- Only hemolytic anemia caused by an acquired (rather than inherited) intrinsic defect in the cell membrane (deficiency of glycophosphatidylinositol leading to the absence of protective proteins on the membrane).
While the term paroxysmal nocturnal hemoglobinuria (PNH) was introduced by Enneking in 1925, case reports dating back to the 1880s can be found. One of the earliest was that of Strubing, who documented the case of a young adult man with fatigue, abdominal pain, and intermittent hemoglobinuria. Strubing also noted that the patient’s plasma was red following the most severe episodes, and he deduced that intravascular hemolysis was the cause. Later in 1937, Ham was able to discover that erythrocytes of individuals with PNH hemolyzed when incubated with normal acidified urine. This resulted in the first diagnostic test for PNH, known as the Ham test (acidified serum test). While complement activation was suspected as the etiology for hemolysis, the theory was not formally proven until 1954. Over the following years, the nature of protein deficiencies affecting PNH erythrocytes was identified, and this paved the way for the identification of the responsible genetic mutation.
PNH is characterized by destruction of RBCs by the complement system (innate immune system)
X-linked gene phosphatidylinositol glycan class A (PIGA) mutation
Glycosylphosphatidylinositol (GPI) protein deficiency: CD55, CD59
(responsible for anchoring other protein moieties to erythrocyte surface)
Complement-mediated lysis of RBCs
This chronic state of hemolysis can be exacerbated if the complement system is activated by stress due to surgery, trauma, or other triggers for inflammation.
Traditionally PNH was characterized by recurrent episodes of intravascular hemolysis, venous thrombosis, and cytopenias associated with bone marrow failure.
Most patients present with nonspecific and variable signs that do not fit any specific syndrome.
- Constitutional symptoms (anemia): Fatigue, generalized malaise, dyspnea
- Dark urine (due to marked hemoglobinuria)
- Renal insufficiency (hemosiderin deposition leading to tubulointerstitial inflammation)
- Smooth muscle dystonia:
- Dysphagia or esophageal spasms
- Abdominal pain, back pain
- Erectile dysfunction
Because signs and symptoms are so variable, it is often difficult to diagnose this condition, and hence, diagnosis is often delayed.
Presumptive diagnosis:Recurrent episodes of intravascular hemolysis and cytopenias, and hemoglobinuria or hemosiderosis can be seen in PNH. Thus markedly increased LDH, low haptoglobin, and unconjugated bilirubinemia would be seen due to intravascular hemolysis.
- Complete blood count with differential (CBC w/ diff):
- Increased reticulocyte count
- Anemia, leukopenia, and thrombocytopenia
- Basic metabolic panel (BMP):
- Renal dysfunction: Increase in serum creatinine and blood urea nitrogen (BUN)
- Electrolyte abnormalities: Seen in chronic kidney disease (CKD)
- Urinalysis (UA):
- Intravascular hemolysis: Hemoglobinuria and hemosiderosis
Clinical blood tests:
- Direct antiglobulin test (DAT, or direct Coombs’ test): Negative (non-immune hemolysis)
- Now obsolete:
- Sucrose lysis test
- Ham’s acid hemolysis test
Flow cytometry (GOLD STANDARD)It utilizes various monoclonal antibodies, and special reagent called fluorescent aerolysin reagent (FLAER) that binds directly to glycosylphosphatidylinositol (GPI) anchored protein, specifically their glycan portion.
- GPI-anchored proteins:
- Decay-accelerating factor (DAF/CD55)
- Membrane inhibitor of reactive lysis (MIRL/CD59)
Differential diagnosis:Differential diagnosis includes other hemolytic anemias, other causes of atypical thrombosis, and conditions that cause bone marrow failure.
In PNH, complement-mediated hemolysis and chronic dysregulation of the alternative complement pathway are the main culprits. Commonly there is a loss of anchoring proteins such as CD55 and CD59, which causes cells to hemolyze and lead to complications like thrombosis, which causes morbidity and mortality.
Anti-C5 monoclonal antibodies therapiesDrugs to block alternative complement pathways are the mainstay of current therapy as in PNH, complement-mediated hemolysis and chronic dysregulation of the alternative complement pathway are the main culprits. These drugs pevent C5 conversion into C5a and C5b factors; thus, effectively inhibit membrane attack complex (MAC) formation and complement-mediated lysis.
- Ravulizumab (longer action, more cost-effective and fewer breakthrough hemolysis episodes)
- Daily oral antibiotic prophylaxis: Due to associated risk of encapsulated bacterial infections
Allogeneic hematopoietic stem cell transplantation (allo-HSCT):Only curative therapy for PNH.