Blue toes and a new pair of shoes—Challenges in diagnosis and treatment of acute myelogenous leukemia
Authors: Nataliya Mar, Maria A. Gorgan, Mark E. Dailey, James J. Vredenburgh
Journal: American Journal of Hematology (2013)

A 63-year-old Caucasian female presented to the emergency department complaining of right foot pain for one day associated with blue toe discoloration for 3 weeks. She initially attributed her symptoms to trauma from a new pair of shoes but became concerned with the onset of pain. Her past medical history included hypertension and cervical cancer treated with hysterectomy 25 years ago. Her family history was noncontributory. She had a 40-pack year smoking history but quit 5 years ago. She was in good health prior to this presentation with an ECOG score of 0. Physical examination was remarkable for a weak right dorsalis pedis pulse and cyanosis of all toes on the right foot. Although a new pair of shoes is a potential explanation for developing blue toes, arterial thrombosis must be ruled out. Interestingly, the patient doesn't seem to have any reported cardiovascular risk factors or a known hypercoagulable state. It is reassuring that she is otherwise healthy and has a good performance status. We need to quickly identify the site of thrombosis and initiate prompt therapy in order to salvage the limb. It is also important to investigate the reason behind thrombus formation. Initial laboratory analysis was as follows: white cell count, 14,400/µL with 85% neutrophils, 7% lymphocytes, 7% monocytes, and 1% basophils; hemoglobin, 13.1 g/dL; mean corpuscular volume, 89 fL; platelets, 86,000/µL; international normalized ratio (INR), 1.5 [normal, 0.8–1.2]; activated partial thromboplastin time (aPTT), 29 sec [normal, 24–35 sec]; blood urea nitrogen (BUN), 18 mg/dL [normal, 8–24 mg/dL]; and creatinine, 2.0 mg/dL [normal, 0.6–1.2 mg/dL]. Peripheral smear showed granulocytosis with left shift but no blasts, 1+ schistocytes, and moderate thrombocytopenia (Fig.1a). The patient was admitted to the surgical service and empirically started on therapeutic-dose heparin drip and intravenous hydration. Arterial lower extremity Doppler showed small vessel occlusive disease without evidence of large vessel thrombosis. Abdominal vascular ultrasound and CT abdomen without contrast were unremarkable. At this time, anticoagulation was stopped. Hematology consult was called for evaluation of thrombocytopenia. Due to the patient's elevated creatinine, more sensitive imaging with contrast was not immediately performed. Although the culprit clot has not been identified, major arterial thrombosis remains high on the differential. Small vessel occlusive disease is unlikely to fully explain the patient's presentation. Her leukocytosis with left shift could represent a reactive process in response to acute inflammation. She also has evidence of coagulopathy, moderate thrombocytopenia, renal dysfunction, and presence of mild schistocytosis on peripheral smear. Differential diagnosis is broad and may include infection, vasculitis, autoimmune connective tissue disorder, and malignancy. Disseminated intravascular coagulation (DIC) with thrombocytopenia from platelet consumption and small renal infarcts is also a possibility. Thrombotic thrombocytopenic purpura (TTP) may present similarly and cases of associated arterial occlusion having previously been reported 1. Finally, the patient may have two distinct processes occurring simultaneously. On day 2 of hospitalization, additional laboratory work-up revealed: white cell count, 16,700/µL; hemoglobin, 11.6 g/dL; platelets, 65,000/µL; INR, 1.9; aPTT, 32 sec; fibrinogen, 125 mg/dL [normal, 205–390 mg/dL]; d-Dimer, 16,108 ng/mL [normal, <230 ng/mL]; lactate dehydrogenase (LDH), 672 U/L [normal, 81–175 U/L]; total bilirubin, 0.4 mg/dL [normal, 0.4–1.4 mg/dL]; haptoglobin, 321 mg/dL [normal, 32–213 mg/dL]; direct Coombs test, negative; and creatinine, 1.0 mg/dL. Repeat peripheral smear showed granulocytosis with left shift and occasional atypical large mononuclear cells, 2+ schistocytes, and worsening thrombocytopenia (Fig.1b). At this time, the patient's right foot pain worsened and loss of dorsalis pedis pulse was noted. Right lower extremity MRI was negative for thrombosis but showed an abnormal marrow signal throughout the skeleton. Whole-body CT scan showed near-complete occlusion of the infrarenal abdominal aorta (Fig.2). The patient was taken for an emergent aortic thrombectomy, with post-procedure improvement in right lower limb perfusion and restoration of pulses. Low-dose heparin drip was initiated due to thrombocytopenia. She was stabilized in the intensive care unit over the next 24 hr. At this point, we can rule out a hemolytic process and her laboratory pattern is suggestive of significant DIC 2, which appears to be worsening. There are occasional atypical large mononuclear cells appearing on the peripheral smear, which can indicate increased bone marrow stress or an evolving hematologic disorder. Contrast-enhanced imaging was performed as renal function improved with hydration, finally identifying the site of major arterial thrombosis. Although DIC can be precipitated by this major vascular catastrophe, it may also be a sign of an underlying acute leukemia when taken in conjunction with peripheral smear findings and abnormal bone marrow signal seen on MRI. Although not specific, MRI has proved to be very sensitive for depicting bone marrow changes in patients with acute leukemia and other hematologic malignancies 3. There is, again, a major concern for an underlying hematologic malignancy, which can precipitate DIC and arterial thrombosis. This patient needs a bone marrow aspirate and biopsy. On day 4 of hospitalization, repeat bloodwork was as follows: white cell count, 24,100/µL; hemoglobin, 12.2 g/dL; platelets, 48,000/µL; INR, 2.0; aPTT, 33 sec; fibrinogen, 88 mg/dL; and d-Dimer, 18,505 ng/mL. Repeat peripheral smear showed many immature mononuclear cells, morphologically consistent with blasts (Fig.1c). A bone marrow biopsy revealed over 20% blast equivalents (i.e., monoblasts and promyelocytes), consistent with acute myelogenous leukemia (AML) FAB M5 subtype. Flow cytometry showed an abnormal population of CD11b+, CD15+, CD33+, CD64+, and CD56+ monocytic cells. Cytogenetics yielded a normal female karyotype. Molecular studies were negative for mutations in NPM1, FLT3, CEBPA, and KIT genes. Pathology from the aortic thrombus showed extensive infiltration by immature leukemic cells (Fig.3a,b). The peripheral blood is now starting to show blasts, suggestive of acute leukemia and bone marrow examination confirms the diagnosis. It is very likely that AML was the precipitant of DIC and abdominal aortic occlusion as evident by extensive infiltration of the aortic thrombus by leukemic blasts. Of note, it is interesting to observe the evolution of leukemic blasts on peripheral smear over time, highlighting the true “acuity” of acute leukemias. Pre-treatment cytogenetics and the mutation status of certain genes have become increasingly important due to prognostic implications on treatment resistance and overall survival in patients with newly-diagnosed AML 4, with cytogenetically-normal AML (CN-AML) comprising the largest subgroup 5. A risk-adapted treatment strategy based on these cytogenetic aberrations in conjunction with clinical factors is commonly used 4. This patient has CN-AML and no associated genetic mutations, which places her into the intermediate-risk prognostic category. She also has few significant comorbidities and a good performance status. She should be initiated on an induction AML regimen with an anthracycline and cytarabine, eventually followed by a stem cell transplant 6. On day 5 of hospitalization, the patient was started on “7+3” induction chemotherapy with cytarabine 100 mg/m2/day and idarubicin 12 mg/m2/day. She had a difficult subsequent hospital course including prolonged pancytopenia, severe mucositis requiring parenteral nutrition, persistent neutropenic fever requiring broad spectrum antibiotic and antifungal coverage, renal failure, hepatic failure, and respiratory failure requiring intubation. She ultimately expired of multi-organ failure 1 month into her hospital stay. Our patient's initial presentation consisted of acute limb ischemia caused by occlusion of the abdominal aorta. Major vascular catastrophes have been associated with the development of DIC while accompanying thrombocytopenia may occur due to a consumptive process 2. An added difficulty in establishing the diagnosis was the absence of classic presenting features of AML. These include signs of leukostasis such as ocular and cerebral dysfunction or bleeding stemming from hyperleukocytosis, as well as symptoms of fatigue, hemorrhage, or infection due to leukemic infiltration of the bone marrow with resulting pancytopenia 7. Blasts typically have round-to-irregular nuclei, distinct nucleoli, and little cytoplasm with fine azurophilic granules and a variable number of Auer rods 7. In AML with monocytic or myelomonocytic differentiation, monoblasts, and promonocytes, but not abnormal monocytes, are counted as blast equivalents 8. Of note, there were no leukemic blasts in the peripheral blood on presentation. Instead, there was an explosion of large mononuclear cells noted on the smear within a matter of days. When scant in number, these cells may erroneously be interpreted as abnormal monocytes rather than blasts. This case highlights the occasional difficulty in establishing a diagnosis of AML, especially when its familiar features are initially absent. A high index of suspicion should be present, particularly in previously healthy patents with seemingly unprovoked thromboses in unusual locations. A key point is to continually re-examine the peripheral smear and perform an early bone marrow biopsy to promptly establish the diagnosis. Thrombosis is a frequently overlooked manifestation of hematologic malignancies, which are traditionally known for their bleeding tendencies. Patients with acute leukemia often present with a hypercoagulable state or laboratory evidence of DIC, even in the absence of active thrombosis 9. Studies note a fourfold increase in thromboembolic events in acute leukemia 10 with the rate of venous thrombosis of 2.09% in untreated patients 11. Among those with AML, the highest incidence of thrombosis is seen in acute promyelocytic leukemia, FAB M3 subtype 12. In one observational study, the cumulative incidence of thrombosis at 6 months from diagnosis was 8.4% in M3 AML and 3.2% in non-M3 AML 13. Further, the risk of thrombosis persists even after achieving remission 10. Thrombosis may also be the sole presenting symptom of AML, with 3.4% of patients first presenting with a thromboembolic event in the above study cohort 13. Although clotting can occur within any vessel, venous thrombosis is seen with a nearly 4 to 1 ratio compared to arterial 14. Arterial thrombi are typically seen in small and medium-sized vessels, often in the brain, spleen, and lungs 15. Large arterial occlusion causing limb ischemia as a presenting symptom of AML has previously been described in only a handful of case reports 15-18. Pathologic analyses of arterial thrombi typically reveal infiltration by leukemic blasts without evidence of atherosclerosis 15, 18. Two main mechanisms contributing to thrombus formation in AML include DIC and hyperleukocytosis, when peripheral blast counts exceed 100,000/µL 10. The pathogenesis of thrombosis in DIC is based on tissue factor-mediated activation of systemic coagulation that is insufficiently contained by physiologic anticoagulant pathways and amplified by impaired fibrinolysis 19. Hyperleukocytosis occurs in 5–13% of adult AML, especially in FAB M4 and M5 subtypes 20. These myeloblasts tend to be larger and less deformable 20, causing sluggish blood flow within the microcirculation, obstruction of microchannels, and formation of blast aggregates 15. There is also increased expression of adhesion molecules and endothelial cell production of cytokines that recruit additional myeloblasts, contributing to thrombus formation 21. Leukemic cells then compete for oxygen in the microcirculation and damage the vessel wall, triggering recruitment of platelets and the coagulation cascade 15. Further, they produce prothrombotic factors such as tissue factor and cancer procoagulant 22. Other factors contributing to thrombosis in acute leukemia include use of central venous catheters and co-morbid thrombophilia as well as certain therapeutic agents such as l-asparaginase, glucocorticoids, gemtuzumab ozogamicin, vascular endothelial growth factors, all-trans retinoic acid, and hematopoietic growth factors 10. Extreme symptomatic thrombocytosis and chromosome 3q translocation has also been linked with thrombus formation in AML 18. Despite high risk of thrombosis, anticoagulation in AML remains controversial due to a concurrent increased risk of hemorrhage, especially in the presence of prolonged thrombocytopenia and DIC. Although no guidelines exist for prophylaxis or treatment of thrombosis in acute leukemia, extrapolation can be made from existing guidelines for management of patients with other malignancies 9. When acute thrombosis occurs, therapeutic anticoagulation should be considered. Continuous infusion of unfractionated heparin is a reasonable option due to its short half-life and reversibility but optimal dosing is not well defined. Weight-adjusted doses may be used without the intention of prolonging aPTT to 1.5–2.5 times the control 13. The use of low-molecular weight heparin in leukemia patients has been addressed in several small studies and was deemed safe and effective 23, 24. Tight maintenance of peak anti-Xa levels between 0.5 and 1.0 IU/mL may improve the risk-benefit ratio for patients with hematologic malignancies and venous thromboembolism 25. Newer antithrombotic agents (i.e., factor-Xa inhibitors or the direct-thrombin inhibitors) have not been studied in this group of patients. Placement of inferior vena cava filters has not been systematically assessed in patients with AML. In spite of their proven efficacy in preventing pulmonary embolism in high-risk patients with absolute contraindications to anticoagulant therapy, the risk for deep venous thrombosis remains significantly increased 25. Similar to our case, use of surgical thrombectomy has been described in patients with large arterial thrombosis 15. Treatment with chemotherapy and leukepharesis as needed may ultimately prevent thrombus propagation and lower further thrombosis risk. However, the best therapeutic approach remains controversial. In summary, this case underscores several key points about AML. At times, the diagnosis can be very elusive if classical features are absent on presentation or blasts are not present in the peripheral blood. It is important to remember that acute leukemias carry a high risk of thrombosis, which can be the sole presenting symptom. A key point is to continually re-examine the peripheral smear for evolution of leukemic blasts. Also, if any aspects of the case are found to be equivocal, such as having a previously healthy patent with seemingly unprovoked thrombosis in an unusual location, a high index of suspicion should be present and an early bone marrow biopsy should be performed.