Thrombotic microangiopathies
Authors:
J. Novotný; M. Penka
Authors‘ workplace:
Oddělení klinické hematologie FN Brno, Jihlavská 20, 625 00 Brno
Published in:
Transfuze Hematol. dnes,26, 2020, No. 2, p. 80-90.
Category:
Overview
Thrombotic microangiopathies are a group of heterogeneous disorders characterized by disseminated microthrombosis in arterioles and capillaries resulting in consumption of platelets and microangiopathic haemolytic anaemia with potential end organ injury. The diagnosis may be complicated because of overlapping presentations of these disorders. Thrombotic thrombocytopenic purpura (TTP) may be diagnosed on the basis of severely decreased ADAMTS13 activity (a disintegrin and metalloprotease with thrombospondin motif 13), which is reduced below 10% with possible detection of an IgG inhibitor. The inherited form of TTP (Upshaw-Schulman syndrome) involves mutations of the ADAMTS13 gene with no inhibitor. Severe reduction of ADAMTS13 is activity leads to an increased concentration of ultra-large von Willebrand factor multimers with potent affinity to platelet glycoprotein Ib (GPIb) resulting in platelet aggregation. Treatment of choice of acquired TTP includes therapeutic plasma exchange with immunomodulation using corticoids and/or rituximab. The inherited form may be treated by plasma infusion only. Haemolytic-uremic syndrome is induced by shiga toxin producing Escherichia coli mainly in young children (typical haemolytic uremic syndrome). Shiga toxins are toxic to the endothelium and activate platelets. In such cases, there is serious impairment of renal functions often necessitating haemodialysis and even renal transplantation in some cases. The manifestation of typical haemolytic uremic syndrome is preceded by haemorrhagic diarrhoea. Therapy is mainly supportive. Atypical haemolytic uremic syndromes are induced by inherited disorders of the alternative pathway of complement activation due to mutations in genes of regulatory complement proteins. Some patients have factor H inhibitors. The main therapeutic approach in these forms is the administration of the complement factor C5 inhibitor eculizumab. Secondary forms of thrombotic microangiopathies are mainly seen in association with disseminated malignancies, pregnancy, auto-aggressive disorders, cobalamin C defect (cblC), infections, following solid organ or haematopoietic stem cells transplantation, malignant hypertension and may also be drug induced. The main differential diagnosis involves exclusion of disseminated intravascular coagulation associated with prolongation of global coagulation tests- aPTT and PT.
Keywords:
HELLP syndrome – thrombotic microangiopathies – haemolytic uremic syndrome – therapeutic plasma exchange – eculizumab – thrombotic thrombocytopenic purpura
Sources
1. Saha M, Mc Daniel JK, Zheng XL. TTP: pathogenesis, diagnosis and potential novel therapeutics. J Thromb Hemost. 2017;15:1889–1900.
2. Caggl M, Aigner C, Sunder-Plassman G, Schmit A. Thrombotische mikroangiopathien. Med Klin Intensivmed Notfmed. 2016;111:434–439.
3. Salaj P. Thrombocytopenické purpury. Vnitř Lék. 2005;91:854–860.
4. Kremer Hovinga JA, Coppo P, Lämmle B, et al. TTP. Nat Rev/Dis Primers. 2017;3:1–17.
5. Moschcowitz E. Hyaline thrombosis of the terminal arterioles and capillaries: a hitherto undesribed disease. Proc N Y Pathol Soc. 1924;24:21–24.
6. Scully M, Hunt BJ, Benjamin S, et al. Guidelines on the diagnosis and management of TTP and other TMAs. Br J Haematol. 2012;158:323–335.
7. Muia J, Gao W, Haberichter SL, et al. An optimized fluorogenic ADAMTS13 assay with increased sensitivity for the incestigation of patients with TTP. Thromb Haemost. 2013;11:1511–1518.
8. Jin M, Cataland S, Bissel M, Wu HM. A rapid test for the dia-gnosis of TTP using SELDI-TOF-mass spectrometry. J Thromb Haemost. 2006;4:333–338.
9. Mackie I, Langley K, Chitolie A, et al. Discrepancies between ADAMTS13 activity assays in patients with TMAs. Thromb Hameost. 2013;109:488–496.
10. Peyvandi F, Palla R, Lotta A, et al. ADAMTS13 assays in TTP. Thromb Haemost. 2010;8:361–340.
11. Fuchs TA, Kremer Hovinga JA, Schatzberg D, et al. Circulating DNA and myeloperoxidase indicate disease activity in patients with TMAs. Blood. 2012;120:1157–1164.
12. Amin Asnafi A, Jalati MT, Pezeshki SMS, et al. The association between HLAs nad ITP, TTP and HIT. J Pediat Hematol Oncol. 2019;41:81–86.
13. Coppo P. Management of TTP. Transfus Clin Biol. 2017;24:148–158.
14. Čermáková Z, Blahutová Š, Kořístka M, et al. První zkušenosti jednoho centra s použitím přípravku Octaplas v léčbě pacientky s vrozenou formou TTP. Transfuze Hematol Dnes. 2012;18:162–164.
15. Stubbs MJ, Low R, McGuckin S, et al. Comparison of rituximab originator (MabThera) to biosimilar (Truxima) in patients with immune-mediated TTP. Br J Haematol. 2019;185:912–917.
16. Peyvandi F, Scully M, Kremer Hovinga JA, et al. Caplacuzimab for acquired TTP. N Engl J Med 2016;374:511–522.
17. Coppo P. Treatment of autoimmune TTP in the more severe forms. Transfus Apher Sci. 2017;56:52–56.
18. Al-Samkari H, Grace RF, Connors JM. Ofatumumab for acute treatment and prophylaxis of a patient with multiple relapses of acquired TTP. J Thromb Thrombolys. 2018;46:81–83.
19. Vigna E, Petrungaro A, Perri A, et al. Efficacy of eculizumab in severe ADAMTS 13 deficient TTP refractory to standard therapy. Transfus Apher Sci. 2018;57:247–249.
20. Dane K, Chaturvedi G. Beyond plasma exchange: novel therapies for TTP. Hematology. 2018;1:539–547.
21. Chen J, Reheman A, Gushiken FC, et al. N-acetylcysteine reduces the size and activity of VWF in human plasma and mice. J Clin Invest. 2011;121:593–603.
22. Mancini I, Ferrari B, Vaisecchi C, et al. ADAMTS 13-specific circulating complexes as potential predictors of relapse in patients with acquired TTP. Eur J Inter Med. 217;39:79–83.
23. Karpman D, Loos S, Tati R, Arvidsson I. HUS. J Inter Med. 2017;281:123–148.
24. Desch K, Motto D. Is there a shared pathophysiology for TTP and HUS? J Am Soc Nephrol. 2007;18:2457–2460.
25. Laurence J, Haller H, Mannuccio Mannucci P, et al. aHUS: Essential aspects of an accurate diagnosis. Clin Adv Hematol Oncol. 2016;14(S11):2–15.
26. Dixon BP, Gruppo RA. Atypical HUS. Pediat Clin N Am. 2018;65:509–525.
27. He X, Ardissino G, Patfield S, et al. An improved method for the sensitive detection of shiga toxin 2 in human serum. Toxins (Basel). 2018;10(2):59.
28. Fakhouri F, Loirat Ch. Anticomplement treatment in atypical and typical HUS. Semin Hematol. 2018;55:150–158.
29. Dixon BP, Gruppo RA. Atypical HUS. Pediat Cli N Am. 2018;65:509–525.
30. Sahutoglu T, Basturk T, Sakaci T, et al. Can eculizumab be discontinued in aHUS? Case report and review of the literature. Medicine. 2016;95:31–37.
31. Kerboua KE, Haiba F, Batouche D. C3:CH50 ratio as a proposed marker for eculizumab monitoring in aHUS. J Immunoasay Immunochem. 2017;38:178–189.
32. Wong EKS, Kavanagh D. Diseases of complement dysregulation – an overwiew. Semin Immunopathol. 2018;40:49–64.
33. Fonseca JE, Mendez F, Catano C, Arias F. Dexamethasone treatment dose not improve the outcome of women with HELLP sy.: a double-blind, placebo controlled, randomized clinical trial. Am J Obstet Gynecol. 2005;193:1591–1598.
34. Gumulec J, Šimetka O, Procházka M, et al. Diferenciální diagnostika trombocytopenie v graviditě. Vnitř Lék. 2010;56(S1):91–97.
35. Wallace K, Harris S, Adison A, Bean C. HELLP syndrome: Patho-physiology and current therapy. Curr Pharmaceut Biotechnol. 2018;19:816–826.
36. Thomas MR, Robinson S, Scully M. How we manage TMAs in pregnancy. Br J Haematol. 2016;173:821–830.
37. Wang XD, Zhang S, Li L, et al. Ticagrelor-induced TTP. A case report and review of the literature. Medicine. 2018;97:26–31.
38. Krishnappa V, Gupta M, Shah H, et al. The use of eculizumab in gemcitabine induced TMA. BMC Nephrol. 2018;19:26–31.
39. Demirsoy ET, Mehtap O, Atesoglu EB, et al. Dasatinib-induced immune mediated TTP. Transfus Apher Sci. 2018;57:222–224.
40. Akkeson A, Zetterberg E, Klintman J. At the cross section of TMA and aHUS: A narrattive review of differential diagnosis and a problematization of nomenclature. Therap Apher Dialys. 2017;21:304–319.
41. Beck BB, van Spronsen FJ, Diepstra A, et al. Renal TMA in patients with cblC defect: review of an under-recognized entity. Pediat Nephrol. 2017;32:733–741.
42. Vaisbich H, Braga A, Gabrielle M, et al. TMA caused by methionine synthase deficiency: diagnosis and teratment pifalls. Pediat Nephrol. 2017;32:1089–1092.
43. Tran PN, Tran MH. Cobalamine deficiency presenting with TMA features. A systematic review. Transfus Apher Sci. 2018;57:102–106.
44. Massias C, Vasu S, Cataland SR. None of above: TMA beyond TTP and HUS. Blood. 2017;129:2857–2863.
45. Villafuerte LHM, Pena PJM, Inigo GP, et al. Severe renal failure and TMA induced by malignant hypertension successfuly treated with spironolactone. Ann Cardiol Angiol. 2018;67:208–214.
46. Haram K, Mortensen JH, Mastrolia SA, Erez O. DIC in HELLP syndrome: how much we really know? Maternal Fetal Neonat Med. 2017;30:779–788.
47. Zhu J, Chaki M, Lu D, et al. Loss of DGKE in mice causes endothelial distress and impairs glomerulal Cox-2 and PGE2 production. Am J Physiol Renal Physiol. 2016;310:F895–F908.
48. Ravindran A, Go RS, Fervenza FC, Sethi S. TMA associated with monoclonal gammopathy. Kidney Int. 2017;91:691–698.
49. Rathnayaka N, Ranathunga PAN, Kularelne SA. TMA, HUS and TTP following Hump-nosed Pit Viper envenoming in Srí Lanka. Wilderness Environ Med. 2019;30:66–78.
50. Román E, Mendizábal S, Jarque I, et al. Secondary TMAs and eculizumab: a reasonable therapeutic option. Nefrologia. 2017;37:478–491.
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Haematology Internal medicine Clinical oncologyArticle was published in
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