Case 8 – summary

Summary of case 8 – PNH

This case demonstrated presenting symptoms of haemolytic anaemia.  This was indicated by a low HB, raised LDH, raised reticulocytes, elevated bilirubin, and low haptoglobin levels.  A negative DAT suggests that this is not an autoimmune cause, however in practice the DAT test should be repeated to confirm the negative result.

The low ferritin level, DAT negative haemolysis and evidence of pancytopenia are all indicators towards a potential diagnosis of PNH.  However PNH is extremely rare and therefore alternative diagnoses should not be forgotten!!

Haemolytic anaemia

Haemolysis is premature destruction of erythrocytes.

The severity of the haemolysis depends on the speed on onset and the extent of erythrocyte destruction.  Mild haemolysis can be asymptomatic, however severe haemolysis can be life threatening.

Hereditary Acquired
Membrane : Hereditary spherocytosis, hereditary elliptocytosis Immune;Autoimmune ; Warm antibody type, cold antibody typeAlloimmune; Haemolytic transfusion reactions

Haemolytic disease of the newborn

Allografts, especially stem cell transplantation

Metabolism: G6PD deficiency, pyruvate kinase deficiency Drug associated
Haemoglobin: Genetic abnormalities (Hb S, Hb C, unstable) Red cell fragmentation syndrome
March haemoglobinuria
Infections – malaria, clostridia
Chemicals and physical agents ; drugs, industrial and domestic substances, burns
Secondary – liver and renal disease
Paroxysmal nocturnal haemoglobinuria

Hemolysis may be an extravascular or an intravascular phenomenon.

  • Extravascular – Autoimmune hemolyticanemia and hereditary spherocytosis (red blood cells are destroyed in the spleen and other reticuloendothelial tissues. )
  • Intravascular hemolysis – prosthetic cardiac valves, G-6-PD deficiency, thrombotic thrombocytopenic purpura, disseminated intravascular coagulation, following transfusion of ABO incompatible blood, and paroxysmal nocturnal hemoglobinuria (PNH).

Paroxysmal nocturnal haemoglobinuria

Paroxysmal nocturnal haemoglobinuria (PNH) is a very rare, acquired bone marrow disorder

The clinical syndrome can present in 3 types of symptoms

(1) an acquired intracorpuscular haemolytic anaemia due to the abnormal susceptibility of the RBC membrane to the hemolytic activity of complement;

(2) thromboses in large vessels, such as hepatic, abdominal, cerebral, and subdermal veins; and

(3) a deficiency in hematopoiesis that may be mild or severe, such as pancytopenia in an aplastic anaemia state. 

The triad of haemolytic anaemia, pancytopenia, and thrombosis makes paroxysmal nocturnal haemoglobinuria (PNH) a truly unique clinical syndrome.

The term “nocturnal” refers to the belief that haemolysis is triggered by acidosis during sleep and activates complement to haemolyse an unprotected and abnormal RBC membrane. However, this observation was later disproved. Haemolysis has been shown to occur throughout the day and is not actually paroxysmal, but the urine concentrated overnight produces the dramatic change in colour.

Who should be screened?

  • Patients with haemoglobinuria
  • Patients with Coombs-negative intravascular haemolysis (based on abnormally high serum LDH), especially patients with concurrent iron deficiency
  • Patients with venous thrombosis involving unusual sites*
  1. Budd-Chiari syndrome
  2. Other intra-abdominal sites (eg, mesenteric or portal veins)
  3. Cerebral veins
  4. Dermal veins
  • Patients with aplastic anemia (screen at diagnosis and once yearly even in the absence of evidence of intravascular haemolysis)
  • Patients with refractory anaemia-MDS
  • Patients with episodic dysphagia or abdominal pain with evidence of intravascular haemolysis

 

Pathophysiology

  • Acquired genetic mutation
  • Leads to an inability to synthesize the glycosyl-phosphatidylinositol (GPI) anchor that binds specific proteins to cell membranes
  • The essential proteins are CD55 and CD59
  • These proteins interact with complement proteins, particularly C3b and C4b, dissociate the convertase complexes of the classic and alternative pathways, and halt the amplification of the activation process.
  • Haemolytic anaemia is due to intravascular destruction of RBCs by complement.
  • Breakdown of RBC membranes by complement leads to the release of haemoglobin into the circulation.
  • Haemoglobin is bound to haptoglobin for efficient clearance from the circulation.
  • After saturating the haptoglobin, free forms of haemoglobin circulates and binds irreversibly with nitric oxide (NO) and depletes NO levels in peripheral blood
  • Depletion of NO levels leads to smooth muscle contraction with consequent vasoconstriction, constriction of the gut, and pulmonary hypertension.
  • Symptoms of abdominal pain, bloating, back pain, headaches, oesophageal spasms, erectile dysfunction, and fatigue are due to NO depletion by scavenging free haemoglobin.

This diagram helps explain the pathophysiology a little clearer!!!

Lack of GPI anchored proteins allows the formation of terminal complement complex (TCC), which renders the cell susceptible to intravascular haemolysis!

Image

Invesitgations

Flow cytometry – detect CD59 and CD55. Absence or reduction of CD59 and CD55 on PNH RBC’s is diagnostic

Image

 

Long term consequences:

  • Progressive chronic renal failure can occur after several years of hemoglobinuria from the acute tubulonecrosis effects of heme and iron (pigment nephropathy)
  • decreased renal perfusion from renal vein thrombosis, and tubular obstruction with pigment casts.
  • high incidence (40%) of thrombotic events (mostly venous) in large vessels (cerebral, hepatic, portal, mesenteric, splenic, and renal veins) and, most recently recognized, arterial thrombosis.
  • Bone marrow failure

Treatments:

  • Transfusion support
  • Folic acid
  • Steroids
  • LMWH – due to risk of thrombosis
  • Transplantation
    • younger patients with acceptable co-morbidities
    •  a suitable donor
    • either severe aplastic anaemia or severe recurrent thrombotic events.
  • Eculizumab
    • New anticomplement agent – monoclonal antibody against terminal protein C5.
    • Shown to be highly effective in reducing intravascular haemolysis.
    • TRIUMPH (Transfusion reduction efficacy and safety clinical investigation using eculizumab in PNH)
      • Reduced transfusion requirements and haemolysis
      • Decreased risk of thrombosis
      • Reduced systemic symptoms
      • Patients require vaccination against meningococcus.

References

Diagnosis and management of paroxysmal nocturnal hemoglobinuria

Blood Journal, July 28, 2005, doi: 10.1182/blood-2005-04-1717

A middle-aged lady having “transfusion-dependant anaemia”.  haematologywatch.net.  Haematology Watch, Vol 3, Issue 2

Paroxysmal nocturnal haemoglobinuria.  readcube.com

Hillmen P, Young NS, Schubert J, et al.  The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med 2006;355:1233-1243

About TeamHaem

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