What are the differences between cTTP and iTTP?

3 min

ADAMTS13
cTTP
Epidemiology
iTTP

There are two main types of TTP*, an inherited form known as congenital TTP (cTTP), and an immune-mediated form, known as immune-mediated TTP (iTTP).1

Black, grey and red infographic with antibody, DNA, and human icons explaining iTTP vs. cTTP and their prevalence
Black, grey and red infographic with antibody, DNA, and human icons explaining iTTP vs. cTTP and their prevalence
Black, grey and red infographic with antibody, DNA, and human icons explaining iTTP vs. cTTP and their prevalence

* Although TTP falls broadly into two main categories, iTTP and cTTP,1 other types of TTP have been described, namely primary and secondary iTTP (including infection-related and drug-induced TTP).6

 

† Autosomal recessive mutations in the ADAMTS13 gene; more than 300 mutations responsible for cTTP have been identified.7

 

‡ A condition is considered rare if it has a prevalence of ≤ 5/10,000 and > 1/100,000 and ultrarare if it has a prevalence of ≤ 1/100,000.8 

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Abbreviations, Glossary and References

Abbreviations

ADAMTS13; A disintegrin and metalloproteinase with a thrombospondin motifs 13

cTTP; Congenital TTP

iTTP; Immune-mediated TTP

TTP; Thrombotic thrombocytopenic purpura

 

Glossary

ADAMTS13; ADAMTS13 (A Disintegrin And Metalloprotease with ThromboSpondin motifs 13) is a constitutively active enzyme (plasma metalloprotease) that catalyzes the breakdown of ultra large and high molecular weight von Willebrand factor (VWF) into smaller multimers, reducing their thrombogenic potential, and maintaining hemostasis.1,9

Incidence; The rate of new cases or events over a specified period for the population at risk for a certain event.

Microangiopathic hemolytic anemia (MAHA); Process of red blood cell destruction within the microvasculature accompanied by thrombocytopenia due to platelet activation and consumption. Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are primary forms of thrombotic microangiopathies.10

Prevalence; The proportion of a particular population found to be affected by a medical condition at a specific time.

Schistocyte; Circulating fragments of red blood cells commonly seen in blood smears from patients with thrombotic microangiopathies including TTP.11

Thrombocytopenia; Refers to a state of reduced peripheral platelets below normal levels (150x109/L) and can be caused by a wide variety of aetiologies that either decrease platelet production or increase platelet consumption.12

Thrombotic microangiopathy (TMA); TMA includes a diverse set of syndromes that can be hereditary or acquired, which can occur in children and adults with sudden or gradual onset.

TMA syndromes, despite being diverse, have a common set of clinical and pathological features: MAHA, thrombocytopenia, organ injury, vascular damage manifested by arteriolar and capillary thrombosis with characteristic abnormalities in the endothelium and vessel wall.13

Thrombotic thrombocytopenic purpura (TTP); TTP is a type of MAHA presenting with moderate or severe thrombocytopenia. There is associated organ dysfunction, including neurologic, cardiac, gastrointestinal and renal involvement; oliguria or anuric renal failure requiring renal replacement therapy is not typically a feature. TTP is confirmed by a severe deficiency (<10%) of ADAMTS13 activity.6

von Willebrand factor (VWF); VWF plays two key roles in hemostasis: 1) in primary (platelet-mediated) hemostasis, VWF binds to collagen and platelets thus promoting platelet activation and aggregation, and 2) in secondary (coagulation factor mediated) hemostasis VWF binds factor VIII (FVIII) protecting FVIII from rapid clearance. When VWF binds to collagen following vascular injury, it releases FVIII, leading to FVIII activation and initiation of the coagulation cascade.14,15

 

References

  1. Kremer Hovinga, J.A., et al., Thrombotic thrombocytopenic purpura. Nat Rev Dis Primers, 2017. 3: p. 17020.
  2. Oladapo, A.O., et al., Patient Experience with Congenital (Hereditary) Thrombotic Thrombocytopenic Purpura: A Conceptual Framework of Symptoms and Impacts. Patient, 2019. 12(5): p. 503-512.
  3. Zheng, X.L., et al., ISTH guidelines for the diagnosis of thrombotic thrombocytopenic purpura. J Thromb Haemost, 2020. 18(10): p. 2486-2495.
  4. Lotta, L.A., et al., ADAMTS13 mutations and polymorphisms in congenital thrombotic thrombocytopenic purpura. Hum Mutat, 2010. 31(1): p. 11-19.
  5. Sukumar, S., B. Lammle, and S.R. Cataland, Thrombotic Thrombocytopenic Purpura: Pathophysiology, Diagnosis, and Management. J Clin Med, 2021. 10(3): p. 536.
  6. Scully, M., et al., Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies. J Thromb Haemost, 2017. 15(2): p. 312-322.
  7. Seidizadeh, O., et al., Estimating the Population-Based Prevalence of Congenital Thrombotic Thrombocytopenic Purpura Using Large-Scale Sequencing Data. Blood, 2023. 142(Supplement 1): p. 693-693.
  8. Pontes, C., et al., Evidence supporting regulatory-decision making on orphan medicinal products authorisation in Europe: methodological uncertainties. Orphanet J Rare Dis, 2018. 13(1): p. 206.
  9. Markham-Lee, Z., N.V. Morgan, and J. Emsley, Inherited ADAMTS13 mutations associated with Thrombotic Thrombocytopenic Purpura: a short review and update. Platelets, 2023. 34(1): p. 2138306.
  10. Arnold, D.M., C.J. Patriquin, and I. Nazy, Thrombotic microangiopathies: a general approach to diagnosis and management. CMAJ, 2017. 189(4): p. E153-E159.
  11. Zini, G., et al., ICSH recommendations for identification, diagnostic value, and quantitation of schistocytes. Int J Lab Hematol, 2012. 34(2): p. 107-116.
  12. Gauer, R.L. and M.M. Braun, Thrombocytopenia. Am Fam Physician, 2012. 85(6): p. 612-622.
  13. George, J.N. and C.M. Nester, Syndromes of thrombotic microangiopathy. N Engl J Med, 2014. 371(7): p. 654-666.
  14. Rauch, A., et al., On the versatility of von Willebrand factor. Mediterr J Hematol Infect Dis, 2013. 5(1): p. e2013046.
  15. Stockschlaeder, M., R. Schneppenheim, and U. Budde, Update on von Willebrand factor multimers: focus on high-molecular-weight multimers and their role in hemostasis. Blood Coagul Fibrinolysis, 2014. 25(3): p. 206-216.
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