Correct!
4. None of the above are true


Intensive transfusion support with platelets and fresh frozen plasma are an important adjunct in the treatment of hemorrhagic complications of DIC and should not be withheld for fear of "fueling the fire." All-trans retinoic acid (ATRA) induces rapid differentiation of neoplastic promyelocytes, ameliorating DIC, and should  be emergently initiated in patients suspected of experiencing fibrinolytic DIC due to APL while awaiting confirmatory test results. The use of heparin in fibrinolytic DIC is controversial, but it may be used in patients with venous or arterial thrombotic complications. Antifibrinolytic therapy and PCC are generally contraindicated in DIC, but may be appropriate in patients with life-threatening bleeding complications.


All-trans retinoic acid (ATRA) 45mg/m2 was emergently administered. The patient developed an upper gastrointestinal hemorrhage despite ongoing intensive transfusion support. Flow cytometry subsequently demonstrated a subpopulation of white cells consistent with acute promyelocytic leukemia (+CD13, +CD33, +CD117, +myeloperoxidase, weakCD34, -CD10 and -CD15), constituting 53% of peripheral WBCC. Additional treatment with arsenic trioxide (ATO) was discussed, but unfortunately the patient’s neurological condition further declined and his wife decided to transition to comfort care to honor the patient’s previously expressed wishes. The duration of his hospitalization was 40 hours. Results of quantitative RAR/PML t(15;17) by real-time PCR are pending. 


Although APL accounts for only 10% of acute leukemia in adults, it is of special importance to critical care practitioners. Once regarded as the most malignant subtype of leukemia, discovery of its biological mechanism led to a novel form of differentiation therapy including ATRA, which achieved 90% 5-year survival. Nevertheless, many patients with APL experience fatal hemorrhage before treatment can be started, emphasizing the importance of rapid clinical recognition.
APL was first reported in the late 1950’s by LK Hillestad and J Bernard who observed patients with hyperacute promyelocytic leukemia often complicated by catastrophic intracranial and pulmonary hemorrhages within the first week of diagnosis (1,2). Elucidation of the unique molecular pathogenesis of APL began in the 1970s with the discovery of an associated translocation between chromosomes 15 and 17 (3). The involved segment on chromosome 15 was shown to be a tumor suppressor gene controlling cell proliferation, senescence and apoptosis, subsequently named the Promyelocytic Leukemia (PML) gene (4). The segment on chromosome 17 was within the locus of the Retinoic Acid Receptor alpha (RAR) gene (5,6). In a healthy promyelocyte cell, transcription of RAR protein promotes transcription of the retinoic acid response elements (RARE) which allow healthy myeloid differentiation. This translocation, uniquely found in over 95% of APL patients, came to be known as PML/RAR (7,8).


The PML/RAR translocation results in a fusion of the two gene products, impairing the function of both. PML/RAR protein complex inhibits transcription of RARE, blocking myeloid precursors in the promyeloid stage (9). In addition, the fusion of PML proteins with RAR inhibits apoptosis, allowing promyelocytes to proliferate without regulation (10). The combined effects of RARE inhibition and PML activation allows promyelocytic cells to progressively accumulate in the bone marrow impairing normal hematopoiesis. 


Fibrinolytic DIC is experienced by the majority of patients with APL and remains the major cause of death. This coagulopathy is caused by overexpression of annexin II (an endogenous tissue plasminogen activator) on the surface of promyelocytes, which triggers fibrinolysis (11). Excessive release of proinflammatory cytokines also likely play a role, as in sepsis-related DIC. APL patients are also less commonly at risk for life-threatening venous and arterial thrombotic complications, caused activation of tissue factor forming a complex with factor VIIa (12) and the increase in thrombin and fibrin by the release of chromatin and phosphatidylserine during APL cell death (13).
ATRA was first proven effective in inducing remission in APL in 1988 (14). The primary mechanism of ATRA is the conversion of the PML/RAR complex into a RARE transcriptional activator that prompts differentiation of promyelocytes into neutrophils (15). ATRA also down-regulates the transcription of annexin II leading to rapid improvement of fibrinolytic DIC (16).

A patient being treated with ATRA for APL develops fever, peripheral edema, acute kidney injury and hypoxic respiratory failure with pleural effusions and diffuse infiltrates. Which of the following that are true? (Click on the correct answer to be directed to the sixth of six pages)

  1. The patient most likely has neutropenic fever and septic shock due to the myelosuppressive effects of ATRA chemotherapy.
  2. Cultures should be obtained and empirical antibiotics started.
  3. ATRA should be immediately discontinued.
  4. Dexamethasone 10mg Q12hourly should be immediately started.
  5. 2 and 4
  6. All of the above

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