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

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]

CCC 700 6

Critical Care

Compendium

Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also the Innovation Lead for the Australian Centre for Health Innovation at Alfred Health and Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of two amazing children.

On Twitter, he is @precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

Leave a Reply

This site uses Akismet to reduce spam. Learn how your comment data is processed.