In a recent Morning Report at WCH, we discussed hemolytic anemias with a specific focus on  thrombotic thrombocytopenic purpura.

Learning Points:

1. Laboratory findings associated with hemolytic anemias
2. Differential diagnosis of hemolytic anemias
3. Differential diagnosis of schistocytes
4. Thrombotic thrombocytopenic purpura (TTP) basics and management

Supportive Labs for Hemolysis:

• increased LDH, reticulocyte count, indirect hyperbilirubin, urobilinogen
• decreased hemoglobin and haptoglobin
• Abnormal blood film findings:
  • Spherocytes-suggestive of autoimmune hemolytic anemia
  • Schistocytes-suggestive of thrombotic microangiopathy
  • Nucleated RBCs-suggestive of severe, chronic hemolysis i.e. Sickle Cell Disease
  • Sickled RBCs-Sickle Cell Disease
  • Bite Cells (Pacman-like), Heinz Bodies (aggregates of denatured hemoglobin)-seen in G6PD deficiency
  • Intracellular parasites-i.e. Babesiosis (maltese cross), malaria (ringed forms)

Hemolytic Anemias:

Differential Diagnosis of Schistocytes:

Thrombotic Thrombocytopenic Purpura (TTP):

• The “Pentad” (usually not present in entirety)
  • Fever
  • microangiopathic hemolytic anemia (anemia + schistocytes)
  • Thrombocytopenia
  • Acute kidney injury
  • Neurologic distrurbance (mental status change, stroke-like syndrome, etc)
• Basic pathophysiology:
  • ADAMTS13 (matrix metalloproteinase) inhibitor (i.e. antibody) or deficiency
  • VWF multimers accumulate and unable to be broken down
    • VWF binds to subendothelial collagen; platelet GB1b receptor binds to it, allowing for platelet adhesion
  • Exposure to platelets leads to platelet aggregation, shear stress, hemolysis
• Supportive Investigations:
  • Evidence of hemolytic anemia (as indicated above) with fragments/schistocytes
  • Characteristically the coagulation indices are unaffected and hence, INR, aPTT fibrinogen, and D dimer should all be NORMAL
• Management Basics:
  • Monitored setting
  • Consent for blood products
  • Hematology and critical care involvement
  • Temporize with FFP infusion
  • Initiate steroids (high dose prednisone vs methylprednisolone)
  • Transfer to plasma exchange centre
  • Multiple options for refractory TTP including:
    • Rituximab
    • Cyclosporin
    • IVIg
    • Vincristine
  • Antiplatelets have a role only if added to PLEX but should be avoided until higher platelet counts are attained as may aggravate bleeding

Final Pearls:

• A rare cause of intermittent hemolytic anemia is paroxysmal nocturnal hemoglobinuria (PNH). This may cause intermittent jaundice, hematuria, and thrombotic events, including rare-site thrombosis like Budd-Chiari syndrome. Diagnosis is by flow cytometry which detects absent/missing cell surface markers (CD55, CD59) that protect cells from complement-mediated destruction. Treatment involves a VERY expensive drug in eculizumab which is a terminal complement inhibitor.
• G6PD deficiency is another rare cause of intermittent hemolytic anemia that relates to a missing enzyme and cellular inability to respond to oxidative stress. Triggers of episodic hemolysis include drugs (sulfa, antimalarials macrobid), infection, and fava beans. Diagnosis involves a G6PD assay which should NOT be done during an acute crisis when reticulocyte counts are elevated. This is because unlike mature RBCs, reticulocytes have higher levels of G6PD and hence, the assay may appear to show falsely normal G6PD levels.

Further Reading:

1. Scully, M; Goodship; T. How I treat thrombotic thrombocytopenic purpura and atypical hemolytic uremic syndrome. British Journal of Haematology (2014), 164:759-766.
2. George, JN. How I treat patients with thrombotic thrombocytopenic purpura. Blood (2010) 116:4060-4069.
3. George, JN;  Nester, CM. Syndromes of Thrombotic Microangiopathy. N Engl J Med. 2014 Aug 14;371(7):654-66. doi: 10.1056/NEJMra1312353