June 2000

DISSEMINATED INTRAVASCULAR COAGULATION

Disseminated intravascular coagulation (DIC) is never a primary disease per se, but a serious and often life-threatening complication of a variety of diseases. DIC can be acute or chronic, and fatal or non-fatal, depending on: the underlying cause; the body’s ability to compensate for and control the process; and the intervention we are able to provide.

The key event in DIC is systemic activation of coagulation to an extent which cannot be contained by the body’s anticoagulant mechanisms. This leads to a sequence of events which result in the clinical and laboratory manifestations of DIC. The pathophysiology of DIC is similar regardless of the initiating cause:

• Activation of the coagulation cascade leads to fibrin (formed from fibrinogen by the action of thrombin) deposition in the microvasculature (thrombosis). Thrombus formation results in ischemia and end-organ damage (manifested clinically as increased liver enzymes, azotemia, cardiac arrhythmias, abdominal pain, respiratory alkalosis, and CNS signs).

• This activation of coagulation results in consumption and depletion of coagulation factors, including procoagulant factors (especially those that are non-enzymatic factors–fibrinogen, factor V, and factor VIII) and anticoagulant factors such as AT-III. This results in prolongation of clotting tests (ACT, APTT, PT), decreased concentrations of fibrinogen and AT-III, and signs of a bleeding disorder.

• Platelets are activated by the thrombin generated from coagulation, become trapped by fibrin deposited in the microvasculature, and participate in formation of intravascular thrombi. This leads to thrombocytopenia. Red cells are also damaged by fibrin in the microvasculature, leading to formation of schistocytes (this is sometimes referred to as microangiopathic hemolysis).

• Plasmin, the active enzyme of fibrinolysis, is generated by tissue plasminogen activator (which is released by endothelial cells in response to thrombin). Plasmin degrades fibrin clots as well as circulating fibrinogen (to form fibrin and fibrinogen degradation products, FDPs). Elevated concentrations of FDPs inhibit platelet function and fibrin polymerization, thereby exacerbating the bleeding diathesis.

• Hypotension and shock in patients with DIC is promoted by plasmin and various kinins, which lead to increased vascular permeability and vasodilation.

• Although clinical signs of bleeding predominate, it is important to remember that organ damage due to thrombosis and ischemia is occurring simultaneously. The clinical signs of bleeding can include petechiation, mucosal surface bleeding, bleeding from venipuncture sites or wounds, subcutaneous hematomas, and deep muscle bleeding. Thrombosis tends to be less clinically obvious, although acral cyanosis and gangrene can occur.

• Endotoxemia, sepsis, systemic inflammatory response syndrome.

• Neoplasia. Although any tumor can cause DIC, hemangiosarcomas and disseminated solid cancers are most often responsible.

• Tissue damage. Shock (e.g., gastric-dilatation volvulus, hemorrhagic shock), massive trauma, heat stroke, tissue necrosis (from infarction, hepatic necrosis, rapid lysis of large tumor burdens by chemotherapy).

• Intravascular hemolysis, especially autoimmune hemolytic anemia.

• Vasculitis. Causes include sepsis, Rocky mountain spotted fever, ehrlichiosis, heartworm disease, feline infectious peritonitis, canine herpes virus infection of neonates, canine adenovirus infection.

• Pancreatitis, hepatitis.

• Snake bikes

DIC can be difficult to diagnose because it can be triggered by many unrelated diseases, the clinical manifestations are variable, and there is quasi-consensus about what constitutes a definitive diagnosis. Diagnosis is based on the following criteria:

• Presence of an underlying disease known to be associated with DIC.

• Multiple abnormalities of the coagulation profile. Not all variables will be abnormal in every case. Some clinicians consider abnormalities in 3 of the following commonly available tests to be sufficient for a diagnosis: Platelet count; ACT, PT and APTT; fibrinogen concentration; AT-III concentration; FDP concentration; presence of schistocytes on a peripheral blood smear.

A retrospective analysis of 41 cases of DIC in dogs revealed sensitivities of these tests for DIC to be as follows: Thrombocytopenia, 80%; APTT prolongation, 87%; PT prolongation, 80%; hypofibrinogenemia, 61%; decreased FDPs, 60%; schistocytosis, 71%.

In cats with DIC, the sensitivities of these tests for DIC are: Thrombocytopenia, 80%; APTT prolongation, 70%; PT prolongation, 30%; hypofibrinogenemia, 25%; increased FDPs, 25%.

Whereas FDPs are elevated in 85-100% of people with DIC, these studies found that increased concentrations of FDPs were not very sensitive indicators of DIC in dogs and cats. The newer tests for D-dimer (a type of FDP) have recently been shown to be highly sensitive and specific for DIC in people and dogs.

In this study, D-dimer and several other FDP tests were evaluated in 20 dogs with DIC, and 30 clinically normal dogs. The D-dimer latex agglutination method assessed was the same one used at Antech Diagnostics. All 20 dogs with DIC had positive D-dimer tests (100% sensitivity), where-as 85-95% of these dogs had positive FDP test results with the other traditional methods. Of the 30 clinically normal dogs, 29 had negative D-dimer results (97% specificity). Therefore, Antech’s D-dimer assay is highly sensitive and specific for DIC, and performs as well as, and perhaps even better than, standard FDP tests. In addition to DIC, elevated (mild to moderate) D-dimer concentrations can also be seen in patients with liver failure, internal hemorrhage, local or regional thrombosis, and trauma. 

TREATMENT OF DIC

Treatment of DIC can be confusing and is often controversial. There is an almost global perception that therapy is often futile and most patients with DIC die. Despite this gloomy prediction, patients with DIC can survive, if the underlying cause is a treatable illness and the coagulation abnormalities are treated appropriately.

While treatment of DIC needs to be individualized, the following principles are helpful:

• Diagnose and remove or treat the underlying cause of the DIC. 

This is, by far, the most critically important aspect of successful out-come. If the underlying cause cannot be identified and removed, or alleviated, even heparin treatment may be of little benefit. 

Unfortunately, the underlying disease itself is often life-threatening.

• Supportive care.

Supportive patient care is an essential component of case management. It is important to maintain good tissue perfusion to dilute activated coagulation factors, flush thrombi from the microvasculature, and maintain tissue integrity. Supportive care includes aggressive therapy with crystalloids or colloids, and prevention and treatment of secondary complications such as hypoxemia, acidemia, cardiac arrhythmias, and bacterial infections.

• Control ongoing DIC with anticoagulant treatment, to inhibit in vivo coagulation. This is a scary concept in a bleeding patient, but is an important component of treatment if the patient continues to bleed or clot significantly.

Heparin is considered the most effective anticoagulant for DIC. Dosage recommendations for heparin use in dogs and cats vary greatly: 5-10 U/kg SC q 6h (mini-dose); 75-100 U/kg SC q 6h (low dose); 200-500 U/kg SC q 6h (intermediate dose); and 750-1000 U/kg SC q 6h (high dose).

Unfortunately, there are no studies to indicate which dosage is most appropriate for animal DIC patients.

In people with DIC, a low dose is used most frequently, and there are studies suggesting that this dosage is as effective as larger doses. This dose of heparin is also unlikely to iatrogenically worsen the bleeding disorder.

Heparin works via increasing the activity of AT-III, which is often decreased in patients with DIC. Transfusion to replace AT-III in order for heparin to be more effective should be considered a routine adjunct to heparin treatment. The preferred source of AT-III for dogs is plasma from which cryoprecipitate has been removed (so-called cryosupernatant plasma, available commercially from animal blood banks). This product is recommended to reduce the amount of fibrinogen and other infused procoagulants. In the presence of uncontrolled DIC, aggressive transfusion of blood products containing fibrinogen may make the DIC worse rather than better.

Aspirin is not an effective treatment in most patients with acute DIC, but can be used to manage chronic cases or help prevent reoccurrence.

• Management of DIC also includes transfusion therapy. If the patient continues to bleed after attempts to treat the triggering cause of the DIC and after initiating anticoagulant therapy, transfusion support to replace consumed coagulation factors (cryosupernatant or fresh-frozen plasma), red cells (packed red cells, whole blood, or hemoglobin product) and/or platelets (fresh whole blood, platelet-rich plasma) may be needed. Repeated transfusions may be necessary.

The prognosis for dogs and cats with DIC is guarded to grave, depending mainly on the initiating cause of the DIC. If, however, the inciting cause can be controlled, animals should recover with appropriate management treatment.

References: Feldman et al, JAVMA 179: 151-154,

1981; Levi and TenCate, N Eng J Med 341: 586-

592, 1999; Bateman et al, JAVMA 215: 798-804,

1999; Stokol et al, AJVR 61: 393-398, 2000.