Haemolytic Anaemia

Created on Mon, 06/29/2015 - 02:41
Last updated on Fri, 07/08/2016 - 01:17

Autoimmune haemolysis had been the subject of Question 11.2 and Question 11.3 from the first paper of 2012. Also, Question 7.1 from the first paper of 2016 presented a case of warm haemolysis with spherocytosis.

Clinical and laboratory features of autoimmune haemolysis

The distinction here is autoimmune destruction of RBCs, as opposed to some other (usually mechanical) process.  Some of the historical features suggestive of mechanical or extravascular haemolysis are listed below:

  • Recent fevers, recent travel (haemolysis is due to a viral haemorrhagic fever or malaria)
  • Recent septic shock (haemolysis is the consequence of DIC)
  • Valve pathology or valve replacement i.e. the cells were broken by shear stress in a mechanical aortic valve
  • Exposure to extracorporeal circuit  i.e. the cells were shredded by the centrifugal pump of ECMO.
  • Splenomegaly: a cause of extravascular haemolysis
  • Features of arterial insufficiency, including leg ulcers (eg. in sickle cell anaemia)

Features of history associated with autoimmune haemolysis

  • Recent blood transfusion (haemolysis is due to a transfusion reaction)
  • Recent fevers, recent travel (haemolysis is due to a viral haemorrhagic fever or malaria)
  • Recent septic shock (haemolysis is the consequence of DIC)
  • Recent commencement of a new medication (drug-inducd haemolysis is caused by 5-FU, methyldopa, quinine, diclofenac, penicillin, cephalosporins, and many others).
  • History of pigmented galstones: suggests chronic haemolysis
  • History of recent infection:  many of the causes listed in the table below are post-infectious
  • History of "stress", eg. for patients with G6PD (this could be surgery, infection, or exposure to an oxidant. Classically, fava beans are mentioned.
  • Weight loss, night sweats, and other features suspicious of haematological malignancy
  • Arthralgia is mentioned in Question 7.1 from the first paper of 2016, and may represent an autoimmune disease such as SLE, or an infective process such as Bartonella.

Features of physical examination

  • Jaundice is mandatory: bilirubin is raised.
  • Dark urine suggests conjugated bilirubin is present in excess; whereas jaundice in the absence of pigmented urine suggests that the bulk of the bilirubin is unconjugated. Theoretically, haemolysis should give rise to a predominantly unconjugated hyperbilirubinaemia, but provided you have a healthy liver this is almost never seen. Usually some fraction of conjugated bilirubin is present, and ends up appearing in the urine. 

Laboratory features common to all haemolytic anaemias

  • Morphologic RBC abnormalities: such as spherocytosis or fragmented RBCs, as well as pathognomonic erythrocytes such as sickle cells.
  • High reticulocyte count: because a normal bone marrow responds to anaemia by ramping up the production of RBCs.
  • High LDH:  lactate dehydrogenase is an enzyme which leaks out of pretty much any damaged cells, and so is not specific for haemolysis. However, nor is bilirubin. Regardless, the college will expect you to mention both in an exam answer.
  • Haptoglobin: the protein responsible for iron transport will usually be low when there is too much iron to transport. It is also an acute phase reactant, which means it does not necessarily have to be low in the presence of haemolysis.
  • Free haemoglobin will be elevated as it spills out of RBCs. There may even be haemoglobinuria.

Laboratory features specific to autoimmune causes of haemolytic anaemia

  • DAT, direct antiglobulin test or direct Coombs Test, demonstrates that the RBCs are coated with antibody and/or complement. Question 7.1 from the first paper of 2016 offers us a DAT which is positive for IgG as well as C3d, unequivocally identifying an autoimmune cause for the haemolysis. An excelent resource which explains DAT is an article by Zantek et al (2012).
  • DAT helps discriminate between a  "warm" and a "cold" haemolytic anaemia.
  • When haemolysis is "warm", the autoimmune haemolytic anaemia is caused by antibodies maximally active at human body temperature, and this is usually caused by IgG. The DAT comes back positive for both IgG and C3d, the latter being a complement product
  • Hamolysis caused by IgM usually occurs in cold conditions, and the DAT comes back positive for C3d but not IgG.

Causes of autoimmune haemolytic anaemia

So, you're haemolysing. Why are you doing that? A good overview of this topic can be found in the American Journal of Haematology. Their breakdown of the classifications of haemolytic anaemia looks a little like the table offered below. Generally, people tend to classify them according to the effects of teperature on antibody reactivity.

Differential Causes of Autoimmune Haemolytic Anaemia
Warm haemolytic anaemia  Cold haemolytic anaemia
  • Idiopathic primary haemolytic anaemia
  • Viral infections, including HIV
  • Drugs, eg. penicillin, methyldopa, 5-FU, diclofenac, etc...
  • Lymhoproliferative disorders:
    • CLL
    • Lymphoma
    • Multiple myeloma
    • Hodgkins lymphoma
    • Waldenstrom's macroglobulinaemia
  • Autoimmune disorders, particularly SLE and rheumatoid arthritis
  • Post-infectious colad agglutinin disease
    • Syphilis
    • Post-viral
    • Mycoplasma pneumoniae
    • EBV, VZV, CMV, HIV
    • Adenovirus
    • Influenza viruses
  • Paroxysmal cold haemoglobinuria
    • Idiopathic
    • Virus-associated (EBV, CMV, etc)

Management of autoimmune haemolysis

"How I treat autoimmune hemolytic anemias in adults" by Lechner and Jäger, who presumably treat it in the same way. In brief, warm haemolysis benefits from steroids and splenectomy, whereas cold haemolysis does not.

Generic management of autoimmune haemolysis

  • Plasmapheresis is only indicated in fulminant acute haemolysis. Only a temporary improvement is to be expected, as this treatment does nothing to treat the underlying autoantibody production.
  • Rituximab, a CD20 monoclonal antibody, has been effective in cases of cold haemolytic anaemia where a B-cell dominant lymphoproliferative disorder is at fault. It seems to be more effective in warm haemolysis.
  • Eculizumab, a terminal complement inhibitor (monoclonal C5 antibody) has been found effective in various case reports (eg. Kim et al, 2016), even though it is indicated only for atypical HUS and paroxysmal nocturnal haemolobinuria.

Specific management of warm haemolysis

  • Corticosteroids appear to be effective as the first-line treatment. Among other thngs, the steroids reduce the synthesis of autoantibodies by B-cells.
  • Splenectomy is the second-line treatment. The spleen's macrophages are responsible for removing IgG-coated RBCs; also the spleen is a site of antibody production.
  • Cyclophosphamide / azathioprine  are reserved for those who fail steroids and splenctomy (or cannot have a splenectomy).
  • IV immunoglobulin is not strongly indicated: some reports show benefit, others don't.
  • Danazol, a synthetic steroid derivative of ethisterone, is very old school (Pignon et al, 1993) - it is mentioned in the college answer to Question 7.1 from the first paper of 2016. It is usually used for endometriosis.

Specific management of cold haemolysis

  • Avoid cold exposure! Without cold, there is no haemolysis.
  • Forget corticosteroids.They are rarely useful.
  • Forget splenectomy. It has no positive effect.

 

References

Zeerleder, S. "Autoimmune haemolytic anaemia-a practical guide to cope with a diagnostic and therapeutic challenge." Neth J Med 69.4 (2011): 177-84.

Gehrs, Bradley C., and Richard C. Friedberg. "Autoimmune hemolytic anemia."American journal of hematology 69.4 (2002): 258-271.

Birgens, Henrik, et al. "A phase III randomized trial comparing glucocorticoid monotherapy versus glucocorticoid and rituximab in patients with autoimmune haemolytic anaemia." British journal of haematology 163.3 (2013): 393-399.

Lechner, Klaus, and Ulrich Jäger. "How I treat autoimmune hemolytic anemias in adults." Blood 116.11 (2010): 1831-1838.

Salama, A., and B. Mayer. "Diagnostic pitfalls of drug-induced immune hemolytic anemia." Immunohematology 30.2 (2014): 80-4.

Zantek, Nicole D., et al. "The direct antiglobulin test: a critical step in the evaluation of hemolysis." American journal of hematology 87.7 (2012): 707-709.

Ma, Kim, and Stephen Caplan. "Refractory IgG Warm Autoimmune Hemolytic Anemia Treated with Eculizumab: A Novel Application of Anticomplement Therapy." Case reports in hematology 2016 (2016).

Pignon, Jean‐Michel, Emmanuelle Poirson, and Henri Rochant. "Danazol in autoimmune haemolytic anaemia." British journal of haematology 83.2 (1993): 343-345.