Since effective antineoplastic therapy is lacking for many tumors associated with Trousseau syndrome, DIC therapy is aimed at suppressing thrombosis. An exception is prostate cancer, where hormonal therapy can markedly decrease the DIC.116 Due to the tumor directly activating coagulation factors, inhibition of active enzymes via heparin has been shown to reduce rates of recurrence compared with warfarin.114,115 Clinical trials have demonstrated that heparin therapy is associated with a lower thrombosis recurrence rate than warfarin.117,118 In some patients, the thrombotic process is so vigorous that new thrombosis can be seen within hours of stopping heparin.112
ACUTE PROMYELOCYTIC LEUKEMIA
There are multiple hemostatic defects in patients with acute promyelocytic leukemia (APL).119 Most, if not all, patients with APL have evidence of DIC at the time of diagnosis. Patients with APL have a higher risk of death during induction therapy as compared with patients with other forms of leukemia, with death most often due to bleeding. Once in remission, APL patients have a higher cure rate than most patients with leukemia. APL is also unique among leukemias in that biologic therapy with retinoic acid or arsenic is effective in inducing remission and cure in most patients. Although effective therapy is available, early death rates due to bleeding have not changed.119
APL patients can present with pancytopenia due to leukemic marrow replacement or with diffuse bleeding due to DIC and thrombocytopenia. Life-threatening bleeding such as intracranial hemorrhage may occur at any time until the leukemia is put into remission. The etiology of the hemostatic defects in APL is complex and is thought to be the result of DIC, fibrinolysis, and the release of prothrombotic extracellular chromatin and other procoagulant enzymes.119,120 The diagnosis of APL can be straightforward when the leukemic cells are promyelocytes with abundant Auer rods, although some patients have the microgranular form without obvious Auer rods. The precise diagnosis requires molecular methods, including obtaining FISH for detecting the t(15;17) in PML/RARA fusion. Upon diagnosis of APL, one should obtain a complete coagulation profile, including INR, aPTT, fibrinogen, platelet count, and D-dimers. Change in fibrinogen levels tends to be a good marker of progress in treating the coagulation defects.
Therapy of APL involves treating both the leukemia and the coagulopathy. Currently, the standard treatment for APL is trans-retinoic acid (ATRA) in combination with chemotherapy or arsenic.121,122 This approach will induce remission in more than 90% of patients, and a sizable majority of these patients will be cured of their APL. ATRA therapy will also lead to early correction of the coagulation defects, often within the first week of therapy.123 This is in stark contrast to the chemotherapy era when the coagulation defects would become worse with therapy. Given the marked beneficial effect of ATRA on the coagulopathy of APL and its low toxicity profile, it should be empirically started for any patients suspected of having APL while genetic testing is being performed. Rare reports of massive thrombosis complicating therapy with ATRA exist, but the relationship to either the APL or ATRA is unknown.
Therapy for the coagulation defects consists of aggressive transfusion therapy support and possible use of other pharmacologic agents to control DIC.124,125 The fibrinogen level should be maintained at over 150 mg/dL and the platelet count at over 50,000 cells/µL.126 Controversy still exists over the role of heparin in therapy of APL.104 Although attractive for its ability to quench thrombin, heparin use can lead to profound bleeding and its use in treating APL has fallen out of favor.
SNAKEBITES
Snake envenomation can lead to direct activation of multiple coagulation enzymes, including factors V, X, thrombin, and protein C, and lead to cleavage of fibrinogen.127,128 Envenomation can also activate coagulation and damage vascular endothelium. The DIC can be enhanced by widespread tissue necrosis and hypotension. The key to management of snake bites is administration of specific antivenom. The role of prophylactic factor replacement is controversial, but this therapy is indicated if there is clinical bleeding.129 One confounder is that some snake venoms, especially rattlesnake, can induce reversible platelet aggregation, which corrects with antivenom.
LOCAL VASCULAR ABNORMALITIES
Abnormal vascular structures, such as vascular tumors, vascular malformations, and aneurysms, can lead to localized areas of thrombin generation that can “spill-over” into the general circulation, leading to DIC. The diagnosis Kasabach-Merritt phenomenon should be reserved for children with vascular tumors such as angioma or hemangioendothelioma.130 Therapy depends on the lesion. Embolization to reduce blood flow of vascular malformations can either be definitive therapy or stabilize the patient for surgery. Aneurysms can be repaired by surgery or stenting. Rare patients with aneurysms with significant coagulopathy may require heparin to raise the fibrinogen level before surgery. Kasabach-Merritt disease can respond to steroids or therapy such as vincristine or interferon.130 Increasing data shows that use of the mTOR inhibitor sirolimus can shrink these vascular abnormalities leading to lessening of the coagulopathy.131
