Keywords
Acute promyelocytic leukemia - anti-coagulation - chemotherapy - thrombosis
Introduction
Acute promyelocytic leukemia (APML), a unique subtype of acute myeloid leukemia, is
commonly associated with a complex life-threatening coagulopathy.[1] Induction therapy with all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO)
usually results in a durable remission. As compared to bleeding manifestations, APML-associated
thrombotic events are less commonly reported.[2] They can occur either before, during, or after the induction therapy (40.4% prior
to induction therapy) and exhibit predilection for both arterial (more common) and
venous vasculature.[3]
[4] About half of these patients (51.6%) have coagulation defects.[4]
Case Report
A 20-year-old daily wage laborer was admitted with the complaints of the left lower
limb swelling for a 2-week duration. Six weeks prior to admission, he was evaluated
in a local hospital for low-grade fever and fatigue. Investigations done there had
revealed anemia (Hb 72 g/L) and normal chest X-ray; peripheral smear was not examined.
He was administered one unit of blood transfusion and discharged on oral haematinics.
Six weeks later (now), he was referred to us for worsening of fatigue in addition
to left lower limb swelling and dry cough. He complained of significant weight loss
for 2 months; past and family history was unremarkable for similar complaints, hemolytic
anemia, high-risk behavior, intravenous drug abuse, and tuberculosis. At presentation,
he had a fever (100.5°F), tachycardia (112 bpm), and normal BP (114/76 mmHg). Apart
from being severely malnourished (body mass index 16.4 kg/m2), he had pallor and left
lower limb pitting edema; liver and spleen were not palpable. Doppler ultrasound revealed
left lower limb deep vein thrombosis [Figure 1]. Two-dimensional ECHO revealed 2.3 cm × 1.5 cm pedunculated mass adherent to the
interventricular septum in the left ventricle [Figure 2] and no features of the right ventricular dysfunction. The left moderate pleural
effusion and bilateral pleural-based pulmonary infarcts were evident on computed tomography
chest [Figure 3]. He was put on subcutaneous enoxaparin. His hemogram revealed normocytic normochromic
anemia (Hb 6.3 g/dL), leukopenia (total leucocyte count [TLC] 1.6 × 109/L), and normal
platelet count (334 × 109/L). Work up for paroxysmal nocturnal hemoglobinuria was
planned in view of bicytopenia with thrombosis. Meanwhile, 34% blasts and atypical
promyelocytes were seen on the peripheral blood smear. Coagulation screen was unremarkable
except isolated prolonged prothrombin time (24 s). Presuming the diagnosis of APML,
ATRA, and ATO-based induction therapy was started promptly, and two units of packed
red blood cells were transfused. Bone marrow examination and flow cytometry were consistent
with APML (CD13+, CD33+, HLA-DR−, no aberrant expression markers) [Figure 4]. PML-RARA fusion gene detection by qualitative reverse-transcriptase-polymerase
chain reaction (RT-PCR) confirmed the diagnosis of APML (low risk). Blood cultures
were sterile; pleural fluid analysis revealed exudative pattern and no malignant cells.
Investigative work up for pulmonary tuberculosis and HIV was inconclusive. Fever resolved
by day 7 of induction therapy. Hemorrhage, ischemia, and differentiation syndrome
were not observed during the induction therapy. The complete hematological response
was achieved on day 27. End of induction bone marrow was in remission, and qualitative
RT-PCR for PML-RARA was negative. Consolidation chemotherapy was continued along with low molecular weight
heparin.
Figure 1: Doppler ultrasonography showing absence of color flowin the left common
femoral vein suggestive of thrombosis
Figure 2: Two dimensional-Echocardiography showing 2.3 cm × 1.5 cm pedunculated mass
within left ventricular cavity adherent to interventricular septum
Figure 3: Computed tomography-chest showing bilateral pleural-based pulmonary infarcts
with left-sided pleural effusion
Figure 4: Bone marrow aspiration slide showing blast with multiple Auer rods (Faggot
cells)
Discussion
Pathogenesis of thrombosis in APML is incompletely understood. Apart from procoagulant
phenotype of leukemic promyelocytes and concomitant diffuse intravascular coagulation
(DIC), ATRA-based therapy per se has also been thought to enhance thrombosis likelihood in such patients.[5]
[6]
[7] High total leukocyte count at diagnosis (> 10 × 109/L), FLT3 positivity, presence of variant translocation, CD2 or CD15 expression, and occurrence
of differentiation syndrome are well-known predisposing factors.[8]
[9] The most commonly reported thrombotic complications before APML induction are cerebrovascular
accidents, DVT/PE, and cardiac thrombotic events (including myocardial infarction
and intraventricular thrombosis).[4] Apart from ATO and ATRA-based therapy, these patients also require anticoagulation
for the thrombus.[10]
[11]
[12]
The index case had an elusive presentation in the form of fever and anemia. Although
the nutritional deficiency is the most common cause of anemia in developing countries,
meticulous peripheral blood smear examination can pinpoint catastrophic etiologies
at an early stage. There was a step-wise clinical progression with lower limb DVT
followed by pulmonary embolism, pulmonary infarction, and cardiac involvement. At
the time of diagnosis, white blood cell (WBC) count was surprisingly low and other
thrombosis predisposing risk factors were conspicuously absent (DIC, FLT3, CD2 or CD15 expression, and differentiation syndrome). The formation of intravascular
leukemic thrombi can be offered as an explanation for low initial WBC count, but the
same could not be proved by histological examination in the index case. Importantly,
neither the existing thromboses worsened nor any new thrombotic events occurred during
ATRA plus ATO therapy. Hence, ATRA-based induction therapy can be safely considered
in APML patients who have thrombosis prior to induction therapy.
Conclusion
Hematological abnormalities should be thoroughly investigated in patients presenting
with thromboembolic manifestations. Thrombosis in APML is an uncommon yet dire complication
that can occur even in the absence of known risk features. Successful outcome in APML
complicated by thrombosis can be achieved with ATRA plus ATO-based therapy.
Informed consent
Informed signed written consent was taken from the patient involved.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms.
In the form, the patient has given his consent for his images and other clinical information
to be reported in the journal. The patient understands that name and initials will
not be published and due efforts will be made to conceal identity, but anonymity cannot
be guaranteed.
