A new paradigm: Diagnosis and management of HSCT-associated thrombotic microangiopathy as multi-system endothelial injury

Abstract

Hematopoietic stem cell transplantation (HSCT)-associated thrombotic microangiopathy (TA-TMA) is now a well-recognized and potentially severe complication of HSCT that carries a high risk of death. In those who survive, TA-TMA may be associated with long-term morbidity and chronic organ injury. Recently, there have been new insights into the incidence, pathophysiology, and management of TA-TMA. Specifically, TA-TMA can manifest as a multi-system disease occurring after various triggers of small vessel endothelial injury, leading to subsequent tissue damage in different organs. While the kidney is most commonly affected, TA-TMA involving organs such as the lung, bowel, heart, and brain is now known to have specific clinical presentations. We now review the most up-to-date research on TA-TMA, focusing on the pathogenesis of endothelial injury, the diagnosis of TA-TMA affecting the kidney and other organs, and new clinical approaches to the management of this complication after HSCT.

Keywords: Complement activation; Eculizumab; Hematopoietic cell transplant; Kidney disease; TA-TMA; Thrombotic microangiopathy.

Fig. 1

Histologic examples of TA-TMA affecting various organs. (A) Renal cortex with glomeruli showing thickened capillary walls and occluded vessel lumens. Red blood cell fragments can be seen (arrows) trapped in the mesangial matrix (H&E stain; magnification ×200). Renal arteriole with separation of the endothelial cell layer and nearly occluded by endothelial debris (arrow heads) (H&E stain; magnification ×200). (B) Lung arteriole showing denuded endothelial layer with large amount of debris nearly occluding vascular lumen (star) Red blood cell fragments extravagated into interstitial tissue (arrow) (H&E stain; magnification ×200). (C) Submucosal arterioles of the small bowel showing injured endothelial cells and red cell extravasation (arrows). Vessel lumen is occupied by schistocytes and fibrinoid debris (star) (H&E stain; magnification ×200). (D) Brain MRI: hyperintense FLAIR signal involving the bilateral (left > right) cortex and subcortical white matter. Effacement of sulci suggests associated swelling. Findings are suggestive of posterior reversible encephalopathy (PRES).

Fig. 2

Algorithm for evaluation of pulmonary hypertension in HSCT patients with TA-TMA.

Fig. 3

Diagnosis and risk assessment algorithm for TA-TMA after HSCT.

Fig. 4

Molecular pathogenesis and potential treatments for thrombotic microangiopathy in the glomerular endothelium. The glomerular filtration barrier consists of fenestrated endothelial cells, the glomerular basement membrane, and the podocyte foot processes. In normal endothelium (bottom half of the figure), podocytes produce vascular endothelial growth factor (VEGF), which binds to receptors in the endothelial cells, maintaining the integrity of the microvasculature. Endothelial cells produce nitric oxide (NO) and prostacyclin (PGI2) and express thrombomodulin on their surface, preventing the activation of the coagulation cascade and complement. Tissue factor (TF) and von Willebrand factor (VWF) remain internalized, and factor H, factor I, and membrane co-factor protein (MCP) block the activation and amplification of complement [54,122,123]. In TMA (top half of the figure), the endothelium becomes damaged and activated. TF is expressed on the cell surface, binding factor VIIa (FVIIa) and VWF, which promote thrombus formation with activated platelets (brown ovals). Plasminogen activator inhibitor-1 (PAI-1) prevents fibrinolysis of the clot. Activated endothelial cells express adhesion molecules (E-selectin, ICAM-1, VCAM-1), permitting the local recruitment of antigen presenting cells (APCs) and lymphocytes. Angiopoietin-2 (Ang-2) is released from the endothelial cell and binds to the Tie2 receptor which leads to vascular destabilization and vascular leakage. Activated APCs expressed tumor necrosis factor (TNF), potentiating the inflammatory response. Activated lymphocytes produce potentially donor specific (DSA, solid organ transplant) or recipient specific (RSA, HSCT) antibody, which can activate the classical complement cascade. Anti-factor H antibody can prevent inhibition of the alternative complement pathway. Activated complement leads to generation of the membrane attack complex (MAC), which induces cell lysis. C4d remains covalently bound to tissue and is a marker of complement activation. Tissue damage and inflammation leads to fibrin deposition. Ultimately, albumin leaks into the urinary space when the integrity of the glomerular filtration barrier is lost [,,,,–127]. Potential treatments for TA-TMA are shown in the boxes. Defibrotide blocks PAI-1 and attenuates the effects of TNF. Rituximab may reduce the production of damaging antibodies (DSA, RSA, or anti-factor H antibody) and plasmapheresis may remove them. Plasmapheresis may also remove Ang-2. Eculizumab stops the progression of the complement cascade to the MAC. Finally, angiotensin converting enzyme inhibitor (ACE) or angiotensin receptor blocker (ARB) therapy reduces proteinuria, preventing inflammation and the progression of CKD [,–130].

Fig. 5

Alternative complement pathway dysregulation and endothelial injury. Activation of C3 by hydrolysis leads to formation of C3b with a reactive thioester moiety, which covalently binds to an endothelial cell surface. C3b binding is enhanced on endothelial cells injured through many convergent pathways. Once C3b is bound to the cell surface, Factor B binds to C3b and is cleaved by Factor D to its enzymatically active fragment Bb. The C3bBb complex serves as a C3 convertase, generating more molecules of C3b, which can in turn complex with new molecules of Bb, leading to amplification of this pathway. C3bBb bound to a second molecule of C3b (C3bBb•C3b) serves as a C5 convertase, which cleaves C5 into C5a and C5b. This fragment of C5b serves as a nidus for the formation of the lytic membrane attack complex (C5b-9) on the endothelial cell surface, furthering endothelial cell injury.

Fig. 6

Eculizumab administration and monitoring schema for HSCT patients with TA-TMA. First eculizumab dose for HSCT-associated TA-TMA should be given based on patient’s weight, as listed in the table (B) according to eculizumab package insert. Subsequent doses and administration timing will be adjusted based on CH50 monitoring. CH50 should be monitored each day during eculizumab induction therapy to determine when the next eculizumab dose is needed, since patients with TA-TMA often require eculizumab dosing more often than weekly in the beginning of the therapy to sustain a therapeutic eculizumab level. To maintain therapeutic eculizumab serum level of ≥99 µg/mL, CH50 level needs to remain adequately suppressed each day as follows: CH50 level should be maintained at less than 10% of the lower limit of normal, corresponding to 0–3 CAE if using a standard enzyme immunoassay or 0–15 CH50 units if the Diamedix hemolytic assay is used. Subsequent eculizumab doses need to be given when CH50 level becomes inadequately suppressed (defined as a CH50 level >3 by enzyme immunoassay and >15 by Diamedix hemolytic assay), but no longer than every 7 day intervals. If CH50 level remains inadequately suppressed by dosing less than 7 day intervals, dose should be increased by 300 mg/dose and daily CH50 monitoring should continue. If CH50 level is adequately suppressed for 7 days, then eculizumab induction doses should be given weekly. When steady CH50 suppression is achieved and hematologic TA-TMA parameters and plasma sC5b-9 level normalize (response), eculizumab should be advanced to a maintenance schedule as listed in table (B) based on patient’s weight, as recommended in eculizumab package insert. CH50 level shall be checked at least prior to each eculizumab dose to assure adequate dosing. If TA-TMA remains controlled after about 4 maintenance doses, eculizumab may be discontinued. Patient should be carefully monitored with twice a week LDH, CBC and differential, weekly urinalysis, and twice a week sC5b-9 for 4 weeks after eculizumab therapy is discontinued. Weekly CH50 level should be checked until it returns to normal. Anti-meningococcal prophylaxis should be provided from the start of the therapy until about 8 weeks after stopping eculizumab.