calreticulin mutated essential thrombocythemia presenting as acute coronary syndrome

7232019 Calreticulin Mutated Essential Thrombocythemia Presenting as Acute Coronary Syndrome

httpslidepdfcomreaderfullcalreticulin-mutated-essential-thrombocythemia-presenting-as-acute-coronary 15

Case Report Calreticulin Mutated Essential Thrombocythemia Presenting as

Acute Coronary Syndrome

Bassel Nazha1 Gwenalyn Garcia2 Ruben Kandov3 and Marcel Odaimi2

983089 Department of Medicine Staten Island University Hospital Staten Island NY 983089983088983091983088983093 USA983090Department of HematologyOncology Staten Island University Hospital Staten Island NY 983089983088983091983088983093 USA983091Department of Cardiology Staten Island University Hospital Staten Island NY 983089983088983091983088983093 USA

Correspondence should be addressed to Bassel Nazha bnazhanshsedu

Received 983090983093 February 983090983088983089983093 Accepted 983089983090 April 983090983088983089983093

Academic Editor Eduardo Arellano-Rodrigo

Copyright copy 983090983088983089983093 Bassel Nazha et al Tis is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Essential thrombocythemia (E) is a myeloprolierative neoplasm characterized by a clonal expansion o megakaryocytes E canresultin both arterial andvenous thrombosis Involvement o the coronary arteries has been reported Patients who harbor a CALRmutation are hal as likely to suffer a thrombotic event as compared to patients with a JAK983090 mutation We report a case o CALR-mutated E whose initial disease maniestation was a non-S segment elevation myocardial inarction

1 Introduction

Essential thrombocythemia (E) is a myeloprolierative neo-plasm characterized by a clonal expansion o megakaryocytes[983089] A Janus Kinase 983090 ( JAK983090) V983094983089983095F activating mutation ispresent in 983093983088ndash983094983088 o E cases An additional 983093ndash983089983088 o patients harbor mutations in the thrombopoietin receptorgene MPL Recently mutations in the calreticulin gene(CALR) havebeen shown to occur in 983094983095 o Epatients withnonmutated JAK983090 or MPL [983090]

E can result in both arterial and venous thrombosiswith the ormeroccurringmore commonly [983091] Te incidenceo acute coronary syndrome (ACS) in E has been reported

as 983090 in a series o 983096983097983089 patients and 983097983092 in a series o 983089983095983088patients [983092 983093]

JAK983090-mutated patients with E are over two times aslikely to suffer a major thrombotic event as compared toCALR-mutated patients [983094 983095] We present a patient with pre-

viously undiagnosed CALR-mutated E whose initial diseasemaniestation was a non-S segment elevation myocardialinarction (NSEMI)

2 Case Presentation

A 983093983088-year-old male presented to the emergency departmentwith a three-day history o progressive retrosternal chest

pain His medical history was signi1047297cant only or acutediverticulitis one year prior to current presentation and a 983091-pack year smoking history He had no history o diabeteshypertension or dyslipidemia He denied personal or amily history o cardiovascular diseases hypercoagulable states orbleeding disorders A review o systems was negative orheadache visual disturbances pruritus easy bruising orerythromelalgia

On presentation the patientrsquos blood pressure was983089983091983089983096983091mm Hg and heart rate was 983096983092 beatsminute Hewas in moderate distress due to pain Auscultation o thelungs revealed clear breath sounds Cardiac exam was

unremarkable No hepatosplenomegaly was detected onpalpation Tere was no erythema or rash on skin exam

Te patientrsquos initial CBC revealed a hemoglobin o

983089983092983094 gdL hematocrit 983092983091983097 WBC count 983089983091983089983088983088mm3 and

platelet count 983089983088983090983094983088983088983088mm3 During his previous emer-gency department visit or acute diverticulitis his platelet

count was 983097983095983094983088983088983088mm3 Tis was elt to be reactive due toacute in1047298ammationand he was discharged on a courseo oralantibiotics He had no subsequent outpatient ollow-up

An electrocardiogram showed a normal sinus rhythmwith wave inversions in leads III and aVF (Figure 983089) Hisinitial troponin I was 983088983089983093 ngmL A repeat level 983094 hourslater increased to 983090983096983091 ngmL suggesting cardiac ischemia

Hindawi Publishing CorporationCase Reports in Hematology Volume 2015 Article ID 161764 4 pageshttpdxdoiorg1011552015161764



983090 Case Reports in Hematology

I

II

III

VI

II

V5

aVR

aVL

aVF

V1

V2

V3

V4

V5

V6

F983145983143983157983154983141 983089 Admission electrocardiogram new showing wave inversions in leads III and aVF suggestive o cardiac ischemia

F983145983143983157983154983141 983090 Cardiac catheterization on hospital day 983089 with a thrombus(arrow) in the right coronary artery with an estimated 983094983088 occlu-sion

His LDL was 983089983088983095 mgdL HDL 983092983091 mgdL and triglycerides983097983096 mgdL His electrolytes BUN and creatinine and liverenzymes were within normal limits

Te patient was transerred to the coronary care unitwith a diagnosis o NSEMI A cardiac catheterizationrevealed a thrombus in the right coronary artery (RCA) witha 983094983088 stenosis and a IMI Grade II 1047298ow ( Figure 983090) Nopercutaneous coronary intervention (PCI) was perormeddue to a perceived high risk o complications speci1047297cally distal embolization given the high platelet count Tepatient was treated with aspirin 983096983089 mg daily prasugrel 983089983088 mgdaily enoxaparin 983089 mgkg every 983089983090 hours and hydroxyurea983089983088983088983088 mg every 983089983090 hours Four days later a repeat cardiaccatheterization showed normal coronaries with dissolutiono the previously ound RCA thrombus and no underlyingatherosclerotic plaques (Figure 983091)

F983145983143983157983154983141 983091 Repeat cardiac catheterization on hospital day 983093 withdissolution o the right coronary artery thrombus

A peripheral blood smear was signi1047297cant or markedthrombocytosis without an increase in immature myeloid ele-

ments Molecular studies were negative or JAK983090 mutationsin V983094983089983095F and exon 983089983090 and positive or a CALR mutation type983089 (del983093983090) esting or BCRABL translocations was negativeHence a diagnosis o E was made on the basis o the clinicalpresentation consistently high platelet count and presence o a clonal marker

Te patient was discharged home in stable conditionon hydroxyurea and low-dose aspirin His platelet count on

discharge was 983096983090983089983088983088983088mm3 wo months later his platelet

count normalized to 983091983090983088983088983088983088mm3 He continued to do wellwith no urther thrombotic or hemorrhagic complications Abone marrow biopsy then was hypocellular and revealed no1047297brosis dysplastic changes or increase in blasts Fluorescence



Case Reports in Hematology 983091

in situ hybridization panel or myelodysplastic syndrome wasalso negative

3 Discussion

E is a clonal myeloprolierative disorder that causes a

persistent increase in platelets Features associated with ahigh risk or thrombosis include age ge 983094983088 and a history o prior thrombosis Te presence o cardiovascular risk actorsconers additional risk While the degree o thrombocytosisas a risk actor is unclear interventions that lower the countreduce the requency o thrombotic events [983091 983096]

Cytoreductive therapy with hydroxyurea has been shownto decrease the incidence o thrombotic events by 983090983088 inhigh-risk patients [983097] Te combination o hydroxyurea andlow-dose aspirin was shown to be superior to the combi-nation o anagrelide and low-dose aspirin in the preventiono arterial thrombosis [983089983088] Our patient presented withNSEMI putting him at high risk or a subsequent throm-

botic event Tus we opted or treatment with hydroxyureain addition to dual antiplatelet therapy

In a retrospective clinical series o 983089983089983092983092 E patientsMontanaro et al report a 983089983092 annual rate o thromboticevents with coronary involvement being the third in termso requency [983089983089] Coronary thrombi are platelet-rich andmay occur at sites with no underlying atherosclerotic plaques [983089983090983089983091] In the presented case the repeat cardiac catheterizationthat was normal is consistent with a de novo thrombus orma-tion as a primary cause or the patientrsquos NSEMI Smoking isknown to increase the risk o arterial complications in E [983097]our patientrsquos three-pack year history may have contributed tothe event

Insufficient data exist to clearly guide the treatment o ACS in E PCI appears to have poor outcomes or throm-botic lesions since distal embolization o thrombotic materialofen occurs [983089983092] Tis was the reason why our team didnot attempt PCI during cardiac catheterization Nonethelesssuccessul cases o PCI or ACS in E are reported [983089983093 983089983094]Te combination o hydroxyurea and aspirin is an acceptedtreatment strategy or patients at high risk o thrombosis [983091]Anagrelide due to its increased risk o arterial thrombosiswhen compared to hydroxyurea [983089983088] as well as rare butserious cardiovascular side effects including ACS limits itsuse in patients with E and ACS [983089983095 983089983096]

Recently mutations in exon 983097 o the CALR gene have

been ound in 983089983093ndash983090983092 o the E population CALR mutationsare mutually exclusive with JAK983090 and MPL mutations Cal-reticulin is an endoplasmic reticulum protein that regulatescalcium homeostasis and quality control o proteins Teexact mechanism by which CALR mutations produce the Ephenotype is at present unclear [983094 983095]

CALR-mutated patients with E have been ound tohave higher platelet counts lower WBC counts and lowerhemoglobin values as compared to JAK983090-mutated patientsTeir clinical course is characterized by a thrombotic risk about hal that o JAK983090-mutated patients [983094 983095] o ourknowledge this is the 1047297rst reported case o ACS in a patientwith documented CALR-mutated E

Our case adds to the increasing body o literature doc-umenting ACS in the setting o E and normal coronary arteries Although CALR-mutated patients are considered tohave a more avorable clinical course as compared to JAK983090-mutated patients they remain at risk or major thromboticevents Further studies aiming at identiying distinct clinical

eatures o this newly discovered subset o patients with Eare warranted

Consent

A written and signed consent to publish the inormation wasobtained rom the patient prior to submission o the paper

Conflict of Interests

Te authors declare that there is no con1047298ict o interestsregarding the publication o this paper

References

[983089] J L Spivak ldquoPolycythemia vera and other myeloprolierativediseasesrdquo in Harrisonrsquos Principles of Internal Medicine D LLongo A S Fauci D L Kasper et al Eds chapter 983089983088983096McGraw-Hill New York NY USA 983089983096th edition 983090983088983089983090

[983090] Klamp1047298 H Gisslinger A S Harutyunyan et al ldquoSomaticmutations o calreticulin in myeloprolierative neoplasmsrdquo TeNew England Journal of Medicine vol 983091983094983097 no 983090983093 pp 983090983091983095983097ndash983090983091983097983088 983090983088983089983091

[983091] R L Levine and R V iu ldquoMyeloprolierative neoplasmsrdquo in American Society of Hematology Self-Assessment Program chap-ter 983089983094 pp 983089983097983096983089ndash983090983090983090983094 Cadmus Communications Richmond VaUSA 983093th edition 983090983088983089983091

[983092] A Carobbio J Tiele F Passamonti et al ldquoRisk actors orarterial and venous thrombosis in WHO-de1047297ned essentialthrombocythemia an international study o 983096983097983089 patientsrdquoBlood vol 983089983089983095 no 983090983090 pp 983093983096983093983095ndash983093983096983093983097 983090983088983089983089

[983093] C Rossi M L Randi P Zerbinati V Rinaldi and A GirolamildquoAcute coronary disease in essential thrombocythemia andpolycythemia verardquo Journal of Internal Medicine vol 983090983092983092 no983089 pp 983092983097ndash983093983091 983089983097983097983096

[983094] G Rotunno C Mannarelli P Guglielmelli et al ldquoImpact o calreticulin mutations on clinical and hematological phenotypeand outcome in essential thrombocythemiardquo Blood vol 983089983090983091 no983089983088 pp 983089983093983093983090ndash983089983093983093983093 983090983088983089983092

[983095] E Rumi D Pietra V Ferretti et al ldquoJAK983090 or CALR mutation

status de1047297nes subtypes o essential thrombocythemia withsubstantially different clinical course and outcomesrdquo Blood vol983089983090983091 no 983089983088 pp 983089983093983092983092ndash983089983093983093983089 983090983088983089983092

[983096] F Cervantes ldquoManagement o essential thrombocythemiardquoHematologyAmerican Society of Hematology Education Pro- gram vol 983090983088983089983089 pp 983090983089983093ndash983090983090983089 983090983088983089983089

[983097] S Cortelazzo G Finazzi M Ruggeri et al ldquoHydroxyurea orpatients with essential thrombocythemia and a high risk o thrombosisrdquo Te New England Journal of Medicine vol 983091983091983090 no983089983095 pp 983089983089983091983090ndash983089983089983091983094 983089983097983097983093

[983089983088] C N Harrison P J Campbell G Buck et al ldquoHydroxyureacompared with anagrelide in high-risk essential thrombo-cythemiardquo Te New England Journal of Medicine vol 983091983093983091 no983089 pp 983091983091ndash983092983093 983090983088983088983093




[983089983089] M Montanaro R Latagliata M Cedrone et al ldquoTrombosisand survival in essential thrombocythemia a regional study o 983089983089983092983092 patientsrdquo American Journal of Hematology vol 983096983097 no 983093pp 983093983092983090ndash983093983092983094 983090983088983089983092

[983089983090] E Alioglu N uzun F Sahin et al ldquoNon S-segment eleva-tion myocardial inarction in patient with essential thrombo-cythemiardquo Trombosis Journal vol 983095 article 983089 983090983088983088983097

[983089983091] M ekin S Gokaslan E Diker and S Aydogdu ldquoDevelopmento acute coronary syndrome in three patients with essen-tial thrombocythemia or polycythemia verardquo urk KardiyolojiDernegi Arsivi vol 983091983094 no 983089 pp 983091983093ndash983091983096 983090983088983088983096

[983089983092] J P S Henriques F Zijlstra J P Ottervanger et al ldquoIncidenceand clinical signi1047297cance o distal embolization during primary angioplasty or acute myocardial inarctionrdquo European Heart Journal vol 983090983091 no 983089983092 pp 983089983089983089983090ndash983089983089983089983095 983090983088983088983090

[983089983093] Watanabe H Fujinaga Y Ikeda et al ldquoAcute myocardialinarction in a patient with essential thrombocythemia whounderwent successul stentingmdasha case reportrdquo Angiology vol983093983094 no 983094 pp 983095983095983089ndash983095983095983092 983090983088983088983093

[983089983094] U Bildirici U Celikyurt and E Ural ldquoEssential thrombo-

cythemia a case o acute S-segment elevation myocardialinarction in a young emalerdquo Clinical Cardiology vol 983091983090 no983090 pp 983089983088983092ndash983089983088983093 983090983088983088983097

[983089983095] Y Lim Y Y Lee J H Kim et al ldquoDevelopment o acutemyocardial inarction in a young emale patient with essentialthrombocythemia treated with anagrelide a case reportrdquo TeKorean Journal of Hematology vol 983092983093 no 983090 pp 983089983091983094ndash983089983091983096 983090983088983089983088

[983089983096] G M Lin Y Chao and W B Wang ldquoAcute coronary syndromes and Anagreliderdquo InternationalJournal of Cardiology vol 983089983089983095 no 983089 pp e983089983095ndashe983089983097 983090983088983088983095



Submit your manuscripts at

httpwwwhindawicom




I

II

III

VI

II

V5

aVR

aVL

aVF

V1

V2

V3

V4

V5

V6

F983145983143983157983154983141 983089 Admission electrocardiogram new showing wave inversions in leads III and aVF suggestive o cardiac ischemia

F983145983143983157983154983141 983090 Cardiac catheterization on hospital day 983089 with a thrombus(arrow) in the right coronary artery with an estimated 983094983088 occlu-sion

His LDL was 983089983088983095 mgdL HDL 983092983091 mgdL and triglycerides983097983096 mgdL His electrolytes BUN and creatinine and liverenzymes were within normal limits

Te patient was transerred to the coronary care unitwith a diagnosis o NSEMI A cardiac catheterizationrevealed a thrombus in the right coronary artery (RCA) witha 983094983088 stenosis and a IMI Grade II 1047298ow ( Figure 983090) Nopercutaneous coronary intervention (PCI) was perormeddue to a perceived high risk o complications speci1047297cally distal embolization given the high platelet count Tepatient was treated with aspirin 983096983089 mg daily prasugrel 983089983088 mgdaily enoxaparin 983089 mgkg every 983089983090 hours and hydroxyurea983089983088983088983088 mg every 983089983090 hours Four days later a repeat cardiaccatheterization showed normal coronaries with dissolutiono the previously ound RCA thrombus and no underlyingatherosclerotic plaques (Figure 983091)

F983145983143983157983154983141 983091 Repeat cardiac catheterization on hospital day 983093 withdissolution o the right coronary artery thrombus

A peripheral blood smear was signi1047297cant or markedthrombocytosis without an increase in immature myeloid ele-

ments Molecular studies were negative or JAK983090 mutationsin V983094983089983095F and exon 983089983090 and positive or a CALR mutation type983089 (del983093983090) esting or BCRABL translocations was negativeHence a diagnosis o E was made on the basis o the clinicalpresentation consistently high platelet count and presence o a clonal marker

Te patient was discharged home in stable conditionon hydroxyurea and low-dose aspirin His platelet count on

discharge was 983096983090983089983088983088983088mm3 wo months later his platelet

count normalized to 983091983090983088983088983088983088mm3 He continued to do wellwith no urther thrombotic or hemorrhagic complications Abone marrow biopsy then was hypocellular and revealed no1047297brosis dysplastic changes or increase in blasts Fluorescence





3 Discussion












Consent




References



























httpwwwhindawicom





3 Discussion












Consent




References



























httpwwwhindawicom
















httpwwwhindawicom

calreticulin mutated essential thrombocythemia presenting as acute coronary syndrome

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