Question 29

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.

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College answer

Condition	TTP	HITTS
Aetiology 1 mark each	Reduction in ADAMTS 13 level Hereditary causes Acquired causes e.g. Sepsis, surgery, pancreatitis, pregnancy 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

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.

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