Case Presentation by Dr. Meena Munshi
CHIEF COMPLAINT: “I feel short of breath.”
HISTORY OF PRESENT ILLNESS:
21-yo F with sickle cell anemia is brought into resuscitation from walk-in triage for tachycardia (HR 150s) with multiple complaints including: shortness of breath, dizzy/lightheadedness, cough with bright red blood-tinged sputum, and “bloody pee”
Shortness of breath occurs at rest and with exertion, without positional component. Has a slight cough with a few drops of blood tinged sputum. Was admitted to the hospital 10 days ago with community acquired pneumonia and acute chest syndrome, given IV antibiotics, an exchange transfusion, and discharged home 4 days ago with doxycycline of which she completed a 7 day course today. Shortness of breath began when she was diagnosed with CAP but improved during hospital stay and with home antibiotics until today when it suddenly got worse. Denies chest pain, wheezing, sick contacts, history of PE, leg swelling, or asthma.
Feels fatigued and lightheaded at rest, with exertional exacerbation. No fever, syncope, weight loss, headache, neck pain, palpitations, diaphoresis, room-spinning sensation, abdominal pain/distention, nausea or vomiting. Loose brown stools today, without melena or hematochezia.
Notes worsening yellowing of her skin related to sickle cell anemia. No petechiae, bruising, pruritis.
What really brought her in was that for the last few hours, she has been “peeing out blood.” States this is not blood-tinged urine but frank blood. Denies previous such occurrence or any suprapubic or flank pain, dysuria, polyuria, urgency, frequency, vaginal bleeding, or menstruation.
PERTINENT REVIEW OF SYSTEMS:
GENERAL: Generalized weakness, chills and fatigue; no fever or night sweats
HEAD: Lightheadedness, without syncope or headache.
EAR, NOSE AND THROAT: No bleeding gums.
CARDIAC: No chest pain, palpitations, orthopnea, PND or leg swelling.
RESPIRATORY: Shortness of breath and hemoptysis
GI: No abdo pain, N/V, melena, hematochezia, hemetemesis. Loose stools.
GU: Gross hematuria, but no dysuria, urgency, frequency, vaginal bleeding
MUSCULOSKELETAL: No myalgias, arthralgias, joint swelling
ENDOCRINE: No heat/cold intolerance, polyuria or polydipsia.
SKIN: Yellowing of eyes and skin, but no bruising, rashes, or pruritis
PMH: Sickle cell anemia (HbSS), recent CAP with acute chest syndrome requiring plasma exchange transfusion and pRBCs. Multiple (4-5) prior blood transfusions for SCA.
PSH: Cholecystectomy, left eye muscle repair.
Meds: Tylenol with Codeine, Motrin.
FH: DM, HTN, and Sickle cell trait. No DVT/PE, cancer or CAD
SH: Denies use of alcohol, tobacco, or drugs.
LMP: Cannot recall; periods are irregular. Not sexually active.
EXAMINATION OF ORGAN SYSTEMS-BODY AREAS:
VITALS: BP 104/76, HR 152, RR 24, oral T 37.7, pulse ox 97% RA
GENERAL: Obese female appears tired and jaundiced, but in no acute distress.
PSYCH: Alert and oriented x4, cooperative.
HEENT: NCAT, PERRLA (4 mm b/l), profound conjunctival pallor and scleral icterus. No epistaxis/rhinorrhea. Pale, moist oral mucosa. No oropharyngeal erythema, exudates or lesions. No cyanosis.
NECK: Supple, no JVD, lymphadenopathy or meningismus. Trachea is midline.
PULMONARY: Tachypnea(30s). CTA b/l without wheeze/rales/ronchi/stidor or use of accessory muscles. Speaks in complete sentences.
CARDIOVASCULAR: Tachycardia (140s to 150s). No murmurs/gallops/rubs/S3/S4.
ABDOMEN: Soft, nontender, nondistended, normal BS. No hepatosplenomegaly. No guarding, rigidity or rebound tenderness. FOBT negative.
MUSCULOSKELETAL: Back and extremities, atraumatic, nontender with FROM. No peripheral edema, calf tenderness or asymmetry. Extremities well perfused.
NEURO: EOMI. Normal speech and hearing. Face is symmetric. Moving all extremities with good and symmetric motor strength. Sensation grossly intact. Gait not assessed. GCS 15. Normal mental status.
SKIN: Pallor with yellow-orange skin discoloration. Scleral icterus. No petechiae, contusions, hematomas or ther acute rashes or lesions.
CBC: today vs baseline
H/H 4.7/14.5 vs 8/24
WBC 30 vs 10-17
Plt 825,000 vs 750,000
Reticulocyte 12% vs 25%
Retic count 186,700 vs 500,000
urine bilirubin 3+
urine protein 3+
Cr 1.2 (baseline 0.6)
T. Bilirubin 4.5 (0-1.5)
D. Bilirubin 1.7 (0-0.4)
Alk Phos 109
Serum preg test: negative
Type and Cross: 2U pRBCs; Blood type B+
Direct Antigen Test: positive
LDH: 1476 (nml 100-240)
EKG: Sinus tachycardia (HR 152)
1) The patient’s symptoms are most likely due to:
a) Aplastic crisis
b) Delayed hemolytic transfusion reaction
c) Splenic sequestration
d) Vaso-occulsive sickle cell pain crisis
2) The patient was normotensive and afebrile throughout her ED stay. Her tachycardia improved (150s–> 110s) with bolus NS hydration. Tachypnea and shortness of breath improved with 2L oxygen via nasal cannula. She remains alert otherwise well. After reevaluating the scenario, you decide to:
a) Continue supportive treatment, observe, hold off on transfusion
b) Transfuse 2U pRBCs
c) Transfuse 1U pRBCs
d) Transfuse whole blood
e) Discharge home with close Hematology follow up
3) In this patient which condition(s) would warrant a blood transfusion?
a) A typical pain crisis
b) Drop in hemoglobin 2 units below baseline with symptomatic anemia
e) Chest pain with cough, fever, purulent sputum
1.B 2.A 3.D and E
The patient’s final diagnosis: Delayed hemolytic transfusion reaction (DHTR).
DHTR is a rare, life-threatening complication of sickle cell disease that should be in the differential diagnosis of acute pain crisis especially after a recent RBC transfusion. Because SCD patients have a chronic hemolytic anemia, vaso-occulusive complications often necessitate RBC transfusion to increase oxygen carrying capacity or improve blood flow.
DHTR in an SCD patient can be tricky to diagnose especially when the presentation mimics a typical pain crisis. Ask about history of transfusion, especially within the last 5-14 days and particularly if the patient was recently hospitalized. A major risk factor for developing DHTR is a history of multiple RBC transfusions, because increased exposure to multi-donor blood antigens increases the patient’s chance for alloimmunization. Alloimmunization – the development of recipient antibodies to donor RBC antigens — is thought to be the major mechanism for DHTR and tends to be higher in SCD than in other chronically transfused populations.
DHTR patients will usually have a significant drop in their absolute reticulocyte count from baseline, develop a more profound anemia after transfusion than they had before the transfusion, demonstrate hemolysis with an increase in LDH and indirect bilirubin assays.
In aplastic crisis patients have a significant drop in their hemoglobin concentration, but it is associated with profound reticulocytopenia (<10,000) and a normal or mildly depressed WBC count. There is no elevation in bilirubin because the problem isn’t related to hemolysis, but to bone marrow infarction caused in a majority of SCD patients by Parvo B19 viral infection.
In hepatic/splenic sequestration, patients will have a significant drop in hemoglobin concentration associated with an elevated reticulocyte count (>100,000), indirect bilirubin and LDH levels, and a rapidly enlarging liver/spleen.
The pathophysiology of worsening anemia after an RBC transfusion is thought to be multimodal. Hemolysis occurs when recipient antibodies destroy transfused cells carrying the targeted antigen. Hyperhemolysis refers to the immunologic response where donor RBCs that are negative for the antigen the antibody is targeting get destroyed, likely due to complement activation. Erythropoesis suppression that is seen with transfusion may also contribute, in addition to an already shortened RBC lifespan to depressed hemoglobin concentrations in SCD.
Diagnosing DHTR : History includes recent transfusion with a history of multiple prior transfusion. Physical exam shows signs of transfusion reaction: fever, chills, myalgias, weakness, dyspnea, red urine, pallor, tachycardia, jaundice and often mimics a pain crisis. Lab tests: CBC (hemoglobin concentration lower than it was prior to transfusion), reticulocyte count (usually markedly depressed), direct and indirect antiglobulin tests (looking for the development of new antibodies but can often be negative), serum bilirubin (total and indirect usually both elevated) and lactate dehydrogenase to assess for increased hemolysis, and a urinalysis to evaluate for hemoglobinuria.
(A negative antibody test does not exclude the diagnosis of a DHTR as the antibody screen often remains negative in these patients. Hemoglobin electrophoresis demonstrates marked destruction of donor RBC seen as a lack of hemoglobin A).3
Management of DHTR in SCD is still done on a case by case basis, however there are a few caveats. If you suspect DHTR, withhold further transfusion unless absolutely necessary as you could herald a worsening hemolysis because of alloimmunization. If RBC transfusion is required, use phenotypically matched blood that is leukocyte-poor, and E, C, and Kell-negative. Restrict the number and volume of blood draws. Do not transfuse these patients to hemoglobin levels exceeding 10-11 g/dL as blood viscosity increases with transfusion, and particularly more so in SCD patients, thereby reducing the oxygen carrying capacity. In all cases, contact Hematology as soon as you suspect DHTR because they may want to start high dose steroids or IVIG. Treat pain crises as you would otherwise. The patients usually improve with supportive therapy as evidenced by improving RBC counts and reticulocytosis.
In SCD, the few absolute indications for transfusion include aplastic crisis, splenic sequestration, development of new stroke-like symptoms, hemodynamic instability, or cardiovascular collapse. A low hemoglobin/hematocrit alone is not a reason for transfusion because chronically anemic SCD patients can tolerate further anemia well.
- Schenunemann LP, Ataga KI. Delayed hemolytic transfusion reaction in sickle cell disease. Am J Med Sci. 2010 Mar; 339(3):266-9.
Follow-up to the case:
The patient was admitted to Hematology floors without being transfused in the ED. The patient’s personal Hematologist had recommended against transfusion to avoid further hemolysis, however the admitting Hematologist was concerned about hemodynamic collapse and recommended transfusion of 1 Unit pRBCS (leuko-poor, etc etc). Because of difficulty with type and crossing for this patient, the blood was unavailable at the time she was admitted to the floor.
Within the first 24 hrs of admission, she dropped her hemoglobin concentration down to 2.9 and was started on high dose steroids and IVIG. She was never transfused but recovered with supportive therapy and was discharged on home a week after admission with a hemoglobin of 6g/dL and a diagnosis of DHTR. Shortly thereafter, in clinic, she was started on hydroxyurea.