Indian Pediatrics 2003; 40:721-730 

Diagnosis and Treatment of Disseminated Intravascular Coagulation

Sameer Bakhshi
L.S. Arya

Disseminated intravascular coagulation (DIC) is a complex clinical syndrome with activation of the procoagulant and fibrinolytic systems along with inhibitor consumption. We discuss regarding the controversies in diagnosis and management of DIC. Bleeding is a more common manifestation of DIC but most of the morbidity and mortality of DIC is due to microvascular thrombosis. Routinely performed tests for DIC such as platelet count and prothrombin time may be normal in chronic DIC. There is no single test that would diagnose DIC, however, estimation of D-dimer appears to be the most sensitive and specific test. Therapy of DIC aims at treating the primary cause. Fresh frozen plasma and platelet concentrates are recommended only in bleeding patients and have the potential risk of adding procoagulant material to the already activated procoagulant system. Role of heparin and antithrombin in patients with sepsis and DIC is discussed.

Disseminated intravascular coagulation (DIC) is a complex pathophysiological disorder in which there is an unregulated thrombin explosion leading to release of free thrombin in the circulation resulting in widespread microvascular thrombosis. In order to counter this, there is release of free plasmin in the circulation. It involves activation of the procoagulant and fibrinolytic systems along with inhibitor consumption. Although hemorrhagic manifestations are more obvious, yet it is the diffuse thrombosis that leads to end organ damage and is responsible for most of its associated morbidity and mortality. DIC is thus defined as a systemic thrombo-hemorrhagic disorder seen in association with well-defined clinical conditions and laboratory evidence of (i) procoagulant activation, (ii) fibrinolytic activation, (iii) inhibitor consumption, and (iv) biochemical evidence of end organ damage or failure(1,2).

Clinical Presentation

Types of DIC

The underlying disease that triggers DIC determines the clinical presentation in two aspects. First, the clinical manifestations of the triggering disease itself and second, the magnitude and rate of exposure of the triggering factor depends on the disease, and this determines the acuteness of clinical presentation of DIC per se. In severe head trauma, burns or sepsis where there is a sudden massive exposure of tissue factor over a brief time period, the control mechanisms are overwhelmed and there is no time for regeneration of coagulation factors. This is referred to as acute or decompensated DIC wherein there would be profound bleeding due to consumption of coagulation factors or diffuse microvascular thrombosis with resultant end organ damage or a combination of the two(1,2). If, however, the triggering factor is exposed slowly and in small amounts such as in malignancies and vasculitis, the control mechanisms in the body replenish the factors by augmented production. This is referred to as chronic or compensated DIC wherein there may be very minimal or no clinical features or there may be only laboratory evidence of DIC(1,2).

Bleeding

It is the relative involvement of the clotting, fibrinolytic and the coagulation inhibitor pathways that determines whether bleeding or thrombosis would predominate. However, it must be remembered that bleeding in skin and mucosa is easily observed and so bleeding is a more common manifestation of DIC seen in 78% of the patients (Table 1)(1,2).

TABLE I

Clinical Features of DIC

Bleeding

Petechiae

Purpura

Hemorrhagic bullae

Surgical & traumatic wound bleeding

Venipuncture site bleeding

Arterial line oozing

Subcutaneous hematoma

Thrombosis & end organ dysfunction

Skin - 70%

Lungs - 50%

Kidneys - 50%

Liver - 35%

Adrenal - 30%

Heart - 20%

 

Thrombosis

A remarkable volume of microvascular and occasionally large vessel thrombosis may occur, which is not clinically obvious, unless and until it is looked for. This may manifest as organ dysfunction particularly that of the kidneys, heart, lungs, and central nervous system (Table 1)(1,3). Unfortunately, it is difficult to differentiate organ dysfunction that results from the primary illness from that which occurs due to DIC related micro-vascular thrombosis(2,3).

There may be cutaneous infarction due to microvascular thrombosis manifesting as acral gangrene. Purpura fulminans is a potentially disabling and life threatening manifestation of DIC seen mainly in children and occasionally in adults. It occurs predominantly in neonates with homozygous protein C or rarely, protein S deficiency; approximately 7 to 10 days after a relatively benign skin infection, such as varicella or scarlet fever; and in conjunction with an acute infectious illness particularly gram-negative septicemia. It develops in 15% to 25% patients of meningococcemia, especially group C isolates(4).

Laboratory Diagnosis (Table II)

Table II

Laboratory Tests for DIC

A. Global laboratory tests

1. Prolongation of PT, aPTT, TT

2. Hypofibrinogenemia

3. Elevated FDPs

4. Peripheral smear - Schistocytes & thrombo-cytopenia with large platelets

B. Tests for procoagulant activation

1. Elevated prothrombin fragment 1 +2

2. Elevated fibrinopeptide A & fibrinopeptide B

3. Elevated thrombin-antithrombin (TAT) complex

4. Elevated D-dimer & soluble fibrin monomer (sFM).

C. Tests for plasmin activation

1. Elevated D-dimer & sFM

2. Elevated fibrinogen degradation products (FDPs)

3. Elevated plasmin

4. Elevated plasmin-anti plasmin complex (PAP).

D. Tests for inhibitor consumption

1. Decreased antithrombin

2. Decreased antiplasmin

3. Decreased protein C and S

4. Elevated TAT complex

5. Elevated PAP complex

E. Tests for end organ damage

1. Elevated LDH

2. Elevated creatinine

3. Decreased pH

4. Decreased paO2

 

Global laboratory tests

Prothrombin time (PT), activated partial thromboplastin time (aPTT) and thrombin time (TT), which are dependent on the conversion of fibrinogen to fibrin polymer, are generally deranged. TT can be observed for clot lysis: if lysis occurs within 10 minutes, it indicates clinically significant amount of plasmin. Schistocytes may be seen in 50% of patients with fulminant DI as a result of fibrin and red cell interactions(5).

Tests for procoagulant activation

Prothrombin fragments 1+2, fibrino-peptide A and thrombin-antithrombin (TAT) complex can all be reliably measured by enzyme linked immunosorbent assay (ELISA)(6-8). D-dimer is a specific fibrin degradation product and also serves as a marker of plasmin activation (Fig 1). This is estimated most reliably by latex agglutination test using the monoclonal antibody against the D-dimer neo-antigen DD-3B6/22 that are specific for the cross-linked fibrin derivatives containing the D-dimer configuration(9,10). The soluble fibrin monomer (sFM), like the D-dimer, serves as a marker for both procoagulant and plasmin activation, and is measured by ELISA(11).

Fig 1. Procoagulant and plasmin activation. Xa generates thrombin from prothrombin by cleaving its N-terminal end and forms prothrombin fragments 1 and 2 (F1+2). Thrombin cleaves fibrinogen into fibrinopeptides A and B (FPA & FPB), and generates fibrin monomers; this gets cross-linked by factor XIII. Plasmin cleaves the carboxy terminal end of fibrinogen and forms X, Y, D and E fragments (fibrinogen degradation products). The X and Y fragments combine with the fibrin monomer and form soluble fibrin monomer, so called since it cannot get polymerized and hence this would aggravate bleeding. D-dimer is a neoantigen formed as a result of plasmin degradation of the cross- linked fibrin.

Tests for plasmin activation

Fibrin(ogen) degradation products (FDPs) are elevated in 85%-100% patients with DIC(12). These are determined using latex particles that are anti-fibrinogen; thrombin clot tubes are used to remove any fibrinogen so that these latex particles do not falsely measure the fibrinogen as FDPs. However, the thrombin clot tubes remove not only fibrinogen but also the early fragments X and Y, and so if fibrinolysis is in the early phase of activation wherein the lysis has not progressed beyond this stage, the FDPs would be falsely negative. The available test method detects the D and E fragments only and so if the plasmin digestion has gone beyond this stage, then again the FDPs may not be detected inspite of profound fibrinolytic activity. Hence, a negative test for FDPs does not rule out DIC(13).

It is difficult to measure plasmin level in plasma since it is rapidly inactivated by anti plasmin and slowly by alpha-2-macro-globu-lin. Plasmin-antiplasmin (PAP) complex can be measured by crossed immunoelectro-phoresis, ELISA and radioimmuno-assays(14). PAP serves as a marker of fibrinolytic activation as well as inhibitor consumption (Fig 1). Recently, tests have been developed to measure tissue plasmino-gen activator and tissue plasminogen activator inhibitor (PAI), but their clinical relevance is not yet clear.

 

Tests for inhibitor consumption

Antithrombin measurement is of para-mount importance not only for diagnosis but also for prognosis and therapy. Studies have shown that synthetic substrate assays are the methods of choice for antithrombin estimation(15).

Usefulness of laboratory tests

It is obvious from the above discussion that no single test can make or refute the diagnosis of DIC. PT, PTT, fibrinogen are affected in 60-75% of patients with acute DIC(16-18). However, these tests may be normal in DIC if the activated thrombin accelerates the formation of fibrin polymer at a stage when the plasmin activation is minimal. As a single test, D-dimer assay was found to be abnormal in 93-100%, antithrombin in 87-97%, fibrinopeptide A in 88-89.5% and FOP titre in 75-100% of patients with DIC(17-21). The D-dimer assay was abnormal in 20%, antithrombin in 6% and fibrinopeptide in 13% of the patients who did not have DIC(21). The sensitivity and specificity of sFM was found to be above 90% in overt DIC(11). The measurement of D-dimer is cost effective and could possibly replace the need to measure FDPs. In chronic DIC, most of the global laboratory tests such as PT, PTT, fibrinogen and platelets may be normal(Table III)(1,2,22,23).

TABLE III

Laboratory Features of Chronic DIC

• Platelet count: usually normal or borderline

• Fibrinogen: normal/increased

• PT: normal/supernormal

• PTT: normal/supernormal

• Schistocytes: 90% patients

• FDP: usually increased

• Fibrinopeptide A: usually increased

• D dimer: usually increased

The decrease in antithrombin is related to outcome, and plasma levels are significantly lower in non-survivors than in survivors. A decrease in antithrombin levels below 50% has been shown to have a strong prognostic value for prediction of subsequent death(24) with a sensitivity of 96% and a specificity of 76% (P <0.001). PAP is elevated early in DIC and changes in parallel with the course of DIC, with levels decreasing in clinical remission(25). A lower ratio of PAP/TAT points towards a poor prognosis and is associated with organ failure(26). Both TAT and PAP appear to be useful for diagnosing pre-DIC(27).

Management of DIC

The heterogeneity of DIC makes it very difficult to evaluate any therapy with controlled trials. The outcome of DIC depends mainly on the triggering disease and so it becomes even more difficult to assess the outcome based on therapeutic intervention for DIC. However, if we keep the patho-physiology of DIC in mind, then one can formulate certain basic principles for therapy. The first and foremost is to take care of the triggering factor. Since the initiation of DIC occurs with increased thrombin generation leading to microvascular thrombosis that is responsible for most of the morbidity and mortality associated with DIC, the next logical step should be to use anticoagulants and hold the process. It is here that most of the controversy exists whether the use of anticoagulant in the phase of hemorrhage would aggravate bleeding or not, and there is no clear answer to this. When bleeding is prominent due to consumption of factors, one would be inclined to use replacement therapy to control bleeding. Here we will discuss the various therapeutic options and their merits, demerits and existing controversies.

Treatment of the triggering disease

The most important guiding principle for therapy of DIC is to identify the triggering disease and manage it aggressively. For example, the early use of antibiotics in sepsis with DIC may sometimes obviate the need for any specific therapy for DIC. Similarly, in abruptio placentae, evacuation of the uterus should be done as soon as possible. Infact, sometimes the need to do a hysterectomy in abruptio placentae in the phase of active bleeding may actually stop the hemorrhagic diathesis once the trigger is removed. In addition, it is equally important to provide supportive care for optimizing hemodynamic stability, maintaining adequate oxygenation and acid base balance. A derangement of any of these would by themselves serve to trigger and aggravate DIC.

Heparin therapy

Heparin is effective anticoagulant with the potential to inhibit thrombin formation and function. Anticoagulant response with heparin alone may not be effective due to low levels of antithrombin in DIC. The indications and dosage for heparin therapy are not clearly defined. Heparin therapy in studies has shown benefit(28), no benefit(29,30) and damage(31). The potential risk with heparin therapy is bleeding. Low molecular weight heparin appears to offer the benefit of decreased bleeding complications compared to unfractionated heparin in the treatment of DIC(32). When heparin is used, it is administered at a dose of 15 U/kg/hr as a continuous infusion(33). There are no controlled trials comparing the efficacy of different dosages of heparin, and the coagulopathy makes it extremely difficult to monitor the therapy. Some authors have preferred subcutaneous administration at a dose of 80-100 U/kg every 4-6 hours as they feel the risk of hemorrhage may be reduced(3). It is reasonable to use heparin in DIC with thrombotic manifestations such as end organ failure, acral gangrene and purpura fulminans. Others have routinely used heparin for DIC even with active bleeding manifestation(3). Heparin is certainly not indicated in DIC with head trauma, massive liver failure and obstetrical accidents. There are no adequate studies of heparin use in DIC with sepsis.

Blood component therapy

Decision regarding component therapy is based on whether the patient is bleeding and if an invasive procedure is planned(Table IV)(33). The risk with FFP and cryoprecipitate is that adding fibrinogen to the blood system in a situation where the level of antithrombin is low would predispose to widespread microvascular thrombosis and aggravate end organ damage. Since plasmin is already activated in the system, it would serve to increase FDPs when fibrinogen is given and may aggravate the bleeding tendency by inter-fering with fibrin monomer polymeriza-tion(3). Although some hematologists would agree with the use of the component therapy as mentioned, there are some who would only use components void of fibrinogen unless the antithrombin level is normalized. They prefer to use washed packed red cells, platelet concentrates and non-clotting protein containing volume expanders such as albumin(3).

Inhibitor therapy

The role of various inhibitors of coagulation such as antithrombin, protein C, tissue factor pathway inhibitor (TFPI) and hirudin has been investigated. Of these, the role of antithrombin seems most promising. One could consider replacing antithrombin to a level above 70-80% of normal in order to correct the haemostatic disorder in patients with DIC and antithrombin deficiency, especially in patients with sepsis(34). Clinical studies have shown a trend towards improved survival of DIC with sepsis when antithrombin was administered alone or with heparin(35). Antithrombin seems to be effective in inhibiting thrombin generation and does not have the risk of inducing bleeding, and so seems to be a better alternative than heparin in ameliorating the clotting process. The binding of antithrombin to the glycosaminoglycans (GAG) of the endothelium occurs via the heparin-binding center of antithrombin and by doing so it releases anti-inflammatory prostacyclins that may be especially important in patients with sepsis. Co-administration of heparin binds to the center thus blocking the drug’s ability to bind to the GAGs and hence abolish the anti-inflammatory potential of antithrombin. Thus antithrombin monotherapy may be better than the combined use of antithrombin with heparin in patients with sepsis(36).

Activated Protein C (APC) inactivates Va and VIIIa, thus decreasing thrombin formation and promotes fibrinolysis by complex formation with PAI. APC has been used in meningococcemia(37), and a recent trial has suggested that in a relatively small dosage APC can improve DIC more efficiently than can heparin, without increasing bleeding(38).

TFPI is a specific inhibitor of the tissue factor-VIIIa complex, thereby inhibiting intravascular coagulation and improve outcome in sepsis(39). Hirudin is a direct thrombin inhibitor and it can also inactivate thrombus-associated thrombin since it is not dependent on antithrombin. It was shown to diminish thrombin activity in patients with hematological malignancy and DIC(40). However, a benefit in clinical outcome has not yet been shown.

Antifibrinolytic agents

Antifibrinolytic agents such as epsilon-aminocaproic acid and tranexamic acid are indicated in DIC only when bleeding continues inspite of using the treatment modalities as described above(3). This is rarely needed in DIC; one exception to this is acute promyelocytic leukemia patients in whom there may be primary activation of the fibrinolytic system(41). It must, however, be remembered that the use of these agents can potentially aggravate intravascular thrombosis.

Miscellaneous therapy

Aprotinin may be used in DIC due to its properties of plasmin inhibition, kallikrein inhibition and platelet protective effects. Gabexate is a synthetic serine protease inhibitor that has an inhibitory effect on several coagulation and fibrinolytic proteases including thrombin and plasmin. It has been shown to be more effective than heparin in treating DIC accompanied by a bleeding diathesis(42).

Therapy of chronic DIC

Therapy of underlying disease is most important, failing which combination anti-platelet therapy with different mechanisms of action (aspirin plus dipyridamole or sulfin-pyrazole and dipyridamole) has been advocated(18). Patients with chronic DIC and Trousseau syndrome with deep venous thrombosis are initially treated with anti-coagulant doses of heparin to maintain a PTT 1.5-2 times normal. In other cases of chronic DIC, low dose (5-10U/kg/hour) of heparin may be sufficient to reverse the coagulopathy(43). Heparin therapy is contra-indicated in patients with intracranial meta-static disease and chronic DIC.

Conclusions

DIC is a clinical syndrome with complex pathophysiology with varying etiological factors. Even though hemorrhage is more obvious, microvascular thrombosis induced end organ damage is responsible for most of the morbidity and mortality. The role of blood component therapy involves the risk of adding fuel to fire while heparin therapy should logically (based on pathophysiology) abrogate thrombin generation yet clear benefits have not been found. There is no consensus yet about the appropriate usage of these modalities of therapy and often the treatment is individualized. Antithrombin has the advantage of inhibiting thrombin and reducing anti-inflammatory response, without having the risk of inducing a hemorrhagic diathesis. Ongoing research will provide an answer to the dilemma of DIC.

Contributors: SB conceptulised and designed the idea, data acquisition from literature review, drafting of manuscript with critical revision. LSA did critical revision and helped in drafting the manuscript.

 

Key Messages

DIC involves activation of procoagulant and fibrinolytic pathways along with inhibitor consumption. Bleeding is the commonest manifestation of DIC, but microvascular thrombosis is a more important cause of morbidity and mortality. Chronic DIC may have normal platelet count and prothrombin time. D-dimer is a useful diagnostic test for DIC. FFP and platelet concentrates need to be used judiciously. Heparin may be useful in DIC with microvascular thrombosis. Role of antithrombin is evolving in sepsis induced DIC.

 References