This document discusses approaches to extracorpuscular hemolytic anemia. It begins by defining extracorpuscular anemias as defects in which red blood cells are normal but destroyed due to mechanical, immunologic, infectious, or metabolic/oxidant damage. It then covers the etiology of non-immune and immune hemolytic anemias, including infections, mechanical factors like prosthetic valves, chemicals/drugs, and autoimmune disorders. Warm and cold agglutinin diseases are described as types of autoimmune hemolytic anemia. The document concludes by covering non-immune causes such as mechanical heart valves, burns, and microangiopathic anemias.

1. Approach to Extracorposcular Hemolytic
Anemia
Dr. Bikal Lamichhane
Internal medicine resident

2. Extracorpuscular defects
 those in which the RBCs are normal but are destroyed due to
 mechanical
 immunologic
 Infectious
 metabolic/oxidant damage.
These abnormalities are almost always acquired.
Exception is familial hemolytic-uremic syndrome (HUS; often referred
to as atypical HUS).

3. Etiology:-

4. Non-immune
Infection
•Intracellular organisms, e.g.
malaria
•Toxins, e.g. C. perfringens
Mechanical
•Prosthetic valves
•Microangiopathic, e.g. DIC,
HUS, TTP
•March haemoglobinuria
Chemical/physical
•Oxidative drugs,e.g. dapsone,
maloprim
•Copper (Wilson’s disease)
•Burns
•Drowning

5. Immune Hemolytic Anemias
 can arise through at least two distinct mechanisms.
1.when an antibody directed against a certain molecule (e.g., a drug)
reacts with that molecule, red cells may get caught in the reaction (the
so-called innocent bystander mechanism)
2.a true auto-antibody is directed against a red cell antigen, i.e., a
molecule present on the surface of red cells .

6.  Based on the Coombs test findings as well as on
the thermal characteristics and the antigenic specificities of the
autoantibodies. AIHA has been classified into subtypes.

7.  Warm Antibody AIHA
 more common type of AIHA.
 the auto-antibody reacts best at 37°C
 may be seen in isolation (and it is then called idiopathic) or as part of
a systemic auto-immune disorder such as systemic lupus
erythematosus (SLE)
 May be seen in chronic lymphocytic leukemia (CLL), after BMT; and
after solid organ transplantation entailing immuno-suppressive
treatment.
 As a side effect of the use of immune checkpoint inhibitors, such as
nivolumab, in patients with various types of cancer

8.  Once a red cell is coated by an autoantibody
 In most cases, the Fc portion of the antibody
will be recognized by the Fc receptor of macrophages, and this will
trigger erythrophagocytosis.
 Thus, destruction of red cells will take place wherever macrophages
are abundant, i.e., in the spleen, liver, and bone marrow.
 Spleen is the predominant site of red cell destruction.

9.  COLD AGGLUTININ DISEASE
 AIHA that usually affects the elderly.
 1. CAD is characteristically a chronic condition—in contrast to the abrupt
onset of warm antibody AIHA.
 Mediated by antibodies, usually IgM, which bind to the red cells at low
temperatures and cause them to agglutinate.
 May cause intravascular haemolysis if complement fixationoccurs.
 Can be chronic when the antibody is monoclonal,or acute or transient when
the antibody is polyclonal.

10.  The term cold refers to the fact that the autoantibody involved reacts with
red cells poorly or not at all at 37°C, whereas it reacts strongly at lower
temperatures.
 As a result, hemolysis is more prominent the more the body is exposed to
the cold.
 The antibody is usually IgM; usually it has
an anti-I specificity (the I antigen is present on the red cells of almost
everybody), and it may have a very high titer (1:100,000 or more has
been observed).
 The antibody is produced by an expanded B lymohocyte clone (a low-grade
mature B cell lymphoma) and sometimes the antibody concentration in the
serum is high enough to show up as a spike in plasma protein
electrophoresis, i.e., as a monoclonal gammopathy.

11. 

12.  Alloimmune haemolytic anaemia

Alloimmune haemolytic anaemia is caused by antibodies against
non-self red cells. It has two main causes, occurring after:

• unmatched blood transfusion.

• maternal sensitisation to paternal antigens on fetal cells
(haemolytic disease of the newbor).

13.  Non-immune haemolytic anaemia
• Mechanical heart valves. High flow through incompetent
valves or periprosthetic leaks through the suture ring
holding a valve in place result in shear stress damage.
• March haemoglobinuria. Vigorous exercise, such as
prolonged marching or marathon running, can cause red
cell damage in the capillaries in the feet.
• Thermal injury. Severe burns cause thermal damage to red
cells, characterised by fragmentation and the presence of
microspherocytes in the blood.

14. Microangiopathic haemolytic anaemia.
 Fibrin deposition in capillaries can cause severe red cell disruption.
 It may occur in a wide variety of conditions:
 Disseminated carcinomatosis,
 malignant or pregnancy-induced hypertension,
 haemolytic uraemic syndrome
 thrombotic thrombocytopenic purpura and
disseminated intravascular coagulation

15. Infection
 Plasmodium falciparum malaria .
 may be associated with intravascular haemolysis;
 Clostridium perfringens sepsis usually in the context of ascending
cholangitis or necrotising fasciitis, may cause severe intravascular
haemolysis with marked spherocytosis due to bacterial production
of a lecithinase that destroys the red cell membrane

16.  Chemicals or drugs
Dapsone and sulfasalazine cause haemolysis by oxidative
denaturation of haemoglobin.
 Denatured haemoglobin forms Heinz bodies in the red cells, visible
on supravital staining with brilliant cresyl blue.
 Arsenic gas, copper, chlorates, nitrites and nitrobenzene derivatives
may all cause haemolysis

17. Thank you