H E M O S T A S I S

Treatment of refractory thrombotic thrombocytopenic purpurawith N-acetylcysteine: a case report

Gloria W. Li,1,2 Siayareh Rambally,1,2 Jasmine Kamboj,1,2 Sean Reilly,3 Joel L. Moake,1

Mark M. Udden,1,2 and Martha P. Mims1,2

BACKGROUND: Thrombotic thrombocytopenic purpura(TTP) is a life-threatening disease resulting in systemicmicrovascular thrombosis. The disease is caused byexcessive platelet (PLT) adhesion to ultra-large (UL)von Willebrand factor (VWF) multimers inadequatelycleaved by the processing enzyme ADAMTS-13. Whilemany cases respond to plasma exchange performedwith or without concurrent corticosteroids, treatmentof the 10% to 20% of patients with refractory diseaseis difficult. Experimental studies demonstrating thatN-acetylcysteine (NAC) inhibits PLT binding toendothelial cell–secreted and anchored UL VWFmultimers suggest that NAC may be useful in thetreatment of TTP.CASE REPORT: A 44-year-old woman presented withmalaise, confusion, chest and abdominal pain, andtransient visual loss. Laboratory results and peripheralblood smear were consistent with TTP. The patient wasbegun on plasma exchange and corticosteroid treat-ment, but after 10 days the PLT count was still lessthan 10.0 × 109/L and she developed a fever. Rituximabwas initiated, but the patient’s condition worsened andshe became comatose. Antibiotics were initiated, butcultures remained sterile. After 3 days of coma andfurther clinical deterioration, treatment with NAC wasbegun. The patient received a loading dose of150 mg/kg NAC intravenously (IV) over 1 hour. Within18 hours the patient awakened abruptly and begancommunicating with medical personnel. Plasmaexchange, corticosteroids, rituximab, and NAC infusion(150 mg/kg IV over 17 hr daily × 10 days) werecontinued and by Day 17 the PLT count was morethan 50 × 109/L. The patient fully recovered and wasdischarged on Day 31.CONCLUSION: This is the first complete report of aTTP patient treated with NAC. NAC was a safe andeffective supplementary treatment for refractory TTPin this patient.

Thrombotic thrombocytopenic purpura (TTP)is a hematologic emergency of excessive platelet(PLT) adhesion or aggregation and thrombosisin the systemic microvasculature often caused

by inadequate cleavage of hyperadhesive ultra-large (UL)von-Willebrand factor (VWF) multimers by ADAMTS-13.1-4 Standard treatment for acquired TTP involvesplasma exchange that provides functional ADAMTS-13activity and removes autoantibodies.5 Immunosuppres-sive therapy with corticosteroids and rituximab is oftenused if there is severely diminished ADAMTS-13 activitydue to autoantibody or in refractory disease.1,2,6 Alterna-tive therapies to inhibit the attachment of PLTs to UL VWFmultimers and decrease microvascular PLT adhesion oraggregation would be attractive.

VWF multimers are composed of polypeptide mono-mers linked via disulfide bonds, a structure similar tothat of the mucin component of mucus. In patientswith pulmonary disease, the free thiol group of inhaledN-acetylcysteine (NAC) decreases mucus viscosity byreducing disulfide bonds between mucin subunits.7,8

Experimental studies demonstrate that NAC may alsoreduce disulfide bonds in VWF and provide effectivetreatment in mouse models of TTP.7 We report a criticallyill patient with refractory TTP who recovered whenNAC was added to plasma exchange, corticosteroids, andrituximab.

ABBREVIATIONS: NAC = N-acetylcysteine; TTP = thrombotic

thrombocytopenic purpura; UL = ultra-large.

From the 1Department of Medicine, Section of Hematology

Oncology, Baylor College of Medicine; 2The Hematology

Service, Ben Taub General Hospital; and the 3Department of

Pharmacy, Harris Health Systems, Houston, Texas.

Address reprint requests to: Martha P. Mims, MD, PhD,

Department of Medicine, Baylor College of Medicine, One

Baylor Plaza, Houston, TX 77030; e-mail: mmims@bcm.edu.

Received for publication May 14, 2013; revision received

July 27, 2013, and accepted July 29, 2013.

doi: 10.1111/trf.12440

TRANSFUSION 2014;54:1221-1224.

Volume 54, May 2014 TRANSFUSION 1221

CASE REPORT

A 44-year-old woman with well-controlled diabetes andhypertension was hospitalized after a week of malaise,intermittent confusion, dizziness, chest and abdominalpain, dyspnea, yellow eyes, dark urine, and transientvisual loss. She had scleral icterus, tachycardia, and atender abdomen and was alert without confusion, weak-ness, or sensory deficit. Pertinent laboratory results arein Table 1. The blood smear demonstrated more than10 schistocytes per high-power field, polychromasia, andthrombocytopenia. Computed tomography was negativefor intracranial abnormalities.

The patient was diagnosed with TTP and givenplasma transfusion immediately, followed by daily plasmaexchange and oral prednisone. Plasma ADAMTS-13 level(by fluorescence resonance energy transfer assay) was lessthan 10%, and an inhibitor was present. On Day 6 afterseveral episodes of chest pain, a transient episode of left-sided numbness, and no improvement in blood counts,corticosteroid dose was increased to 125 mg methylpred-nisolone intravenously (IV) daily. The PLT count improvedslightly on Day 7, but subsequently declined with anabrupt increase in lactate dehydrogenase (LDH). Withcontinued decline in PLT count and the patient’s clinicalstatus, rituximab therapy was initiated on Day 10. On thesame day she became febrile (temperature, 39.7°C) andcomatose. Antibiotics were given, but cultures remainedsterile and she did not improve. Repeat ADAMTS-13 activ-ity was 10% with inhibitor again detected. After 3 days ofcoma (Day 13), treatment with NAC was begun basedon reports of its activity in vitro and in vivo (in mice) andher deteriorating condition (persistent coma, decrease inblood pressure, continued fever). A 150 mg/kg IV dose ofNAC was administered over 1 hour (11,086 mg in 200 mLof 5% dextrose in water) after plasma exchange. Cortico-steroids were switched to 40 mg of dexamethasone IVdaily. Eighteen hours after initiation of NAC therapy, thepatient abruptly awakened and (although confused)communicated with medical personnel. Daily NAC infu-sion continued for an additional 10 days at 150 mg/kgadministered over 17 hours after plasma exchange.Plasma exchange was performed twice on Days 15 and 16.

By Day 16, the PLT count improved to 25 × 109/L and LDHdeclined. On Day 17, dexamethasone was reduced, oncedaily plasma exchange resumed, and a second dose ofrituximab administered. Fever resolved and antibioticswere stopped (Day 18). Figure 1 summarizes the hospitalcourse. Renal function remained normal throughouthospitalization. Day 28 ADAMTS-13 activity was 65%.The patient was discharged (Day 31) with no confusionon dexamethasone. One week later, PLT count and hemo-globin (Hb) were normal.

DISCUSSION

Response to plasma exchange in TTP is variable andunpredictable;1,2,6 some patients improve rapidly whileothers have a prolonged or refractory course. The status ofpatients with refractory disease can deteriorate quickly,and subsequent interventions including escalating steroiddose, twice-daily plasma exchange, and rituximab infu-sion often fail to reverse rapidly the disease course.9-12

These patients may experience ongoing thromboticand bleeding events related to TTP, as well as infectionslinked to the plasma exchange catheter, steroid-inducedimmune suppression, and, in comatose patients, aspira-tion due to failure to protect the airway.

NAC has been proposed as a possible supplementarytreatment for TTP.7,13 Addition of NAC to plasma pro-longed time to formation of occlusive PLT plugs, and IVNAC injection into wild-type mice resulted in size reduc-tion of VWF multimers.7 Time to thrombus resolutionin both wild-type and ADAMTS13−/− mice improvedafter NAC infusion.7 Initially it was suggested that NACmight exert a beneficial effect on TTP by reducing the sizeof soluble VWF multimers; however, a more importantmechanism may derive from reduction of the A1 1278 to1458 disulfide bond, which is crucial for binding to PLTGPIbα. This concept is supported by studies demon-strating that NAC inhibits PLT binding to endothelialcell-secreted and anchored UL VWF multimeric stringswithout reducing the size of the EC-anchored UL strings.13

Based on the patient’s rapidly deteriorating condition,and the relative safety of NAC, we initiated treatment.Within 18 hours the patient abruptly became fully

TABLE 1. Laboratory data at admission, at discharge, and one week later

Variable Reference Admission Discharge1 week after

discharge

Hematocrit (%) 37%-47% 19.4 29.8 36.3Hb (g/dL) 12-16 g/dL 6.7 9.9 12.1White blood cell count (×109/L) 4.5-12 × 109/L 7.1 13 7.5PLT count (×109/L) 150-400 9 153 233Mean corpuscular volume (μm3) 82-92 97 106 101Reticulocytes (%) 0.5-1.5 17.4 3.3LDH (U/L) 84-246 1032 232Haptoglobin (mg/dL) 32-214 <7.5 146Prothrombin time (sec) 11.8-15 13.8

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conscious, and over the ensuing few days the PLT countrecovered and her clinical condition improved. Becauseher clinical course had been so difficult, corticosteroids,rituximab, and plasma exchange were continued until itwas clear that she would recover.

Although one could argue about which treatmentor combination of treatments led to the patient’s clinicalimprovement, several pieces of evidence support NACas the intervention that ultimately reversed this life-threatening TTP episode. First, the patient’s mental statusabruptly improved after NAC infusion in the face ofongoing deterioration over the previous few days. She didnot improve with increased steroid dose or institutionof rituximab, but within 18 hours of receiving NAC thepatient became fully awake and able to interact with hos-pital personnel. Interestingly, this occurred before anyimprovement in her PLT count. Corticosteroids alonedid not improve her clinical status and, in fact, PLT countdecreased when 60 mg of prednisone was changed to125 mg of methylprednisolone sodium succinate daily, a65% increase in corticosteroid potency. A subsequent sub-stitution of 40 mg of dexamethasone daily was unlikelyto have improved her condition abruptly. In a large reviewof pooled data from 100 patients with acute refractoryor chronic relapsing nonfamilial TTP, the median time toPLT recovery was 14 days after the first dose of rituximab,

consistent with the plasma half-life ofIgG antibodies that inhibit ADAMTS-13activity—which is weeks.12 Our patient’sPLT count began to increase within 6days of rituximab, but within 2 to 3 daysof NAC initiation, suggesting that theaddition of NAC was important in herrecovery.

This is the first complete reportof a TTP patient treated with NAC.We are aware of an additional patientreported to have refractory idiopathicTTP who did not respond to the addi-tion of NAC therapy, but did respond toeculizumab.14 Details on the dose andlength of NAC therapy for this patientare not included in the case report.Interestingly, the authors have recentlypublished a follow-up suggesting that,in fact, the patient had a disease processinvolving both TTP and atypical hemo-lytic uremic syndrome with normalADAMTS-13 levels measured at a timewhen he had thrombocytopenia and amutation identified in the complementfactor H gene.15 The initial dose of NACfor our patient was based on recom-mendations for acetaminophen toxicity(150 mg/kg IV over 1 hr). In the absence

of precedent in refractory TTP, we continued NAC forseveral days beyond PLT recovery as one would do withplasma exchange. These subsequent doses were infusedover 17 hours daily after plasma exchange with the ideathat after the loading dose, the longer infusion wouldmaintain effectiveness, but avoid the known side effectsof nausea, vomiting, and flushing. NAC has been associ-ated with increased blood loss and may reduce the activ-ity of vitamin K–dependent clotting factors.16,17 Thus,a potential contraindication to the use of NAC may beactive bleeding or high risk of bleeding. Our patientreceived NAC in the intensive care unit. She experiencedno bleeding, despite severe thrombocytopenia, and noanaphylactic reactions or other adverse effects. There areno data in the literature to guide clinicians in the use ofNAC to treat refractory TTP, although our experience sug-gests that in the absence of contraindications it is a safeand effective supplementary treatment for critically illpatients who are not responding to standard therapy. Athree-patient clinical trial testing the effect of adding NACto plasma exchange in TTP has recently been activatedand will add to our understanding of the role of NAC inthe treatment of TTP.18 This report of the use of NAC inone refractory TTP patient suggests that NAC may be asafe, inexpensive, and rapidly acting agent for the treat-ment of this disorder.

Fig. 1. LDH and PLT counts during hospital course. Daily corticosteroid doses are

shown in the boxes across the top of the figure. Timing of plasma exchange (PLEX)

is shown in the dashed boxes across the middle of the figure. Administration of NAC

is indicated in the shaded box. Open arrows represent rituximab administration

(375 mg/m2). Asterisk represents day the patient awakened from coma.

TREATMENT OF TTP WITH N-ACETYLCYSTEINE

Volume 54, May 2014 TRANSFUSION 1223

CONFLICT OF INTEREST

The authors report no conflicts of interest or funding sources.

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