Transfusion and Apheresis Science 44 (2011) 257–262

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Transfusion and Apheresis Science

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Early diagnosis and management of postpartum hemolytic uremicsyndrome with plasma exchange

Manisha Shrivastava a,⇑, Gopesh Modi b,1, Rakesh Kumar Singh c,2, Seema Navaid a

a Department of Transfusion Medicine, Bhopal Memorial Hospital and Research Centre, Raisen Bye Pass Road, Near Karond Chowk, Bhopal 462038, MP, Indiab Samarpan Kidney Institute and Research Center, B-288, C Sector Shahpura, Bhopal 462039, MP, Indiac Chirayu Cardiac Centre, 6, Malipura, Bhopal 462001, MP, India

a r t i c l e i n f o

Keywords:Hemolytic uremic syndrome

Plasma exchangeThrombocytopeniaHemodialysis

1473-0502/$ - see front matter � 2011 Elsevier Ltddoi:10.1016/j.transci.2011.04.004

⇑ Corresponding author. Mobile: +91 94250122748309.

E-mail addresses: manishasdr@gmail.com (M. Sbhopal@rediffmail.com (G. Modi), singhrkdr@gmail.

1 Tel.: +91 755 4026900; mobile: +91 9424414026919.

2 Mobile: +91 9303132892.

a b s t r a c t

The likelihood of survival in cases of postpartum hemolytic uraemic syndrome (HUS) is ashigh as 80–90% with early diagnosis and aggressive treatment using plasma exchange (PE).The patients, referred to our center, diagnosed as postpartum HUS presented with throm-bocytopenia, microangiopathic hemolytic anaemia with or without fever and severe renalfailure, were managed aggressively with PE in conjunction with hemodialysis. All patientsshowed clinical improvement, along with laboratory indicators like normal renal functiontests, increased platelet counts and decreased lactic dehydrogenase levels. Awarenessamongst treating physicians, early diagnosis and treatment with PE could be the key fac-tors in reducing maternal mortality due to postpartum HUS in developing countries.

� 2011 Elsevier Ltd. All rights reserved.

1. Introduction

The thrombotic microangiopathies are a group of com-mon microvascular occlusive disorders characterized bythrombocytopenia, microangiopathic hemolysis and multi-organ dysfunction. These include hemolytic uremic syn-drome (HUS), thrombotic thrombocytopenia purpura(TTP), and a third rare event, confined to puerperium,termed as postpartum renal failure [1]. Amongst thethrombotic microangiopathies, TTP was first described in1924 by Moschcowitz as a pentad of thrombocytopenia,hemolytic anemia, fever, neurological abnormalities andrenal dysfunction in a 16 year old girl [2]. In 1955, Gasserand colleagues, introduced the term HUS in their descrip-tion of an acute fatal syndrome in children, characterizedby features very similar to TTP except the predominance

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hrivastava), kidney_com (R.K. Singh).8651; fax: +91 755

of severe renal abnormalities [3]. A clinical distinctionbased on multi-organ involvement in TTP and renalinvolvement in HUS is not always apparent [4]. Althoughmany attempts have been made to differentiate TTP andHUS, none of the proposed criteria clearly separates thetwo syndromes [5,6]. Even the most widely used criteria,the presence of neurological symptoms in TTP and of renalfailure in HUS, fails to distinguish TTP from HUS since neu-rological involvement has been observed in HUS also. Thefundamental pathological lesion, thrombotic microangiop-athy, is identical in TTP and HUS, and identical aetiologicalagents and pathogenetic mechanisms have been proposedfor both syndromes and thus the term TTP/HUS has beenused to describe the patients of thrombotic microangiopa-thy representing a spectrum of single disease.

During pregnancy, TTP usually presents in the secondtrimester [7] where as HUS usually occurs as a single epi-sode, immediately after or some weeks after the delivery[8]. Postpartum HUS is a rare (1 per 25,000 pregnancies),acknowledged problem in pregnancy, associated with highmaternal mortality and severe long-term morbidity [9].Early diagnosis and distinction of TTP–HUS from morecommon obstetric complications having similar features,preeclampsia and HELLP syndrome (hemolysis, elevated

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liver function tests, low platelets) are key clinical issuespresenting with diagnostic difficulties. Plasma exchange(PE) is the essential therapy for women with pregnancyassociated or postpartum TTP–HUS. The survival of pa-tients with otherwise fatal disease has dramatically im-proved from less than 10–80% [10]. The decision toinitiate PE therapy is based on judgment that spontaneousrecovery following delivery is unlikely and that progressivemulti-organ failure and death are possible. Over the yearsthe decreased stringency of classic diagnostic features(thrombocytopenia, microangiopathic hemolytic anaemia,neurologic and renal abnormalities) has lead to seven foldincrease in number of patients treated for TTP–HUS [11].However, in developing countries like India most patientsdeliver at home or primary health care units in rural areas,develop complications and die undiagnosed as a result oflack of awareness among the treating midwives, physiciansor obstetricians and unavailability of guidelines of referral.The facilities for PE and resources for patient transfer arealso limited in these areas.

We evaluated our experience of early management ofpatients diagnosed as postpartum TTP–HUS with PE. Theresponse of treatment in terms of clinical recovery wasexamined. We present herein the course of illness andtreatment outcomes of three patients in whom complica-tions necessitated the early initiation of PE.

2. Patients and methods

2.1. Patient characteristics

Cases I and II aged 27 and 25 years and case III aged30 years were referred on postpartum day 6, 5 and 3 fromlocal district hospital and from a government medical col-lege hospital, respectively (during 2004–2009) after theydeveloped complications. Case I was a primigravida whilecases II and III were multigravidae. All patients had anuneventful obstetric history, antenatal period and themode of delivery was by caesarian section with alive new-borns (cases I and II) and normal vaginal delivery with still-birth (case III). The onset of postpartum complicationsbegan on day 3 of delivery in cases I and II and only 3 hpost delivery in case III.

Table 1Patients characteristics.a

Features Case I

Age (Years) 27Gravida PrimiMode of delivery Term

LSCSb

Status of baby AliveObstetric history UneventfulAntenatal period UneventfulPostpartum onset Day 3Arrival at our hospital Day 6Referring hospital DistrictHospital stay 10 days

a Common signs and symptoms were pallor, oliguria, oedema, hematuria purb Lower segment caesarean section.

2.2. Clinical course

Though all patients presented with more or less similarclinical features of headache, nausea, vomiting, oedemaand purpura all over the body, their clinical course of ill-ness was different. Case I developed oliguric acute renalfailure, generalized pitting oedema of the upper and lowerextremities, blurred vision, purpuric patches all over thebody, anaemia and mild jaundice, 3 days after a caesareansection delivery. On day 4 of delivery, she developed fever,bodyache, pupuric spots on the injection sites with furtherreduction in urine output, haemoglobin levels 4.5 g/dl andplatelet count of 38,000/cumm, subsequent to which shewas shifted to another hospital for hemodialysis. Shereceived 4 units of packed red blood cells and 10 units offresh frozen plasma. Despite this her clinical conditioncontinued to deteriorate and on day 6 of delivery, shewas admitted in our hospital after she had two episodesof haematemesis. Almost a year later case II was referred,3 days following delivery by caesarean section, after devel-oping anuria, pallor and puffiness of face with oedema overextremities. On further deterioration of her condition shewas shifted to our hospital directly on day 6 of deliverywith suspicion of developing postpartum HUS. A fewmonths later case III was referred for management whenshe developed reduced urine output 4 h after still birth,normal vaginal delivery, deteriorated further on day threewith hematuria. A summary of comparison of basic charac-teristics of patients is presented in Table 1.

2.3. Laboratory investigations

All patients had a laboratory profile with in normal limitsimmediately after delivery. Lactic dehydrogenase (LDH) wasnot done in all cases after delivery. On arrival at the hospital,cases I, II and III had low haemoglobin levels (7.8, 9.2, 6.3 gm/dl) and platelet counts (39,000, 78,000, 60,000 per cu mm),raised LDH levels (908, 2950, 3850 U/L), blood urea levels(238, 194, 173 mg/dl), and serum creatinine levels (6.13,6.36, 7.7 mg/dl) respectively. All cases had normal coagula-tion profile, negative coomb’s test, the peripheral smearshowed the presence of schistocytes and helmet cellssuggesting microangiopathic hemolysis. Table 2 depicts

Case II Case III

25 30Multi (G-2, P2) Multi (G4, P3)Term TermLSCSb VaginalAlive StillbirthUneventful UneventfulUneventful UneventfulDay 3 4 hDay 5 Day 3District Medical college30 days 17 days

puric spots over extremities, nausea and vomiting.

Table 2Laboratory data of patients.

Investigation Hemoglobin (gm/dl) Platelet count (per cumm) Blood urea (mg/dl) Serum creatinine LDH (U/L)Normal range 11.5–16.5 1.5–4 � 1011 10–50 0.6–1.2 240–480

Case I Delivery day 10.8 200,000 20 1.2 NAa

On admission 7.8 38,000 238 6.13 980After PE 10 300,000 125 1.98 520At discharge 7.8 310,000 105 1.1 240

Case II Delivery day 10.2 250,000 22 1.1 NAa

On admission 9.2 78,000 194 6.36 2950After PE 9.0 290,000 22 3.15 656At discharge 9.7 320,000 51 2.2 360

Case III Delivery day 6.0 76,000 63 3.0 NAa

On admission 6.3 60,000 173 7.7 3850After PE 6.0 220,000 93 2.29 826At discharge 6.3 278,000 21 1.83 459

Note: Coagulation profile, liver function tests [bilirubin-direct and indirect, alanine transaminase (ALT) or serum glutamic pyruvate transaminase (SGPT),aspartate transaminase (AST) or serum glutamase oxalacetatic transaminase (SGOT), alkaline phosphate (ALP)] were within the normal limits and Coombstest was negative throughout the course of illness in all cases.

a Not available.

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the laboratory data of relevance on day of delivery and onadmission of the patients at the hospital.

2.4. Radiological investigations

In all three cases, ultrasound showed bilateral raised re-nal echogenicity suggestive of renal parenchymal diseasewhile the renal size was normal.

2.5. Diagnosis

All three patients were diagnosed as postpartum HUSon the basis of anemia (acute onset) with microangiopathicchanges (i.e., schistocytes, burr cells, or helmet cells) onperipheral blood smear, signs of renal injury (acute onset)evidenced by hematuria, elevated creatinine levels, raisedLDH levels and a low platelet count detected early in theillness.

2.6. Treatment with PE

Cases I, II and III were treated with 5, 5 and 4 high vol-ume PE procedures, respectively, using a cell separator(Haemonetics, MCS plus). All patients received PE therapythrough a percutaneous dual lumen central venous cathe-ter placed either in femoral or internal jugular vein. Thewhole blood flow rate was typically 80–100 ml/min.Replacement fluid used in all patients was blood groupspecific single donor plasma. All patients were put oncardiac monitors through out the procedures.

2.7. Treatment with hemodialysis

All three patients, under the specialized care of anephrologist, underwent hemodialysis for the treatmentof renal failure and were monitored by regular renal func-tion tests (Fresenius, USA, hemodialyser system).

2.8. Supportive treatment

Steroid therapy, seizure prophylaxis, anti platelet drugs,and blood transfusions were used as supportive manage-ment options.

3. Results

The duration of hospital stay was 10, 30 and 17 days incases I, II and III, respectively. After completion of all thecycles of PE cases I, II and III had hemoglobin levels (7, 9,6 gm/dl), platelet counts (300,000; 290,000; 220,000 per -cu mm), LDH levels (520, 656, 826 U/L), blood urea levels(125, 105, 93 mg/dl), serum creatinine levels (1.98, 3.15,2.29 mg/dl) respectively. The laboratory profile of cases I,II and III on the day of discharge from the hospital showedhemoglobin levels (7.8, 9.7, 6.3 gm/dl), platelet counts(310,000; 320,000; 278,000 per cu mm), LDH levels (240,360, 459 U/L), blood urea levels (105, 51, 21 mg/dl), serumcreatinine levels (1.1, 2.2, 1.83 mg/dl) respectively. A sum-mary of laboratory profile of the patients after treatmentwith PE and at the time of discharge from the hospital isshown in Table 2.

All patients showed clinical improvement followingaggressive treatment with PE therapy, as well the labora-tory parameters proportionately returned towards normallimits. Renal function tests returned to normal, plateletcount improved and LDH continuously decreased with PE(Fig. 1). Hemoglobin levels did not improve much even atthe time of discharge from the hospital in all cases.

Six months follow up of cases I and II was done whilecase III was lost on follow up. Cases I and II had hemoglo-bin levels 12.1 and 10.2 gm/dl, platelet counts 390,000 and408,000/cu mm; blood urea 40 and 48 mg/dl; serum creat-inine 1.1 and 2.41 mg/dl and LDH levels 93 and 333 U/L,respectively. Both cases were clinically doing well withno major symptoms or signs of any complications of thedisease.

Fig. 1. Improvement in key laboratory parameters after treatment with PE.

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4. Discussion

Most of the deliveries in India occur in small set upsincluding home and primary health centres. Many of themortalities and complications perhaps go unreported dueto lack of awareness amongst the treating midwives,nurses and doctors. The three cases reported by us, re-ferred to us from centres, which did not have a facility ofPE and specialized nephrology units, to our knowledge,are the only published reports of successful managementof postpartum HUS with PE from India. Moreover, the firstcase after successful treatment of otherwise 90% fatal dis-ease became an example of understanding the course ofthis disease and the possibility of its occurrence in ourobstetric settings. A retrospective study from USA for aperiod of 25 years (1972–1997) described only 11 out of275,000 women with 13 pregnancies complicated bythrombotic microangiopathy representing an incidence ofone per 25,000 births. In three pregnancies (23%), diseasedeveloped in mid-pregnancy and in 10 other the diseasedeveloped either peripartum (62%) or several weeks post-partum (15%) [9]. Thus the condition is uncommon occur-ring mostly immediately after delivery. In the above study,

a team of transfusion specialists, hematologists and neph-rologists made the diagnoses and decisions regarding ther-apeutic interventions, similar to our hospital setting andthe immediate survival of patients was good with promptand aggressive PE therapy. However, long-term morbidityand mortality was common, which could not be analyzedin our cases due to short duration of follow-up. PostpartumHUS is associated with poor prognosis in the long term butthe apparent improvement in survival in recent years aredue to earlier diagnosis, better management by early insti-tution of PE and dialysis. Recognition of efficacy of PE ther-apy in various randomised trials and reports has lead toearly diagnosis of TTP/HUS and the number of patientstreated for the disease has increased seven fold [12,13].Women in postpartum period with microangiopathic hae-molytic anaemia and unexplained thrombocytopenia withnormal coagulation profile and liver enzymes should bediagnosed as TTP/HUS and should undergo PE therapy.Two consecutive episodes of postpartum HUS with a goodoutcome have been reported in a single case that had twoprevious normal pregnancies and deliveries [14]. In ourcases prompt diagnosis was made on basis of clinicalexamination, laboratory investigations and clinical cause

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of the illness. Alternative diagnosis like HELLP syndromewas carefully excluded on the basis of appropriate investi-gations like coagulation profile and liver function tests [bil-irubin-direct and indirect, alanine transaminase (ALT) orserum glutamic pyruvate transaminase (SGPT), aspartatetransaminase (AST) or serum glutamase oxalacetatic trans-aminase (SGOT) and alkaline phosphate (ALP)]. TTP andHUS are considered overlap syndromes; however, in pastfew years the pathophysiology of inherited and idiopathicTTP has become better understood and clearly differs fromHUS. Recent genetic and molecular studies have shed morelight on the pathogenesis of thrombotic microangiopathyin atypical HUS, that is, disturbances of various aspects ofthe complement system, and in TTP, that is, von Wille-brand factor regulation by ADAMTS13, which are alsohelpful in the differential diagnosis [15]. The pathogenesisof inherited (Upshaw–Schulman syndrome) and idiopathicTTP is related to a deficiency of, or antibodies to, a metal-loprotease that cleaves vWF and ADAMTS13, respectively.This defect alone, however, is not sufficient to result inTTP as individuals with a congenital absence of ADAMTS13develop TTP only episodically. Additional provocative fac-tors have not been defined. An antibody to ADAMTS 13 isfound in many but not all sporadic cases of adult TTP/HUS. ADAMTS13 antibody-mediated TTP (idiopathic TTP)appears to respond best to PE therapy. ADAMTS13 levelsare generally reported to be normal in HUS, although occa-sionally they have been reported to be decreased. AsADAMTS13 assays improve, they may help in defining asubset that better fits a TTP diagnosis and may respondto PE therapy. Assays with sufficient sensitivity and speci-ficity to direct clinical management have yet to be defined[16]. Our follow-up has not shown any significant prob-lems so far with the patients, but women after successfultreatment could be tested for antigenic absence of ADAM-TS 13 to prevent further episodes during pregnancy. Onecase has been reported where a patient of pre-eclampsiadeveloped postpartum HUS. The authors have demon-strated the absence of HF1 (C-257T promoter region) andMCP mutations and a polymorphic variant of the HF1 gene(C-257T promoter region) by a genetic study [17]. We havenot subjected our patients to test assays like complementre exclusions, ADAMTS 13 or genetic studies due to limita-tion of resources and local unavailability of tests.

Response to PE therapy was excellent in our cases mak-ing the possibility of atypical HUS and hereditary TTP lesslikely than Primary or Idiopathic TTP/HUS. Periodic plasmainfusion may abort or prevent attacks in congenitally ADAMTS 13 deficient patients [18]. Idiopathic cases respondbetter to PE (78% response rate versus 63% for plasma infu-sion) [12]. In a prospective analysis of ADAMTS 13 activityand inhibitor levels in 37 adult TTP patients receiving PEtherapy, a mortality rate of 15% for idiopathic TTP and59% for nonidiopathic TTP was reported in addition to pre-dictive value of these assays in terms of outcome and tai-loring of treatment [19]. Plasma infusion or PE therapyhas not been shown to alter the overall course in atypicalHUS, the mortality is higher, approximately 25%, end stagerenal failure in 50% of patients with rejection in 20–50% ofthose transplanted [20]. Bringing attention to the outcomeof certain pregnancies in form of postpartum TTP/HUS will

definitely make obstetricians in developing countries,aware of the disease entity and management options avail-able. Early diagnosis of TTP–HUS and treatment with PE,regardless of the time during pregnancy, the presence ofhypertension, and the decision for delivery is critical.Persistence or progression beyond postpartum day threediminishes the hope for spontaneous recovery andstrengthens the indication for intervention with PE treat-ment [21]. The Oklahoma TTP–HUS registry where 301consecutive patients, who had their first episode of clini-cally diagnosed TTP–HUS, were enrolled, suggests thatthe risk for recurrent TTP–HUS with a subsequent preg-nancy may be low. With careful counseling and sharedassessment of risks by the patient and her physicians,and with careful prenatal management, a future pregnancyin such patients may be a safe and an acceptable decision[22]. The patients have to be on close observations duringfuture pregnancies and only long term follow up could behelpful to draw any conclusions regarding the diseaseoutcome.

5. Conclusions

Patients presenting with thrombotic microangiopathycan be saved with prompt diagnosis and aggressive PEtherapy. The treating midwives or clinicians must maintaina high index of suspicion for thrombotic microangiopathyand women in the postpartum period with unexplainedthrombocytopenia and haemolytic anaemia with normalcoagulation profile and liver enzymes should be diagnosedas suffering from TTP/HUS and undergo PE therapy. Manywomen present initially with symptoms that are non-spe-cific or may be confused with preeclampsia. In case of nonresponders to PE therapy other diagnosis like atypical HUSor hereditary HUS should be contemplated. Although a re-sponse to PE will not separate hereditary from IdiopathicTTP/HUS but the hereditary form has a 100% recurrencein pregnancy and could be prevented with prophylacticplasma therapy. However, there is a need for developingguidelines and increasing awareness for early diagnosis,primary treatment, transport and referral of such patientsto tertiary centers where appropriate facilities of urgentintervention with PE are available.

Acknowledgement

Sincere thanks to Pavesh Charokar, PGDCA, for assis-tance during preparation of the manuscript.

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