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Pediatria Polska - Polish Journal of Paediatrics
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vol. 96
Review article

Transplant-associated thrombotic microangiopathy

Tomasz Jarmoliński
1, 2

  1. Department of Bone Marrow Transplantation, Oncology and Paediatric Hematology, Wroclaw Medical University, Wroclaw, Poland
  2. Children’s Division, Five Holy Brothers Miedzyrzecki Hospital in Miedzyrzecz, Poland
Pediatr Pol 2021; 96 (3): 207–212
Online publish date: 2021/09/29
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Thrombotic microangiopathies (TMA) are a heterogenic group of diseases characterized by small vessel endothelial damage which lead to erythrocytes destruction, platelet consumption and end organ damage. The “endovascular disaster” causes platelet activation and sequestration resulting in formation of clots harming erythrocytes and closing microcirculation with clinical consequences in thrombocytopenia, hemolytic anemia and multiorgan failure [1]. Among TMA one can identify thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), HELLP syndrome (hemolysis, elevated liver enzymes, low platelet count), and transplant-associated TMA (TA-TMA), the last illness mentioned was recently excluded from secondary HUS. Simplified clinical classification of TMA is presented in Table 1, whereas more detailed classifications have been recently published elsewhere [2].
Although TA-TMA was initially reported after pancreas transplantation, it is rather unfrequently diagnosed amongst solid organ recipients [3, 4]. Owing to the fact that TA-TMA usually appears after hematopoietic stem cell transplantation (HSCT), derived both from bone marrow and peripheral blood, many authors define it as thrombotic microangiopathy related to HSCT [5]. Clinically TA-TMA differs from HUS with respect to the renal component – acute kidney injury (AKI) is not essential for the diagnosis and other renal symptoms like proteinuria and hypertension are earlier hallmarks of the disease. As a complication of HSCT TA-TMA occurs during the first 100 days after transplantation, typically at the end of 1st and in 2nd post-transplant month, regardless of the age and sex of donor and recipient, more often in allogeneic (allo-HSCT) than in autologous HSCT (allo-HSCT) [6]. The overall frequency is difficult to establish because of different diagnostic criteria – about 30 definitions of the disease have been enunciated and six of them are widely used (Table 2) [7-12]. Among them Jodele’s criteria derived from the experience of Cincinnati Children’s Hospital as well as the American multi-center studies are the only dedicated to pediatric population. Their applications allow us to recognize TA-TMA in 16% of children who underwent HSCT [13]. Mortality rate is very high reaching up to 90% in severe cases with multi-organ dysfunction syndrome (MODS). Risk factors in allo-HSCT pertain to recipient (congenital defects of complement system), treatment during peritransplantation period (busulphan and total body irradiation in conditioning, calcineurin inhibitors [CNI]), and “immunologic” HSCT complications (graft versus host disease [GvHD]; viral infections). In auto-HSCT TA-TMA appears almost exclusively in patients with neuroblastoma. There are some specific causes for this group of patients to be at susceptible to these peculiar risk factors e.g. repetitive platinum based chemotherapy, radiation to the kidney and tandem HSCT [14]. The central pathogenic event is endothelial destruction initiated by action of cyclosporine A, viruses (CMV, EBV, ADV) and stimulated donor’s lymphocytes T engaged in the process of GvHD [15]. Main role in further endovascular surface damage is played by complement system activated via classical and alternative pathway. At the end of both of them there is a formation of C5b-9 complex called membrane attack complex (MAC). C5b-9 is a pivotal particle in TA-TMA (Figure 1). Current researches highlighted important role of stimulated neutrophils producing a network of extracellular DNA fibers called neutrophil extracellular traps (NETs) in alternative pathway activation [16]. Clinical picture of TA-TMA consists of nonimmunologic hemolytic anemia (direct Coombs test negative), thrombocytopenia and symptoms reflecting endothelial injury-related organ failure derived from kidney, skin, heart, lungs, liver, intestines and central nervous system (Table 3). The diagnosis is confirmed by certain laboratory abnormalities. According to Jodele’s criteria 5 out of 7 events should be simultaneously detected: severe hemolytic anemia de novo (or red blood cell transfusion dependency), thrombocytopenia < 50 G/l de novo (or platelet transfusion dependency), elevated lactate dehydrogenase (LDH) activity (above upper normal value), schistocytes present in peripheral blood smear, arterial hypertension de novo (or necessity of essential intensification of antihypertensive treatment), proteinuria (> 30 mg/dl in two urine samples or Pr/Cr ratio > 2.0 mg/mg in morning urine), elevated plasma C5b-9 concentration (above upper normal value 244 ng/ml). In the case of typical histopathological picture of TMA in tissue biopsy no other criteria are required to establish a diagnosis [12].
A three-step protocol of treatment was historically proposed to stop endothelial damage and coagulation activation:
I – CNI withdrawal,
II – effective treatment of GvHD and/or viral infections and,
III – intravenous immunoglobulins ± defibrotide ± plasmapheresis ± rituximab [6].
Symptomatic management was comprised of antihypertensive drugs, transfusions of red blood cells and platelets and occasionally also renal replacement therapy. All these methods were of limited value and they didn’t improve prognosis in the most severe cases. In the early 21st century humanized monoclonal antibody against human complement compound C5 called eculizumab was introduced to the therapy of two complement dependent diseases: paroxysmal nocturnal hemoglobinuria and primary atypical HUS. It was first time successfully used in TA-TMA in 2011 by Chandran et al. and the patient was 34-year-old woman with TMA after combined kidney and pancreas transplantation [17]. Two years later de Latour et al. administered this biological agent to 61-year-old man with TA-TMA after HSCT performed for multiple myeloma and the patient recovered completely [18]. In 2014 Jodele et al. described a group of 6 children suffering from TA-TMA with MODS treated with eculizumab with good response in 4 of them [19]. Several studies comparing anti-C5 treatment to previous methods have been reported since that time. Preliminary results are promising but long-time follow-up presents high mortality caused by infections in eculizumab treated groups [20]. In the largest population of 64 children treated with the complement blocker reported by Jodele et al. eculizumab was effective in 64% of patients and 1-year post-HSCT survival improved from 16,7% in historical control to 66.0% [21]. This sophisticated first-line causative treatment should be reserved for high-risk TA-TMA only, defined as presenting proteinuria and elevated C5b-9 or one of those concomitantly with MODS (Table 4). The same authors noticed, that 65% of children affected with TA-TMA presented with congenital abnormalities in complement system, most often in inhibitory particles CFH i CFI [22].
There is no clear-cut data about the length of eculizumab treatment (Table 5). Current option is to stop the drug after TA-TMA sustainable resolution (or after 3 months of therapy), then supervise laboratory parameters and to restart in seldom cases when a relapse is diagnosed [6, 23]. Jodele et al. proposed pharmacokinetics/pharmacodynamics driven mode of treatment with eculizumab trough level, CH50 and C5b-9 measuring [21]. Last years new anti-C5 monoclonal antibody called ravulizumab was introduced to prolonged therapy [24]. In refractory cases recombinant bug C5 inhibitor coversin is tested [25]. It is worthy to point out that it was within our department where eculizumab was successfully administered for the first time in Poland to 19-year-old girl with TA-TMA after HSCT for acute myeloid leukemia. Improvement was achieved after one dose and three doses brought the remission of anemia, thrombocytopenia, dialysis-dependent AKI and severe skin changes [26]. Currently we are also taking part in phase III clinical trial for coversin.


The authors declare no conflict of interest.


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