Complications and Management of Coagulation Disorders in Leukemia Patients

Investigations

Routine coagulation tests may reveal overt DIC with prolongation of PT, variable aPTT, low fibrinogen levels and platelet counts, and elevated d-dimer and fibrin-degradation products.⁵⁸ However, these variables do not correlate well with the severity of bleeding or thrombosis.⁴¹ No single test can confirm or rule out DIC. The International Society on Thrombosis and Haemostasis overt DIC score may miss subclinical DIC in acute leukemia.¹⁰ A recent study showed that a high d-dimer level >4 mg/L was most predictive for thrombosis in AML-non-M3 patients.⁵⁹ Other tests of activated clotting like prothrombin fragment 1+2, thrombin–AT complex, and fibrinopeptide A may be helpful, but are not routinely available. Elevated white-cell count (>20×109/L) is an independent predictor of early hemorrhagic death in APL.⁶⁰

Treatment

Both ATRA and arsenic trioxide (ATO) can reverse the coagulopathy of APML within 4–11 days. This underscores the importance of starting ATRA in the emergency department whenever a diagnosis of APML is suspected. The incidence of thrombosis in the ATRA era is higher than in the pre-ATRA era.⁴⁰However, the incidence of TE in ATRA + ATO is lower than in ATRA + chemotherapy in non-high-risk APML patients.⁶¹ European Leukemia Net guidelines recommend fresh frozen plasma, fibrinogen, and/or cryoprecipitate to maintain the fibrinogen concentration above 100–150 mg/dL. In APML, the platelet-transfusion threshold is more liberal, and the aim is to maintain a count >30–50×10⁹/L. The role of heparin, tranexamic acid, or other anticoagulant or antifibrinolytic therapy is unclear and not recommended as part of routine practice.⁶² On the contrary, combining ATRA with tranexamic acid may lead to fatal thromboembolism.⁶³ There is insufficient evidence to recommend thrombopoietin mimetics, recombinant factor VIIa, antifibrinolytics, desmopressin, activated protein C, or recombinant human soluble thrombomodulin to prevent or treat bleeding in hematological malignancies.^64–66 The role of leukapheresis in hyperleukocytosis to prevent early mortality is also unclear; in fact, it may lower platelet counts and fibrinogen and prolong prothrombin time.^67,68 Early cytoreductive chemotherapy and supportive care with platelets, fresh frozen plasma, cryoprecipitate, or fibrinogen concentrates are the only recommended measures to prevent or treat bleeding associated with DIC in AML.⁶⁹ In summary, the patient had APML with DIC manifesting as acute arterial thrombosis of the extremities. She was managed with ATRA + ATO and supportive transfusions without anticoagulation. She survived the leukemia, but lost her limbs to gangrene.

COAGULATION DISORDERS IN MYELOPROLIFERATIVE NEOPLASMS

Case vignette

MS, a 19-year-old man, presented with a 1-month history of abdominal pain. He had a massive splenomegaly with thrombosis of the splenoportal axis. His blood counts at presentation were hemoglobin 108 g/L, platelets 668×10⁹/L, and white cells 5.6×10⁹/L, with a normal differential count. His bone marrow suggested a diagnosis of essential thrombocytosis (ET). His JAK2^V617F-mutation status was positive. The final diagnosis was high-risk ET with splanchnic vessel thrombosis. On upper gastrointestinal endoscopy, he had no esophageal varices, but had multiple small gastric varices at diagnosis. He was given LMWH and bridged to warfarin titrated to an INR of 2–3. Aspirin was withheld, due to gastric varices. He was also started on hydroxyurea 500 mg orally twice a day titrated to a normal platelet count. He had an episode of hematemesis a year later, requiring interruption of warfarin and glue injection of the gastric varices. Given the risk of gastric variceal bleeding with aspirin, and considering the risk:benefit ratio of anticoagulation, he was restarted on warfarin. The plan is to continue indefinite anticoagulation, with periodic upper gastrointestinal endoscopy for varices.

Epidemiology

Of the chronic myeloproliferative neoplasms (MPNs), polycythemia vera (PV), ET, and primary myelofibrosis (PMF) are most associated with thrombosis and bleeding. The prevalence of TE at the time of diagnosis in PV, ET, PMF is 4%–11%, 2%–8%, and 3%–7%, respectively. The incidence of TE thereafter is 2%, 0.6%, and 0.6% per year, respectively.⁷⁰ Arterial thrombosis (70%) is more common than venous TE (30%). MPNs are also the etiology in abdominal splanchnic vessel thrombosis (extra- + intrahepatic veins leading to Budd–Chiari syndrome [BCS], portal vein thrombosis, and mesenteric vein thrombosis). The prevalence of latent or manifest MPNs is 40% in BCS and 30% in portal vein thrombosis. JAK2^V617F mutation without manifest MPNs is seen in 17.1% of BCS and 15.4% of portal vein thrombosis.⁷¹ In chronic myeloid leukemia (CML), tyrosine-kinase inhibitors increase the risk of arterial (4.78%) and venous (0.72%) TE. The risk is higher with newer tyrosine-kinase inhibitors (0.96%) than imatinib (0.27%).⁷² In contrast to thrombosis, serious bleeding occurs in 5.5% of MPN patients.⁷³ The incidence of dasatinib-induced platelet dysfunction leading to serious bleeding in CML patients is 7%.⁷⁴ The incidence of thrombosis in PV at our center is 25%, with equal numbers of arterial and venous events.⁷⁵ The incidence of thrombosis and bleeding in ET at our center is 33.3% and 8.3%, respectively. A quarter of thrombotic events are arterial (Varma et al, unpublished data).

Pathophysiology

The mechanism of thrombosis in MPNs is multifactorial (Figure 3). Besides thrombocytosis, platelets aggregate due to upregulation of p-selectin, thrombospondin and GPIIB/IIIA receptors.⁷⁶ Besides leukocytosis, activated leukocytes form aggregates with platelets.^77,78 Erythrocytosis causes hyperviscosity; erythrocytes also show increased adherence to vascular endothelia.⁷⁹ Other mechanisms of thrombosis include microparticles and inflammation-mediated activation of endothelia.^80,81 Using novel gene-expression meta-analysis, certain coagulation-related genes have been identified to be associated with thrombosis in MPN. These include IGF2R, PROS1, SELPLG, and ITGB2.⁸² The etiology of bleeding in MPN is multifactorial. Acquired von Willebrand syndrome is seen in patients with platelet counts >10×10⁹/L.⁸³ At these high counts, vWF binds to platelets and undergoes proteolysis with a resultant depletion of large multimers.⁸⁴ Besides this, there is evidence of platelet dysfunction in ET.⁸⁵ Other reasons for bleeding include treatment for disease and TE, thrombocytopenia due to disease progression, hypersplenism, liver dysfunction, and acquired hemophilia.⁸⁶

(To view a larger version of Figure 3, click here.)