Causes of Anemia/Autoimmune Hemolytic Anemia

I. Review Broad Classification Schemes for Anemia
Two ways to think about anemia, Destruction/Blood Loss vs Underproduction

A.  Destruction/Blood Loss
1.  Blood Loss - bleeding (GIB, menstruation, trauma, etc).
2.  Hemolysis
a)  Intrinsic Causes – something structurally wrong with the RBC or hemoglobin, that predisposes to hemolysis

• Glucose-6-phosphate dehydrogenase
• Sickle Cell Anemia
• Thalassemias
• Hereditary Spherocytosis
• Paroxysmal Nocturnal Hemogloburia

b)  Extrinsic Causes

• Autoimmune Hemolytic Anemia
• Infections – Malaria, Babesiosis
• Microangiopathic Hemolytic Anemias – DIC, TTP-HUS
• Hypersplenism
• Traumatic (e.g. shearing from mechanical valve)

 

B.  Underproduction
Here, the morphological approach based on MCV is helpful, although many of these overlap with things in the increased destruction category
1.  Microcytic (MCV < 80) = TICS (Thalassemias, Iron Deficiency, Chronic Disease, Sideroblastic  Anemia)

2.  Macrocytic (MCV >100) - I love my mnemonic HALF MD (which I made up when was I was half of an MD in 3rd year of medical school).

• Hypothyroidism
• Alcoholism
• Liver disease
• Folate/B12 deficiency – Megaloblastic anemia
• Myelodysplastic Syndrome
• Drugs – e.g. AZT and other drugs that interfere with folate metabolism (5-FU, Methotrexate)
• Unfortunately, this mnemonic does not include Reticulocytosis which is a very common cause of macrocytosis (since reticulocytes are bigger than mature RBCs).

3.  Normocytic (MCV 80-100) – Anemia of Chronic Disease and basically everything else

 

 

II.  Overview of Autoimmune Hemolytic Anemia
AIHA refers to acquired, antbody-mediated RBC destruction.
A.  Warm Antibody AIHA:

• Mechanism - Abs opsonize RBCs at body temperature, and RBCs are removed by the reticuloendothelial system (mainly the spleen). 
• Often idiopathic, but can be due to: viral infections, autoimmune diseases (SLE), malignancies of immune system (CLL etc), prior HSCT, and drugs (cephalosporins, PCN, NSAIDs, quinine derivatives)
•  See spherocytes on smear (due to RBC membrane deformity)
• Potive direct coombs for IgG +/- C3
• Can be associated with venous thromboembolism
• Treatment: Initial treatment with corticosteroids, if poorly responsive or resistant disease, consider elective splenectomy.  For patients unwilling or unable to undergo splenectomy, or for those who have failed or relapsed following splenectomy, consider other immunosuppressive or cytotoxic agents (ie. rituximab, azathioprine, cyclophosphamide, cyclosporine). There is insufficienct information from RCTs to choose one of these agents over another.

B.  Cold Antibody AIHA:

•  Mechanism: IgM's that agglutinate at cold temperatures (<37 degrees), which leads to complement fixation and intravascular hemolysis (as opposed to warm Ab AIHA where RBCs are removed by the spleen).
•  See anti C3-d on direct coombs
• Often associated with malignancy (CLL, lymphoma, etc) or infection (mycoplasma, mononucleosis)
• Treatment is usually directed at the underlying cause (ie. infection) and avoidance of cold triggers.  In contrast to warm ab AIHA, steroids are generally ineffective, and more commonly hematologists will jump to other immunosuppressants like Rituximab. 

 

 

 

Overview of Evans syndrome (Coombs’-positive autoimmune hemolytic anemia and thrombocytopenia)

• AIHA: Results when IgG present which reacts with RBC antigens at room temperature
  • Causes: viral infections, autoimmune disease (e.g. SLE), immune deficiency, liquid tumors, post-hematopoietic stem cell transplant
  • Pathophysiology: IgG (and subsequently fixed complement) adhere to phagocytes, resulting in partial ingestion and creation of spherocytes, which are cleared by spleen
  • Direct complement lysis is rare, as this requires two IgG molecules to be bound to RBC (as opposed to one in IgM-mediated hemolysis)
• In Evans syndrome, antibody is directed against the Rh locus

 

• Treatment:
  • Steroids: induce remission in 2/3 of patients
  • If disease refractory to steroid taper, can initiate steroid-sparing immunosuppression
  • Splenectomy: equivalent efficacy to steroids
  • IVIG: only occasionally effective (unlike in ITP)
• Prognosis:
  • Often refractory so standard AIHA/ITP therapy, with more chronic, relapsing course
  • Following steroids and splenectomy, optimal therapy unclear
  • Responses in hemoglobin and platelets is often discordant - immune hemolysis may protect platelets, as spleen is saturated
  • Death often results from infection, cardiovascular complications, or underlying malignancy

 

 

(Christopher Woo MD, 6/9/11)

(Chanu Rhee MD, 5/16/11)