Complications and Management of Coagulation Disorders in Leukemia Patients

COAGULATION DISORDERS IN ACUTE MYELOID LEUKEMIA

Case vignette

RM, a 28-year-old lady, presented with a 4-day history of gangrenous changes in both hands (left > right) and feet. On clinical examination, she had absent ulnar, dorsalis pedis, and posterior tibial artery pulse bilaterally. Her investigations revealed hemoglobin 63 g/L, platelets 39×10⁹/L, and white cell count 33.2×10⁹/L with 85% blasts + promyelocytes. Her coagulogram showed PT 20 seconds, control 14 seconds, INR 1.4, aPTT 31 seconds, control 25–32 seconds, and elevated d-dimer and fibrin-degradation products. Her fibrinogen levels were normal, however. She was started on treatment with all-trans retinoic acid (ATRA) and arsenic on suspicion of acute promyelocytic leukemia (APML) and DIC. This is the first line at our center, even in high-risk APML.³⁴ She was given prophylactic steroids plus hydroxyurea to prevent differentiation syndrome. Computed tomography angiography confirmed the presence of arterial thrombosis in the distal ulnar and posterior tibial arteries. This is a rare presentation of APML, but included here to emphasize the management issues in this case. Given her state of established gangrene with line of demarcation and DIC, she could not be started on any vascular intervention or anticoagulation/antiplatelets. ATRA + arsenic and platelet support was continued. She attained complete remission at the end of 4 weeks. She underwent bilateral below-knee amputation with left phalangeal disarticulation for her dry gangrene 6 months later. She continues to be in remission 4 years later. This outcome is similar to what has been described in case reports.³⁵

Epidemiology

Most cases of AML-M3/APML have DIC at diagnosis. The incidence of DIC in AML-non-M3 is 10%–50%, depending upon the subtype of leukemia and diagnostic criteria for DIC.^36,37 The incidence of thrombosis in AML-non-M3 and APML at diagnosis is 3.2% and 9.6%, respectively. The same at follow-up is 1.7%–8.5% and 8.4%–11% respectively.^38,39 In APML, most cases occur before or during induction therapy with ATRA. Arterial events are commoner than venous events. Thrombosis and severe hemorrhage co-occur in 15% of cases.⁴⁰ The incidence of isolated severe bleeding remains high in APML – around 21%. The case-fatality rate of these episodes can be as high as 50%. The incidence of early-death rates in APML has remained unchanged over the years: at 5%–10%, even in the ATRA era.⁴¹ The incidence of thrombosis in APML at our center is 7.4% (n=136), with equal numbers of arterial and venous TE. The incidence of severe bleeds is 28%, with the early-death rate due to bleeding being 7.4% (Varma et al, unpublished data). Predictors of thrombosis include elevated white-cell count, Bcr3 isoform, FLT3 internal tandem duplication, and expression of CD2 and CD15 on promyelocytes.⁴² Though not a coagulation defect in principle, hyperleukocytosis can be seen in AML when the white-cell count is >100×10⁹/L. This leads to leukostasis and vascular occlusion in any vital organ.⁴³

Pathophysiology

The DIC seen in APML is a double-edged sword for thrombosis and bleeding (Figure 2). Procoagulant forces are CP expressed on leukemic promyelocytes.⁴⁴ TF from endothelial cells is exposed by cytokines (IL1 and TNFα) released from apoptotic leukemic cells.^45–47 TF is the site of activation of factor VII. TF-expressing microparticles in APML have procoagulant activity.⁴⁸ Anticoagulant forces are elevated uPA and tPA and low PAI1.^49,50 Leukemic promyelocytes express annexin II, which accelerates the conversion of plasminogen to plasmin and thus causes primary fibrinolysis.⁵¹ Cerebral endothelial cells also express this annexin II, which explains the high incidence of intracerebral bleeds seen in APML.⁵² Emerging evidence points to podoplanin expression on leukemic promyelocytes causing platelet aggregation as a novel mechanism for bleeding.⁵³ The role of proteases like elastase and chymotrypsin released from leukemic promyelocytes on fibrinolysis, if any, is minor.⁵⁴ ATRA can reverse these changes through various mechanisms of reduced expression of TF, CP, and annexin II and counteracting the effect of cytokines.⁵⁵ ATRA may in fact tilt the balance to a prothrombotic state, as it reverses the procoagulant proteins earlier than anticoagulant proteins, similar to l-asparaginase.⁵⁶A novel cell-death pathway termed “ETosis” has been described recently in APML blasts treated with ATRA. This process releases intact chromatin in the extracellular space. This extracellular chromatin has multifold effects of increasing thrombin and plasmin generation and causes fibrinolysis resistance and endothelial activation.⁵⁷

(To view a larger version of Figure 2, click here.)