Hemolytic anemia

Background

• Wide variety of clinical presentation given the large differential diagnosis
• Clinical presentation and lab findings differ depending on intravascular vs. extravascular hemolysis, acute vs. chronic
• Common findings
  • low hemoglobin and hematocrit
  • reticulocytosis
  • elevated indirect bilirubin
• Most important lab to elucidate diagnosis is blood smear
• Most common emergent presentations are due to acute intravascular hemolytic anemias

Etiologies

Divided by etiology: acquired vs. hereditary

• Acquired:
  • Microangiopathic (MAHA), autoimmune, infection
• Hereditary:
  • Sickle cell disease, thalassemia, G6PD, hereditary spherocytosis

Clinical Features

History

• Anemia symptoms
  • Dyspnea/dypsnea on exertion
  • Fatigue
• Stigmata of intravascular hemolysis
  • Jaundice (new onset)
  • Dark urine
  • Changes in stool color
  • Neuro (TTP)
    • Headache
    • Altered mental status
    • Seizure
    • Focal neuro deficits
    • Coma
  • Rectal bleeding (HUS)
• Stigmata of thrombocytopenia
  • Petechiae
  • Bleeding
• Stigmata of extravascular RBC destruction
  • Abdominal pain
  • Back pain
• Systemic Symptoms
  • Fever
  • Night sweats
  • Weight loss
  • Confusion
• Other
  • Trauma
  • Initiation of new medication
  • Recent travel
  • Recent insect bites

PMH

• Hereditary spherocytosis
• Sickle cell disease
• G6PD Deficiency recently started new medication:
  • Dapsone
  • Phenazopyridine
  • Nitrofurantoin
  • Primaquine
  • Rasburicase
  • Methylene blue
  • Tolonium chloride (toluidine blue)
• Malignancy
• Renal failure
• Connective tissue disease
• Family history of Anemia/Bleeding

Physical Exam

• Cardiovascular
  • Tachycardia with flow murmur
  • Heart murmur – prosthetic heart valve
• Abdominal Exam
  • Hepatomegaly, splenomegaly
  • Ascites
• Skin
  • Petechiae
  • Bruising
  • Lymphadenopathy
  • Brown recluse spider bites

Differential Diagnosis

Acquired Hemolytic Anemia

Microangiopathic Hemolytic Anemia

• HUS
• TTP
• DIC
• Hypertensive emergency

Autoimmune

• Autoimmune hemolytic anemia

Infection

• Malaria
• Babesia

Other

• Brown recluse spider venom

Hereditary/Congenital Hemolytic Anemia

• G6PD – medication induced hemolytic anemia
• Sickle cell disease
• Thalassemia
• Hereditary spherocytosis

Evaluation

Workup

• CBC
  • Low hemaglobin/hematocrit
  • Low platelet count -> microangiopathic hemolytic anemia
• Blood smear
• Reticulocyte count
• CMP
  • Most important: indirect bilirubin and creatinine
• UA (for hemoglobin, hemosiderin), uHCG
• PT/INR
• Hemolysis labs
  • LDH
  • Haptoglobin
  • Fibrinogen
• Direct Anti-Globulin Test or Coombs test
• If concern for Malaria:
  • Thick and thin prep
  • Parasitemia
• HIV
• Blood cultures, urine cultures
• Consider LP if neuro symptoms

Lab Interpretation

Microangiopathic Hemolytic Anemia	H/H	Platelets	Indirect Bili	Creatinine	Blood Smear	PT/INR	LDH	Haptoglobin	Fibrinogen	DAT/Coombs Test	Thick/Thin Prep
HUS	low	low	elevated	highly elevated	schistocytes	wnl	elevated	low	wnl	negative	negative
TTP	low	low	elevated	elevated	schistocytes	wnl	elevated	low	wnl	negative	negative
DIC	low	low	elevated	elevated	schistocytes	elevated	elevated	low	low	negative	negative
Malignant Hypertension	low	low	elevated	variable	schistocytes		elevated	low		negative	negative
Autoimmune	H/H	Platelets	Indirect Bili	Creatinine	Blood Smear	PT/INR	LDH	Haptoglobin	Fibrinogen	DAT/Coombs Test	Thick/Thin Prep
Warm Antibody AHA	low	wnl	elevated		spherocytes		elevated	low	wnl	positive	negative
Infection	H/H	Platelets	Indirect Bili	Creatinine	Blood Smear	PT/INR	LDH	Haptoglobin	Fibrinogen	DAT/Coombs Test	Thick/Thin Prep
Malaria	low	wnl	elevated		see thick/thin prep	variable	elevated	low	wnl	negative	paracytes
Babesia					see thick/thin prep					negative	paracytes
Other	H/H	Platelets	Indirect Bili	Creatinine	Blood Smear	PT/INR	LDH	Haptoglobin	Fibrinogen	DAT/Coombs Test	Thick/Thin Prep
Brown recluse	low	wnl	elevated				elevated			positive	negative

Management

• ABC’s and resuscitation if necessary, 2 large bore IVs
• Emergent hematology consultation if patient is very ill appearing

Acquired Hemolytic Anemia

Microangiopathic Hemolytic Anemia

• HUS
  • Supportive Care
    • Hydration
    • Pain control
  • Hemodialysis if acute renal failure
  • Do NOT give antibiotics: results in increased expression of Shiga Toxin from E. Coli O157:H7
• TTP
  • Avoid platelet transfusion, except in life-threatening bleeding or intracranial hemorrhage
  • Plasma exchange
  • If Plasma exchange cannot be performed immediately, give FFP and plasmapharese later.
  • Factor VIII concentrate
• DIC
  • Platelet transfusion if count is <50,000 and/or significant bleeding
  • pRBC if active bleeding or hemodynamically unstable
  • FFP if active bleeding
  • Cryoprecipitate if fibrinogen <150 and bleeding
  • TXA is only indicated for active or massive bleeding
• Malignant hypertension
  • Reduce blood pressure as clinically indicated

Autoimmune

• Warm antibody autoimmune hemolytic anemia
  • High-dose corticosteroids PO (1-2mg/kg per day for 3-4 weeks)
  • Monoclonal antibodies and immunosuppressive agents
  • Plasma exchange for severe hemolysis
  • Allogeneic RBC transfusion for life-threatening anemia

Infection

• Malaria
  • Visit CDC website to determine resistance pattern: https://www.cdc.gov/malaria/diagnosis_treatment/treatment.html
  • CDC Malaria Hotline: (770) 488-7788 or (855) 856-4713 toll-free Monday-Friday 9 am to 5 pm EST - (770) 488-7100 after hours, weekends and holidays
• Babesia
  • Mild/moderate Disease
    • Atovaquone 750mg PO q12hr PLUS azithromycin 500mg PO on day 1, then 250mg/day PO
  • Severe Disease
    • Adult: clindamycin 300-600mg IV qid or 600mg PO TID PLUS quinine 650mg PO TID x 7-10 days
    • Consider exchange transfusion if parasitemia >10%
  • Supportive treatment

Other

• Brown recluse spider bite
  • Supportive care
    • Hemodynamic support with fluids and pressers if necessary
    • Blood product transfusion if necessary

Hereditary/Congenital Hemolytic Anemia

• G6PD
  • Stop new medications
  • Treat any infections aggressively
  • Ovoid oxidant drugs
  • Blood transfusion if severe illness
• Sickle Cell Disease, Thalassemia, Hereditary spherocytosis
  • Hemolytic anemia in the above diseases typically chronic, usually does not require treatment in ED

Disposition

• Depends on severity, complications, etc.

See Also

• Anemia

References

• Dhaliwal G, Cornett P, Tierney LM Jr. Hemolytic Anemia. Am Fam Physician. 2004 Jun 1;69(11):2599-606.
• Rother RP, Bell L, Hillmen P, Gladwin MT. The Clinical Sequelae of Intravascular Hemolysis and Extracellular Plasma HemoglobinA Novel Mechanism of Human Disease. JAMA. 2005;293(13):1653-1662. doi:10.1001/jama.293.13.1653
• Barcellini W, Fattizzo B. Clinical applications of hemolytic markers in the differential diagnosis and management of hemolytic anemia. Disease markers. 2015 Dec 27;2015.
• Bain BJ. Diagnosis from the blood smear. New England Journal of Medicine. 2005 Aug 4;353(5):498-507.
• Tefferi A. Anemia in adults: a contemporary approach to diagnosis. In Mayo Clinic Proceedings 2003 Oct 31 (Vol. 78, No. 10, pp. 1274-1280). Elsevier.
• Wada H, Matsumoto T, Yamashita Y. Diagnosis and treatment of disseminated intravascular coagulation (DIC) according to four DIC guidelines. Journal of Intensive Care. 2014;2(1):15. doi:10.1186/2052-0492-2-15.
• McDade, Jenny et al. Brown Recluse Spider (Loxosceles reclusa) Envenomation Leading to Acute Hemolytic Anemia in Six Adolescents. The Journal of Pediatrics, Volume 156, Issue 1, 155 - 157
• Albert E. Anderson, Paul B. Cassaday, George R. Healy. Babesiosis in Man: Sixth Documented Case American Journal of Clinical Pathology Nov 1974, 62 (5) 612 618; DOI:10.1093/ajcp/62.5.612