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Utility of dynamic contrast-enhanced MRI to assess small bowel perfusion in paroxysmal nocturnal hemoglobinuria before and after eculizumab

Published:August 17, 2018DOI:https://doi.org/10.1016/j.ejim.2018.08.005
      Thrombosis is the leading cause of morbidity and mortality in paroxysmal nocturnal hemoglobinuria (PNH), accounting for 40–67% of deaths and is frequently observed in atypical sites, such as abdominal and intracranial veins [
      • Peacock-Young B.
      • Macrae F.L.
      • Newton D.J.
      • Hill A.
      • Ariëns R.A.
      The prothrombotic state in paroxysmal nocturnal hemoglobinuria: a multifaceted source.
      ]. Moreover, microvascular thrombosis are thought to be responsible for typical PNH presenting symptoms as dysphagia, abdominal pain, headache, and erectile dysfunction. There is now increasing interest in the identification of subclinical ischemic lesions by mean of highly sensitive radiologic techniques. Whole body MRI has been reported able to identify previously undiagnosed renal and bone infarctions in PNH [
      • Alashkar F.
      • Schemuth H.
      • Nensa F.
      • Dührsen U.
      • Schlosser T.W.
      • Röth A.
      The role of whole-body magnetic resonance imaging (WB-MRI) in patients with Paroxysmal Nocturnal Hemoglobinuria (PNH).
      ]. Moreover, in a pilot study of brain MRI evaluation in neurologically asymptomatic PNH patients, more than 50% of cases showed a white matter ischemic lesion, with an overall greater severity compared with an age and sex matched healthy population [
      • Barcellini W.
      • Scola E.
      • Lanfranconi S.
      • et al.
      Paroxysmal nocturnal hemoglobinuria (PNH): brain MRI ischemic lesions in neurologically asymtomatic patients.
      ]. Finally, Dynamic Contrast-Enhanced (DCE) MRI showed impaired mesenteric perfusion in PNH with abdominal pain, suggesting the possible micro-thrombotic origin of this symptom [
      • De Cobelli F.
      • Pezzetti G.
      • Margari S.
      • et al.
      New insights in abdominal pain in Paroxysmal Nocturnal Hemoglobinuria (PNH): a MRI study.
      ]. Today, eculizumab, a humanized monoclonal antibody that inhibits terminal complement activation, has dramatically changed the natural history of the disease, providing a 92% reduction in the risk of thromboembolism [
      • Peacock-Young B.
      • Macrae F.L.
      • Newton D.J.
      • Hill A.
      • Ariëns R.A.
      The prothrombotic state in paroxysmal nocturnal hemoglobinuria: a multifaceted source.
      ,
      • Hill A.
      • Rother R.P.
      • Wang X.
      • et al.
      Effect of eculizumab on haemolysis-associated nitric oxide depletion, dyspnoea, and measures of pulmonary hypertension in patients with paroxysmal nocturnal hemoglobinuria.
      ]. Here we evaluated the changes of vascular perfusion by DCE-MRI in two young women with PNH before and after eculizumab therapy. MRI imaging evaluation was performed as previously described4 on a 1.5 T MRI scanner (Achieva Nova; Philips Medical Systems, Best, the Netherlands) with high-performance gradients (maximum strength of 33 mTm1; slew rate of 150–180 mTm-1s-1) and a 16-elements SENSE phased-array coil. Areas under the signal-intensity curve from the time of injection of Gadolinium to 60 and 90 s post-injection (AUC60 and AUC90) were calculated by cubic interpolation and digital integration. Ktrans, a measure of capillary permeability, was calculated by measuring the accumulation of gadolinium-based contrast agent in the extravascular-extracellular space. All the measurements were performed in blind by two experienced operators. Due to the too small sample size, only descriptive statistics were performed. The study was approved by the Ethical Committee of Human Experimentation and patients gave informed consent in accordance with the Declaration of Helsinki. Fig. 1 (left panel) shows clinical and hematological parameters at diagnosis and after eculizumab therapy. The first patient was diagnosed in 1996 and displayed chronic anemia, mild neutropenia and thrombocytopenia together with altered hemolytic parameters and hemosiderinuria. Coombs test as well as assays for congenital erythrocyte membrane and enzyme defects were negative. Flow cytometry showed a PNH clone of 83% on granulocytes and 17.5% on erythrocytes. Bone marrow aspirate and trephine biopsy showed hypocellularity, with some myeloid and erythroid dysplastic features. Cytogenetic analysis demonstrated chromosome 8 trisomy on 3 out of 20 metaphases. Oral folic acid and repeated intravenous iron supplementation were performed and patient's hemoglobin levels maintained around 8–10 g/dL, with further increase of LDH levels (2–3 × ULN). During the follow-up, breakthrough hemolytic crisis (Hb nadir 6.8 g/dL and LDH increase up to 5.7 × ULN) concomitant to infections (flu-like syndrome and pharyngitis) occurred in 2007, 2008 and 2009, without thrombotic events or transfusion requirement. Since September 2012, the patient became symptomatic for abdominal pain, initially attributed to mild gastritis, with negative findings at esophageal-gastric endoscopy and ultrasounds. Eculizumab was proposed, given the clinical picture of symptomatic active-hemolytic PNH, but the patient repeatedly refused because she wished to become pregnant and no sufficient pregnancy safety data were available at that time. Between 2013 and 2015, 4 unsuccessful hormonal stimulations, along with anticoagulant prophylaxis with low molecular weight heparin, were performed. In the meanwhile abdominal pain and hematuria episodes became more frequent, and in April 2016, the patient accepted eculizumab therapy (anti-meningococcal vaccination for serotypes ACYW135 was performed). Since then she experienced progressive increase in Hb, platelets and neutrophil values, LDH normalization and abdominal pain resolution. The second patient presented to our outpatient facility to be screened for congenital hemolytic disease, as she was a young woman, already subjected to cholecystectomy at 15 years old, and suffering from mild chronic anemia, splenomegaly, and persistent abdominal pain. Ultrasounds showed 10.3 cm maximal spleen diameter, and gastro-esophageal endoscopy was negative. Laboratory data showed mild normocytic anemia with increased LDH (1.95 × ULN). Family history and assays for congenital hemolytic anemias, as well as Coombs test, were negative. Flow-cytometry showed a PNH clone of 69% on granulocytes and hemosiderinuria was strongly positive. Bone marrow examination was unremarkable, and both inherited and acquired causes thrombophilic conditions were excluded. Considering the presence of symptomatic hemolytic PNH, eculizumab was started after routinely anti-meningococcal vaccination for serotypes ACYW135. The patient experienced a rapid Hb increase to normal values, LDH normalization, and disappearance of abdominal pain. As shown in Fig. 1 (right panel) all perfusion parameters on duodenum, jejunum and ileum separately and on the whole small bowel were higher after eculizumab therapy than before treatment, mirroring an increase of the blood flow in the micro-circulation and a restoration of endothelial permeability. In particular, in the whole small bowel both the mean AUC60 and AUC90 increased after eculizumab (for the former from 94.81 ± 13.59 to 200.29 ± 26.28, and for the latter from 119.97 ± 7.27 to 249.97 ± 8.3). The same behaviour was seen in the whole small bowel for Ktrans (from 0.0330 ± 0.0071/min before to 0.0923 ± 0.0171/min after treatment). It is known that thrombotic events are driven by complement direct platelets aggregation/activation and endothelial damage11 through various mechanisms, including the release of high amount of free hemoglobin and subsequent depletion of nitric oxide (NO), a smooth muscle tone regulator [
      • Peacock-Young B.
      • Macrae F.L.
      • Newton D.J.
      • Hill A.
      • Ariëns R.A.
      The prothrombotic state in paroxysmal nocturnal hemoglobinuria: a multifaceted source.
      ]. Consistently, eculizumab has been shown to ameliorate endothelial dysfunction and consequent vasculopathy/ischemia by reducing nitric oxide depletion in PNH patients with pulmonary hypertension [
      • Hill A.
      • Rother R.P.
      • Wang X.
      • et al.
      Effect of eculizumab on haemolysis-associated nitric oxide depletion, dyspnoea, and measures of pulmonary hypertension in patients with paroxysmal nocturnal hemoglobinuria.
      ,
      • Hill A.
      • Sapsford R.J.
      • Scally A.
      • et al.
      Under-recognized complications in patients with paroxysmal nocturnal haemoglobinuria: raised pulmonary pressure and reduced right ventricular function.
      ]. In this report we observed a complete resolution of abdominal pain that is however not unique of PNH. The findings of DCE MRI evaluation before treatment were important to clarify the origin of the abdominal pain and to decide eculizumab initiation. Although further studies would be necessary to further confirm these preliminary data, the use and implementation of high sensitive MRI techniques is advisable and may help the decision to start therapy with complement inhibitors.
      Fig. 1
      Fig. 1Left panel: clinical and hematologic parameters of PNH patients at diagnosis and before/after eculizumab. t > ULN: times over the upper limit of normal. Median values at diagnosis: WBC were 3.68 × 103/mmc (range 1.7–7.04 × 103/mmc); PMN 2.22 × 103/mmc (0.5–3.7 × 103/mmc); PLT 160 × 103/mmc (38–362 × 103/mmc); Median values at last follow up: WBC 3.91 × 103/mmc (2.6–5.04 × 103/mmc); PMN 2.24 × 103/mmc (1.16–2.76 × 103/mmc); PLT 159 × 103/mmc (range 81–322 × 103/mmc); Normal ranges: WBC 4.8–10.8 × 103/mmc; PMN 1.50–6.50 × 103/mmc; PLT 130 - 400 × 103/mmc; Hb male 13.5–17.5 g/dL, Hb female 12.0–16 g/dL; LDH 135–214 U/L; Reticulocytes 20–100 × 103/mmc. Right panel: assessment of dynamic contrast-enhanced (DCE)-MRI parameters before and after eculizumab therapy: A) AUC60 and AUC90 in the whole small bowel B) AUC60 and AUC90 in duodenum, jejunum and ileum; C) Ktrans in the whole small bowel; D) Ktrans in duodenum, jejunum and ileum; Errors bars: standard deviations. AUC represents the integrated area under the contrast medium concentration–time curve at different time points post contrast agent injection (i.e. 60 and 90 s). Ktrans is a measure of capillary permeability calculated by measuring the accumulation of gadolinium-based contrast agent in the extravascular-extracellular space.

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