The Different Faces of Disseminated Intravascular Coagulation in Solid Tumors: How to Identify and Manage

The general incidence of disseminated intravascular coagulation (DIC) is hard to define. In one large series in a critical care setting, the incidence was reported to be 8.5%.[1] Although infections are frequently associated with DIC, various other conditions, including neoplasms, obstetric complications, snakebites, vascular disorders, and trauma are also seen. In this issue of ONCOLOGY, Dr. Donald Feinstein focuses mainly on DIC in patients with solid tumors.[2] The association of DIC with solid tumors has been reported at variable rates, depending on the series.[3]

Mechanisms and manifestations

DIC is a state in which both micro- and macrovascular thrombosis, along with secondary fibrinolysis, happen simultaneously. It can also be described as “consumptive coagulopathy,” a condition in which both pro- and anticoagulants are consumed.

The constant battle between procoagulation and anticoagulation and fibrinolysis and antifibrinolysis systems maintains equilibrium in plasma. Conventionally, we divide the procoagulation system into extrinsic and intrinsic systems, even though the goal of both is to activate factor X into Xa, which can be accomplished by either the tissue factor–VIIa complex or the factor IXa–VIIIa-calcium-phospholipid complex. Further, in the presence of factor Va, Xa-phospholipid-calcium complex activates prothrombin into thrombin, one of the very potent procoagulant serine proteases. Thrombin ultimately converts fibrinogen to fibrin, which is polymerized by factor XIIIa. Natural anticoagulants, such as antithrombin, protein C, and its cofactor, protein S, inhibit procoagulants. The thrombin-thrombomodulin complex can function in two ways. It not only activates thrombin-activatable fibrinolysis inhibitor (TAFI) and stabilizes fibrin clots, but also activates protein C and functions as an anticoagulant.

The fibrinolysis system includes plasminogen–plasminogen activator–plasmin. Inhibitors of fibrinolysis include not only serine proteases like TAFI, but also serpins (serine protease inhibitors) like plasminogen activator inhibitor and antiplasmin. Thrombin is also a potent platelet agonist, leading to further platelet activation and degranulation and adding tremendously to the “fire” of DIC and to platelet aggregation and consumption. Various mechanisms, including upregulation of tissue factor expression, downregulation of thrombomodulin, tumor-derived cytokines, microparticles, and hyperfibrinolysis, have been identified.[4,5]

DIC is one of the few thrombotic states in which the thrombosis can be venous or arterial or both. Both bleeding and thrombosis can be signs of DIC associated with solid tumors. Bleeding can be mucocutaneous and/or from intravenous access or surgical sites, since DIC is both a platelet- and coagulation factor–deficient state.

Risk factors and diagnosis

As noted in the study by Sallah et al, tumor necrosis, advanced age, and disease stage, including the presence of liver metastasis, are strong risk factors for DIC.[6] Okajima et al showed that the frequency of excess fibrinolysis is significantly higher in DIC patients with liver disease than in DIC patients without liver disease,[3] which could explain the above finding. Different tools are available for diagnosing DIC.[7] Despite some differences, all groups recommend evaluating clotting factors (fibrinogen level, prothrombin time), platelet count, fibrinolysis parameters (D-dimer level), and fibrin degradation products. The International Society on Thrombosis and Haemostasis (ISTH), the Japanese Ministry of Health and Welfare, and the Japanese Association for Acute Medicine guidelines have been validated prospectively.[7] As Dr. Feinstein notes, however, none has yet been validated exclusively in solid tumors. Schistocytes are not seen in all cases of DIC.[8] Fibrinogen degradation products, eg, fragment X, Y, D, or E, represent fibrinogenolysis and not fibrinolysis in particular; therefore, they are not specific for DIC. D-dimer, which is the smallest of the fibrinolysis products-along with fibrin degradation products, such as DY and XXD-are specific for DIC.

Treatment options

“Treat the underlying cause” has been the classic mantra for the treatment of DIC. Whenever feasible in DIC associated with solid tumors, this principle appears to hold good. DIC can improve after initiation of antineoplastic chemotherapy.[4,9] The ISTH has recently formulated recommendations specifically for the treatment of cancer-associated DIC.[10]

Low-molecular-weight heparin or unfractionated heparin?

As Dr. Feinstein points out, low-molecular-weight heparin (LMWH) appears to have an advantage over unfractionated heparin (UFH ). Both UFH and LMWH mediate their actions through antithrombin, which is decreased in DIC. In rabbit models of DIC, Tazawa et al have shown nicely that LMWH appears to have a higher anti–factor Xa–antithrombin activity ratio, even in the setting of severe antithrombin deficiency.[11] This could explain why LMWH appears to have an advantage in this setting. In the CLOT study, the majority of the patients had solid tumors. Although CLOT did not specifically compare LMWH with heparin in patients with DIC-related venous thromboembolism, LMWH clearly demonstrated greater benefit than warfarin.[12] When there is a need for anticoagulation, Dr. Feinstein prefers UFH because it has a shorter half-life and is reversible with protamine. However, in patients who are at low risk for bleeding (no active bleeding, platelet count > 50,000/μL, and fibrinogen level > 100 mg/dL) and who have severe antithrombin deficiency, LMWH would be a reasonable choice as well.

Other treatment options

Platelet transfusions should be limited to patients with bleeding, and antifibrinolysis therapies should be avoided. While recombinant human soluble thrombomodulin improved the DIC score in patients with solid tumors in a single-arm study,[13] it has not yet been studied in a randomized controlled clinical trial in solid tumors (although such trials have been conducted in hematologic malignancies).[14] Other natural anticoagulants, including activated protein C and recombinant antithrombin, have been studied only in sepsis-associated DIC.

In summary, solid tumor–associated DIC has to be identified and treated appropriately. Dr. Feinstein’s review gives valuable, practical guidance on how to do this. Improved understanding of the role of other players in thrombosis and inflammation, such as neutrophil extracellular traps and extracellular histones, as well as of the role of these entities in solid-tumor–associated coagulopathies, is awaited.

Financial Disclosure:The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

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