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  1. I/V hemolysis                  
  2. Pancytopenia                 
  3. Increase risk of venous thrombosis
PNH occurs in patients who are unable to bind the regulatory proteins, DAF(CD 55),, HRF or MIRL(CD 59)  on their red cell surfaces. Spontaneous complement – mediated lysis of erythrocytes occurs.
  1. Hemolysis in PNH is due to an intrinsic abnormality of the red cell, which makes it exquisitely sensitive to activated complement, whether it is activated through the alternative pathway or through an antigen-antibody reaction.
  2. The former mechanism is mainly responsible for intravascular hemolysis in PNH.
  3. The latter mechanism explains why the hemolysis can be dramatically exacerbated in the course of a viral or bacterial infection.
  4. Hypersusceptibility to Complement is due to deficiency of several protective membrane proteins, of which CD59 is the most important because it hinders the insertion of C9 polymers into the membrane.
  5. The molecular basis for the deficiency of these proteins is due to the shortage of a unique glycolipid molecule, GPI, which, through a peptide bond, anchors these proteins to the surface membrane of cells.
  6. The shortage of GPI is due in turn to a mutation in an X-linked gene, called PIG-A, required for an early step in GPI biosynthesis.
In these patients GPI linked protein CD59, CD55, which are Surface protein are deficient. Normally these proteins protect
RBC from complement

Two kinds of membrane proteins: transmembrane and glycosyl phosphatidyl inositol (GPI)-linked. The latter are anchored to cell membranes through a covalent attachment to a glycosyl phospatidyl inositol moiety. In PNH, GPI cannot be synthesized, leading to a global deficiency of GPI-linked membrane protein

Clinical Features of P.N.H.
  1. Intravascular hemolysis
  1. Most of the clinical features of P.N.H. can be attributed to intravascular hemolysis. The hemolysis is paroxysmal and usually occurs in the night.
  2. During sleep at night, we all tend to Retain CO2 leading to mild respiratory acidosis the pH of the blood gets slightly reduced, low pH leads to activation of the complement
  3. Activation of the complement in turn causes intravascular hemolysis, leukopenia, thrombocytopenia (Pancytopenia)
  4. This is also the basis for Ham's acidified serum test which is used to diagnose P.N.H. When the blood is placed in acidic medium, it undergoes hemolysis.
  5. Splenomegaly is not a feature.
  1. Thrombosis (LQ 2012)
  1. Platelets are decreased in P.N:H. But 'despite the presence of thrombocytopenia, PNH is associated with increase incidence of thrombosis.
  2. Budd Chiari syndrome is one of the common clinical manifestations of thrombosis, it occurs due to hepatic vein thrombosis. Ascites with Acute hepatomegaly with pain abdomen, with out previous liver disease

Diagnosis of PNH
(1) HAMS test                     
(2) Sucrose lysin test                          
(3) Flow cytometry
  1. Flow cytometry is the Gold standard in diagnosis. Analysis GPI linked proteins CD 59, DAF
  2. Bone Marrow in P.N.H.
    1. Normoblastic hyperplasia is the characteristic finding in P.N.H. (Pancytopenia with normoblastic hypercellular BM)
    2. Important Points:: Normoblastic hyperplasia is a feature of PNH. At some stage of disease BM may become hypocellular or even aplastic (25%cases – aplastic) (LQ 2012)
  3. Leucocyte Alkaline Phosphatase in P.N.H.
    1. The level of neutrophil alkaline phosphatase is decreased in P.N.H. (LQ 2012)
      a. Hb↓   
      b. MCV↑
  4. HAM test is based upon susceptibility of RBC’s to complement mediated lysis in patients with PNH. In acidified serum complement is activated by the alternate pathway.
Extra Edge: 

Causes of hypercellular marrow with pancytopenia (LQ 2012)

  1. PNH
  2. Myelodysplasia
  3. Some cases of acute leukemias
  4. Paraneoplastic syndrome specially in CA lung


Complication: AML can occur in 10% cases

Natural History of PNH
  1. Aplastic anemia can occur          
  2. AML can occur                              
  3. Spontaneous recover can occur but it rare
Causes of Death:
  1. Venous thrombosis                       
  2. Infection                           
  3. Bleeding
Note (Most common cause of death in PNH is cortical vein thrombosis)

Treatment: FA, Blood transfusion, BMT

Recent Advances: New Drug Eculizumab
Eculizumab is a monoclonal antibody that specifically binds to the complement protein C5, thus inhibiting terminal complement mediated intravascular hemolysis in PNH patients.

It is also useful in rheumatoid arthritis and other chronic inflammatory diseases, e.g. nephritis. 

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