Compare and contrast heparin induced thrombotic thrombocytopaenia syndrome (HITTS) and thrombotic thrombocytopaenlc purpura (TTP) with respect to their pathogenesis, clinical features, relevant laboratory findings, and treatment.

[Click here to toggle visibility of the answers]

College answer

Condition

TTP

HITTS

Aetiology

1 mark each

  1. Reduction in ADAMTS 13 level
    1. Hereditary causes
    2. Acquired causes e.g. Sepsis, surgery, pancreatitis, pregnancy
  2. Anitbodies to ADAMTS 13:

Autoantibodies to platelet factor 4 (PF4) complexed with heparin

Clinical

Features

1 mark each

Small vessel thrombosis-

Microangiopathic haemolytic anaemia with multisystem involvement but renal and CNS dominate- 

Occurs within 4-10 days of heparin administration- arterial and venous thrombosis, thrombocytopenia

Laboratory

2 marks each

Low platelets, intravascular haemolysis with evidence of micrangiopathic changes to RBC morphology. LDH, Haptoglobin, COOMBS test, ADAMTS 13 deficiency

Ant PF4 antibody, Functional

Assays- (serotonin release,

Heparin induced platelet activation)

Treatment  1 mark each

Plasmapharesis is the mainstay of treatment for Acquired TTP, FFP for hereditary TTP

Cessation heparin

Non heparin based anticoagulation

( Lepuridin etc)

Discussion

A "compare and contrast" question is typically something that benefits from a tabulated answer.

Observe:

Domain HITS TTP-HUS
Pathogenesis
  • IgG directed against PF4 complexed with heparin (PF4 is "Platelet Factor 4", a little cytokine which is normally released from platalet α-granules)
  • When anti-PF4 antibodies bind to PF4 it  activating more platelets and triggers the release of more PF4, providing more substrate for antibody binding in a positive feedback loop
  • The IgG-coated platelets are then removed by reticuloendothelial system macrophages. Thrombocytopenia ensues.
  • The patient is ADAMTS 13 deficient (ADAMTS 13 is a von Willebrand factor cleaving protein).
  • A trigger such as infection, surgery, pancreatitis, pregnancy, produces endothelial activation.
  • When endothelial activation occurs and ADAMTS 13 activity is low (often due to an autoantibody inhibitor), large vWF multimers accumulate causing microvascular thrombosis and haemolysis.
  • An excess of vWF leads to a systemic prothrombotic state, with microvascular thrombosis responsible for all the organ system damage.
Clinical features
  • Onset 5-10 days after heparin exposure
  • Thrombosis
  • Thrombocytopenia
  • No other cause for thrombocytopenia

Classic "pentad"

  • Anaemia
  • Thrombocytopenia
  • Microangiopathic haemolytic anaemia
  • Schistocytosis
  • Neurological symptoms
  • Fever and renal failure are actually uncommon
Laboratory findings
  • Thrombocytopenia
  • Anti-PF4 antibodies
  • Positive serotonin release assay (SRA)
  • Thrombocytopenia
  • Raised urea and creatinine
  • Blood film abnormalities, eg. schistocytes and fragmented RBCs

  •  
Treatment
  • Anticoagulation
  • Withdrawal of heparin
  • Plasmapheresis
  • Repacement with FFP

References

References

George, James N. "Thrombotic thrombocytopenic purpura." New England Journal of Medicine 354.18 (2006): 1927-1935.

Peyvandi, Flora, et al. "von Willebrand factor cleaving protease (ADAMTS‐13) and ADAMTS‐13 neutralizing autoantibodies in 100 patients with thrombotic thrombocytopenic purpura." British journal of haematology 127.4 (2004): 433-439.

Tsai, Han-Mou. "Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura." Journal of the American Society of Nephrology 14.4 (2003): 1072-1081.

Oh's Intensive Care manual: Chapter 97 (pp. 993)  Therapeutic  plasma  exchange  and  intravenous  immunoglobulin  therapy  by Ian  Kerridge,  David  Collins  and  James  P  Isbister

Kakishita, Eizo. "Pathophysiology and treatment of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS)."International journal of hematology 71.4 (2000): 320-327.

Noris, Marina, and Giuseppe Remuzzi. "Hemolytic uremic syndrome." Journal of the American Society of Nephrology 16.4 (2005): 1035-1050.

Kappler, Shane, Sarah Ronan-Bentle, and Autumn Graham. "Thrombotic Microangiopathies (TTP, HUS, HELLP)." Emergency Medicine Clinics of North America (2014).

Moake, Joel L. http://www.danielyoung.net/articles/NEJM%20TTP-HUS%202002.pdf "Thrombotic microangiopathies." New England Journal of Medicine 347.8 (2002): 589-600.

Arepally, Gowthami M., and Thomas L. Ortel. "Heparin-induced thrombocytopenia." New England Journal of Medicine 355.8 (2006): 809-817.

Patel, Vipul P., Matthew Bong, and Paul E. Di Cesare. "Heparin-induced thrombocytopenia and thrombosis." AMERICAN JOURNAL OF ORTHOPEDICS-BELLE MEAD- 36.5 (2007): 255.

Greinacher, Andreas. "Heparin-induced thrombocytopenia." New England Journal of Medicine 373.3 (2015): 252-261.