THROMBOTIC MICROANGIOPATHY. Jun-Ki Park 7/19/11

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1 THROMBOTIC MICROANGIOPATHY Jun-Ki Park 7/19/11

2 TMAs are microvascular occlusive disorders characterized by systemic or intrarenal aggregation of platelets, thrombocytopenia, and mechanical injury to erythrocytes. TMA is a descriptive name for the histologic abnormalities: - Thrombi in the glomeruli and arterioles. - EM: subendothelial widening of the glomerular capillary wall due to the deposition of fibrin-like material. - During healing, mucoid intimal thickening and then onion-skin hypertrophy of the interlobular arteries.

3 In addition to TTP and HUS, TMA may occur in other disorders, such as: - malignant HTN - scleroderma - anti-phopholipid antibody syndrome -SLE - preeclampsia - radiation nephropathy - renal allograft rejection - HIV infection - allogenic HSCT - disseminated malignancy

4 History Thrombotic thrombocytopenic purpura (TTP) Moschowitz described in 1924 as a new disease characterized by unique pathological findings of hyaline thrombi in many organs. Amorosi and Ultmann defined in 1964 the classic clinical features: - Thrombocytopenia - MAHA - neurologic symptoms - renal dysfunction - fever Hemolytic-uremic syndrome (HUS) First described by Gasser et al. in 1955 in a report of five children with acute renal failure who died with renal cortical necrosis. Current childhood HUS is a different disorder, noticed since 1980 with the appearance of Shiga toxin-producing Escherichia coli (usually E. coli O157:H7, most recent outbreak of O104:H4 )

5 Incidence D. R. TERRELL et al. Journal of Thrombosis and Haemostasis, 3: , 2005

6 For the 206 patients with an initial episode of clinically suspected TTP-HUS in whom the decision to initiate plasma exchange treatment was made, the clinical setting in which these patients presented included the following: Idiopathic 37 percent Drug-associated 13 percent Autoimmune disease 13 percent Infection 9 percent Pregnancy/postpartum 7 percent Bloody diarrhea prodrome 6 percent Hematopoietic cell transplantation 4 percent D. R. TERRELL et al. Journal of Thrombosis and Haemostasis, 3: , 2005

7 Definitions - TTP TTP: A syndrome of MAHA, thrombocytopenia with or without renal or neurologic abnormalities, without another etiology, such as systemic infection or another cause of TMA. Diagnosis of TTP requires treatment with PLEX. Congenital TTP (Upshaw-Schulman Syndrome): A rare syndrome caused by congenital ADAMTS13 deficiency, may occur at any age. Treatment with plasma infusion sufficient.

8 Definitions - HUS Typical HUS: A syndrome of MAHA, thrombocytopenia and renal failure with a diarrhea prodrome caused by infection with Shiga toxin-producing bacteria. Primarily in children < 5yrs, ~90-95% if childhood HUS. E.coli O157:H7 most common etiology; most recent outbreak of HUS in Germany d/t serotype O104:H4 Occurs most frequently in children under 5 years with an incidence of 6.1 per , as compared with overall incidence of 1-2 cases per Atypical HUS: A syndrome of MAHA, thrombocytopenia and renal failure without a diarrheal prodrome. Primarily in children < 5yrs, 5-10% of childhood HUS; abnormalities of complements regulation may be the most common etiology.

9 Pathophysiology - TTP Monomers of vwf (280kD) are linked by disulfide bonds to form multimers ranging into millions of daltons. Multimeres of vwf are constructed within megakaryocytes and endothelial cells; stored within platelet alpha-granules and endothelial Weibel-Palade bodies. ADAMTS13 (vwf cleaving metalloprotesase) in plasma normally prevents the persistence of large multimers of vwf (ULVWF) and its entry in to circulation. Mutations in the gene for ADAMTS13 leads to familial TTP, acquired TTP usually characterized by presence of Auto-Abs against ADAMTS13.

10 Joel L. Moake NEJM 2002

11 Normal plasma contains VWF-cleaving activity JF Dong, Blood 2002

12 Cleavage of the ULVWF strings with adherent platelets by normal plasma, TTP plasma, or ADAMTS-13. JF Dong, Blood 2002

13 Plasma from patients with TTP did not cleave the ULVWF strings with adherent platelets JF Dong, Blood 2002

14 Effect of TTP plasma on the ULVWF-cleaving activity of ADAMTS-13 JF Dong, Blood 2002

15 Effect of TTP plasma on the ULVWF-cleaving activity of ADAMTS-13. Summary of multiple sample analyses. Results expressed as means SEM, n 3 JF Dong, Blood 2002

16 Gerorge JN, Blood 116 (20): , 2010

17 Joel L. Moake NEJM 2002

18 Joel L. Moake NEJM 2002

19 Pathogenetic Scheme of Atypical HUS H-M Tsai, Kidney International (2006) 70, 16-23

20 Plasma Exchange vs Plasma Infusion Rock GA et al. NEJM 1991; 325:392-7

21 Rock GA et al. NEJM 1991; 325:392-7

22 A companion study reported outcomes of 24 pts with oliguric renal failure who were excluded from the randomized trial because they could not be assigned to plasma infusion group because of risk of volume overload. The survival of these 24 pts treated with PLEX was 83%. (Rock GA et al. Transfusion 2002) These observations document that PLEX is beneficial for patients who meet the diagnostic criteria for TTP with or without renal failure.

23 Exceptions to General Recommendation of PLEX in TTP-HUS Secondary to HSCT or cancer treatment: From 23 Pts with clinical features of TTP after allogeneic HSCT who received PLEX, 22 died. Autopsies showed that systemic infection were the most common cause of death and demonstrated no e/o systemic microvascular thrombosis. These pts had renal TMA. Acute versus host disease was usual etiologies for MAHA and thrombocytopenia. To avoid unnecessary PLEX, the name of this syndrome has been changed to HSCT-associated TMA. There are only sporadical and anecdotal reports that suggest efficacy of PLEX for chemotherapy induced TTP-HUS (e.g. gemcitabine) George JN, Blood 116 (20): , 2010

24 Exceptions to General Recommendation of PLEX in TTP-HUS Post-diarrheal HUS in children The typical diarrhea-associated HUS of young children, most often caused by enteric infection by E. coli O157:H7, usually resolves spontaneously, following supportive therapy alone. PLEX may be considered in patients with severe neurologic abnormalities or persistent disease.

25 Gerorge JN, Blood 116 (20): , 2010

26 Athrombocytopenic Thrombotic Microangiopathy 30 yr retrospective cohort who underwent kidney biopsies before 2007 and were found to have intimal proliferaton and/or endothelial swelling with luminal fibrin deposition in arterial or capillary beds but no signs of vasculitis, acute rejections or extensive microthrombosis. De Serres and Isenring, NDT (2009) 24:

27 Athrombocytopenic Thrombotic Microangiopathy De Serres and Isenring, NDT (2009) 24:

28 De Serres and Isenring, NDT (2009) 24:

29 Athrombocytopenic Thrombotic Microangiopathy TMA lesions could present with normal PLT and lead to substantial renal damage quite commonly. These observations raise the concern that athrombocytopenic TMA may not be considered for timely therapeutic interventions based on current diagnostic criteria or because of delayed identification Prospective trials aimed at determining the usefulness of plasmapheresis in atypical forms of TMA needed.

30 THANK YOU!