Haemolytic anaemia

Reviewed and revised 27 October 2016

OVERVIEW

Definition

• Haemolytic anaemia is anemia due to shortened survival of red blood cells (RBCs) in the circulation
• Normal RBC lifespan is about 120 days, therefore it is useful to think of hemolytic anemia as representing RBC survival of <100 days

Shortened lifespan can be due to RBC destruction from:

• intravascular or extravascular mechanisms
• immune or non-immune-mediated
• extrinsic causes or intrinsic RBC abnormalities

The approach to haemolytic anaemia involves:

• confirm haemolysis
• identify cause
• specific management

In the critically ill, always consider:

• ABO incompatibility due to recent transfusion
• Clostridium sepsis and malaria
• Medications causing an autoimmune response
• Extra-corporeal circuits

PATHOGENESIS

Haemolysis can occur intravascularly or extravascularly, or both

• intra-vascular haemolysis occurs inside the blood vessels
• extra-vascular haemolysis occurs in other parts of the body (e.g. spleen)
• causes may overlap and haemoglobin from extravascular haemolysis may still enter the circulation

Immune-mediated

•  binding of immunoglobulin molecules to the red cell surface is followed by interaction with monocytes and complement and removal of these erythrocytes
• Alloimmune haemolysis:
  • incompatibility of fetal/ neonatal RBCs with maternal RBCs (haemolytic disease of the newborn)
  • transfusion of incompatible RBCs
• Autoimmune haemolysis
  • host immune system becomes sensitized to its own red cell antigens
  • “warm” is IgG-mediated
  • “cold” is complement-mediated or IgG-mediated (e.g. PCH)
• haemolysis can occur both intravascularly and extravascularly

Non-immune

• results from physical destruction of RBCs through mechanisms such as shear stress, osmotic effects, thermal injury, infection, inflammatory responses or direct cellular trauma

DIFFERENTIAL DIAGNOSIS

INTRAVASCULAR

Immune

• ABO or Rhesus incompatibility
  • Haemolytic disease of the newborn (HDN)
  • Transfusion mismatch
• IgG-mediated “warm” autoimmune haemolytic anaemia (AIHA)
  • drugs e.g. methyldopa, penicillin, cephalosporins, erythromycin, probenecid, paracetamol and ibuprofen
  • autoimmune diseases e.g. antiphospholipid syndrome, SLE, Rheumatoid arthritis
  • lymphoproliferative diseases e.g. lymphoma, CLL
  • idiopathic
• “cold” AIHA
  • complement-mediated
    • Mycoplasma infection
    • EBV infection
    • lymphoproliferative diseases e.g. lymphoma, CLL
    • idiopathic
  • IgG-mediated targeting the P antigen
    • Paroxysmal cold hemoglobinuria (PCH) (Donath-Landsteiner syndrome; usually caused by an infection producing antibodies that cross-react with the P antigen on the RBC surface)

Non-immune

• mechanical
  • e.g. cardiac peri-prosthetic or peri-valvular leaks, intravascular devices (e.g. TIPS), extracorporeal circuits (e.g. ECMO, RRT)
• infection
  • e.g. severe sepsis, malaria (e.g. blackwater fever), Clostridium perfringens, babeosis
• hypotonic solutions and drowning
• toxins
  • e.g. heavy metals (e.g. lead, mercury, copper)
  • e.g. oxidants (e.g. causes of methemoglobinaemia), arsine gas, sodium chlorate
• Microangiopathic haemolytic anaemia (MAHA)
  • e.g. envenoming (e.g. australian elapid), malignancy, malignant hypertension, sisseminated intravascular coagulation (DIC), preeclampsia/ eclampsia
  • Thrombotic microangiopathy (MAHA, thrombosis and thrombocytopenia), e.g. HUS, TTP and HELLP
• Trauma
  • e.g. burns, footstrike hemolysis, March hemoglobinuria
• Liver disease
  • e.g.  Zieve’s syndrome due to alcoholic cirrhosis, Wilson’s disease

EXTRAVASCULAR

Intrinsic to the RBC (only PNH is acquired rather than congenital/ hereditary)

• enzyme abnormalities
  • G6PD deficiency (X-linked, African or Mediterranean descent, exposure to fava beans or drugs such as  dapsone, primaquine, nitrofurantoin, supportive Rx)
  • pyruvate kinase deficiency
• membrane abnormalities
  • hereditary spherocytosis
  • hereditary eliptocytosis
  • paroxysmal nocturnal hemoglobinuria
• hemoglobinopathies
  • sickle cell disease
  • thalassemia

Extrinsic to the RBC

• hypersplenism
  • portal hypertension from liver disease
  • myeloproliferative diseases
  • tropical splenomegaly syndrome

CLINICAL FEATURES

History

• Clinical presentation and findings (see below)
• Lifelong or family history?
• Ethnicity?
• Medication/drug precipitants  e.g. G6PD, AIHA?
• Acute versus chronic duration?
• Concomitant medical illnesses?
• Recent or current blood transfusion?
• Recent fever or travel?

Examination

• New onset of pallor and anemia
• Jaundice
• Gallstones
• Splenomegaly
• +/- hepatomegaly

INVESTIGATIONS

Confirm haemolysis

• Increased
  • absolute reticulocyte count
  • LDH (elevation is more pronounced in intravascular haemolysis)
  • Indirect Bilirubin (i.e. unconjugated)
  • Plasma free haemoglobin (PFHb)
• Decreased
  • Haptoglobin (intravascular haemolysis)
• Urine
  • Haemoglobin
  • Haemosiderin (useful in the diagnosis of intravascular haemolysis)

Identify cause (history + peripheral blood film are the keys)

• FBC (thrombocytopenia? abnormal WCC?)
• Blood film
  • spherocytes (AIHA, hereditary spherocytosis)
  • helmet cells
  • blister cells (oxidative damage in G6PD deficiency)
  • schistocytes (TTP or DIC with thrombocytopenia) or heart valve hemolysis (with thrombocytopenia)
  • acanthocytes (liver disease)
  • Heinz bodies (oxidative stress in G6PD deficiency, liver disease, thalassemia, splenectomy)
• G6PD deficiency
  • history of drug + at risk ethnic group
  • Heinz body prep
  • G6PD level once Hb normalises
• Direct antiglobin test (Coombs)
  • warm or cold IgG antiglutinin-mediated autoimmune hemolytic anaemia (AIHA) (can be negative if massive haemolysis)
• Coagulation profile (distinguishes DIC, from HUS, HELLP, TTP, MAHA etc)
  • D-dimer, fibrinogen, INR, aPTT
• UEC (renal failure in MAHA, HUS and TTP)
• ADAMTS13 level (TTP)
• If recent or current blood transfusion send donor and recipient blood for repeat group, screen and cross-match
• Donath–Landsteiner test (PCH)
• Peripheral blood flow cytometry (PNH)
• free Hb (ECMO, LVAD to check for hemolysis)

MANAGEMENT

• Resuscitation
• Treat underlying cause and complications
  • remove precipitants
  • blood product replacement (not platelets in TTP!)
  • immunosuppression for AIHA
    • Plasmapheresis (temporary improvement of fulminant acute haemolysis, does not treat the underlying autoantibody production)
    • Rituximab(CD20 monoclonal antibody; used for warm AIHA, may be effective in cold AIHA due to B-cell dominant lymphoproliferative disorder)
    • Eculizumab (monoclonal C5 antibody; case reports in AIHA – also used for atypical HUS and PNH)
  • warm AIHA
    • corticosteroids (first line; decrease IgG production)
    • splenectomy (second line; site of antibody production and macrophage mediated clearance of antibody bound RBCs)
    • cyclophosphamide or azathioprine (third line)
    • role of IV Ig is uncertain (used in case reports)
    • danazol (synthetic steroid, used previously)
  • cold AIHA
    • keep patient and fluids warm – avoidance of cold prevents haemolysis
    • splenectomy and corticosteroids are ineffective
  • consider splenectomy for extravascular causes
• Supportive care
• Haematology consult

References and Links

LITFL

• LITFL CCC — Anaemia
• LITFL CCC — Blood film

Journal articles

• Barcellini W, Fattizzo B. Clinical Applications of Hemolytic Markers in the Differential Diagnosis and Management of Hemolytic Anemia. Disease markers. 2015:635670. 2015. [pubmed]
• Lechner K, Jäger U. How I treat autoimmune hemolytic anemias in adults. Blood. 116(11):1831-8. 2010. [pubmed]
• Packman CH. The Clinical Pictures of Autoimmune Hemolytic Anemia. Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie. 42(5):317-24. 2015. [pubmed]
• Pan KC, McKenzie DP, Pellegrino V, Murphy D, Butt W. The meaning of a high plasma free haemoglobin: retrospective review of the prevalence of haemolysis and circuit thrombosis in an adult ECMO centre over 5 years. Perfusion. 31(3):223-31. 2016. [pubmed]
• Simon TG, Bradley J, Jones A, Carino G. Massive intravascular hemolysis from Clostridium perfringens septicemia: a review. Journal of intensive care medicine. 29(6):327-33. 2014. [pubmed]