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Hematological System

Thrombotic Thrombocytopenic Purpura (TTP)

Thrombotic thrombocytopenic purpura (TTP) is a rare disorder of the blood-coagulation system, causing extensive microscopic clots to form in the small blood vessels throughout the body.

Thrombotic thrombocytopenic purpura (TTP) is a rare disorder of the blood-coagulation system, causing extensive microscopic clots to form in the small blood vessels throughout the body.

  • Autosomal recessive inheritance

Etiology

Known and unknown players involved in TTP:
Known and unknown players involved in TTP: Among the known players involved in TTP occurrence, ADAMTS13 severe deficiency, either acquired via specific autoantibodies or inherited via ADAMTS13 gene mutations, is the only causing factor identified so far. Other factors are well established as predisposing factors for acquired TTP (ie, female sex, black ethnicity, HLA-DRB1*11, and obesity). Also, pathophysiological conditions increasing plasma VWF levels such as inflammation, sepsis, or pregnancy are known to potentially act as precipitating factors of acute episodes of either acquired or inherited TTP. Other still unknown players are suspected to be involved in TTP occurrence: these may be either proteins of the ADAMTS13/VWF system or cellular candidates such as platelets or endothelial cells. | Joly, B. S., Coppo, P., & Veyradier, A. (2017). Thrombotic thrombocytopenic purpura. Blood, 129(21), 2836 LP-2846. Retrieved from http://www.bloodjournal.org/content/129/21/2836.abstract

Pathophysiology

Inhibition/deficiency of ADAMTS 13 (vWF metalloprotease)

↓ Degradation of vWF multimers → ↑ large vWF multimers

↑Ž Platelet adhesion

↑ Platelet aggregation and thrombosis

Pathophysiology for TTP
Pathophysiology for TTP: In physiologic conditions, ultralarge VWF multimers released from endothelial cells are cleaved by ADAMTS13 in smaller VWF multimers, less adhesive to platelets. In TTP, because of the absence of functional ADAMTS13 (either absent by congenital defect or inhibited by specific autoantibodies), ultralarge VWF multimers are released into the blood and bind spontaneously to platelets to form aggregates within the arterial and capillary microvessels. The VWF–platelet aggregates are large enough to form microthrombi inducing tissue ischemia, platelet consumption, and microangiopathic hemolytic anemia (schistocytes on blood smear). | Joly, B. S., Coppo, P., & Veyradier, A. (2017). Thrombotic thrombocytopenic purpura. Blood, 129(21), 2836 LP-2846. Retrieved from http://www.bloodjournal.org/content/129/21/2836.abstract

HUS vs TTP:

Hypothetical model for shared pathophysiology between HUS and TTP
Hypothetical model for shared pathophysiology between HUS and TTP. In this proposed model, the inciting event for both HUS and TTP is a similar endothelial insult brought about by any of a variety of sources (or combination of sources) that results in widespread endothelial activation, inflammation, and damage, including the release of VWF and other contents of the Weibel-Palade bodies. The subsequent events may be determined in part by the level of systemic ADAMTS13 activity. In the case of systemic ADAMTS13 deficiency (top), ADAMTS13 is not available to process the newly released VWF, resulting in the widespread formation of VWF and platelet thrombi throughout the arteriolar circulation and the clinical picture of TTP. Conversely, in the case of systemic ADAMTS13 sufficiency (bottom), TTP is avoided by ADAMTS13-mediated release of platelet/VWF thrombi throughout the arteriolar circulation. For reasons that are not understood, circulating ADAMTS13 is not able to cleave efficiently VWF that is released in the glomerular microcapillary circulation, resulting in thrombus formation, increased inflammation, glomerular damage, and the clinical picture of HUS. Potential reasons for the inability of ADAMTS13 to cleave VWF in the glomerular circulation may include unfavorable shear stress not permissive for the proper unfolding of VWF (decreasing access of ADAMTS13 to the sessile bond within the folded VWF A2 domain) and the local presence of molecules that may interfere with ADAMTS13 activity or with its interaction with VWF. | Figure 1. (2022). Journal Of The American Society Of Nephrology. Retrieved from https://jasn.asnjournals.org/content/18/9/2457/F1

Presentation

Classic presentation (<10% cases):

  • Pentad: FAT RN
    • Fever
    • Neurologic symptoms
    • Thrombocytopenia
    • Reduced kidney function
    • Hemolytic anaemia (microangiopathic hemolytic anemia)
HUS - TTP

Diagnosis

  • Peripheral blood smear (PBS):
    • Schistocytes
  • ↑ LDH
  • Normal coagulation parameters
Flowchart for ADAMTS13 investigation in TTP
Flowchart for ADAMTS13 investigation in TTP: ADAMTS13 investigation is mandatory in the management of TMA because it is the unique marker able to definitely establish the diagnosis of TTP. ADAMTS13 activity is always the screening assay to perform. If ADAMTS13 activity is less than 10%, the clinical suspicion of TTP is confirmed. Thus, to document the mechanism for ADAMTS13 severe deficiency, detection of anti-ADAMTS13 IgG is the second-rank assay, whereas ADAMTS13 gene sequencing is a third-rank assay limited to selected indications. Data provided by ADAMTS13 monitoring during follow-up are also important to elucidate the mechanism for ADAMTS13 severe deficiency. In almost all cases, this panel of assays performed during both TTP inaugural episode and follow-up allows us to identify the 3 forms of TTP: acquired autoimmune TTP, acquired TTP of unknown mechanism (apparently not linked to ADAMTS13 autoantibodies), and inherited TTP (USS). In some exceptional cases, however, TTP remains with an unknown etiology. | Joly, B. S., Coppo, P., & Veyradier, A. (2017). Thrombotic thrombocytopenic purpura. Blood, 129(21), 2836 LP-2846. Retrieved from http://www.bloodjournal.org/content/129/21/2836.abstract
f4-large2
Flowchart for ADAMTS13 investigation in TTP: ADAMTS13 investigation is mandatory in the management of TMA because it is the unique marker able to definitely establish the diagnosis of TTP. ADAMTS13 activity is always the screening assay to perform. If ADAMTS13 activity is less than 10%, the clinical suspicion of TTP is confirmed. Thus, to document the mechanism for ADAMTS13 severe deficiency, detection of anti-ADAMTS13 IgG is the second-rank assay, whereas ADAMTS13 gene sequencing is a third-rank assay limited to selected indications. Data provided by ADAMTS13 monitoring during follow-up are also important to elucidate the mechanism for ADAMTS13 severe deficiency. In almost all cases, this panel of assays performed during both TTP inaugural episode and follow-up allows us to identify the 3 forms of TTP: acquired autoimmune TTP, acquired TTP of unknown mechanism (apparently not linked to ADAMTS13 autoantibodies), and inherited TTP (USS). In some exceptional cases, however, TTP remains with an unknown etiology. | Joly, B. S., Coppo, P., & Veyradier, A. (2017). Thrombotic thrombocytopenic purpura. Blood, 129(21), 2836 LP-2846. Retrieved from http://www.bloodjournal.org/content/129/21/2836.abstract

Management

  • Plasmapheresis
  • Steroids
Current and Emerging Therapeutic Approaches for TTP and Their Targets
Current and Emerging Therapeutic Approaches for TTP and Their Targets: Therapeutic options indicated in bold (plasma exchange, rituximab, and glucocorticoids) are those approved and commonly used in 2016. Splenectomy is in italics because it is the only surgical procedure listed and is rarely used. The asterisk indicates that recombinant ADAMTS13 has not been tested in humans yet. Other drugs are either historical therapies (vincristine, cyclophosphamide, and cyclosporine) or emerging therapies (caplacizumab, N-acetylcysteine, eculizumab, and bortezomib). | Veyradier, A. (2016). Von Willebrand Factor — A New Target for TTP Treatment? New England Journal of Medicine, 374(6), 583–585. https://doi.org/10.1056/NEJMe1515876

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