Disseminated Intravascular Coagulation: A Bigger Problem as Cancer Therapy Improves

Bleeding and thrombosis in cancer patients cause significant morbidity and are a leading cause of mortality well before the malignancy is directly life-threatening.[1] This was first appreciated in solid tumors, but the incidence of thrombotic and bleeding complications is high in hematologic tumors as well, including in lymphoma.

The mechanisms of activation of the coagulation system are diverse; there are direct activators of coagulation factors in both the intrinsic and extrinsic pathways. The balance between coagulation and fibrinolysis determines the phenotype of bleeding or thrombosis; despite appearances, these events are not polar opposites but come from the same processes of enzymatic activation. At the moment that a patient may be bleeding from a venipuncture site from inadequate local hemostasis, the creatinine level may be rising due to microvascular thrombosis in the kidneys. Direct activation of factor X, expression of tissue factor, and activation of factor XII may be demonstrated in a variety of tumors and can lead to coagulation and, in the case of factor XII, activation of fibrinolysis as well as vasoactive precursors.[2]

Newer assays provide more sensitive detection of coagulation activation and a better reflection of its occurrence. Either the presence of thrombosis or the detection of disseminated intravascular coagulation and fibrinolysis (DIC) augurs a poor outcome, even with therapy. Sensitive assays for D-dimer levels can provide a strong negative indication that DIC is not occurring; however, levels can be elevated for numerous reasons, reaching into the thousands of micrograms per liter following orthopedic surgery or trauma.

Dr. Feinstein nicely reviews the mechanisms of coagulation activation by tumor cells and indirect activation through augmentation of expression of tissue factor.[3] He then distills the analysis of a patient into a few questions that can elucidate the phenotype of the clinical situation: bleeding alone, bleeding with evidence of thrombosis, no bleeding or thrombosis but abnormal platelet count and fibrinogen level, and thrombosis without apparent bleeding. This approach helps to clarify clinical thinking in what is often a complicated and stressful clinical situation. The interpretation of coagulation test results must be done cautiously, as the prothrombin time may be prolonged in part due to the inhibitory effects of circulating fibrin fragments. But Dr. Feinstein’s recommendation to replace clotting factors vigorously when measured levels are low and either bleeding or a procedure is required deserves emphasis. He correctly notes that the International Society on Thrombosis and Haemostasis (ISTH) scoring for DIC has not been validated in patients with solid tumors.

Caution is required when using either activated clotting factor concentrates or recombinant factor VIIa in a setting where there is any evidence of thrombosis, as the risk of additional thrombosis may be significant; there are reports of thrombosis with recombinant VIIa and factor VIII inhibitor bypass activity (FEIBA) in settings without known DIC.[4] Where replacement is contemplated, it is important to recall that each unit of apheresis platelets contains nearly one and one-half units of plasma in addition to the platelets that contribute to hemostasis enhancement.

The frequent use of central venous catheters, tunneled catheters, peripherally inserted central catheters (PICCs), and ports contributes to the incidence of thrombosis. The presence of activated coagulation should prompt consideration of treatment initiation before the insertion of a long-term catheter when possible, as the evidence for mitigation of coagulation activation with active chemotherapy is apparent.[5] Despite the significant increase in chemotherapy activity in solid tumors, the potential for failure to reduce coagulation activation remains high, and further definition of the role of novel anticoagulants in reducing the risk of fatality in the early phases of treatment deserves attention.

The key points to take away from Dr. Feinstein’s article are:

1. DIC in patients with solid tumors can be diagnosed with straightforward testing of platelet count, fibrinogen level, prothrombin time, and D-dimer level.

2. The phenotype of the DIC must be carefully characterized: bleeding alone, bleeding with evidence of thrombosis, no bleeding or thrombosis but abnormal platelet count and fibrinogen level, and thrombosis without apparent bleeding.

3. Use clotting factors for immediate resuscitation, and treat thrombosis with anticoagulants; unfractionated heparin is still probably best in this setting.

4. Treat the malignancy with active therapy.

Even treated DIC portends a serious outcome and deserves similarly serious investigative effort and new approaches.

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:

1. Khorana AA, Francis CW, Culakova E, et al. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemostasis. 2007;5:632-4.

2. Bick RL, Strauss, JF, Frenkel EP. Thrombosis and hemorrhage in oncology patients. Hematol Oncol Clin North Am. 1996;10:875-907.

3. Feinstein DI. Disseminated intravascular coagulation in patients with solid tumors. Oncology (Williston Park). 2015;29:96-102.

4. Hay CRM. Thrombosis and Recombinant VIIa. J Thromb Haemostasis. 2004;2:1698-9.

5. Mast C, Ramanathan RK, Feinstein DI, Rosen P. Disseminated intravascular coagulation secondary to advanced pancreatic cancer treated successfully with combination chemotherapy. Oncology. 2014;87:266-9.