnosis relies on evaluating laboratory test results.

Not only is there no highly specific test for DIC, but some tests lack sensitivity. In addition to a complete blood count, a serum chemistry profile, and urinalysis, the laboratory tests for evaluating any hemostatic disorder, including DIC, ideally consist of a prothrombin time (PT), an activated partial thromboplastin time (APTT), a platelet count, fibrinogen concentration measurement, fibrin degradation products (FDPs) measurement, a D-dimer assay, antithrombin activity measurement, and a blood smear evaluation (Table 2).10

Table 2. Test Results to Help Differentiate Among Acquired Bleeding Disorders

Clotting times

When evaluating a patient that you suspect has DIC, it is important to remember that thrombin or plasmin may predominate or both may contribute to initiating DIC. If excessive thrombin is driving DIC (peracute form), organ damage secondary to microvascular thrombosis may be evident as renal impairment, pulmonary dysfunction, gastrointestinal dysfunction, or neurologic deficits. Although of uncertain clinical relevance, the APTT and PT may be decreased or normal depending on the chronicity of the primary disease.8 A more sensitive test for acute thromboembolism may be a D-dimer concentration in dogs.9,11 If plasmin is driving DIC (acute form), secondary hemostatic abnormalities are usually present and clotting times are prolonged. The latter is due to plasmin's role in inactivating factors V, VIII, IX, and XI. If both thrombin and plasmin are driving DIC (chronic form), clinical evidence of overt thrombosis and hemorrhage may not be present, so making a diagnosis is challenging.

If a patient's clotting times are normal and an underlying disease is identified that predisposes the patient to DIC, perform serial platelet counts and measure the fibrinogen concentration. In patients with microvascular thrombosis, thrombocytopenia is expected because platelet consumption usually exceeds bone marrow thrombopoiesis (depending on chronicity). And because thrombin converts fibrinogen into fibrin, the fibrinogen concentration is expected to be low in patients with DIC. However, fibrinogen is an acute phase protein, and with chronic inflammation it may be elevated in patients with DIC.5 Furthermore, dogs have a tremendous capacity to replenish fibrinogen.

One study revealed a prolonged APTT in 87% of dogs with DIC, a prolonged PT in 80%, thrombocytopenia in 80%, and a low fibrinogen concentration in 61%.12 Another study revealed a prolonged APTT in 100% of cats with DIC, a prolonged PT in 71%, thrombocytopenia in 57%, and a low fibrinogen concentration in 5%.1 Thrombocytopenia and low fibrinogen concentrations are not specific for DIC.

Platelet count

It is important to evaluate sequential platelet counts. Counts that decrease over time are consistent with a consumptive process. Our clinic evaluates for evidence of megathrombocytosis (increased mean platelet volume). Our clinical impression is that megathrombocytosis is a sensitive indicator of immune-mediated or consumptive coagulopathy even with mild serial decreases in platelet counts.

If the patient has normal platelet counts and clotting times, acute DIC is unlikely. If you suspect peracute or chronic DIC based on a decreasing platelet count or fibrinogen concentration, additional laboratory tests are justified. We recommend a D-dimer assay and antithrombin activity measurement.

D-dimers, FDPs, antithrombin, and fibrinogen

D-dimers are cross-linked fibrin-derived degradation products and result when fibrinolysis is activated with ongoing coagulation, thus D-dimers indicate activation of both the fibrinolytic and coagulation systems.4,10,13,14 FDPs are produced with primary fibrinolysis or fibrinolysis secondary to coagulation. Their presence does not distinguish between fibrinogen or fibrin-derived products.4,10,13 Thus FDPs only indicate activation of the fibrinolytic system. Since most forms of DIC activate both systems, D-dimer concentration measurement appears to be a sensitive ancillary test for DIC in dogs.9 D-dimers can be detected in association with degradation of any blood clot, so the results of a D-dimer assay must be interpreted with caution.

An increased D-dimer concentration is not diagnostic for DIC but supports the diagnosis in patients that have predisposing diseases and consumptive thrombocytopenia. In the face of elevated D-dimer concentrations or low antithrombin activities in patients with decreasing platelet and fibrinogen concentrations over time, DIC is probable. One study evaluating a point-of-care test showed that with normal D-dimer concentrations, DIC is highly unlikely.9 And in one study of dogs with DIC, FDP concentrations were elevated in 61% (correlated with low fibrinogen) and antithrombin activities were low in 85% of the patients.12 D-dimer concentrations greater than 500 mg/ml were 100% sensitive for acute thromboembolism.11 In a study in cats with DIC, FDP concentrations were elevated in 24% of the cats.1

Blood smears

In addition to the above tests, peripheral blood smears can help support a diagnosis of DIC. Fibrin deposits on the endothelium shear red blood cells. Schistocytes are found in about 71% of dogs and 67% of cats with DIC.1,12

Diagnostic criteria

Analysis of the above tests may suggest the presence of DIC, but no test is pathognomonic. When presented with a patient with evidence of thrombosis or hemorrhage or with a condition that predisposes a patient to DIC, our clinic requires at least three of the following to establish a diagnosis:

  • Decreasing serial platelet count in the face of megathrombocytosis

  • Prolonged PT

  • Prolonged APTT

  • Increased FDP concentration

  • Decreased fibrinogen concentration

  • Increased D-dimer concentration

  • Decreased antithrombin activity

  • Schistocytosis

TREATMENT AND MONITORING

Treating DIC is difficult, especially without 24-hour intensive care and monitoring and point-of-care testing. Although unproven, early recognition of patients with DIC should facilitate the likelihood of a positive outcome. Once DIC has been confirmed or if the clinical suspicion is high, treatment should begin immediately. The goals of therapy are to

  • Eliminate the underlying cause

  • Control excessive intravascular coagulation

  • Maintain organ perfusion

  • Replace coagulation components, if necessary

Coagulation times and fibrinogen concentrations may normalize within hours of appropriate therapy. However, FDPs and thrombocyte counts take days to normalize. A favorable response to therapy is associated with clinical improvement and daily improvements in laboratory test results. The platelet count should increase in response to effective treatment.

Eliminate the underlying cause

DIC is always secondary to an underlying disease or disorder, so DIC will persist until the disease or disorder is eliminated. It is often impossible to eliminate the inciting cause quickly. Some exceptions include splenectomy to treat hemangiosarcoma, aggressive intravenous antibiotic treatment of bacteremia, surgical treatment of external or internal abscesses, and surgical excision of selected malignancies. Aggressive treatment is necessary and should never be overlooked. Once the procoagulant stimulus is controlled, spontaneous recovery is possible.7

Control excessive intravascular coagulation

Based on the pathophysiology of DIC and the likelihood the syndrome is being driven by both thrombin and plasmin, attenuating intravascular coagulation would prevent microvascular thrombosis and the consumption of platelets and coagulation inhibitors. This can be achieved by administering exogenous coagulation inhibitors. Antithrombin is the most important endogenous inhibitor of coagulation, so systemic therapy with heparin sodium, a cofactor of antithrombin, is recommended in veterinary medicine.

Heparin

No controlled studies of heparin therapy in DIC exist in the veterinary or human medical literature. So the benefit of such therapy is controversial. In addition, without appropriate antithrombin activity (which can be low secondary to consumption), heparin therapy will be of little benefit. Natural anticoagulants (i.e. antithrombin activity) may be decreased in patients with severe inflammatory diseases that predispose patients to DIC.15 Plasma antithrombin activity has to be below 70% for heparin therapy to be ineffective.16

As a sole treatment, heparin is contraindicated in patients with acute DIC and secondary hemostatic abnormalities. These patients should receive antithrombin and coagulation factors in the form of fresh frozen plasma with heparin. We add 5 to 10 U/kg heparin sodium to plasma before administration. Patients with peracute or chronic DIC with no secondary hemostatic abnormalities may benefit from heparin treatment alone depending on antithrombin activity. Therefore, with few exceptions, systemic heparin therapy is recommended for patients with DIC (Table 3). However, no single dosage can be recommended, and therapy should be tailored to the individual patient. Traditionally, the four dose ranges for heparin sodium are1

  • Mini-dose: 5 to 10 U/kg given subcutaneously three times a day or added to plasma components 30 minutes before plasma administration

  • Low-dose: 100 to 200 U/kg given subcutaneously three times a day

  • Intermediate-dose: 300 to 500 U/kg given subcutaneously three times a day

  • High-dose: 750 to 1,000 U/kg given subcutaneously or intravenously three times a day; this dose is rarely used in our clinic and not recommended.

Table 3. Clinical Forms of DIC and General Treatment Guidelines*

In our clinic, we routinely administer the low dose (100 to 200 U/kg) of heparin sodium in patients that have chronic DIC without evidence of microvascular thrombosis. For patients with peracute DIC and normal clotting times, we recommend the intermediate dose (300 to 500 U/kg) with the goal of prolonging the APTT one-and-one-half to two times normal baseline. During heparin therapy in patients with peracute DIC, we recommend monitoring the APTT, not the activated clotting time. The APTT is prolonged when any factor in the intrinsic and common pathway is decreased to less than 30% activity.17 A prolonged activated clotting time is seen with only more profound (> 30%) decreases in factor activity. Because of poor sensitivity, it may be dangerous to use the activated clotting time for monitoring.

We recommend beginning at the lower dose and increasing the dose to the endpoint based on changes in platelet count and coagulation times. In our experience, high-dose heparin is rarely justified and can be dangerous. In case of heparin overdosage, 1 mg protamine sulfate can be given for each 100 U heparin to be inactivated.18 The protamine dose should be reduced by half for every 30 minutes lapsed since the last heparin administration.18 This dose should be given slowly intravenously at a rate not to exceed 50 mg over a 10-minute period.18 Administer protamine with caution because of the possibility of acute anaphylaxis.

Low-molecular-weight heparins

Low-molecular-weight heparins can be used as substitutes for unfractionated heparin (heparin sodium). Important differences exist between low-molecular-weight heparins and heparin sodium. Unlike heparin sodium, low-molecular-weight heparins cannot bind to antithrombin.19 Low-molecular-weight heparins have better activity against active factor X while minimally affecting clotting times.20 Low-molecular-weight heparins also bind less to macrophages, proteins, and platelets.19 As a result, low-molecular-weight heparins are associated with a decreased incidence of bleeding and more predictive anticoagulant activity because of better bioavailability.20

Because of the low-molecular-weight heparins' minimal effect on clotting times, APTT cannot be used to monitor efficacy. Instead, antifactor Xa activity should be used to monitor antithrombotic efficacy. In people, the targeted therapeutic range of antifactor Xa activity is 0.35 to 0.7 U/ml.19 During preliminary studies in cats, therapeutic concentrations of antifactor Xa activity were achieved at a low-molecular-weight heparin dose of 100 U/kg.19

Many low-molecular-heparin preparations are available with different pharmacokinetics. In our clinic, we use dalteparin at a dosage of 100 U/kg given subcutaneously twice a day for DIC in dogs and cats. Studies documenting dalteparin's efficacy have not been published. One disadvantage of low-molecular-weight heparin is cost. A 9.5-ml vial containing 10,000 U/ml costs about $450.

Taper anticoagulant therapy

Once the test results are within target ranges and the underlying disease process is eliminated, heparin sodium or dalteparin therapy is continued at tapering doses (maintaining the same frequency of daily administration) over a five-day period to prevent hypercoagulation.

Maintain organ perfusion

Patients with DIC are predisposed to microvascular thrombosis and resultant decreased organ perfusion and risk of multiple organ dysfunction. Aggressive fluid therapy, in the form of crystalloids or colloids, is recommended to flush microthrombi from the circulation, dilute activated clotting factors, and maintain organ perfusion to ensure delivery of essential nutrients to tissues.1 Crystalloids, such as lactated Ringer's solution, are administered at one-and-one-half to two times maintenance volumes (i.e. 60 to 90 ml/kg/day). Colloids, such as hetastarch (hydroxyethyl starch), are administered at a dosage of 10 to 20 ml/kg/day.

Replace coagulation components

The replacement of coagulation components is generally reserved for patients that have acute DIC with active evidence of hemorrhage or for patients with decreased antithrombin activity. Ideally, antithrombin activity would be measured. However, if this is not possible, it should be assumed to be low in most patients with DIC. Coagulation components can be replaced by administering whole blood or fresh frozen plasma, depending on the patient.

Administering blood or blood products is controversial because of potential, but unproven, adverse effects of fibrinogen, which can lead to severe microvascular thrombosis and multiple organ dysfunction syndrome. It is unfortunate that there is no source of antithrombin replacement that does not contain other coagulation factors. We limit blood and blood product administration to patients that are actively bleeding, patients in which the bleeding can be catastrophic and lead to death, or patients with markedly decreased (< 70%) antithrombin activity.

PROGNOSIS

Treating DIC is complicated and must be individualized for each patient. Recognizing DIC early should provide a better chance of a positive outcome. So patients that present with a disease process capable of initiating DIC should be carefully monitored and receive appropriate therapy to decrease morbidity and mortality. The prognosis for patients with acute DIC is grave. However, if the primary disease can be eliminated and DIC is appropriately treated, most other patients recover.1 Severe organ failure or thrombosis is often life-threatening.

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

REFERENCES

1. Couto CG. Disseminated intravascular coagulation in dogs and cats. Vet Med 1999;94:547-554.

2. Bateman SW, Matthews KA, Abrams AC. Disseminated intravascular coagulation in dogs: review of the literature. J Vet Emerg Critic Care 1998;8:29-45.

3. 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.

4. Mammen EF. Disseminated intravascular coagulation (DIC). Clin Lab Sci 2000;13:239-245.

5. Hackner SG. Approach to the diagnosing of bleeding disorders. Compend Contin Educ Pract Vet 1995;17:331-349.

6. Bakhshi S, Arya LS. Diagnosis and treatment of disseminated intravascular coagulation. Indian Pediatr 2003;40:721-730.

7. Greene CE. Disseminated intravascular coagulation in the dog: a review. J Am Anim Hosp Assoc 1975;11:674-687.

8. Weiss DJ, Rashid J. The sepsis-coagulant axis: a review. J Vet Intern Med 1998;12:317-324.

9. Griffin A, Callan MB, Shofer FS, et al. Evaluation of a canine D-dimer point-of-care test kit for use in samples obtained from dogs with disseminated intravascular coagulation, thromboembolic disease, and hemorrhage. Am J Vet Res 2003;64:1562-1569.

10. Caldin M, Furlanello T, Lubas G. Validation of an immunoturbidimetric D-dimer assay in canine citrated plasma. Vet Clin Pathol 2000;29:51-54.

11. Nelson OL, Andreasen C. The utility of plasma D-dimer to identify thromboembolic disease in dogs. J Vet Intern Med 2003;17:830-834.

12. 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.

13. Moresco RN, Vargas LC, Voegeli CF, et al. D-dimer and its relationship to fibrinogen/fibrin degradation products (FDPs) in disorders associated with activation of coagulation or fibrinolytic systems. J Clin Lab Anal 2003;17:77-79.

14. Matsuo T, Kobayashi H, Kario K, et al. Fibrin D-dimer in thrombogenic disorders. Semin Thromb Hemost 2000;26;101-107.

15. de Laforcade AM, Freeman LM, Shaw SP, et al. Hemostatic changes in dogs with naturally occurring sepsis. J Vet Intern Med 2003;17:674-679.

16. 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.

17. Feldman BF, Kirby R, Caldin M. Recognition and treatment of disseminated intravascular coagulation. In: Kirk's Current Veterinary Therapy Small Animal Practice XIII. Philadelphia, Pa: WB Saunders Co, 2000:190-194.

18. Plumb DC. Protamine sulfate. In: Veterinary drug handbook. Ames: Iowa State Press, 2002:711-712.

19. Smith CE, Rozanski EA, Freeman LM, et al. Use of low molecular weight heparin in cats: 57 cases (1999-2003). J Am Vet Med Assoc 2004;225:1237-1241.

20. Rozanski E. Management of the hyper-coagulable patient: anticoagulant therapy, in Proceedings. Tufts Anim Expo 2002.

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