PNH: A progressive, destructive, and life-threatening disease that causes thrombosis, end organ damage, and impaired quality of life1,2,3
PNH RBCs lack a terminal complement inhibitor.
PNH RBCs are susceptible to complement attack.
PNH RBCs are lysed, and contents are released into the surrounding plasma.
Study description: Researchers followed 80 consecutive patients with PNH referred to Hammersmith Hospital. They were treated with supportive measures, such as oral anticoagulant therapy after established thromboses and transfusions.
Thrombosis and renal failure are leading causes of death4,5
PNH may be diagnosed at any age; median age is in the early 30s5
Diagnosis is typically delayed from 1 to more than 10 years6
What causes PNH?
PNH is an acquired hematopoietic stem cell disorder in which blood cells lack a key, naturally occurring terminal complement inhibitor on the cell surface.2,7,8
In PNH there is an expansion of hematopoietic stem cells that possess a mutation of the phosphatidylinositol glycan class A (PIG-A) gene. PIG-A is one of several genes involved in the protein synthesis of an enzyme responsible for assembly of a fatty acid tail, known as a glycosyl- phosphatidylinositol (GPI) anchor. GPI anchor synthesis is a necessary step in surface attachment of some proteins.7,8
In PNH, the lack of these protective proteins renders RBCs vulnerable to lysis by complement. Without this protective complement inhibitor shield, PNH RBCs are destroyed (hemolysis), which can result in thrombosis, end organ damage, and increased mortality.9
Normal red blood cells (RBCs) are protected from complement attack by a shield of terminal complement inhibitors created by 2 crucial proteins, CD59 and CD55. These protective proteins inhibit uncontrolled complement activation and the formation of the terminal complement complex (TCC), also known as C5b-9 or the membrane attack complex (MAC).2,7,8
Free Hemoglobin/Nitric Oxide Depletion
Hemolysis leads to free hemoglobin and nitric oxide (NO) depletion2
During chronic hemolysis, excess free hemoglobin depletes plasma nitric oxide (NO), which may play an important role in normal platelet function.10
NO may down regulate platelet aggregation, adhesion, and regulating molecules in the coagulation cascade. Therefore, NO depletion may lead to platelet activation and aggregation.10 Reduced NO can also lead to processes considered to be precursors to thrombotic events such as:2,10,11
Platelet activation and aggregation
In addition, reduced NO can have an array of consequences for PNH patients, including smooth muscle dystonias.2 These dystonias include:
Vascular constriction, leading to pulmonary and systemic hypertension and erectile dysfunction12
Gastrointestinal contractions that can cause abdominal pain and dysphagia2
Complement is a complex array of more than 20 proteins present in the blood and plays a fundamental role in the body’s innate immune response against infection.13,14
Insufficient regulation of the complement cascade can have highly destructive effects15
In PNH, the deficiency of complement inhibitors leads to chronic, uncontrolled complement activation, resulting in chronic hemolysis and granulocyte and platelet activation2,16,17,18
The complement cascade is a sequential process13,14
Triggered by infectious agents, foreign molecules, and immune complexes
Proceeds through an enzymatic cascade capable of lysing susceptible cells
Compartmentalized into proximal and terminal complement pathways
The proximal complement pathway14
Initially triggered via 3 different pathways: lectin, classical, and alternative
All 3 pathways aid in the generation of C3 convertase complexes; these complexes facilitate the cleavage of C3, yielding C3a and C3b
These cleaved fragments are important to the proximal complement pathway, as individuals with C3 deficiencies are susceptible to polysaccharide-coated bacterial infections14
The terminal complement pathway14
C3 components also required for the downstream engagement of the terminal complement pathway
Individuals harboring C3 deficiencies have reduced abilities to opsonize infectious pathogens and mount an inflammatory response
Initiated when C5b complexes with other factors, forming C5 convertases, which then cleave C5, yielding C5a and C5b
C5b interacts with C6-C9, allowing for the formation of the terminal complement complex (TCC)
Deposition of TCC on erythrocytes, as in PNH, results in hemolysis14