Acquired as a paraneoplastic manifestation of pancreatic cancer

Abeer Arain1a , Ibrahim N Muhsen2 and Maen Abdelrahim1,3,4

1Houston Methodist Cancer Center, Houston Methodist Hospital, Houston, TX 77030, USA 2Department of , Houston Methodist Hospital, Houston, TX 77030, USA 3Cockrell Center for Advanced Therapeutic—Phase I program, The Methodist Hospital Research Institute, Houston, TX 77030, USA 4Weill Cornell Medical College, Institute of Academic Medicine, Houston, TX 77030, USA ahttps://orcid.org/0000-0001-6295-4318

Abstract

Acquired haemophilia is a severe haematological disorder characterised by the presence of anti-factor VIII antibodies. Although rare, it can lead to serious complications. Acquired haemophilia can be seen in patients with malignancies as a paraneoplastic phe- nomenon. This is a case of a 52-year-old patient who presented with haematuria and retroperitoneal bleeding soon after being diagnosed with pancreatic adenocarcinoma and subsequently was found to have acquired haemophilia. The treatment of underly- ing malignancy with chemotherapy may accelerate the eradication of anti-factor VIII antibodies. Case Report Keywords: acquired haemophilia, pancreatic cancer, inhibitor treatment, paraneoplastic phenomenon

Introduction

Acquired haemophilia (AH), although rare, has been associated with potentially serious Correspondence to: Maen Abdelrahim complications, such as life-threatening haemorrhages [1]. The incidence is about 0.2 to Email: [email protected] 1.48 per 100,000 population per year [2]. The mortality is between 8% and 44%, much 2020, :1053 higher compared with inherited haemophilia [2]. Unlike the traditional haemophilia, AH is ecancer 14 https://doi.org/10.3332/ecancer.2020.1053 not secondary to a familial history [2]. It occurs from the lack of immune tolerance lead- ing to the formation of autoantibodies (IgG oligoclonal or restricted polyclonal) directed Published: 04/06/2020 Received: 18/03/2020 against the functional epitope factor of factor VIII (FVIII) [3]. This results in increased clearance or neutralisation of FVIII [4]. Bleeding in AH is mostly in the form of mucosal, or Publication costs for this article were supported by ecancer (UK Charity number 1176307). deep subcutaneous and less commonly with haemarthrosis which occurs more in inher- ited haemophilia [4]. Copyright: © the authors; licensee ecancermedicalscience. This is an Open Access AH commonly presents in a biphasic age distribution. For instance, it occurs in women article distributed under the terms of the in the younger years mostly during the post-partum period due to the formation of anti- Creative Commons Attribution License (http:// creativecommons.org/licenses/by/3.0), which bodies. Among older patients, there is increased male predominance, between the ages permits unrestricted use, distribution, and of 68–80 years [5]. Most of the time, approximately 50%, the antibody formation is idio- reproduction in any medium, provided the original pathic in nature [6]. It is also can be associated with autoimmune disease, such as Grave’s work is properly cited.

ecancer 2020, 14:1053; www.ecancer.org; DOI: https://doi.org/10.3332/ecancer.2020.1053 1 the cancer with chemotherapy leadsto therecovery of hisfactor VIII levels. pancreaticcancer, andsoondeveloped severe refractory anaemiaand was diagnosed with AH inthesetting of malignancy. The treatment of We presentofa case a52-year-oldman presentedwho fatigue,with weight lossandabdominalpain, was found to have locally advanced malignancy [6]. disease, as well as hepatitiswith B or C,diabetesand pulmonary mellitus diseases. About10% of patients with AH have anunderlying ecancer 2020, 14:1053; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1053 extent of pancreatic mass (circled), pancreatic ductdilatation (yellow arrow) andthenarrow superior mesenteric artery (red arrow). artery (SMA)/superior mesenteric vein No (SMV). evidence of any regional lymphadenopathy or liver metastasis. The figure illustrates theapproximate Figure 1.CT Abdomen showed 3.5x2.5cmprimary tumour inpancreatic head/uncinate process mass with complete encasement of superior mesenteric 142 U/mL (ref 0–35U/mL). reportedmass pancreaticadenocarcinoma, patientthe was foundto have locally advanced disease nodistantwith metastases. CA19-9 was placedcommon inthe Post-ERCP,bile duct. patient was discharged hometo follow-upin theoncology clinic. The biopsy of thepancreatic dilatationductal was alsoreported. The patientunderwent endoscopic retrograde cholangiopancreatography (ERCP) andametal stent was in sizecm andencasingthesuperior mesenteric artery andoccluding thesuperior mesenteric vein near thesplenoportalconfluence. Biliary A CTof scan reportedabdomen the anewly-foundpancreatic mass inthepancreatic head/uncinated process (Figure3.5 ×2.5 1),about loss, diarrhoea,poor appetite andsevere nausea. ruralof part Texas for pancreatitis and was discharged home. The patient presented afew weeks later with progressive jaundice and weight medical orpast surgical history. The patient reported heavy alcohol andtobacco usefor >10 years. He was initially treated at ina ahospital Our patient was a52-year-oldman initiallywho presented to thehospital abdominalpain, with weight lossand fatigue. He hadnosignificant Case presentation 2

Case Report ecancer 2020, 14:1053; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1053 sided (thick arrow) andleft sided (thin arrow). It illustrates theasymmetry withright side retroperitoneal haemorrhage beinglarger insize. Figure 2.CT Abdomen showing severe anasarca andretroperitoneal haemorrhage. The figure shows thebilateral retroperitoneal haemorrhages both right and possiblecystitis. The patient received 1dose weekly of for rituximab 3 weeks at adoseof 375mg/m tion, cyclophosphamide andrituximab were considered, however, rituximab was favoured given thepatient presentation haematuriawith prednisone was started atand 1 mg/kg was alsogiven forfirst the 2 weeks followed by taperingcourse. Given theseverity of thepresenta- every 6hours andthenevery 12hours) and was usedinthefirst 2 weeks of admission,guidedby thepatient’s haemoglobin. Following that, were added. The recombinant factor VIIa was given at adoseof 70mcg/kg decreasingwith frequency (initially every 2hours, followed by wereon hold put at that timeand patient was started initially on recombinant factor VIIa (rVIIa), and afterwards prednisone and rituximab was sentand results shown high levels of factor VIII inhibitor which was 13.2(ref <0.5) with factor VIII of <1%.Plans for chemotherapy pointingperiod, towards decreased factor VIII activity. These results were suggesting thepresence of afactor inhibitor. Bethesda assay titer ity. Mixing studies revealed prolonged PT and PTT 1:1 mix correctionwith of PT and nocorrection of PTT and a 14.2 seconds post-incubation levels wereand patient’s normal coagulationfactors studies were unremarkable, except for severe decrease inhisfactor VIII activ- tive for spherocytosis or schistocytosis. A work-upof thepatient bleeding yielded no signs of acute haemolysis (or deep venous ), K given active haematuria.Mixing studies were ordered to further evaluation of thederanged panel.Peripheral smear was nega- 0.7–1.2 mg/dL andpatient’s baselineof 0.9mg/dL). Patient was initially managed with bloodtransfusions, intravenous fluids,IV (IV) (ref 23–36.0sec) andinternational normalisedratioof 1.4.Chemistry results showed acute renal injury creatininewith of 3.6mg/dL (ref showed elevated prothrombinof (PT) time 17.9seconds (ref 12–15seconds), elevated partialthromboplastin (PTT)of time 104.9seconds 4.5 g/dL (ref 14–18g/dL), mildleukocytosis of 12.17k/µL (ref 4.5–11.0k/µL),andnormalplatelet count of 202k/µL.Coagulation studies was found to have a newly-developed retroperitoneal bleed (Figure 2). Initial haematology labs reported severe anaemia Hbwith level of The patient, however, presented to theER dyspnoea,with fatigue, nausea,generalised abdominalpainandhaematuria. Upon imaging,he 2 ). 3

Case Report ecancer 2020, 14:1053; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1053 into consideration andsubsequently work-up shouldbetailored to theexclusion of theseetiologies. However, itismore commonin cases of haematologic cancers particularly myeloma [11]. These causesof bleedingdiathesis mustbetaken happen when there isaqualitative or quantitative decrease infibrinogen, secondarywhich canhappen to congenital andacquired diseases. in solidcancers but bleeding inhaematologicwith Dysfibrinogemia/hypofibrinogenemia malignancies. isanother important differential that Additionally, certain patterns of DICare seenindifferentof types cancer; for instance, DICislikely to present with hypercoagulable pattern dysfibrinogemia, etc.Certain cancers are atrisk of certain as diseases, such Acquired von Willebrand diseaseincasesof lymphoma[10]. patientcorrecton the therapy. Cancer patientsare atrisk of bleedingdisorders, multiple includingDIC,bleedingrelated to anti-coagulants, any possiblecause. Althoughthe priority isalways thestabilisation of thepatient, diagnosingthepatient to iscrucial beableto startthe invasion of large vessels by thetumour [3]. The approach to patients with bleedingdiathesis starts with abroad differential to avoid missing tois crucial thinkofit same time the other the differentials asfactorsuch VIII deficiency, disseminated intravascular coagulation (DIC)or with Acquiredin theform haemophilia of casereports Studieshave reportedassociation the of solidorgan asgastrointestinal such malignancies, stromal tumours, duodenalor pancreatic cancers for thephysician and further increases thechances of complications for thepatient, asincreasing such riskof bleeding[3]. associated about 10%of the time[6]The spontaneous emergence of factor VIII inhibitor in patients cancerwith creates a clinical challenge bleeding usually involvedand soft theskin, muscles Several tissues. diseases have beenassociated with AH inthe literature. Malignancies are is consideredAH to beassociated high riskofwith bleedingandincreased riskof complications asfrequent such haemorrhages [7].The Discussion however, later patient andthefamily wished to change goal of care to hospice. patientunfortunately developedseptic fromshock Gram-negative bacteraemia andsevere respiratory failure that was treated andstabilised, received hissecond cycle of chemotherapy usingtheGemcitabine andnab-Paclitaxel regimen (Figure started (along with Rituximabinfusions andhigh-dosesteroids which were alsogiven), anditreached to the value of 50%by thetimepatient doses of Rituximab, andcycle 1of chemotherapy. Steroids were tapered slowly. Factor VIII level started to increase asthechemotherapy was firstplanned andthe cycle was given while inpatient. Patient hadaprolonged stay hospital of 4 weeks hereceived andinthistime atotal of 3 AH, it was decided to start chemotherapy as soon as the patient is stable. Four cycles of dose-adjusted Gemcitabine andnab-Paclitaxel were The patient’s pancreaticcancer was found to beunresectable.Given hisclinicalpresentation with locally advanced pancreatic cancer and Figure 3.Increasing factor VIII level aschemotherapy was given, also shows timeline of other usedimmunosuppressive therapies. [8, 9].Bleeding canbeaconsequence of chemotherapy induced side-effects, at but 3). Later, inhiscourse of treatment, 4

Case Report ecancer 2020, 14:1053; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1053 the final version of thedraft. AA andMA wrote thefirst draftof themanuscript. All authors vouch for theaccuracy andcontents of themanuscript. All authors approved Authorship contributions No fundingsupport was obtained. Funding statement None of theauthors declare any relevant conflicts of interest. Conflicts of interest ogy of antibodies formation inmalignancy. ered too. Nevertheless, initialefforts shouldbe targeted to the stabilization of patients. More arestudies needed to clarify the pathophysiol - a diagnosis that shouldbe considered in cancer patients presenting with bleeding; however, other causes of should be consid- immunosuppressivewith therapy,the initiationcase supports this of chemotherapy intreating acquired haemophilia. Acquired haemophiliais In thispaper, weofa case discussed acquiredtodue haemophilia pancreatic cancer. Few caseshave beenreported intheliterature. Along Conclusions cancer therapies. stabilisationto accelerate andaugmentsbenefitthe of AH-directed therapy andavoid recurrent admissions andinterruptions intheir primary chemotherapy regimen was started for primary malignancy. Our recommendation isto startchemotherapy casesoonafter insuch patient using therecommended protocols. Interestingly in our patient, theeradication of the antibodies against factor VIII was accelerated when sion. Thishighlights case importancethe of identifyingfactor VIII inhibitor, or in patientsAH, malignancywith andprompt management Rituximabinfusions [14,15]. We alsostarted chemotherapy for pancreatic cancer usinggemcitabine andnab-paclitaxel inthesameadmis- centres takes afew weeks to show response. clinical Therefore, along rituximab with high-dosesteroids isanalternative regimen beingusedat most [13]. Steroids aloneor incombination cyclophosphamidewith has alsobeenarecommended first-line therapy. This combination, however, therapy usuallythe recombinant includes factor VII or activated prothrombin complex concentrate isuseduntil thebleedingiscontrolled haemostaticthe therapy forhaemorrhage the andimmunotherapy inorder to eradicate theantibodies [8] . Atmost centres, thefirst-line highlighted thefirst-linetherapy for patient presenting bleeding secondarywith to acquired haemophilia. The two mainlinesof therapy are the treatment decisionsshouldbeguidedby theseverity of bleedingandnot by Bethesda titers [8].Different reports intheliterature have The coagulation profilebe thoroughly must checked mixing studies and and uponsuspicion, Bethesda assay shouldbe ordered. However, AH shouldbeconsidered inevery patient who comes an unexplainedwith bleedingepisoderegardless of theunderlyingcomorbidities [8]. Our patient likely benefited from thetherapy of AH given, high-dosesteroids, including andrVIIa. rituximab 3. The riseof factor reductionVIII andthe of antibody the were noticed around of thetime cycle 1 when thechemotherapy was administered. in our patient, he receivedwhen chemotherapy for pancreaticcancer, hehadasubsequent increase inhisfactor VIII levels asshown inFigure that chemotherapy, surgery or hormonal manipulation has led to the disappearance of factor VIII inhibitor reported were prostate cancer insolidtumours andchronic leukaemiainhaematological lymphocytic [9]. malignancies The study reported [12]. Sallah et al Studiesliteraturein the have reportedoutcomes the of patients the who have malignancy andare alsofound to have factor VIII deficiency [3, 8].For our patient, we opted for thecombination regimen andusedrecombinant factor VII initially along with steroids followed by studied a [9] retrospectivestudied analysis of 41 patients with cancer and acquired haemophilia. The most common malignancies [9]. Similar response was observed 5

Case Report 15. 14. 13. 12. 11. 10. ecancer 2020, 14:1053; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1053 References 9. 8. 7. 6. 5. 4. 3. 2. 1. org/10.1182/asheducation-2005.1.429 treatment hemophilia in perspectives Kessler CM(2005)New https://doi.org/10.1055/s-0038-1650169 Green DandLechner K(1981) Asurvey of patients non-hemophilic 215 Factortoinhibitors with VIII https://doi.org/10.1046/j.1468-0734.2001.00050.x WatsonChee HG, YL, andGreaves M(2001)Rare acquired bleedingdisorders https://doi.org/10.1097/SMJ.0b013e3181e1ddf9 PMID: Kumar(2010) Acquired B a paraneoplasticas hemophilia manifestation of gastrointestinal stromal tumor lambda light chainHaematologica 92e111https://doi.org/10.3324/haematol.11837 PMID: Dear A, Brennan SO, andSheatMJ, et al(2007)Acquireddysfibrinogenemia causedby production monoclonal of immunoglobulin HematolAm J 82(1)55–58https://doi.org/10.1002/ajh.20760 Eikenboom JC, Tjernberg P, and Van M, 124(5) 730–734PMID: SallahNguyen S, NP, and Abdallah JM, 19–27 PMID: disease autoantibody ofreview current a Sborov a: DWhemophilia andRodgers(2012) Acquired GM 3848(12)70019-1 PMID: Reevesand Key BN (2012) Acquired NS in malignancy hemophilia Acquired Haemophilia (EACH2) Registry BaudoF, Collins P, andHuth-Kuhne A, et al(2012)Management of bleedinginacquired hemophilia resultsA: from theEuropean https://doi.org/10.1080/10245330500276642 PMID: Franchiniand M Veneri(2005) Acquired D coagulation inhibitor-associated bleedingdisorders: anupdate Boggio LNandGreen D(2001)Acquired hemophilia case andreview of theliterature Case Rep Gastrointest Med 2012203801PMID:22966469PMCID:3432527 Murray NP, Moncada and MoranJC, (2012) Duodenal M tumor presenting asacquired hemophiliain an88-year-old woman: aclinical 152–153 https://doi.org/10.1016/j.thromres.2017.09.009 28917114 PMID: NapolitanoM andSiragusa (2017) ProlongedS treatment inpatients with cancer: Where do we stand? 3536(96)80067-9 PMID: Cohen and KesslerAJ (1996) Acquired CM inhibitors 22398803 10782157 22682137 8800509 et al(2000)Acquiredhemophilia inpatients with hematologic malignancies et al(2007)Acquiredoptions therapeutic and problems vonsyndrome:Willebrand diagnostic Blood 120(1)39–46https://doi.org/10.1182/blood-2012-02-408930 PMID: PMID: 6792737 Rev ClinExpHematol 5(4)389–404quizfollowing 31 16321808 20531061 Baillieres Clin Haematol Hematol Am Soc Hematol Educ Program 2005429–435https://doi. Thromb Res 129(Suppl https://doi.org/10.1016/S0049- 1)S66–S68 Rev ClinExpHematol 9(2) 331–354https://doi.org/10.1016/S0950- 18024387 Thromb Haemost 5(4) 405–429quizfollowing 31 Clin Adv Hematol Oncol

South Med J South Arch Pathol Lab Med 103(7) 704–705 22618709 Thromb Res 10(6) 443–449 45(3) 200–203 10(1) 158 6

Case Report