Acute Common Iliac Artery Thrombosis with Concurrent Pulmonary Embolism Revealing AML M2: Role of Elevated Plasma Tissue Factor Activity

Background: Cancer patients are exposed to an increased risk of thrombohemorrhagic events. Whereas patients with solid tumors are prone to venous thromboembolism, acute leukemia may cause coagulopathy associated with thrombocytopenia leading to life-threatening bleeding. Disordered coagulatory system is predominant in AML M3 and to a lesser extent in hyperleukocytic AML M4 and M5. Thromboembolic events are rare in the context of unrecognized AML. Risk factors for arterial thrombosis in AML are not well described. Tissue Factor (TF) is being increasingly acknowledged as an important player in cancer thrombosis. We report a case of non-hyperleukocytic AML M2 revealed by an arterial occlusion with concurrent pulmonary embolism (PE) highlighting the potential role of elevated plasma TF activity as a precipitating event and a risk factor for thrombosis.

Clinical Case: A 67-year-old non-smoker patient presented to emergency department because of a 6-hour history of pain in the right lower limb with pallor and coolness. Pulses were abolished in all arteries of the right lower limb without any sensory loss or motor deficit. Contralateral pulses were normal. Clinical examination was otherwise normal. She had no history of intermittent claudication. Past medical history was remarkable for hypertension, thyroid disease and obesity treated two years ago by a gastric bypass surgery complicated by a first episode of PE treated by low molecular weight heparin (LMWH). No further testing for thrombophilia was performed at that time.

A total occlusion of the right common and external iliac arteries was confirmed by a CT-scan angiography. The distal arterial tree was healthy. A chest X-ray found bilateral condensations. A helical CT-scan of the chest disclosed bilateral PE with pulmonary infarction. A lung ventilation/perfusion scan confirmed PE. A transthoracic echocardiography found no intracavitary thrombus nor patent foramen ovale.

Laboratory values were hemoglobin 9.8 g/dl, WBC 13.8 × 10³ µl^-1, platelets 60 × 10³ µl^-1, 80% blasts in the peripheral blood smear. Routine coagulation tests were within usual values (UV).

Bone marrow (BM) aspiration found AML M2, myeloblasts were 80% with a cup-like nuclear morphology. Immunophenotyping of BM blasts disclosed CD34 and HLA-DR negativity. The karyotype was normal. Molecular evaluation found NPM1 gene mutation and FLT3 gene internal tandem duplication (FLT3-ITD). Jak2 gene was not mutated.

Treatment consisted in LMWH followed by standard induction chemotherapy. Complete remission was achieved after induction followed by 2 courses of consolidation. Of note, the patient still suffers from intermittent claudication of the right leg.

Extensive testing for thrombophilia excluded antithrombin, protein C, protein S and protein Z deficiencies, factor II and factor V mutations and antiphospholipid antibody syndrome. Homocysteinemia was normal. Procoagulant activity of intact blasts evaluated by a one-step plasma recalcification time assay was normal. Plasma TF activity was quantified by a one-stage kinetic chromogenic assay. Briefly, this assay is based on the ability of plasma TF to bind to FVIIa and on the capacity of the TF-FVIIa complex to generate FXa. At diagnosis TF activity was elevated at 2.92 pmol (UV<0.45). After remission it returned to normal.

Discussion: To the best of our knowledge this is the first report of concurrent arterial and venous thromboses at presentation of AML. Classical risk factors for thrombosis in AML include coagulopathy and hyperleukocytosis yet neither were present here. Laboratory work-up for thrombophilia was negative. The only abnormal finding was an elevated plasma TF activity before chemotherapy. Interestingly, procoagulant activity on circulating blasts was normal, suggesting TF might have been generated from other sources than AML cells such as activated endothelium and/or normal white blood cells (monocytes, polynuclear neutrophils). TF activity returned to baseline after remission, strongly suggesting it was AML-associated either directly or via innate immunity.

Conclusion: We report a case of non-hyperleukocytic AML M2 with an unusual presentation including an occlusion of a large artery with concurrent PE. TF activity could be considered in the future as a risk factor for arterial and/or venous thrombosis in AML independently of classical conditions such as hyperleukocytosis and coagulopathy.