Allogeneic reactivity–mediated endothelial cell complications after HSCT: a plea for consensual definitions

Simona Pagliuca, David Michonneau, Flore Sicre de Fontbrune, Aurélien Sutra del Galy, Aliénor Xhaard, Marie Robin, Régis Peffault de Latour and Gérard Socie

Article Figures & Data


  • Figure 1.

    Spectrum and pathophysiology of post-HSCT endothelial complications. The Venn diagram highlights the overlap of endothelial syndromes, both diagnostically and pathophysiologically, with GVHD. Many clinical and pathophysiological features of GVHD parallel those of other EC activation syndromes in which a single organ is targeted. Here, atherosclerosis and several delayed forms of IPS have been proposed as late endothelial dysfunction syndromes overlapping with chronic GVHD. DAH, diffuse alveolar hemorrhage; PERDS, peri-engraftment respiratory distress syndrome.

  • Figure 2.

    Proposed management of endothelial syndromes.


  • Table 1.

    Diagnostic criteria for TA-TMA

    Clinical/laboratory findingBMT-CTN criteria32IWG-EBMT criteria5Overall TMA criteria33Refined TMA criteria34
    Normal coagulation assays*YesYesYesNR
    Schistocytosis>2 per HPF on PS>8 per HPF on PS>2 per HPF on PSYes
    Increase in serum LDHYesYesYesYes
    Decrease in serum haptoglobinNRYesYesNR
    Negative Coombs testYesNRYesNR
    Renal and/or CNS involvementYesNRNRNR
    ProteinuriaNRNRNRRandom urinalysis proteinuria concentration ≥30 mg/dL
    HypertensionNRNRNR3-18 y: BP at 95th percentile value for age, sex, and height; >18 y: BP ≥140/90 mm Hg
    Terminal complement assayNRNRNRElevated plasma concentration of sC5b-9
    • Doubling of serum creatinine from baseline (baseline creatinine before hydration and conditioning) or 50% decrease in creatinine clearance from baseline.

    • BP, blood pressure; BMT-CTN, Blood and Marrow Transplant Clinical Trials Network; CNS, central nervous system; HPF, high-power field; IWG, International Working Group; LDH, lactose dehydrogenase; PS, peripheral smear.

    • * Coagulation assays included prothrombin time and activated partial thromboplastin time.

    • De novo, prolonged, or progressive thrombocytopenia (platelet count 50 × 109/L or 50% reduction from previous counts).

    • Parameters of severity of TMA, according to Jodele et al.34

  • Table 2.

    Principal studies reporting patients treated for endothelial syndromes

    ReferencesCharacteristicsPatients, nMedian age (range), yDiagnostic criteriaOnset, days from HSCT (range)Response rate or survival, n (%)
      Au et al93Retrospective rituximab (375 mg/m2 per wk × 4)548 (1-56)BMT-CTN42 (18-505)CR 4/5 (80)
      Jodele et al44Prospective biological study; rituximab (375 mg/m2 per wk for 2-10 courses)63.5 (2-17)O-TMA32 (9-111)CR 4/6 (67)
      Corti et al94Retrospective (40 mg/kg p.o. daily for 30-50 d)1226 (1-55)Hemolytic anemia, antiglobulin test (−), schystocytosis, haptoglobin ↓, LDH ↑, thrombocytopenia, CNS or renal involvement47 (9-100)CR 5/12 (42)/PR 3/12 (25)
      Yeates et al95Retrospective: median dose in ped: 30 mg/kg per d (range, 25-60); in ad: 400 mg/kg per d (range, 200-800)39 (22 ped/17 ad)8 (0-17)/40 (18-63)O-TMA51 (10-215)/33 (15-152)17/22 (77)/13/17 (77)
      Silva et al96Retrospective: 1-2 mg IV weekly or 0.2 mg IV daily (associated with PE and CCS)624.5 (13-35)Hemolytic anemia, antiglobulin test (−), LDH ↑, thrombocytopenia, CNS or renal involvement49 (19-110)CR 1/6 (17), PR 2/6 (33)
      Mateos et al97Retrospective: 1 mg once daily IV on days 1, 4, and 8 ± day 11718 (6-48)Anemia, LDH ↑, thrombocytopenia, schistocytosis49 (25-276)CR 6/7 (86)
      Jodele et al49Prospective: induction dose: 600 (<40 kg) or 900 mg (>40 kg); maintenance dose: 900 or 1200 every 14 d65 (2-10)O-TMA49 (6-390)CR 4/6 (67)
      de Fontbrune et al48Retrospective: induction dose: 900 mg weekly for 4 wk, followed by maintenance (1200 mg every 14 d)12 (3 ped/9 ad)39 (1.2-66)+121 (37-455)OR 6/12 (50)
      Jodele et al78Prospective: induction dose: 600 mg (<40 kg) or 900 mg (>40 kg), subsequent doses based on CH50 monitoring184.6 (2-15.2)Refined TMA30 (18-55)CR 11/18 (61)
      Bohl et al98Retrospective: 900 mg once weekly until clinical response, followed by maintenance therapy (1200 mg every 14 d)2448 (23-66)O-TMA180 (15-984)OR 13/15 (93)
      Yanik et al80Retrospective anti-TNF+CCS (2 mg/kg per d)1521 (1-60)14 (9-87)10/15 (66)
      Yanik et al81Prospective randomized ARM A: anti-TNF+CCS (2 mg/kg per d). ARM B: placebo + CCS (2 mg/kg per d).A: 16; B: 18A: 10/16 (62); B: 12/18 (66.7)
      Yanik et al92Prospective phase 2 anti-TNF+CCS (2 mg/kg per d)3911 (1-17)20 (6-119)20/39 (71)
      Thompson et al82Retrospective anti-TNF+CCS (2 mg/kg per d)2356 (35-72)233 (104-555)10/23 (43)
    • Note the lack of studies concerning endothelial syndromes other than TA-TMA and IPS.

    • ad, adults; BMT-CTN, Blood and Marrow Transplant Clinical Trials Network criteria; CCS, corticosteroid; CH50, complement inhibition 50; CR, complete response; LDH, lactate dehydrogenase; OR, overall response; O-TMA, overall TMA criteria; PE, plasma exchange; ped, pediatrics; p.o., by mouth; PR, partial response.