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COAGULATION DISORDERS IN ACUTE LYMPHOBLASTIC LEUKEMIA
Case vignette
GK, a 39-year-old woman diagnosed with pre-B-cell acute lymphoblastic leukemia (ALL), standard risk was started on the Berlin–Frankfurt–Münster (BFM)-90 protocol. Her blood counts at presentation were hemoglobin 45 g/L, platelets 18×109/L, and white-cell count 1.2×109/L. She received native Escherichia coli l-asparaginase as part of the induction therapy. In the fourth week after completion of the l-asparaginase course, she presented with generalized tonic–clonic seizures and right-sided hemiparesis. Computed tomography suggested bifrontal hemorrhage. Magnetic resonance venography of brain confirmed superior sagittal sinus thrombosis. Her blood counts were hemoglobin 80 g/L, platelets 85×109/L, and white-cell count 2.8×109/L. Her fibrinogen levels were normal throughout the course of l-asparaginase. She was started on a therapeutic dose of low-molecular-weight heparin (LMWH). LMWH was dose-modified for thrombocytopenia during the intensive phase. She was not rechallenged with l-asparaginase during the reinduction phase. She remains in complete remission, with minimal residual disease negative at end of induction. LMWH was continued for 6 months. Her focal neurological deficit recovered, and she had no recurrence of thrombosis.
Epidemiology
The reported incidence of TE in childhood ALL varies from 1.1% to 36.7%.4 This wide variation is due to differences in TE diagnosis and treatment protocols. This incidence is even higher in adolescent and young adult (34%) and adult patients (43%) on l-asparaginase.5 The commonest sites for TE are central nervous system (CNS; 50%) and deep vein thrombosis (43%). The overall mortality of TE in ALL varies from 0 to 4.8%.4 On the contrary, deaths due to bleeding in ALL are less common than in acute myeloid leukemia (AML).6
Pathophysiology
The clinical presentation of TE or bleeding is an outcome of the delicate balance between procoagulant and anticoagulant forces at play in a patient (Figure 1). There are several studies showing increased thrombin generation shown by thrombin–antithrombin (AT) complexes at diagnosis and in initial therapy for ALL.
(To view a larger version of Figure 1, click here.)
Factor VIII, von Willebrand factor (vWF), and fibrinogen are positive acute phase reactants.7 Besides this, ALL cells also express cancer procoagulant (CP).8 CP activates factor X directly, independently of factor VII.9 Disseminated intravascular coagulation (DIC) is underrecognized in ALL, with prevalence of around 14% at diagnosis and doubling to 27% during induction therapy.10
Chemotherapy in ALL augments the thrombogenic potential. Of these, l-asparaginase, which depletes the ALL cells of the essential amino acid asparagine, also ends up depleting the procoagulant (fibrinogen, factors V, VII, VIII, IX, X, and XI) and anticoagulant (AT, plasminogen, protein C/S) proteins. l-Asparaginase may in fact cause a prothrombotic state, as it reverses the procoagulant proteins earlier than anticoagulant proteins.11 E. coli asparaginase, which is more potent than Erwiniaasparaginase, has more effect on the coagulation parameters.12 Steroids add to the prothrombotic state by increasing plasma levels of prothrombin, factor VIII/vWF, and PAI1 and decreasing plasminogen and fibrinogen.13 Dexamethasone may be associated with less risk of TE than prednisone.14 Central venous lines are the other reason for TE, with incidence as high as 30%, depending on the technique and site of insertion.15 A variable 18%–40% of cases may have inherited thrombophilia.16 Use of granulocyte/granulocyte-monocyte colony-stimulating factors during episodes of neutropenia is also associated with thrombosis at an incidence of 1.2% and 4.2%, respectively. This is through increased tissue-factor (TF) and factor-VIII levels.17 T-cell ALL patients are at higher risk of both TE and hemorrhagic complications, due to hyperleukocytosis.18 Thrombocytopenia – at diagnosis or therapy-related – is one of the major factors contributing to bleeding in ALL. Infections can tilt the balance either way of systemic inflammatory response syndrome or consumptive coagulopathy.
Investigations
Recommended tests include activated partial thromboplastin time (aPTT), international normalized ratio (INR), and fibrinogen levels (AT optional) prior to, during native asparaginase dosing, and 1 week after polyethylene glycol–asparaginase therapy. For prevention of TE, research using AT prophylaxis have shown reduced incidence of TE, but this was not powered for efficacy, and hence the role of AT replacement remains inconclusive.19 Though prophylactic fresh frozen plasma/cryoprecipitate to replace AT is associated with no CNS TE events, neither it nor LMWH lower the incidence of TE on l-asparaginase.20,21 Some centers use both anticoagulation and AT replacement for AT levels <60%.22 At our center, we give cryoprecipitate for fibrinogen <100 mg/dL.
Treatment
Development of TE while on l-asparaginase used to lead to discontinuation of asparaginase in up to 75% patients, which led to inferior event-free survival outcomes.23,24 However, with current strategies of rechallenging asparaginase and continued anticoagulation, outcomes have been similar.5 Current expert recommendations are to discontinue asparaginase only for CTCAE (Common Terminology Criteria for Adverse Events) grade 4 CNS thrombosis or bleed. For all grade 3 events and grade 4 non-CNS events, asparaginase needs to be withheld till resolution of clinical signs and either anticoagulation or coagulant therapy is stable. Asparaginase may be resumed at lower doses and/or longer intervals. Asparaginase need not be withheld for asymptomatic lab abnormalities.25 As regards prophylactic platelet transfusions, the restrictive strategy with the standard trigger set at 10×109/L has remained unchanged over the past decade.26
There have been no prospective randomized control trials on anticoagulant choice, dose, and duration in patients with leukemia. Most recommendations have been derived from extrapolation from studies done in patients with solid-organ malignancies. These guidelines endorse the use of LMWH as first-line therapy during the first 3–6 months after the diagnosis of malignancy-associated venous TE (VTE) based on the 2003 CLOT study.27–30 There have been recent expert recommendations on managing thrombosis in the setting of leukemia with thrombocytopenia.31–33 The consensus for anticoagulation dose modification in the setting of thrombocytopenia is as given in Tables 1 and 2. For catheter-related VTE, recommendations are to keep the catheter and continue anticoagulation till the catheter is in place or at least 3 months, whichever is longer. Catheter removal is only required if the device is dysfunctional, infected, or not required. For non-catheter-related TE, anticoagulation is recommended for at least 6 months and indefinitely for active malignancy or persistence of risk factors for recurrence.3 The decision to stop anticoagulation beyond 6 months in patients under treatment of a malignancy that is in complete remission is unclear. This is on a case-by-case basis after taking the risk:benefit ratio into consideration. To summarize, in this case, the patient had a grade 4 CNS vascular event on l-asparaginase, despite normal fibrinogen levels. She was managed with dose-modified anticoagulation as mentioned, and not re-challenged with l-asparaginase.
(To view a larger version of Table 1, click here.)
(To view a larger version of Table 2, click here.)
