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Hemolytic anemic



Extra Edge: 

Hemolysis is said to occur when the mean RBC survival is less than 120 days


Important Points :

  1. All intracorpuscular causes of hemolysis are inherited (Hemoglobinopathy, Enzyme defects, membrane defects)  except PNH which is due to acquired somatic mutation (LQ 2012)
  2. All extracorpuscular causes of hemolysis are acquired except heredity hemolytic uremic syndrome (where there is excess compliment activation)


Table - Classification of Hemolytic Anemias
  Intracorpuscular Defects Extracorpuscular Factors
Hereditary Hemoglobinopathies Familial hemolytic uremic syndrome (HUS)
  Membrane-cytoskeletal defects  
Acquired PNH Mechanical destruction (microangiopathic)
    Toxic agents
Important Points:
Table - General Features of Hemolytic Disorders
General examination Jaundice, pallor
Other physical findings Spleen may be enlarged; bossing of skull in severe congenital cases
Hemoglobin From normal to severely reduced
MCV, MCH Usually increased
Reticulocytes Increased
Bilirubin Increased (mostly unconjugated)
LDH Increased (up to 10X normal with intravascular hemolysis) 
Haptoglobin Reduced to absent

Important Points: Features of hemolytic anemia
  1. Reticulocyte count (Most important criteria) 
  2. ↑ Unconjugated bilirubin  
  3. ↑ LDH            
  4. Splenomegaly can lead to hypersplenism which can cause = ↓ TLC, thrombocytopenia
  5. Hypercellular BM
  6. Hb level is reduced  
  7. MCH ↑, MCV ↑
  8. Urobilinogen +
  9. P/S polychromasia increase nucleated RBC, Macrocytes. 
  10. Erythroid hyperplasia in marrow (Meyloid erythroid ratio is decreased)
  11. Cr 51 labeled RBC is used to assess the life span.
  12. Gall stone (Pigment)  
  13. Intra vascular hemolysis → Hemoglobinuria can cause → Hemosiderinuria → IDA
  14. Extra vascular hemolysis = Blood Transfusion → Fe overload → Secondary Hemochromatosis can cause CHF
Important Points::
Compensated Hemolytic anemia = Hemoglobin normal = due to increase erythropoietin
Decompensate (Hb reduced) a. Pregnancy b. Renal failure c. Folic acid deficiency d.  Parvo virus infection

Important Points::
  1. The increase or decrease of one cell lineage (myeloid vs. erythroid) compared to another is obtained by a differential count of nucleated cells in a bone marrow smear [the myeloid/erythroid (M/E) ratio].
  2. A patient with a hypoproliferative anemia and a reticulocyte production index < 2 will demonstrate an M/E ratio of 2 or 3:1.
  3. In contrast, patients with hemolytic disease and a production index > 3 will have an M/E ratio of at least 1:1. Maturation disorders are identified from the discrepancy between the M/E ratio and the reticulocyte production index
  4. As haptoglobin is indeed an acute-phase protein, any inflammatory process (infection, extreme stress, burns, major crush injury, allergy, etc.) may increase the levels of plasma haptoglobin.
Extra Edge: Hemoglobinopathies including thalassemia cause extravascular hemolysis
Causes of intravascular hemolysis Causes of extravascular hemolysis
  1. Blood transfusion
    1. ABO mismatched transfusion
  2. Thermal burns
  3. Snake bites
  4. Sepsis
    1. Bacterial/parasitic infections
    2. Clostridial sepsis
    3. Malaria
    4. Mycoplasma pneumoniae
  5. Mechanical heart valves
  6. Paroxysmal hemoglobinuria
    1. PNH
    2. PCH
  7. Favism
  8. March hemoglobinuria (LQ 2012)
  9. Microangiopathic
  1. Drug-induced hemolysis
    1. G6PD deficiency
    2. Autoimmune drug reactions
    3. Strong oxidant drugs/chemicals
  2. Autoimmune hemolysis
    1. Warm-reacting (IgG) AIHA
    2. Cold-reacting (IgM) AIHA
  3. Hemoglobinopathies
    1. Thalassemia
  4. Membrane structural defect
  1. Hereditary spherocytosis
  2. Acanthocytosis
  1. Environmental disorders
  1. Malignancy / DIC, TTP, HUS
  2. - Eclampsia or Preeclampsia

In burns patient reduced free haptoglobin levels are masked by increase production (AIIMS Nov 09)

Difference between intravascular and extravascular hemolysis
Features Intravascular hemolysis Extravascular hemolysis
Hemoglobinemia Θ
Hemoglobinuria Θ
Hemosiderinuria Θ
Heptoglobin ↓↓
Hemopexin ↓↓
Methemoglobinemia Θ
Meth-albuminemia Θ
S. bilirubin (unconjugated) ↑↑↑
LDH ↑↑↑
S. ferritin (n) or ↑
Tissue iron (n) or ↑
Iron def anaemia May be present No

Microangiopathic HA due to problem in Blood vessel
(Fragmented RBC) Helmet cell, Burr cell, Schistocyte
Causes: a. HUS b. TTP c.  Prosthetic Metallic valve,  d. Malignant Hypertension, e. SLE.
Important Points: Spur cell anemia = hemolytic anemia occurring in hepatocellular disease.

Important Points:: Causes of HA


  1. Membrane abnormalities (hereditary spherocytosis, hereditary elliptocytosis, acanthocytosis, stomatocytosis)
  2. Hemoglobin abnormalities (thalassanemias, hemoglobin S, C, D)
  3. Red cell enzyme defects (G6PD, pyruvate kinase, hexokinase, glutathione reductase deficiency).


A. Immune

  1. Isoimmune        
  2. Autoimmune
  1. Warm antibody type (Ig G)
    Idiopathic, SLE, lymphoma, chronic lymphatic leukemia, ovarian teratoma, Evan’s syndrome, drug – methyl dopa.
  1. Cold antibody type (Ig M)
    Cold hemagglutinin disease, paroxysmal cold hemoglobinuria (PCH), mycoplasma pneumonia, lymphoma, infectious mononucleosis, SLE, viral infections,
  1. Drug related
    1. Drug adsorbed onto RBC surface: penicillin, cephalosporins
    2. Immune complex mediated: Sulphonamide, quinidine
  2. Alloimmune (antibodies acquired by blood transfusions, or pregnancy, directed against transfused RBCs).
  1. Nonimmune
  1. Mechanical (artificial valves, burns, march hemoglobinuria)
  2. Infection (malaria, Clostridium welchii, bartonellosis) Q
  3. Drugs (sulfonamide, snake venom – viper, nitrofurantoin )
  4. Dyserythropoietic (paroxysmal nocturnal hemoglobinuria) Q.
  5. Shiga toxin–producing Escherichia coli O157:H7, Clostridium perfringens sepsis


  1. Blood film shows polychromasia, macrocytosis, spherocytes (hereditary spherocytosis) Q, elliptocytes, sickles cells (sickle cell anemia Q), target cells (thalassanemias Q).
  2. Direct Coombs’s test: This test identifies red cells coated with antibody and/or complement Q and a positive result usually indicates an immune cause for the hemolysis.
  3. Life span of RBC: This is determined by chromium labelling and the major site of RBC breakdown may also be identified.
  4. Urinary hemosiderin: The presence of this indicates intravascular hemolysis Q.
  5. Other tests: Increased serum bilirubin (usually does not exceeds 6 mg%), indicate intravascular hemolysis, increased LDH, decreased haptoglobin and increased urinary urobilinogen suggest hemolytic Q jaundice.
Important Point:
  1. Haptoglobin levels that are decreased but do not accompany signs of anemia may indicate liver damage, as the liver is not producing enough haptoglobin to begin with. (AIIMS Nov 09)
  2. As haptoglobin is indeed an acute-phase protein, any inflammatory process (infection, extreme stress, burns, major crush injury, allergy, etc.) may increase the levels of plasma haptoglobin.
Mechanical Red Cell Fragmentation Syndrome
Macro angiopathic (Large vessel) Microangiopathic (Small vessel)
1.  Direct Red Cell trauma from an abnormal vascular surface.
a.  Prosthetic Heart Valves
b.  Synthetic vascular grafts
2.  Large vessel disorders that may cause shearing of Erythrocytes
a.  Cavernous Hemangioma (Kasabach-Merritt syndrome)
1.  Abnormalities in microcirculation that cause turbulent blood flow.
2.   DIC
3.   TTP
4.   HUS
5.   Vasculitis (Collagen Vascular Disorders)
6.   Malignant hypertension / Eclampsia
7.   Disseminated carcinomatosis (Metastasis)
8.   Drugs / Radiation
9.   Antiphospholipid syndrome

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