Paroxysmal Nocturnal Hemoglobinuria


Cascade Biotechnology INC | Complement Therapeutics; novel approach to CNS/PNS disease management using the innate complement system.

Blood Disorders

Paroxysmal nocturnal hemoglobinuria (PNH)


  • When the complement system is activated, it triggers a variety of events leading to cleavage of protein C5. Once C5 is cleaved, a variety of events occur that propagate the formation of the membrane attack complex (MAC). 

  • This MAC generates pores, or holes, in cells ultimately leading to the cellʼs demise of the system that are needed. These regulators sit on the outer membrane of cells, so the complement system recognizes that these cells are of the self. 

  • When those regulators are missing, as is the case in PNH, this leads to the destruction of the cells that are missing  protein shields.  Some of those shields, (2 proteins known as CD 55 and CD 59) are anchored the cell surface by a ‘tailʼ.

  • We call this tail a GPI anchor – but in PNH this GPI anchor is missing because of a mutation in a gene called PIG-A. This defective gene causes the cellʼs inability to form this GPI anchor. 

  • So the complement regulator proteins are lost because they arenʼt anchored to the cell surface. 

  • When the complement system becomes highly active from infections, surgery, or similar events, it creates increased cell death of those cells missing this protein shield.

  • Because of the missing CD 59 protein [note: CD 55 is not mentioned here] on the surface of the red blood cell the membrane attack complex takes place, which makes the holes and pores on the cell surface, releasing the hemoglobin inside the cell through the holes – the hemoglobin escapes the cell walls. 

  • This is the point where hemolysis occurs. Eventually the cell completely ruptures, releasing all the free hemoglobin intravascularly. 

  • That has a variety of consequences, including hemolytic anemia , thrombosis because of inflammation, and kidney problems because of free hemoglobin filtering through the kidney tubes—leading to hemoglobinuria (red urine). 

  • Continued hemoglobinuria can lead to kidney damage.(Expert Rev Hematol. 2014 October ; 7(5):583–598).

  • Because of the missing CD 59 protein [note: CD 55 is not mentioned here] on the surface of the red blood cell , the membrane attack complex takes place, which makes the holes and pores on the cell surface, releasing the hemoglobin inside the cell through the holes – the hemoglobin escapes the cell walls. 

  • This is the point where hemolysis occurs. Eventually the cell completely ruptures, releasing all the free hemoglobin intravascularly. 

  • That has a variety of consequences, including hemolytic anemia , thrombosis because of inflammation, and kidney problems because of free hemoglobin filtering through the kidney tubes—leading to hemoglobinuria (red urine). 

  • Continued hemoglobinuria can lead to kidney damage. In its normal form, patients present with overt hemolysis and hemoglobinuria. Subclinical PNH implies that you have a PNH clone with defective hemolysis.

  • The ability of high-sensitivity flow cytometry to identify a small amount of PNH clones has resulted in the classification called ‘subclinical PNHʼ. So these patient may not present with hemolysis but once a PNH cline is identified, it is important to monitor the sized of the clone and understand the potential consequences of clone growth and the potential for hemolytic events to begin (Jamile Shammo, MD, FACP, FASCP  Interviews with the Experts: The Complement System in PNH | Aplastic Anemi and MDS International Foundation  (AA MDS) Sun, 03/31/2013 - 8G37pm. Last updated on Fri, 03/11/2016).