https://orcid.org/0000-0001-5925-2753
Haematopoietic stem cell transplantation–associated thrombotic microangiopathy in SSc is a severe complication resembling scleroderma renal crisis.
Dear Editor, Autologous haematopoietic stem cell transplantation (HSCT) in dcSSc can improve outcomes significantly, but also carries risks of severe complications [1]. We report a case of dcSSc developing thrombotic microangiopathy (TMA) with multiorgan failure shortly after HSCT, resembling scleroderma renal crisis (SRC).
A non-smoking, Caucasian woman, with a history of breast carcinoma (complete remission after surgery) and pacemaker implantation after complete heart block, presented with RP, telangiectasias, skin thickening (modified Rodnan Skin Score (mRSS) of 14 in a diffuse pattern) and joint contractures at age 64. She had a positive ANA test but negative ENA. Despite 3 months of MTX (25 mg/week) followed by 2 months of MMF (3 g daily), skin involvement rapidly increased (mRSS 25) and she developed lung fibrosis. HSCT was chosen as the next treatment step and was done according to the non-myeloablative ASTIS (Autologous Stem Cell Transplantation International Scleroderma) regimen, including i.v. CYC and G-CSF for mobilization, followed by CYC and rabbit anti-thymocyte globulin (rbATG) and reinfusion of autologous CD34+ stem cells [1]. ACE inhibition was started prior to mobilization to prevent SRC. Mobilization and conditioning were uneventful. However, 3 days after stem cell reinfusion, the patient developed cardiac tamponade necessitating pericardiocentesis. The cardiac event was initially attributed to CYC-related toxicity. However, in the following days she also developed haematemesis, thrombocytopenia, hypertension, renal impairment (serum creatinine 250 µmol/l, proteinuria 1.9 g/l) and cardiac failure (troponin 754 ng/l, NT-proBNP 15.7 pg/ml). Blood tests showed haemolysis with normocytic anaemia (Hb 4.6 mmol/l), increased reticulocytes (203 × 109/l), high lactate dehydrogenase (1100 U/l), low haptoglobin (0.10 g/l), normal Coombs test and schistocytes, consistent with TMA (Fig. 1). The enzymatic activity of von Willebrand factor cleaving protease was normal (61%). Viral infections were excluded.
Blood results and mean arterial pressure in our patient over time
After haematopoietic stem cell transplantation platelet levels and haemoglobin dropped significantly, and lactate dehydrogenase (LDH) and creatinine levels increased, (A) the right y-axis shows haemoglobin (Hb) (mmol/l); the left y-axis shows thrombocytes (×109/l) and LDH (U/l); (B) the left y-axis shows creatinine (µmol/l); the right y-axis shows mean arterial pressure (MAP) (mmHg).
At this point, SRC was considered the cause of TMA, although risk factors like glucocorticoid use and anti-polymerase III auto-antibodies were absent and prophylactic ACE inhibition (enalapril 5 mg/day) had been applied. The patient was transferred to intensive care and treated with high-dose ACE inhibitor (lisinopril 20 mg/day), haemodialysis, diuretics and i.v. immunoglobulin (KIOVIG 75 g/day for 2 days). Despite treatment, renal and cardiac function deteriorated, suggesting an alternative cause of TMA. aPLs were not present, C3 and C4 levels were normal (C3 1.44 g/l, C4 0.45 g/l) and serum-induced ex vivo C5b9 formation on microvascular endothelial cells (HMEC-1; ATCC; Manassas; VA) was performed in order to detect endothelium-restricted complement activation (formation depicted as a percentage as compared with normal serum) [2]. In our patient, massive ex vivo C5b9 formation was found (i.e. 428%). Factor H auto-antibodies that affect complement regulation, described in some patients after HSCT [3], were not found. At this stage, HSCT-TMA with complement overactivation was suspected. Eculizumab was considered, but our patient decided to opt for euthanasia because of her poor health and prospects.
Although HSCT-TMA in haemato-oncological diseases has been described [4], no cases in SSc have yet been reported. The pathogenesis of HSCT-TMA is multifactorial. In the background of genetic susceptibility, endothelium damage can be triggered by external factors like medication and infections. High-dose chemotherapy, in this case CYC and rbATG, have been associated with endothelial damage and HSCT-TMA in haemato-oncological diseases. Endothelial injury triggers IL-8 release, neutrophil extracellular traps and eventually activates both classical and alternative pathways, resulting in C3B formation, C5 cleavage and formation of C5-B9 lytic membrane attack complexes. This process leads to more endothelium damage, and ultimately to ischaemia through microthrombi formation [4].
Recognition of HSCT-TMA remains challenging due to similarities with other complications in transplant settings [5]. Hypertension is often the first sign, followed by gastrointestinal and pulmonary bleeding, renal failure and cardiac failure due to cardiac tamponade or myocardial damage. Serum levels of C3B, C5-B9 and CH50 can be increased. Moreover, elevated C5-B9 levels and schistocytes indicate poor prognosis [4]. HSCT-TMA in haemato-oncological diseases is associated with high mortality, though in recent years promising results with C5 inhibitor eculizumab have been reported. An observational cohort of 64 children with HSCT-TMA demonstrating improved survival 1-year post-HSCT at up to 66% compared with a historical 17% [6]. Additionally, a review of cases [7] showed a response in 92% of 26 patients at 1 year follow-up. Notably, interventions seem most effective when administered at an early stage, before multiorgan failure has occurred [4].
HSCT-TMA resembles SRC in pathogenesis and clinical presentation, which further complicates early recognition [8]. Serum C5-B9, C3 and C4 levels can be decreased and kidney biopsies show C4d and C5-B9 depositions in SRC as well. Also, treatment with eculizumab has been described in SRC [8].
In conclusion, our case illustrates the diagnostic challenges and dramatic course of HSCT-TMA in SSc. Empirical treatment targeting complement activation, such as eculizumab, could be a promising addition to ACE inhibition and supportive care, although pre-existing SSc-related organ damage may compromise full recovery. More research is needed to gain insight into pathogenesis, risk factors and therapeutic strategies for HSCT-TMA in SSc.
Funding: The authors received no specific funding for this work.
Disclosure statement: The authors have declared no conflicts of interest.
Data availability statement
The data underlying this article cannot be shared publicly due to privacy of the individual.
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