Thrombotic thrombocytopenic purpura natural history, complications and prognosis
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sogand Goudarzi, MD [2] Anum Ijaz M.B.B.S., M.D.[3]
Overview
If left untreated, >90% of patients with TTP may progress to develop renal dysfunction, neurological disorders (mild headache, onset of behavioural anomalies, transient sensory and motor deficits, coma), ischaemic gastrointestinal complications (abdominal pain) and retinal detachment.
Natural History, Complications, and Prognosis
Natural History
- The symptoms of TTP(acquired) usually develop in the 4th decade of life, and start with no specificity of the signs, symptoms and laboratory findings; symptoms such as fever, renal dysfunction, neurological disorders (mild headache, onset of behavioural anomalies, transient sensory and motor deficits, coma), ischaemic gastrointestinal complications (abdominal pain) and retinal detachment.[1]
- Neurological symptoms at onset do not occur approximately more than 35% of patients.
- Fever and renal dysfunction are present among only a small minority of patients.
- The symptoms of TTP typically develop after 40 years.
- Early morbidity and mortality in iTTP are primarily caused by microvascular thrombosis leading to ischemic organ injury such as myocardial infarction and stroke.[2]
- A clinical response to acute iTTP treatment is characterized by normalization of platelet count, reduction in serum lactate dehydrogenase, and absence of new or progressive ischemic organ injury.[2]
- Patients who achieve a clinical response may still have persistent ADAMTS13 activity below 10% due to circulating anti-ADAMTS13 autoantibodies. Up to 38% of patients experience disease exacerbation within 30 days after stopping therapy (plasma exchange and caplacizumab).[3],[4]
Remission
- Clinical remission is defined as sustained normalization of platelet count (150 x 109/L) for at least 30 days without therapeutic plasma exchange or caplacizumab. and ADAMTS13 activity of 20% or greater.[2]
- During remission, regular laboratory monitoring including complete blood count,LDH level, and basic metabolic panel ( every 1 to 3 months) and ADAMTS13 ( once monthly in first year of first episode and then every 3-6 months thereafter) activity has been suggested to detect recurrence early.[5]
- Symptoms such as fatigue, petechiae, and neurologic complaints may signal impending relapse and require urgent evaluation.[5]
- During clinical remission, patients should have periodic ADAMTS13 monitoring, and preemptive rituximab is recommended when ADAMTS13 activity falls (commonly <20%) to restore enzyme levels and reduce the risk of relapse. [6],[5],[7]
Relapse
- Clinical relapse is defined by thrombocytopenia after remission with or without new ischemic organ injury and severe ADAMTS13 deficiency.[2]
- Approximately 16% of patients experience clinical relapse within 6 months after the initial episode.[7]
- Approximately one-third of patients experiencing a TTP episode have a relapse within 10 years following their first attack.
Exacerbation
- Exacerbation refers to recurrence of iTTP symptoms within 30 days of discontinuing therapeutic plasma exchange or caplacizumab therapy.[2]
- Exacerbation occurs because therapeutic plasma exchange and caplacizumab do not eliminate the underlying autoimmune process causing ADAMTS13 deficiency.[2]
- Patients with persistent severe ADAMTS13 deficiency (<10%) remain at risk for recurrence after discontinuation of therapy.[2]
- In an exacerbation of iTTP, therapeutic plasma exchange should be restarted.[8]
- Caplacizumab initiated at the time of exacerbation (if not previously given) shows a high response rate of approximately 93%.[9]
Refractory TTP
- Refractory iTTP is defined by failure of platelet recovery or persistent thrombocytopenia (<50 × 10⁹/L) with elevated lactate dehydrogenase after at least five plasma exchange treatments.[2]
- Refractory disease occurs in approximately 4%–14% of patients.[9]
Complications
- Acute iTTP may cause ischemic complications including stroke, myocardial infarction, and organ dysfunction due to microvascular thrombosis.[10]
- Common complications of TTP(restrict blood flow to organs such as the brain, kidneys, and heart) include:[1][11]
- Early death in approximilaty of patients are not diagnosed.
- Neurological problems(personality changes,mild headaches, confusion and slurred speech, coma)
- Abnormal kidney function
- Cardiovascular disease is the leading non-TTP cause of death among survivors.[12]
Prognosis
- The mortality rate is approximately 90% for untreated cases, but the prognosis is reasonably favorable (80-90%) for patients with idiopathic TTP diagnosed and treated early with plasmapheresis.[11]
- Approximately one-third of patients experiencing a TTP episode have a relapse within 10 years following their first attack.
- Secondary TTP still has a dismal prognosis, with mortality rates despite treatment being reported as 59% to 100%.
- Current treatment has reduced 30-day mortality to approximately 6.6%.[10]
- Predictors of 30-day mortality include neurologic manifestations (headache, stupor, seizure, or focal deficit) on presentation, advanced age (≥60 years), and markedly elevated lactate dehydrogenase levels ( >10 times of upper limit of normal).[13]
- Elevated troponin or impaired consciousness ( GCS ≤14) at presentation is associated with higher mortality risk.[14]
- Survivors have higher long-term mortality than an age- and sex-matched population.[12]
References
- ↑ 1.0 1.1 Rizzo C, Rizzo S, Scirè E, Di Bona D, Ingrassia C, Franco G, Bono R, Quintini G, Caruso C (October 2012). "Thrombotic thrombocytopenic purpura: a review of the literature in the light of our experience with plasma exchange". Blood Transfus. 10 (4): 521–32. doi:10.2450/2012.0122-11. PMC 3496241. PMID 22790258.
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 Cuker A, Cataland SR, Coppo P, de la Rubia J, Friedman KD, George JN, Knoebl PN, Kremer Hovinga JA, Lämmle B, Matsumoto M, Pavenski K, Peyvandi F, Sakai K, Sarode R, Thomas MR, Tomiyama Y, Veyradier A, Westwood JP, Scully M (April 2021). "Redefining outcomes in immune TTP: an international working group consensus report". Blood. 137 (14): 1855–1861. doi:10.1182/blood.2020009150. PMID 33529333 Check
|pmid=value (help). - ↑ Scully M, Cataland SR, Peyvandi F, Coppo P, Knöbl P, Kremer Hovinga JA, Metjian A, de la Rubia J, Pavenski K, Callewaert F, Biswas D, De Winter H, Zeldin RK (January 2019). "Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura". N Engl J Med. 380 (4): 335–346. doi:10.1056/NEJMoa1806311. PMID 30625070.
- ↑ Peyvandi F, Scully M, Kremer Hovinga JA, Cataland S, Knöbl P, Wu H, Artoni A, Westwood JP, Mansouri Taleghani M, Jilma B, Callewaert F, Ulrichts H, Duby C, Tersago D (February 2016). "Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura". N Engl J Med. 374 (6): 511–22. doi:10.1056/NEJMoa1505533. PMID 26863353.
- ↑ 5.0 5.1 5.2 Akwaa F, Antun A, Cataland SR (August 2022). "How I treat immune-mediated thrombotic thrombocytopenic purpura after hospital discharge". Blood. 140 (5): 438–444. doi:10.1182/blood.2021014514. PMID 35667044 Check
|pmid=value (help). - ↑ Zheng XL, Vesely SK, Cataland SR, Coppo P, Geldziler B, Iorio A, Matsumoto M, Mustafa RA, Pai M, Rock G, Russell L, Tarawneh R, Valdes J, Peyvandi F (October 2020). "ISTH guidelines for treatment of thrombotic thrombocytopenic purpura". J Thromb Haemost. 18 (10): 2496–2502. doi:10.1111/jth.15010. PMC 8091490 Check
|pmc=value (help). PMID 32914526 Check|pmid=value (help). - ↑ 7.0 7.1 Doyle AJ, Stubbs MJ, Dutt T, Lester W, Thomas W, van Veen J, Hermans J, Cranfield T, Hill QA, Clark A, Bagot C, Austin S, Westwood JP, Thomas M, Scully M (January 2023). "Long-term risk of relapse in immune-mediated thrombotic thrombocytopenic purpura and the role of anti-CD20 therapy". Blood. 141 (3): 285–294. doi:10.1182/blood.2022017023. PMID 36322971 Check
|pmid=value (help). - ↑ Sayani FA, Abrams CS (June 2015). "How I treat refractory thrombotic thrombocytopenic purpura". Blood. 125 (25): 3860–7. doi:10.1182/blood-2014-11-551580. PMC 4473115. PMID 25784681.
- ↑ 9.0 9.1 Izquierdo CP, Mingot-Castellano ME, Fuentes AE, García-Arroba Peinado J, Cid J, Jimenez MM, Valcarcel D, Gómez-Seguí I, de la Rubia J, Martin P, Goterris R, Hernández L, Tallón I, Varea S, Fernández M, García-Muñoz N, Vara M, Zarzoso MF, García-Candel F, Paciello ML, García-García I, Zalba S, Campuzano V, Gala JM, Estévez JV, Jiménez GM, López Lorenzo JL, Arias EG, Freiría C, Solé M, Ávila Idrovo LF, Hernández Castellet JC, Cruz N, Lavilla E, Pérez-Montaña A, Atucha JA, Moreno Beltrán ME, Moreno Macías JR, Salinas R, Del Rio-Garma J (December 2022). "Real-world effectiveness of caplacizumab vs the standard of care in immune thrombotic thrombocytopenic purpura". Blood Adv. 6 (24): 6219–6227. doi:10.1182/bloodadvances.2022008028. PMC 9792393 Check
|pmc=value (help). PMID 35930694 Check|pmid=value (help). - ↑ 10.0 10.1 Abou-Ismail MY, Zhang C, Presson AP, Chaturvedi S, Antun AG, Farland AM, Woods R, Metjian A, Park YA, de Ridder G, Gibson B, Kasthuri RS, Liles DK, Akwaa F, Clover T, Baumann Kreuziger L, Sridharan M, Go RS, McCrae KR, Upreti HV, Gangaraju R, Kocher NK, Zheng XL, Raval JS, Masias C, Cataland SR, Johnson AD, Davis E, Evans MD, Mazepa M, Lim MY (February 2024). "A descriptive analysis of fatal outcomes in immune thrombotic thrombocytopenic purpura in the USTMA TTP Registry". Blood Adv. 8 (3): 620–623. doi:10.1182/bloodadvances.2023010807. PMC 10838690 Check
|pmc=value (help). PMID 38100454 Check|pmid=value (help). - ↑ 11.0 11.1 Scully M, Hunt BJ, Benjamin S, Liesner R, Rose P, Peyvandi F, Cheung B, Machin SJ (August 2012). "Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies". Br. J. Haematol. 158 (3): 323–35. doi:10.1111/j.1365-2141.2012.09167.x. PMID 22624596.
- ↑ 12.0 12.1 Sukumar S, Brodsky M, Hussain S, Yanek L, Moliterno A, Brodsky R, Cataland SR, Chaturvedi S (February 2022). "Cardiovascular disease is a leading cause of mortality among TTP survivors in clinical remission". Blood Adv. 6 (4): 1264–1270. doi:10.1182/bloodadvances.2020004169. PMC 8864652 Check
|pmc=value (help). PMID 34461629 Check|pmid=value (help). - ↑ Benhamou Y, Assié C, Boelle PY, Buffet M, Grillberger R, Malot S, Wynckel A, Presne C, Choukroun G, Poullin P, Provôt F, Gruson D, Hamidou M, Bordessoule D, Pourrat J, Mira JP, Le Guern V, Pouteil-Noble C, Daubin C, Vanhille P, Rondeau E, Palcoux JB, Mousson C, Vigneau C, Bonmarchand G, Guidet B, Galicier L, Azoulay E, Rottensteiner H, Veyradier A, Coppo P (August 2012). "Development and validation of a predictive model for death in acquired severe ADAMTS13 deficiency-associated idiopathic thrombotic thrombocytopenic purpura: the French TMA Reference Center experience". Haematologica. 97 (8): 1181–6. doi:10.3324/haematol.2011.049676. PMC 3409815. PMID 22580997.
- ↑ "Presenting ADAMTS13 antibody and antigen levels predict prognosis in immune-mediated thrombotic thrombocytopenic purpura - ScienceDirect".