▪ Specific type of tumor: adenocarcinomas (ovary, pancreas, colon, stomach, lung, and kidney)

▪ Nutritional status of the patient

▪ Type of chemotherapy

▪ Response to chemotherapy (e.g., tumor lysis syndrome)

▪ Liver and renal function

▪ Patient immobility and venous stasis

▪ Circulating tumor cells adhere to the vascular endothelium and form a nidus for clot formation.

▪ Tumors may penetrate the vessel, destroying the endothelium and promoting clot formation.

▪ Neovascularization associated with many tumors may stimulate clotting.

▪ Arterial thrombosis associated with tumors may result from vasospasm.

▪ A systemic hypercoagulable state develops (e.g., decreased protein C).

▪ External compression of vessels by tumor masses impedes blood flow and leads to stasis and clot development.

▪ Thromboplastic substances in granules from promyelocytes of acute promyelocytic leukemia (DIC may worsen with therapy). There is a significant concomitant fibrinolysis in many patients.

▪ Sialic acid from mucin produced by adenocarcinomas of the lung or gastrointestinal tract

▪ Trypsin released from pancreatic cancer

▪ Impaired fibrinolysis associated with hepatocellular carcinoma

▪ DIC in any patient may be fostered by sepsis or other causes of the systemic inflammatory response syndrome (SIRS).

▪ An unexplained thromboembolic event occurs after the age of 40 years.

▪ Thromboses occur in unusual sites.

▪ The thromboses affect superficial as well as deep veins.

▪ The thromboses are migratory.

▪ The thromboses tend not to respond to the “usual” anticoagulant therapies.

▪ An unexplained thrombosis occurs more than once.

a. The use of central arterial or venous catheters has markedly facilitated the delivery of chemotherapy, but all such catheters are associated with a 5% increase in the risk of vascular thrombosis. This risk level is lower than was previously suspected. The empiric use of low doses of warfarin (1 mg/day) or low-dose low-molecular-weight heparin (LMWH) has been evaluated in recent randomized trials, and both drugs failed to show any reduction in symptomatic catheter-associated thrombosis. The risk of catheter-associated thrombosis appears to be higher in children. In a recent large randomized trial, there was an increased risk of bleeding in patients treated with low-dose warfarin.

b. Many chemotherapy agents cause significant chemical phlebitis. The most common offending agents are mechlorethamine (nitrogen mustard), anthracyclines, nitrosoureas, mitomycin, fluorouracil, dacarbazine, and epipodophyllotoxins.

c. L-asparaginase inhibits the synthesis of proteins, including coagulation factors. This inhibition may cause either hemorrhage or thrombosis. Patients with pre-existing hemostatic disorders are at particular risk for complications when using L-asparaginase. L-asparaginase also decreases antithrombin-III (AT-III) activity.

d. Tamoxifen, when used as an adjuvant, has been associated with a two- to sixfold increased risk of thromboembolic events. This effect may be magnified when tamoxifen is combined with chemotherapeutic agents. When tamoxifen is used for primary prevention, the risk of deep vein thrombosis and PE is 1.6% and 3.0%, respectively. Other selective estrogen receptor modulators, like raloxifene, are also associated with an increase in the risk of thromboembolic events. Aromatase inhibitors have a lower risk of thromboembolism than tamoxifen and are preferred for postmenopausal women, particularly if there are additional risk factors for thrombosis.

e. Estrogens may increase the risk of thromboembolism. This is likely due, at least in part, to a decrease in protein S and an increase in coagulation factors.

f. Superior vena cava syndrome is nearly always associated with thrombosis in the thoracic venous system cephalad to the site of obstruction and may lead to upper-extremity thrombosis.

g. Antiangiogenic or targeted therapy may be associated with a significant increase in the risk of VTE events. Thalidomide and lenalidomide in combination with corticosteroids or chemotherapy increases the risk of symptomatic VTE in patients with multiple myeloma. Prophylaxis with low doses of anticoagulation therapy has not been formally evaluated in this group of patients.

a. General guidelines. Therapy should be directed at controlling the neoplasm. As an anticoagulant, heparin is superior to warfarin in these patients. Warfarin and antiplatelet drugs have been used with varying degrees of success in some patients with thromboembolism associated with tumors. The use of heparin, warfarin, and antiplatelet agents alone or in combination may be associated with normalization of hemostatic parameters. Despite this, patients with malignant disease are often resistant to anticoagulant therapy and may continue to have thrombotic events even while receiving what appears to be adequate treatment. Great care must be exercised in the use of both heparin and warfarin in patients with malignant disease because hemorrhage into areas of necrotic tumor can be hazardous. The use of anticoagulant therapy is generally contraindicated in patients with central nervous system metastases. Bulky disease is a relative contraindication, especially if central necrosis of the tumor is suspected and particularly if the lesion is in the mediastinum or pleural spaces.

The decision to treat thromboembolism occurring in a patient with malignancy may be difficult. One must carefully
weigh the risks of therapy against expected benefits. The patient’s life expectancy, concurrent therapy, and type of malignancy also influence the decision.

b. Heparin. Low doses of heparin (5000 U given via the subcutaneous [SC] route every 12 hours) can be used to protect patients with malignant disease from thromboembolism during perioperative periods.

Heparin may be used as the initial or long-term therapy for thromboembolic events in patients with malignant disease. Heparin may be administered either by the intravenous (IV) or SC routes. Generally, the IV route is preferred for initial therapy so that the anticoagulant effect begins at once and adjustment of doses can be easily achieved. An initial dose of 5000 U (70 U/kg) of heparin is given as an IV bolus followed by 1000 to 1200 U (15 U/kg)/h as a continuous infusion. One should check the aPTT 1 hour after the heparin bolus to ensure that the patient is heparinizable (i.e., not AT-III deficient), 6 hours after beginning therapy, and 6 hours after any change in the dose of heparin. Some patients with malignant disease may appear to be refractory to heparin; in all likelihood, this reflects low levels of AT-III, owing to poor production or increased consumption, both of which may occur in patients with malignant disease. (Infusion therapy with L-asparaginase has been associated with reduced levels of AT-III.) As long as the AT-III activity is above 50% of normal, it is usually possible to achieve the desired anticoagulant effect if adequate doses of heparin are given. If AT-III activity is less than 50% of normal, AT-III may be replaced using AT-III concentrates or FFP.

Heparin may be administered by the SC route for both the acute and the chronic management of thromboembolism associated with malignancy. Using the SC route may be less desirable when treating acute events because the onset of anticoagulant effect is somewhat slower (2 to 3 hours), and adjusting the therapeutic effect may be more difficult. SC heparin can be considered for chronic therapy provided that the patient can manage the twice-daily injection and weekly monitoring of the aPTT. In a patient who has been receiving IV heparin, half the total dose of IV heparin received in the previous 24 hours should be given SC twice a day (e.g., 1000 U/h by IV infusion equals 12,000 U SC twice a day). For the patient being started on SC heparin, the initial dose is 7500 to 10,000 U SC twice a day. The aPTT should be checked 6 hours after the third dose of heparin. Otherwise, the aPTT should be checked 6 hours after a SC dose of heparin. The goal for the aPTT should be similar to that of IV heparin, namely, 1.5 to 2 times the patient’s baseline aPTT.

LMWHs should now be considered as the first line of therapy or prevention of VTE in patients with malignant disease. LMWH is preferred to unfractionated heparin as it can be given as an outpatient more easily and has a lower risk of heparin-associated thrombocytopenia. LMWH may have specific antineoplastic effects separate from its effect to reduce VTE. There are a number of ongoing trials designed to evaluate this antineoplastic effect. Monitoring of LMWH is indicated if the patient suffers from liver or kidney dysfunction or if the patient is significantly malnourished or debilitated. One must use anti-Xa levels as the aPTT is not indicative of the anticoagulant effect of LMWH.

c. Warfarin. In the past, warfarin was the therapy of choice for the chronic management of thromboembolic events associated with malignant disease. The use of warfarin in this setting is of concern because patients with malignant disease are frequently taking multiple medications that can alter the patient’s response to warfarin. An additional concern about the use of warfarin in patients with malignancy is the development of purpura fulminans. This complication may be due to lower-than-normal protein C levels in patients who had DIC before initiation of warfarin therapy. Warfarin should not be used as the primary drug to manage VTE events or future prevention of events in patients with malignant disease.

d. The use of platelet-inhibiting drugs such as aspirin, other nonsteroidal anti-inflammatory agents, and dipyridamole has met with varying degrees of success in the prevention of repeated thromboembolic events in patients with malignant disease. Care must be taken with the use of such drugs, especially in thrombocytopenic patients, because the risk of bleeding associated with thrombocytopenia is increased.

e. Fibrinolytic therapy. Systemic malignancy is a relative contraindication to fibrinolytic therapy.

f. Vascular interruption devices such as inferior vena cava filters should only be used in patients who cannot tolerate anticoagulant therapy or who develop emboli while on adequate anticoagulant therapy.

g. Anticoagulation therapy should be continued as long as the patient is receiving anticancer therapy or has evidence of active cancer.

▪ Urgently correct shock (if present).

▪ Treat the underlying disease process. When it is not possible to treat the underlying disease process, it is unlikely that the complicating DIC can be successfully managed.

▪ Replace depleted blood components (e.g., platelets, cryoprecipitated antihemophilic factor [AHF] for fibrinogen and factor VIII, FFP for other factors) if clinically significant bleeding is present.

▪ Consider the use of heparin only in the following situations:

These latter two complications of DIC are most likely to occur as a component of SIRS, and the treatment of the underlying cause of SIRS is necessary in addition to treatment with heparin. There is no evidence that chronic warfarin therapy is of value for treating the chronic DIC seen in some patients with neoplasia if thromboses are absent. Warfarin may predispose to the development of purpura fulminans in the presence of chronic DIC due to acquired protein C deficiency.