INTRODUCTION

Thrombotic microangiopathy (TMA) is a rare but life-threatening condition, characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia and microvascular thrombosis that conditions ischemic injuries in different organs.^1-9 It consists of a spectrum of different disorders that damage the endothelium through multiple mechanisms.^1,3,5-8,10 Brocklebank V. et al published in 2018 a practical organization for TMAs classifying them as primary/secondary syndromes or as associated with infections.^1,8 Primary syndromes include thrombotic thrombocytopenic purpura (TTP), that results from ADAMTS13 deficiency, and complement-mediated TMA (formerly known as atypical hemolytic uremic syndrome [aHUS]).^1,3-5,7-10 Secondary TMAs may be due to multiple causes such as severe hypertension (HTN), drugs or glomerular diseases.^1,3-5,7-11 Lastly, TMAs may be associated with infections, as the Shiga toxin-mediated HUS (ST-HUS).^{1,3 4,8,10} These conditions encompass significant increased risk of mortality and morbidity (e.g. end stage renal disease), so that its early treatmentis crucial to improve prognosis.^1,3,4,10

Hypertension emergencies (HE) are a heterogenous group of acute hypertensive disorders defined as the presence of grade 3 HTN (≥180/110 mmHg) associated with acute HTN-mediated organ damage.^11,12 These patients frequently require treatment with intravenous blood pressure lowering agents to reach recommended blood pressure targets in the designated timings.^{11 12}

Lastly, Multiple Sclerosis (MS) is a chronic, inflammatory, demyelinating and neurodegenerative disease of the central nervous system, considered the commonest non-traumatic disabling disease to affect young adults.^5,13,14 Interferon-beta (IFN-β) is one of the most widely prescribed medications for relapsing-remitting MS with a well-established favourable safety profile.^{3,5 9,13, 15} Rare serious and potentially life-threatening side effects have been reported, which may have a fulminant clinical onset several years after a well-tolerated treatment.^3-5,9,15,16

CASE REPORT

We report a case of a 47-year-old female patient with relapsing-remitting MS, diagnosed 18 years ago and medicated with IFN-β 1-a (44mg, 3 times/week) since then. She had no other known medical conditions neither was under other medical treatment. There was no history of allergies.

The patient presented to the ED referring 8-day left eye hypovision. On physical examination, relevant findings were grade 3 HTN (blood pressure of 240/110 mmHg), bilateral upper-limb petechiae and mild hand and periorbital edema. Ocular fundus examination revealed grade III retinopathy.

Initial complementary exams performed demonstrated a TMA, composed of MAHA (hemoglobin of 9.7 g/dL; undetectable haptoglobin; lactate dehydrogenase [LDH] of 715 U/L; total bilirubin of 1.1 mg/dL; peripheral blood smear evidencing schistocytes; negative direct coombs test) and thrombocytopenia (platelet count of 57 000). Acute kidney injury (AKI) (serum creatinine of 3.7 mg/dL) was also present and urinary sediment revealed non-dysmorphic erythrocytes and proteinuria. Spot urine protein-to-creatinine ratio estimated a 24h proteinuria of 4g. Serum albumin was normal. Renal doppler ultrasound revealed symmetric normodimensioned kidneys and renal artery stenosis was excluded. Additionally, secondary myocardial injury (troponin level of 52.1 ng/L) was documented, with no electrocardiographic signs of myocardial ischemia. Echocardiogram evidenced normal thickened ventricular walls, no segmental kinetic changes, normal diastolic pattern and preserved ejection fraction. A cranioencephalic computed tomography scan was performed and excluded ischemic or hemorrhagic lesions.

The patient was admitted to the Intensive Care Unit and blood pressure lowering was immediately initiated with labetalol. Of the remaining complementary study gradually available, immunological study was unremarkable (antinuclear, antineutrophil cytoplasmic, antitopoisomerase I, anticentromere-B, antiglomerular basement membrane and antiphospholipid antibodies were negative as were rheumatoid factor) and there was no evidence of complement consumption. Also, HCV, HBV and HIV serologies were negative. In the absence of gastrointestinal symptoms, Shiga-toxin was not tested for. The ADAMTS 13 activity was normal. Additional causes of secondary HTN were also excluded (normal plasma and urinary 24h fractionated metanephrines, normal TSH and free-T4 and normal 24h urinary-free cortisol). Renin-angiotensin-aldosterone axis study was deferred because patient was under non-neutral treatment.

The diagnosis of INF-induced TMA was considered the most likely and IFN-β was withdrawal. Switch to oral anti-hypertensive drugs was made and blood pressure was maintained within the recommended targets. Hemolysis and thrombocytopenia resolved progressively, and serum creatinine decreased until it stabilized at value of 2.5 mg/dL.The patient was discharged at day 7, medicated with perindopril 10mg, amlodipine 10mg, furosemide 40mg and bisoprolol 5mg. During follow-up anti-hypertensive therapy was successfully down-titrated to perindopril 10mg, amlodipine 5mg and furosemide 40mg.During follow-up anti-hypertensive therapy was successfully down-titrated. There was no further evidence of hemolysis and kidney function improved progressively (at the 5 months follow up, serum creatinine was 1.5 mg/dL; CKD-EPI glomerular filtration rate of 41 mL/min/1.73m²). There was also no relapsing of MS.

DISCUSSION

Hypertensive emergencies are characterised by acute-HTN mediated target organ lesions due to severe HTN.^11,12 They may present differently, however, a classical example is that of malignant HTN, composed of grade 3 HTN with grade III or IV hypertensive retinopathy, AKI and/or TMA probably due to excessive secretion of renin leading to secondary hyperaldosteronism.^1,11,17 Many pathophysiological mechanisms have been involved in the development and maintenance of malignant HTN, however, initial triggers remain incompletely characterized.^11,15,17

The defining laboratory features of TMA comprise thrombocytopenia, resulting from platelet aggregation and consumption and MAHA, identified by evidence of erythrocyte fragmentation on peripheral blood smear. This occurs in areas of turbulent flow in the microcirculation due to partial occlusion by platelet aggregates.^1,3,5-7,9,10 Raised LDH results from cell lysis and tissue ischemia, haptoglobin is low and the direct coombs test is negative (except in pneumococcal HUS).^1,5,10 AKI is a common manifestation of TMA as consequence of kidney ischemic injury.^1,17

Once established the diagnostic criteria, etiologic investigation must be pursued to differentiate secondary from primary TMA, since there are specific treatments for TTP and complement-mediated TMA that should be initiated promptly.^1,4,11,18 Regarding the primary TMA syndromes, a normal ADAMTS13 activity excluded the diagnosis of TTP. As this assay is not immediately accessible, PLASMIC score may be applied to access the likelihood of TTP and the need for plasma exchange therapy. In our case, PLASMIC score was less than 4 points, consistent with a low risk of severe ADAMTS13 deficiency and no plasma exchange therapy was instituted.¹⁸ On the other hand, formerly exclusion of complement-mediated TMA may be difficult in clinical practice. Although decreased levels of complement factors or the presence of anti-complement factor H antibodies may suggest the disease, normal complement levels do not eliminate its possibility and therapy cannot be based exclusively on this.²⁰ In other case reports, authors describe empiric treatment with eculizumab given the difficulties in formally excluding the diagnosis.¹Beyond secondary TMA syndromes, severe HTN is one of the well-known implicated systemic disorders.^1,11 The presumably acute severe blood pressure elevation documented in our patient could have been the trigger and/or perpetuator of TMA. Although severe HTN may cause TMA as in malignant HTN, the endothelial damage induced by TMA can also promote blood pressure elevation, hindering to assure if is the cause or consequence.^1,10,19

IFN-β is a first-line immunotherapy for MS that may rarely course with renal toxic adverse effects.^3-5,9,16 The attribution of a causal relationship between a drug and development of TMA is difficult and requires high quality evidence.^5,6,15 As these drug-induced TMAs are rare and may occur after years of well-tolerated treatment, an association is unlikely to be detected in randomised clinical trials.^4-6,15 Therefore, causality with TMA is inferred from isolated case reports that mentioned toxic dose-related TMA occurring in MS patients treated with IFN for several years.^6,15,16 The pathophysiological mechanisms behind remains unexplained.^3-5 Consequently, many cases of INF-associated TMA have been reported in literature using diverse terms including complement-mediated TMA or malignant HTN, each implying a different pathophysiological process.⁶ A detailed clinical analysis of type I INF-induced TMA patients referred to a United Kingdom TMA reference centre reported by Kavanagh et al suggested that INF-β therapy was associated with a direct drug-induced TMA characterised by a gradual onset, exposure to high drug dose, for long periods and absence of immunogenicity.^3,6 It has also been reported that INF may cause endothelial cell damage directly by a decrease in vascular endothelial growth factor production.^3-5 Results of kidney biopsies performed were consistent with TMA.^5,16

Finally, in our case report, INF-associated TMA seems to have been the initial trigger for the acute blood pressure rising potentially through mechanisms of renal vasoconstriction and microvascular damage. Additionally, association between severe HTN and TMA is well described in malignant HTN and was responsible for hypertensive mediated target organ damage such hypertensive retinopathy.^4,17 Both TMA and severe HTN may have also contributed to the development of AKI. The cessation of the causal agent and blood pressure control allowed the TMA process to resolve and the renal function to progressively recover.

In conclusion, we intend to highlight that MS patients under treatment with IFN-β may have a regular control of blood pressure and renal function and clinicians shall have a high index of suspicion when these patients present with headache and/or HTN for an earlier recognition of this rare but severe adverse effect.^5,6,15

  BIBLIOGRAFIA  

References

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