Can Paroxysmal Nocturnal Hemoglobinuria (PNH) present with schistocytes due to intravascular hemolysis?

Paroxysmal Nocturnal Hemoglobinuria (PNH) and Schistocytes

Yes, Paroxysmal Nocturnal Hemoglobinuria (PNH) can present with schistocytes in peripheral blood smears due to the intravascular hemolysis that characterizes this disease.

Pathophysiology of Hemolysis in PNH

• PNH is a rare acquired hematopoietic stem cell disorder characterized by deficiency of glycosyl-phosphatidylinositol (GPI)-linked membrane proteins, particularly CD55 and CD59, which leads to complement-mediated intravascular hemolysis 1
• The loss of CD59 especially leads to 'paroxysms' of acute intravascular hemolysis during events of stress 2
• Patients with PNH clone size >60% of granulocytes have significantly higher risk of thrombosis and hemolysis 3, 4

Laboratory Findings in PNH

• Microangiopathic hemolytic anemia in PNH is characterized by:
  • Non-immune hemolytic anemia (negative direct Coombs test) 3
  • Elevated LDH levels 3, 5
  • Reduced haptoglobin levels 3, 6
  • Presence of schistocytes in peripheral blood smear 3, 6
• While schistocytes >1% is a robust cytomorphological threshold that favors a diagnosis of thrombotic microangiopathy (TMA), the absence of schistocytes should not exclude an earlier diagnosis of TMA due to the low sensitivity of the test 3

Mechanisms of Schistocyte Formation in PNH

• Intravascular hemolysis in PNH occurs due to unrestricted complement activation on red blood cells lacking CD55 and CD59 2
• Complement-mediated damage to red blood cells can result in fragmentation and formation of schistocytes 6
• Thrombotic events, which are common in PNH, can also lead to mechanical fragmentation of red blood cells as they pass through partially occluded vessels, resulting in schistocyte formation 4, 2

Clinical Significance of Schistocytes in PNH

• The presence of schistocytes in PNH indicates active intravascular hemolysis 6
• Schistocytes may be particularly prominent during acute hemolytic episodes or in patients with concurrent thrombotic complications 4, 2
• In patients treated with eculizumab (anti-C5 therapy), schistocytes may decrease but not completely disappear due to:
  • Pharmacokinetic or pharmacodynamic breakthrough hemolysis 1
  • Continuing low-level residual intravascular hemolysis 1, 7
  • Extravascular hemolysis (which may not produce schistocytes) 7

Differential Diagnosis

• When schistocytes are present along with non-immune hemolytic anemia and thrombocytopenia, it is essential to distinguish between:
  • PNH
  • Thrombotic thrombocytopenic purpura (TTP) - requires urgent ADAMTS13 activity testing 3
  • Atypical hemolytic uremic syndrome (aHUS) 3
  • Other causes of thrombotic microangiopathy 6

Diagnostic Approach

• Flow cytometry to detect GPI-anchored proteins (CD55 and CD59) is the primary diagnostic test for PNH 2, 5
• Fluorescein-labeled proaerolysin variant (FLAER) has significant advantages over CD55 and CD59 testing 2
• Complete blood count with peripheral blood smear examination to identify schistocytes 3, 6
• Measurement of LDH, haptoglobin, and indirect bilirubin levels 3, 6
• Negative direct Coombs test to confirm non-immune hemolysis 3

Treatment Implications

• Eculizumab, a humanized monoclonal antibody against complement C5, is the standard treatment for PNH with hemolysis 1, 5
• Despite eculizumab treatment, some patients may continue to show signs of hemolysis including the presence of schistocytes 7
• Patients who become direct Coombs-test positive during eculizumab treatment may have extravascular hemolysis due to C3 opsonization of PNH erythrocytes 7
• Monitoring for thrombotic complications is essential, as PNH is strongly associated with thrombosis, particularly in unusual sites such as Budd-Chiari syndrome (9-19% of cases) 3, 4

Monitoring Recommendations

• Regular peripheral blood smear examination to assess for schistocytes and other signs of hemolysis 3, 6
• Monitoring of LDH levels as a marker of intravascular hemolysis 5, 8
• In patients on eculizumab, evaluation of free eculizumab levels and terminal pathway activity to personalize dosing 7
• Vigilance for signs of thrombosis, which remains a significant cause of morbidity and mortality in PNH 3, 4, 8