Complications and Management of Coagulation Disorders in Leukemia Patients

Investigations

Acquired von Willebrand syndrome should be ruled out in all patients with platelet counts >10×10⁹/L before starting these patients on aspirin. Diagnosis of acquired von Willebrand syndrome involves showing a reduced function:antigen ratio (vWF:Act/Ag, vWF:Act or ristocetin-cofactor assay<30%) and loss of high-von Willebrand multimers.⁸⁷

Treatment

Risk factors for recurrent thrombosis in PV and ET are age >60 years, history of thrombosis, JAK2/MPL-mutation status, JAK2-allele burden, and cardiovascular (tobacco use, hypertension or diabetes mellitus, leukocytosis >11×109/L) in ET.⁸⁸ The goal of treatment in PV/ET is to prevent thrombohemorrhagic complications. Phlebotomy to achieve a hematocrit level <45% is standard treatment in all PV patients.⁸⁹ All low-risk PV and ET patients, except those with acquired von Willebrand syndrome, should get low-dose aspirin (40–100 mg/day). For high-risk PV or ET patients, hydroxyurea is recommended to target a platelet count in the normal range. All these measures reduce the risk of vascular events, including thrombosis and bleeding.⁹⁰ Anagrelide is falling out of favor, due to its increased risk of arterial thrombosis and major bleeding.⁹¹ The requirement of phlebotomy on hydroxyurea correlates with the risk of thrombosis in PV patients.⁹² Both aspirin and hydroxyurea reduce platelet–leukocyte complex formation and downregulation of leukocyte TF expression by hydroxyurea.^78,93 Ruxolitinib, a JAK2 inhibitor, is approved to treat MF and hydroxyurea-intolerant PV. It causes thrombocytopenia in 68% of patients and grade 3–4 thrombocytopenia in 13% of patients.⁹⁴A meta-analysis has shown that ruxolitinib reduces the risk of both arterial and venous thrombosis in PV and PMF patients. This is believed to be due to inhibition of JAK-mediated inflammation by ruxolitinib.⁹⁵

As regards treatment of VTE events, standard LMWH and vitamin K antagonists (VKAs) are used. The risk:benefit ratio of bleeding versus recurrent thrombosis needs to considered on a case-by-case basis. The combination of LMWH/VKAs and aspirin increases the risk of bleeding to 2.8% per patient-year.⁷³The decision to stop anticoagulant therapy at 3–6 months is influenced by the preferences of an informed patient and risk of thrombosis. Recurrent VTE/cerebral or hepatic vein thrombosis, life-threatening VTE, and progressive MPNs uncontrolled with cytoreductive therapy would require indefinite treatment.⁹⁶ Because the risk of recurrent thrombosis is doubled on stopping anticoagulation and the risk of bleeding on VKA is the same as the non-MPN population, secondary prophylaxis should be continued for an indefinite period.⁹⁷ Aspirin should be continued in patients stopping anticoagulation. There are sparse data on the use of direct oral anticoagulants in hematological malignancies. These show no significant risk reduction in major bleeding compared to LMWH.⁹⁸However, there are ongoing randomized trials addressing this issue.⁹⁹ If their use is considered, attention must be given to interactions with drugs used for treatment of the underlying disease (Table 3).¹⁰⁰ To summarize, the young patient had high-risk JAK2 + ET and splenoportal vein thrombosis. He was managed with hydroxyurea and VKAs. He could not be given aspirin, due to the presence of gastric varices. He will need indefinite anticoagulation, given the risk of recurrent thrombosis in this population.

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

COAGULATION DISORDERS IN CHRONIC LYMPHOCYTIC LEUKEMIA

Case vignette

HK, a 62-year-old lady, with known chronic lymphocytic leukemia (CLL) with 11q deletion and unmutated IGHV after early relapse on bendamustine–rituximab, was started on ibrutinib 420 mg daily for bulky lymphadenopathy in April 2016. Her complete blood counts at baseline were hemoglobin 100 g/L, platelets 79×10⁹/L, and absolute lymphocyte count 231×10⁹/L. Her baseline coagulogram was normal (PT 15 seconds, INR 1.2, aPTT 32 seconds, control 32 seconds). Within 2 weeks, her absolute lymphocyte count had risen to 412×10⁹/L and platelets had dropped to 44×10⁹/L. She had gum bleeding with a spontaneous hematoma of 10×15 cm in her left gluteal region. HK had grade 1 thrombocytopenia at baseline. She developed grade 3 thrombocytopenia with major but non-life-threatening bleeding. Her repeat coagulogram was normal (PT 14 seconds, control 14 seconds, INR 1, aPTT 31 seconds, control 32 seconds). This drop in platelet counts was due to ibrutinib, and was held till the resolution of hematoma and platelet count >50×10⁹/L. Ibrutinib was restarted at the same dose. There was no recurrence of bleeding. At 1-year follow-up, her platelet count is up to 100×10⁹/L.

Epidemiology

The incidence of at least one episode of severe bleeding in CLL is reported to be as high as 18%.¹⁰¹This is often seen with autoimmune or disease-related thrombocytopenia. Acquired hemophilia with inhibitors to factor VIII are rare causes of bleeding.¹⁰² Bleeding assumes much more importance in the era of ibrutinib. While early studies showed major bleeding episodes occurred in 9% and 4% of CLL patients on anticoagulants and antiplatelets, later studies have this incidence at 2% and 1%, respectively.^103,104 CLL has not been associated with a high incidence of thrombosis. However, recent studies have shown incidence rates may be as high as other leukemias – 5%–11%.^105,106 The risk factors for VTE is these studies were age >60 years, advanced stage of CLL, CLL treatment, and inherited thrombophilia.

Pathophysiology

At baseline, CLL patients have impaired platelet function assessed by platelet-function assay using epinephrine and adenosine diphosphate. Collagen-induced platelet aggregation is further impaired on initiating ibrutinib. Though factor VIII and vWF levels are elevated at baseline in most patients, their levels decline with ibrutinib. Low levels of factor VIII, vWF, and epinephrine-closure time on platelet-function assay predict bleeding in patients taking ibrutinib. There is no difference in platelet counts in patients who do and do not bleed. Bleeding risk decreases over time.¹⁰⁷

Investigations

Recommended tests include PT, aPTT, INR, and platelet counts at baseline. Bone-marrow examination should be done at baseline in thrombocytopenic patients to confirm or rule out a diagnosis of autoimmune thrombocytopenia. PT, aPTT, INR, and platelet counts should be repeated whenever there is clinical bleeding. Platelet counts should be repeated before each monthly cycle.

Treatment

Patients need to be told to report any bleeding episodes and hold ibrutinib for any medical or dental procedures. Ibrutinib needs to be held for at least 3–7 days pre- and postsurgery, depending upon the surgery and risk of bleeding.¹⁰⁸ While there are no guidelines to hold ibrutinib if thrombocytopenia is due to disease, ibrutinib may be held for drug-related grade 4 thrombocytopenia (<25×10⁹/L) or grade 3 thrombocytopenia (<50×10⁹/L) with bleeding. It is restarted when platelet count rises to ≥50×10⁹/L.¹⁰⁹ Treatment of idiopathic thrombocytopenic purpura, disease-related thrombocytopenia, and acquired hemophilia involves steroids or immunosuppression to treat underlying CLL. Anticoagulation is required in 5%–10% of patients on ibrutinib who develop atrial fibrillation.¹¹⁰ Using direct oral anticoagulants in this setting needs interactions with ibrutinib to be taken in to consideration (Table 3).¹¹¹ Patients on concurrent anticoagulants or antiplatelets should be watched for bleeding.¹¹²The CLL patient mentioned in the vignette had grade 4 thrombocytopenia with non-life-threatening bleeding on ibrutinib. This mandated holding ibrutinib till platelet recovery. Subsequently, her platelet counts rose to >100×10⁹/L, as has been suggested to happen in 68% of patients on ibrutinib by 6 months.¹⁰⁷