Hemolysis

Basics

Description

Premature destruction of RBCs, either intravascularly or extravascularly, leading to a shortened red cell survival time. The premature destruction can be caused by intrinsic factors (defects within the RBC itself) or extrinsic factors (factors outside the RBC leads to premature destruction).

Risk Factors

Acquired (extrinsic): ABO and/or Rh incapability is a risk factor in the newborn period.
Hereditary (intrinsic): Although many hereditary disorders are autosomal dominant, 20% of these patients represent new spontaneous mutations and have no affected family members.

Genetics

Hemoglobinopathies are generally autosomal recessive or the result of compound heterozygosity.
RBC membrane defects and enzyme defects may be autosomal dominant, recessive, or X-linked.

General Prevention

Acquired (extrinsic): Most causes of acquired, non–transfusion-related hemolytic disease are not preventable.
Hereditary (intrinsic): Although there is no way to prevent hereditary forms of hemolysis, newborn screening can help identify and allow proper management of some conditions. Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency should be counseled to avoid triggers such as fava beans, broad beans, and mothballs.

Pathophysiology

Intravascular hemolysis occurs within the circulation as a direct result of trauma, complement fixation, and cellular destruction.
Extravascular hemolysis generally occurs in the spleen (or liver) as misshaped and/or older red cells are recognized and destroyed by the RE system.

Etiology

Extrinsic or acquired disorders
- Infectious
- Drug-induced
- Immune mediated
- Microangiopathic
Intrinsic or hereditary disorders
- Hemoglobinopathies
- RBC membrane and enzyme defects

Diagnosis

History

Pallor, fatigue, and jaundice may occur with either intravascular or extravascular hemolysis.
Hemoglobinuria is a sign of intravascular hemolysis.
General goal is to establish existence of hemolysis rather than other causes of anemia, such as blood loss and hypoproduction.
Determine acuity and severity of the anemia and hemolysis:
- With acute onset, there will be evidence of unstable vital signs and possibly heart failure.
- Parents may give a history of a rapid deterioration of the child’s physical and/or mental state.
- Patients with chronic anemia that has progressed slowly may have a low hemoglobin yet be well compensated with fairly normal vital signs (except for tachycardia).
- CBC with a corrected reticulocyte count will help determine if there is an appropriate bone marrow response to the level of anemia and, therefore, whether the process is hypoproductive or hemolytic.
Determine the cause of hemolysis. Treatment approaches will vary depending on the underlying etiology.
Question: History of anemia, splenectomy, or early cholecystectomy in multiple family members?
Significance:
- Although many hereditary membrane defects and enzyme deficiencies are autosomal dominant, some are autosomal recessive or X-linked. Thus, a negative familial history does not always rule out these diagnoses.
- In some cases, the diagnosis of hereditary spherocytosis (HS) has not been made, yet multiple family members have had their gallbladders removed at an early age, which may indicate the presence of this defect.
- Thalassemia (especially β-thalassemia) and sickle cell anemia may present in early childhood with chronic hemolysis with or without a familial history.
Question: History of travel?
Significance: Malaria is endemic to Africa, India, and parts of Central America.
Question: Recent medications, transfusions or new food exposures?
Significance:
- Specifically ask about exposure to fava beans, mothballs, and antibiotics. Drugs can themselves cause hemolysis or can induce hemolysis if there is an underlying disorder such as G6PD deficiency.
- Delayed hemolytic transfusion reactions are rare but can be seen days to a week or so later.
Question: Age at first signs and symptoms of hemolysis (pallor or jaundice)?
Significance:
- Hereditary causes of hemolysis are most often chronic or recurrent, although the diagnosis may be delayed until the child is older if the process is mild.
- Acute, acquired hemolytic disorders may also recur.

Physical Exam

Hemolysis that is a secondary problem (e.g., related to infection, tumors) may be found incidentally during evaluation of the primary process.

Finding: Acute processes such as autoimmune hemolytic anemia (both warm and cold antibody mediated) may present with a child in extremis.
Significance:
- Tachycardia is a common finding in nearly all cases of acute hemolysis.
- Hypotension is a late finding.
Finding: More chronic processes, such as HS, G6PD, PK deficiencies, thalassemia intermedia, and sickle cell disease, may be picked up at well visits or by laboratory examination.
Significance: These children often appear well (except for jaundice) but may become more anemic with an acute illness.
Finding: Splenomegaly (often impressive) and hepatomegaly are common findings in extravascular hemolysis.
Significance:
- Hepatomegaly may be more pronounced if the child is in heart failure due to acute, severe anemia.
- Splenomegaly may be either the cause of or, more frequently, a result of a hemolytic process.
- If significant lymphadenopathy is present, look for an underlying cause such as lymphoproliferative disorders or malignancy.
Finding: skin changes
Significance:
- Pallor is nearly a universal finding in acute hemolysis and in exacerbations of chronic hemolysis.
- Jaundice is more common in intravascular hemolysis.
- Presence of ecchymoses or petechiae suggests DIC or thrombocytopenia.

Differential Diagnosis

Acquired (extrinsic)
- Allergic/inflammatory/immune
  - Autoimmune hemolytic anemia
    - Warm antibody mediated
    - Cold antibody mediated
    - Hemolytic transfusion reaction
- Congenital/anatomic
  - ABO blood type incompatibility and Rh incompatibility between infant and mother
  - Cardiac lesions with turbulent flow; left-sided more common than right-sided
  - Prosthetic heart valve (especially aortic)
  - Kasabach-Merritt syndrome
  - Hypersplenism
- Infectious
  - Congenital infections with syphilis, rubella, cytomegalovirus, and toxoplasmosis
  - Malaria
  - Bartonellosis
  - Clostridium perfringens (via a toxin)
  - Mycoplasma pneumoniae
  - HIV
  - Hemolytic uremic syndrome
- Toxic, environmental, drugs
  - Immune complex “innocent bystander” mechanism
    - Quinidine
    - Acetaminophen
    - Amoxicillin
    - Cephalosporins
    - Isoniazid
    - Rifampin
  - Immune complex drug adsorption mechanism
    - Penicillin
    - Cephalosporins
    - Erythromycin
    - Tetracycline
    - Isoniazid
  - Drug-induced autoimmune hemolytic anemia: α-methyldopa
  - Toxic drug–induced hemolysis: ribavirin (generally mild and not clinically significant)
  - Snake and spider venoms
  - Extensive burns
- Mechanical hemolysis
  - Cardiac hemolysis
  - Abnormal microcirculation
    - Thrombotic thrombocytopenic purpura (TTP)
    - Disseminated intravascular coagulation (DIC)
    - Malignant hypertension
    - Eclampsia
    - Hemangiomas
    - Renal graft rejection
  - March hemoglobinuria (prolonged physical activity)
- Tumor
  - Lymphomas
  - Thymoma
  - Lymphoproliferative disorders

Hereditary (intrinsic)
- Genetic/metabolic
  - RBC membrane defects
    - HS
    - Hereditary elliptocytosis
    - Pyropoikilocytosis
    - Paroxysmal nocturnal hemoglobinuria (can be acquired)
  - Enzyme defects
    - PK deficiency
    - G6PD deficiency
  - Thalassemias (β-Thalassemia major is the most severe.)
  - Hemoglobinopathies
    - Sickle cell anemia (Hgb SS and SC variants)
    - Unstable hemoglobins

Diagnostic Tests and Interpretation

Initial Tests

CBC with differential and reticulocyte count
- Interpret level of anemia and the reticulocyte count together. Chronic hemolysis in HS, for example, may have a nearly normal hemoglobin count but usually has an increased reticulocyte count.
- With a rapid fall in hemoglobin, as in acute autoimmune hemolytic anemia, the reticulocyte count may be low at the start, rise in response to anemia, and fall during recovery.
- Thrombocytopenia should raise suspicions about TTP or hemolytic uremic syndrome.
Peripheral blood smear
- Fragmented RBCs, schistocytes, and helmet cells are seen in DIC, TTP, hemolytic uremic syndrome, and cardiac valve hemolysis.
- Helmet or bite cells are nearly pathognomonic for G6PD deficiency.
- Other findings on the smear that may be helpful are spherocytes (HS and warm autoimmune hemolytic anemia), target cells (hemoglobin C and thalassemias), and acanthocytes (anorexia nervosa).
Bilirubin
- Total and unconjugated bilirubins are elevated in most cases.
Urinalysis
- Hemoglobinuria is present in intravascular hemolysis; established by a urine dipstick positive for heme with no intact red cells microscopically
- Myoglobinuria can also give this picture.
Coombs test
- Direct Coombs test (direct antiglobulin test) detects antibodies or complement fragments present on the patient’s RBCs.
- Indirect antiglobulin test detects antibodies in the patient’s serum that can bind normal RBCs.
- Direct antiglobulin test provides direct evidence of immune-mediated hemolysis.
- Warm antibody autoimmune hemolytic anemia is caused by an IgG antibody that coats RBCs, which are subsequently removed by the spleen.
- Cold antibody autoimmune hemolytic anemia is caused by an IgM antibody that binds RBCs, fixes complement, and can cause both extravascular and intravascular hemolysis.
Haptoglobin, hemopexin, and lactate dehydrogenase (LDH)
- In intravascular hemolysis, haptoglobin levels may be undetectable, hemopexin is reduced, and LDH increased.
- In extravascular hemolysis, haptoglobin is decreased (but detectable) and LDH may be increased but not to the level seen in intravascular hemolysis.
Chest radiograph to assess cardiomegaly and evidence of pulmonary edema

Tests Considerations

Blood for diagnostic RBC enzyme, RBC membrane, or hemoglobinopathy studies must be drawn prior to transfusion to assure only the patient’s red cells are studied.
Bone marrow aspiration is rarely indicated, but if done, erythroid hyperplasia may be seen.

Treatment

General Measures

Avoid triggers of hemolysis (i.e., foods, medications, etc.) for patients with known G6PD deficiency.
Extended cross-match for minor red cell antigens prior to transfusions in patients with hemoglobinopathies to decrease risk of delayed hemolysis.

Medication (Drugs)

Depends on cause and severity of hemolysis and anemia

First Line Medication

Supportive care with fluids, oxygen, etc.

Second Line Medication

Red cell transfusion may be indicated for symptomatic anemia regardless of cause: Rate and volume of blood to be transfused will depend on severity of anemia and speed of onset (generally slower transfusion rate needed in chronic anemia).
Plasmapheresis for TTP
Withdrawal of inducing drug/agent (G6PD)
Corticosteroids (Solu-Medrol^® 1 to 2 mg/kg/dose q6–12h) may be indicated for hemolytic transfusion reactions and/or immune-mediated hemolysis

ALERT
Factors that constitute an emergency:

Hemoglobin <5 g/dL, especially with signs of cardiovascular compromise
- Attempts to stabilize cardiovascular compromise with volume should be undertaken with care because hemodilution may occur.
- Transfusion may be riskier in autoimmune hemolysis because of potential problems with cross-matching.
Renal failure may accompany severe hemolysis in TTP or hemolytic uremic syndrome.
Hemolysis in the neonatal period secondary to ABO or Rh incompatibility may require exchange transfusion either for anemia or for hyperbilirubinemia.

Issue for Referral

Most patients with severe, acute hemolysis or an underlying chronic hemolytic disorder will need to be evaluated by a hematologist.
Suspected RBC membrane and enzyme defects, as well as hemoglobinopathies, should be referred for initial evaluation.

Inpatient Consideratons

Unstable vital signs with acute hemolysis, significant exacerbation of chronic hemolysis

Ongoing Care

Follow-Up Recommendations

Patient Monitoring

May need ICU for unstable vital signs
Inpatient care may be required until acute hemolysis slowed or stopped.
Monitor CBC, reticulocyte, LFTs every 3 to 7 days until at baseline.

Diet

Avoid food triggers of hemolysis for G6PD-deficient patients.

Patient Teaching

Sign and symptoms of hemolysis, splenic palpation; learn to identify and avoid triggers of hemolysis.

Prognosis

Generally excellent with early recognition and intervention when warranted

Complications

Severe, especially if acute, hemolysis may cause cardiovascular insufficiency and/or compromise.
Chronic hemolysis may lead to gallstones, acute cholecystitis, and require cholecystectomy and/or splenectomy.
TTP may recur although frequency is hard to predict.

Additional Reading

Gallagher PG. Update on the clinical spectrum and genetics of red blood cell membrane disorders. Curr Hematol Rep. 2004;3(2):85–91. [PMID:14965483]
Lo L, Singer ST. Thalassemia: current approach to an old disease. Pediatr Clin North Am. 2002;49(6):1165–1191. [PMID:12580361]
Maisels MJ, Kring E. The contribution of hemolysis to early jaundice in normal newborns. Pediatrics. 2006;118(1):276–279. [PMID:16818575]
Old JM. Screening and genetic diagnosis of haemoglobin disorders. Blood Rev. 2003;17(1):43–53. [PMID:12490210]
Perkins SL. Pediatric red cell disorders and pure red cell aplasia. Am J Clin Pathol. 2004;122:S70–S86. [PMID:15690644]
Shah S, Vega R. Hereditary spherocytosis. Pediatr Rev. 2004;25(5):168–172. [PMID:15121908]

Codes

ICD-9

282.7 Other hemoglobinopathies
283.0 Autoimmune hemolytic anemias
774.0 Perinatal jaundice from hereditary hemolytic anemias
773.1 Hemolytic disease of fetus or newborn due to ABO isoimmunization
999.89 Other transfusion reaction

ICD-10

D58.2 Other hemoglobinopathies
D59.1 Other autoimmune hemolytic anemias
P58.9 Neonatal jaundice due to excessive hemolysis, unspecified
P55.1 ABO isoimmunization of newborn
P58.8 Neonatal jaundice due to other specified excessive hemolysis
T80.89XA Oth comp fol infusion, transfuse and theraputc inject, init

SNOMED

73320003 Hemolysis (finding)
413603009 Autoimmune hemolytic anemia (disorder)
80141007 Hemoglobinopathy (disorder)
32858009 Hemolytic disease of fetus OR newborn due to ABO immunization
387705004 Hemolytic disease of fetus OR newborn due to isoimmunization (disorder)

FAQ

Q: When are blood transfusions indicated in patients with active hemolysis?
A: Patients with severe, acute hemolysis that is causing cardiovascular compromise may require a transfusion if the process cannot be stopped with standard therapy (e.g., steroids for warm autoimmune hemolytic anemia, plasmapheresis for TTP). Transfusions must be given slowly if the hemolytic process has been chronic and the patient’s blood volume is expanded.
Q: Can hemolysis always be identified on a peripheral blood smear?
A: No. Schistocytes, fragments, spherocytes, targets, and other morphology may provide clues to specific diagnoses but are not always present. The presence of a hemolytic process is inferred from a fall in hemoglobin, rise in the reticulocyte count, and elevation of the bilirubin and LDH levels.

Authors

Julie W. Stern, MD