Abstract

Introduction:aHUS is a life-threatening, chronic, progressive disease of complement mediated thrombotic microangiopathy (TMA), commonly associatedwith pregnancy, 10-20% of all cases (P-aHUS), that usually occurs in late pregnancy and postpartum, primiparous women. Plasma exchange (PEX) may transiently maintain hematologic parameters, but does not treat the underlying systemic disease. Clinical studies have shown excellent effectiveness of eculizumab (Soliris®), the only complement inhibitor, used in PNH treatment. In 2011, eculizumab was approved for the treatment of aHUS. We report the 1st case of aHUS treated with eculizumab, in Greece, which was pregnancy related.

A 29 years old female, on the 16th week of gestation was referred, due to anemia (Hgb 6.9 g/dL) and thrombocytopenia (plt 78.000/μL). Family history: father with renal transplantation. Clinical examination: no abnormal findings. Laboratory exams: coagulation tests normal, low fibrinogen, 5-6 schistocytes/hpf, retics 12%, normal liver function, LDH 975 IU/L (normal range, nr 0-248), inDBil 2,5 mg/dl, ESR 41, CRP negative. Renal function was mildly deteriorated, urea 50 mg/dL, creatinine 1.3 mg/dL, proteinurea (urine protein 1 g/24h). The patient was diagnosed with pregnancy associated TMA and underwent daily PEX plus steroids. Partial response for the first 3-4 days. IVIgG was added. Rapid relapse with fall in Hgb, Hct, plt, schistocytes 6-8/hpf, decrease in fibrinogen, LDH and inDBil elevation. Pregnancy was terminated on the 8th day of hospitalization, by uterine section. She was transferred to the ICU: diffuse bleeding from operative wound/drains. She had daily PEX and RBCs, PLTs, FFPs, CPs transfusions, schistocytes 12-18/hpf. Rituximab 375 mg/m2/5 days × 5 cycles, begun 2 weeks after PEX initiation.

Diagnostic testing: antiphospholipid antibodies (PTTLa, anti-B2GPI, ACAs) negative, APC-R positive, FVL heterozygous, virology tests (anti-HIV, HBsAg, anti-HCV) negative, immunology tests (ANAs, anti-ds-DNA, anti-ENAs) negative, stool cultures negative, Verotoxin/E. Coli 0157 antibodies negative, PNH test by high sensitivity flow cytometrynegative, complement levels at the lower normal, normal ADAMTS13 activity. Post-operatively, daily PEX and RBCs, FFPs transfusions, replenish fibrinogen. Refractory arterial hypertension (furosemide, clonidine, amlodipine). Severe kidney involvement (urine protein 14-44g/24h). Laboratoryresults: Hgb 6.6 mg/dL, plt 52.000/μL, creatinine 1.04 mg/dL, inDBil 2 mg/dL, LDH1100 IU/L. So, the patient showing no response to treatments, was in poor clinical condition, multitransfused, with whole body edema.

The diagnosisof aHUS was confirmed by clinical and laboratory findings. The patient was vaccinated against Neisseria meningitidis with tetravalent conjugated, serogroups A, C, W-135, and Y (Menveo®) and serogroup Β strains (Bexsero®) and eculizumab was started,on day 47, in the suggested protocol, 900 mg/week × 4 weeks, 1200 mg, week 5, following maintenance with 1200 mg/2 weeks, indefinitely. She experienced immediate “weaning” from PEX withrapid and stable improvement of all pathological parameters andgradual resolution of proteinuria. Recent laboratory tests: normal blood counts, LDH 161 IU/L, creatinine 0.7 mg/dL, urine protein 1 g/24h. Renal biopsy performed after remission identified morphological (segmental double contour of glomerular basic membrane, focal segmental glomerular sclerosis and mesangiolysis) and immunohistochemical (subendothelial, subepithelial and mesangial IgM, C3d, C1q deposition), all consistent with TMA, HUS type. Molecular genetics by NG Sequencing for CFH, MCP, CFB, C3, CFI, THBD, CFHR5, ADAMTS13, C6A, C9B, C9, CFD and DGKE genes, identified no mutations known as a cause for aHUS, by now. However, aHUS is a genetically complex and heterogeneous disorder.

Conclusions: Therapy with eculizumab was life saving in our case, inducing rapid response of all active TMA markers and renal involvement recovery. Only 16% of P-aHUS occurs during the 2nd semester of pregnancy, as in our case. Multiple risk factors during pregnancy may trigger an acute episode of TMA in predisposed women and a contributing effect of hereditary thrombophilia plays a role in the pathophysiology of aHUS. The co-existence of hereditary thrombophilia, FVL heterozygous, might have played a role in the aHUS presentation during pregnancy, in our patient.

Disclosures

No relevant conflicts of interest to declare.

Author notes

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