So this happened about 2 weeks into my Heme rotation, thought it was an incredible experience:
Our patient is a 79 year old male with a pmhx of htn, GERD, OA presenting from an outside hospital with several day history of increased dyspnea on exertion and chest pain. He initially presented to his PCP with these symptoms and was noted to have petechiae pm exam and CBC showed thrombocytopenia, and was sent for direct admission to the hospital. On admission, his d-dimer was >20, and CT PE protocol did not show a PE. Platelets were <10, and he was sent to the Hematology service for leukemia/lymphoma workup.
Our patient reported that he had been SOB for 3 days prior to admission, generally with rest, associated with chest pain. His chest pain was described as a burning, substernal sensation that was non-radiating and disspiated with rest. He denied any current chest pain on admission, as well as pleuritic chest pain. He denies fever, chills, productive cough.
He also endorsed increased brusing over his arms and legs for past couple of weeks. Some he could trace to minor trauma, whereas others he could not remember. He denied nose bleeds, headaches, vision changes, bleeding from gums, hematuria, blood, melena in stools.
PMHx: as above
PSHx: cholecystectomy, laparoscopy
FHx: Gastric cancer in father, rheumatic heart disease in mother, sister is alive and well
SHx: Non-contributatory
Exam:
Vitals were: BP 153/81 | Pulse 89 | Temp 36.7 °C (98.1 °F) (Oral) | Resp 16 | Ht 1.854 m (6' 1") | Wt 100.971 kg (222 lb 9.6 oz) | BMI 29.37 kg/m2 | SpO2 97%
Remainder of exam significant for:
General: healthy, alert, and in no distress
HEENT:PERRL EOMI Normocephalic/atraumatic and petechia on the oral palate. Tongue midline
CV: Regular rate and rhythm, Regular S1 and S2, 2/6 mid-systolic murmur along the LSB
Chest: clear to auscultation, full, normal breath sounds
Abd: soft without significant tenderness, masses, organomegaly, or guarding, +BS
Ext: no cyanosis, clubbing, or edema, pulses full and symmetrical
Neuro: The patient's neurological exam was without focal findings. CN III-XII grossly intact.
Skin: Scattered ecchymosis and petechia
HEENT:PERRL EOMI Normocephalic/atraumatic and petechia on the oral palate. Tongue midline
CV: Regular rate and rhythm, Regular S1 and S2, 2/6 mid-systolic murmur along the LSB
Chest: clear to auscultation, full, normal breath sounds
Abd: soft without significant tenderness, masses, organomegaly, or guarding, +BS
Ext: no cyanosis, clubbing, or edema, pulses full and symmetrical
Neuro: The patient's neurological exam was without focal findings. CN III-XII grossly intact.
Skin: Scattered ecchymosis and petechia
Assessment/Plan:
Our assessment of this patient was that he had APML (subset of AML) with possible DIC given his low d-dimer, low platelets. A review of his smear also showed significant number of promyelocytes. We started him immediately on ATRA (all-trans retinoic acid) on presentation, with a planned bone marrow biopsy for the following day. We were also going to continue platelet/cryoprecipate transfusions for his DIC.
The following is a day-by-day breakdown of his progression, along with some review of basic science/mechanisms of drugs we used.
Day 1:
Started on ATRA, continued to develop dyspnea and required increasing oxygen for breathing.
Quick Review of APML.
APML (Acute promyelocytic leukemia) is a subset of AML (Acute Myelocytic Leukemia) that is characterized by the classic t(15:17) translocation. Note that while there are other translocations that are possible, this is the most common (~92%). This translocation affects the RARA (retinoic acid receptor alpha) gene. The PML gene (the mutation) fuses with the RARA gene to form an aberrant retinoic acid protein. This protein then heterodimerizes with the Retinoic Acid receptor (RXR) and the resulting complex binds to elements on target genes that are involved with myeloid differentiation, effectively inhibiting differentiation. APML is an interesting leukemia because while it has a high mortality (less than 1 month median survival if left untreated), it is also one of the most curable, specifically because of it's pathophysiology. Because the problem here is a lack of differentiation of promyelocitic blasts, triggering differentiation effectively 'fixes' the problem, and decreases the number of blasts. This is done through ATRA (All trans retinoic acid), which dissociates the aberrant protein from the RXR receptor and enhances differentiation of the blasts.
Important aspect of treating APML is to start ATRA if you have a high clinical suspicion of APML (smear, cbc, presentation with DIC) as delaying treatment b/c of waiting for cytogenetics can be harmful to the patient.
Day 1 evening:
Our patient developed significantly worse SOB as well as chest pain. An EKG showed was significant for new ST depressions/T wave abnormalities in leads I, aVL, V4-V6. CXR also showed some engorgement of the pulmonary vasculature w/ cephalization, and a worsening LLL opacity. Troponins were elevated to 1.08.
Changes were consistent with ACS in setting of differentiation syndrome from ATRA treatment. At the time, given his DIC, there was concern about starting heparin. Was started instead on morphine for pain control and a beta blocker. He was given lasix for diuresis, and was also started on dexamethasone 10mg bid for differentiation syndrome.
Brief review of Differentiation Syndrome
Because ATRA dissociates the complex from the target genes, there is a sudden increase in the number of differentiated myelocytes. This causes release of vasoactive cytokines that contributes to the pathogenesis of differentiation syndrome.
Risk factors: High blast load prior to start of ATRA, high BMI,
Clinical picture: Varies, usually fever, peripheral edema, pulmonary opacities, hypoxemia, respiratory distress, hypotension, renal/hepatic dysfunction, rash, serositis, pericardial effusion, cerebral edema, pulmonary hemorrhage. Varies in intensity (mild, moderate, severe) based on clinical presentation.
Differential: Lung infection, sepsis, thromboembolism, heart failure
Treatment: Dexamethasone 10mg bid with *continuation* of ATRA unless patient has severe differentiation syndrome (then it is recommended that it be discontinued)
Day 2 -5:
The next four days were characterized by our patient having improvement of dyspnea in the morning, with worsening of symptms in the evening/early morning. We continued to diurese, as we thought his symptoms were due to continued differentiation syndrome. However, he continued to have increased oxygen requirements and during the morning of Day 5, after desatting twice the night before, the decision was made to discontinue his ATRA. Later that evening, our patient began to ooze blood from his PICC line, and on further review of his chest x-ray, there was concern that the opacities seen in his lungs represented pulmonary hemorrhage. He was transferred to an intermediate level of care, with an increase in his steroids as well as the start of a lasix drip.
Day 5 (evening):
We started a regimen of Heparin + Amicar for patient's DIC.
This patient also had DIC, which was initially managed with platelet and cryo transfusions, as well as monitoring of d-dimer/fibrinogen levels. However, as his d-dimer continued to be high, the decision was made to treat his DIC with heparin and amicar (aminocaproic acid).
To review briefly, the MoA of heparin is to potentiate antithrombin 3, which inhibits factor 10a and factor 2a (thrombin). Amicar (or aminocaproic acid) is a lysine analog that binds to plasminogen (plasminogen has a lysine binding site for fibrin), and prevents plasminogen from binding to fibrin, and breaking down the fibrin clot. It also works by increasing antiplasmin levels (though I'm unsure of this mechanism). Amicar effectively inhibits fibrinolysis.
Relatively speaking, treatment of DIC with heparin is a reasonable option to decrease thrombogenesis. However, Amicar is actually contra-indicated by UpToDate in the treatment of DIC due to concerns of inducing a pro-thrombotic state. The effectiveness of the combination of these two drugs, however, can be seen if we review the coagulation cascade above.
With inhibition of factor 2a and 10a, we've effectively induced an anti-thrombotic state; for the actively bleeding DIC patient, however, this might not be ideal, as some degree of thrombosis is preferred. By including Amicar in the treatment regimen, we are also stabilizing any fibrin clots that may have already formed. I like to think of it as placing a huge stop sign in the DIC process.
As a side note, this treatment combination has been used for years at my institution, and the hematologists that develop this claim they've lost only 1 DIC patient with it (pretty huge decrease from the 20-40% rate, though their report might be a little subjective).
Day 5-10:
Patient remained in the ICU from Day 5-10 - this was a very critical period for him. During this time, he required intubation due to severe hypoxic respiratory failure, with ALI (acute lung injury) from ATRA differentiation syndrome resulting in pulmonary hemorrhage (Bronchoalveolar lavage showed bloody sputum). The hematology service (which was now consulting) started idarubicin in order to decrease his white cell count, with a plan to re-start ATRA once he had recovered from his current ICU stay. Patient remained intubated and sedated for about 3 days during his ICU stay. Around Day 8, sedation was weaned, and he became slightly more responsive. He was extubated on Day 10 and subsequently transferred to an intermediate level of care, with the Hematology service resuming primary responsibilities.
Day 11 - current:
Since transferring to intermediate care, patient has improved with regards to his oxygen requirements, and began satting well on room air by Day 23. While his heparin and amicar regimen was initially held on Day 12, it was restarted by Day 13 due to increasing d-dimer levels and decreasing alpha-2-antiplasmin levels. DIC appeared resolved by Day 16, so heparin and amicar was discontinued then, and has not been started since. ATRA was re-started on Day 14. Patient did develop mucositis by Day 16 (thought secondary to idarubicin), as well as thrombocytopenia also thought secondary to idarubicin. Patient continued to improve symptomatically, and received intermittent doses of furosemide to improve his shortness of breath. Most recently, on Day 24, patient reports he is feeling great and is able to tolerate a PO diet. His vitals show a BP of 109/67, pulse 94, temp 36.5°C, RR 16, and he is satting at 96% on room air. His exam is significant for lesions in his mouth consistent with mucositis, with some mild frank blood. His platelets remain low at 7, and his white count is 1.6. We will continue to follow his course until discharge from the hospital.
-Ope
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