Acquired hemophilia A should be taken into account in the differential diagnosis of perioperative bleeding in patients without any apparent reason for activated partial thromboplastin time prolongation

CORTEGIANI, Andrea

Foresta, G

GIARRATANO, Antonino

Montalto, F

RAINERI, Santi Maurizio

RUSSOTTO, Vincenzo

Strano, MT

Clinical Case Reports

PubMed

Andrea Cortegiani

Vincenzo Russotto

Grazia Foresta

Francesca Montalto

Maria Teresa Strano

Santi Maurizio Raineri

Antonino Giarratano

Crossref

A perioperative uncontrollable bleeding in an elderly patient with acquired hemophilia A: a case report

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CASE REPORTA perioperative uncontrollable bleeding in an elderlypatient with acquired hemophilia A: a case reportAndrea Cortegiani, Vincenzo Russotto, Grazia Foresta, Francesca Montalto,Maria Teresa Strano, Santi Maurizio Raineri & Antonino GiarratanoDepartment of Biopathology, Medical and Forensic Biotechnologies (DIBIMEF), Section of Anesthesiology, Analgesia, Emergency and IntensiveCare, Policlinico “P. Giaccone”, University of Palermo, Via del Vespro 129, 90100, Palermo, ItalyCorrespondenceAndrea Cortegiani, Department ofBiopathology, Medical and ForensicBiotechnologies (DIBIMEF), Section ofAnesthesiology, Analgesia, Emergency andIntensive Care, Policlinico “P. Giaccone”,University of Palermo, Via del Vespro 129,90100, Palermo, Italy. Tel: 00390916552727;Fax: 00390916552715;E-mail: andreacortegiani@alice.itFunding InformationNo funding information provided.Received: 12 April 2013; Revised: 27 May2013; Accepted: 6 June 2013doi: 10.1002/ccr3.2Key Clinical MessageAcquired hemophilia A should be taken into account in the differential diagno-sis of perioperative bleeding in patients without any apparent reason for acti-vated partial thromboplastin time prolongation.KeywordsAcquired hemophilia A, bleeding disorders, bypassing agents.IntroductionAcquired hemophilia A (AHA) is a rare and potentiallylife-threatening hemorrhagic disorder. It is caused by theproduction of autoantibodies against factor VIII (FVIII)[1]. It could be associated with several underlying condi-tions as pregnancy, autoimmune disorders, drugs, andmalignancies. However, etiology remains unknown in upto 50% of cases [2]. Bleeding usually involves soft tissues,muscles, insertion sites of vascular accesses, retroperito-neal space and, eventually, traumatized tissues and organs.The diagnosis of AHA is usually based on an isolatedprolongation of activated partial thromboplastin time(APTT) in a bleeding patient without known coagulationdisorders, a low level of FVIII activity and a high level ofFVIII antibodies [3]. We report the case of a man admit-ted to our general intensive care unit (ICU) because of aperioperative uncontrollable acute bleeding, severeanemia, and isolated prolongation of APTT.Case ReportAn 82-year-old Caucasian man presented to the emer-gency room (ER) of the University General Hospital(Policlinico P. Giaccone) in Palermo, Italy, because of a3-day history of right lower back pain radiating to theabdomen and superficial bruising on the right lumbarregion. The day before, he had fallen in the bathroomduring a lipothymic episode. Thus, his general physicianreferred him to the ER, where he was admitted as “yellowcode” (necessitating urgent care). His past medical historyincluded hypertension (treated with carvedilol and furose-mide), chronic renal failure (stage II) [4], glaucoma, andcancer (hemicolectomy 7 years before and nephrectomy6 months before). Once arrived to ER, he was febrile(38°C), tachypnoic (26 breaths/min), and tachycardic(106 beats/min). Noninvasive blood pressure was 110/70 mmHg and peripheral O2 saturation was 99% on air.Inspection revealed bruising on the legs and on the rightlumbar region. Physical examination revealed a rigid, ten-der abdomen. Arterial blood gas analysis showed a pH of7.49, PaCO2 of 23 mmHg, PaO2 of 104 mmHg, HCO3of 17.4 mEq/L, and a base excess of 4.9 mmol/L. Labo-ratory tests revealed a hemoglobin (Hb) level of 7.6 g/dL,white blood count of 18.56 9 103 lL, serum creatinine of4.26 mg/dL, potassium of 7 mEq/L, and a myoglobin of1025 ng/mL. His first-line coagulation parameters wereplatelets 356 9 103 lL, international normalized ratioª 2013 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use,distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.1(INR) 0.96, APTT 101 sec (normal range 24–36 sec), andfibrinogen 705 mg/dL. Once asked, the patient denied anybleeding episodes or family history of coagulation disor-ders. A computerized tomography (CT) with contrastrevealed an active retroperitoneal bleeding. As soon ascalled on consultation, the surgeon suggested an explor-ative laparotomy, due to the active retroperitoneal bleed-ing and the recent trauma history. A preoperative dialysiswithout heparin was executed because of the high potas-sium level and the finding of peaked T-waves on electro-cardiogram. After hemodialysis, potassium level decreasedto 3.9 mEq/L and the patient was conducted to theoperating theater where general anesthesia was inducedwithout complications. The explorative laparotomyrevealed a blood congested right ileo-psoas muscle withan active, oozing and diffuse hemorrhage. Intraoperativearterial blood gas analysis and coagulation tests showed areduction in Hb level (6.6 g/dL) and an APTT >220 sec.The anesthesiologist started a transfusion of fresh frozenplasma (FFP) and packed red blood cells (PRBCs). As anadequate hemostasis was not achievable, the surgeon posi-tioned two retroperitoneal drains and sutured the bleed-ing abdominal wall. Then, the patient was admitted toour ICU under mechanical ventilation and sedation.Despite the preload optimization, he was hemodynamicallyunstable and norepinephrine infusion was started. The in-tensivist continued the transfusion of PRBCs and FFP andrequired clotting factors dosages. FVIII level was <2%(normal range: 50–150%). Lupus anticoagulant activitytest was negative. Suspecting an AHA, he requested thedosage of FVIII inhibitors and the result was 20.64Bethesda Units/mL. The hematologist suggested theadministration of FVIII inhibitor bypass activity (FEIBA,Baxter AG, Vienna, Austria) 50 international units/kg(I.U./kg) twice a day and methylprednisolone 125 mgonce a day. Despite antihemorrhagic therapy, clinical sta-tus and coagulation tests did not improve significantly.After an initial decrease (APTT 63 sec on day 1), APTTremained >100 sec and Hb levels continued to lower.Bleeding was clinically evident from the surgical wound,requiring several changes of surgical dressing (Figs. 1 and2). Moreover, it was also evident from arterial line andvenipuncture sites. On day 4, the intensivist, after a newhematology consultation, started a second-line bypassingtherapy with recombinant activated FVII (rFVIIa; Novo-Seven RT, Novo Nordisk AS, Bagsværd, Denmark)90 lg/kg every 3 h and added a prothrombin complexconcentrate (UmanComplex D.I, Kedrion, CastelvecchioPascoli, Italy) 2000 I.U. twice a day. Immunosuppressivetherapy was shifted to dexamethasone 8 mg/die. On day9, bleeding increased from the cited sites. Conjunctivaland mucosal hemorrhage and diffuse ecchymosis in theback appeared. He died on day 11.DiscussionAHA is a rare hemorrhagic disorder with an estimatedincidence of 0.2–1 million/year and a mortality rate of7.9–22% [3]. Demographic and clinical data of 501patients with AHA, included in the European AcquiredHaemophilia Registry (EACH2), have been recently pub-lished [5]. According to previous case series, no associ-ated medical condition is identified in 51.9% of cases [6].The average age at diagnosis is 74 with a positive linearcorrelation between incidence and age [5]. Cancer is asso-ciated with AHA in 11.8% of cases. The relationshipFigure 1. New surgical dressing. Day 1: 8.30 AM.Figure 2. Bleeding from surgical wound and insertion sites ofsurgical drains. Day 1: 10.30 AM.2 ª 2013 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.Perioperative Uncontrollable Bleeding and AHA A. Cortegiani et al.between hematologic malignancies and production ofFVIII inhibitors is well established but the correlationwith solid tumors is still unclear [6]. Although cancer wasreported in the past medical history of our patient, areview of his medical records revealed that both the colonadenocarcinoma and the renal pelvis urothelioma weretreated with radical surgery and neither signs (i.e., physi-cal examination and abdominal CT scan) nor symptomswere suggestive of a cancer recurrence or metastases. Thecancer markers, CEA and CA19.9, dosed 1 month beforeas part of a periodic follow-up, resulted within normalrange. Therefore, a definitive relationship between cancerhistory and AHA could not be established. Associatedautoimmune disorders are present in 11.6% of AHA cases[5]. In these patients, the level of inhibitors is usuallyhigh and do not decrease with steroid therapy alone [6].In our patient, despite the high level of inhibitors and thepoor response to steroidal therapy, the diagnosis of anunderlying autoimmune disease was refuted by negativeautoantibodies screening tests, negative personal and fam-ily history and the absence of any other clinical findingconsistent with an autoimmune disorder. A drug-inducedAHA was excluded as his chronic therapy had remainedstable for years without previous bleeding episodes, evenduring his previous two surgical interventions. Initialbleeding event is spontaneous in the majority of cases(77.4%). Trauma is recognized as the cause of the initialbleeding episode in only 8.4% of cases [5]. Although rela-tives reported a traumatic event during the lipothymicepisode, a source of bleeding was not identified duringsurgery. Moreover, it could be possible that the lipothy-mic episode was a consequence of the hypotension andthe low Hb level due to the underlying, spontaneousbleeding. After a benefit-risk analysis, surgery representedthe first-line treatment because of the CT-scan finding ofan active retroperitoneal bleeding and history of trauma.As soon as the diagnosis of AHA was confirmed, an anti-hemorrhagic treatment strategy was promptly started.Cornerstones of therapy are hemostatic treatment withbypassing agents and inhibitor eradication with immuno-suppressive therapy [7]. Bypassing agent is a definitionfor a drug with the property of promoting thrombin gen-eration bypassing platelets surface activity of activatedFVIII and IX (FVIIIa–FIXa, tenase complex) which islacking in AHA [8]. Both rFVIIa and FEIBA mechanismsof action were reinterpreted in light of the cell-basedmodel of hemostasis which, in contrast to the coagulationcascade model, provides an explanation of bleeding epi-sodes in AHA in spite of two different, though converg-ing, coagulation pathways [9]. The mechanism of actionof FEIBA mainly relies on the presence of the activatedfactor X (FXa) complex with prothrombin (factor II, FII),which protects FXa from inhibition and enhances theformation of prothrombinase complexes on platelet sur-faces. Conversely, rFVIIa acts activating small amounts ofFX on platelet surface bypassing tenase complex activityand then promoting thrombin generation and fibrin clotformation. FEIBA and rFVII are the only bypassing agentscoagulation factor concentrates available at the momentfor bleeding control in AHA [1, 2]. Although not directlycompared for AHA treatment, rFVIIa and FEIBA seemequally efficacious for bleeding control, according to theobservational data of the EACH2 registry. We decided toadopt FEIBA as the first-line bypassing agent [8]. Bypass-ing therapy response was primarily monitored on a clini-cal basis. As no adequate bleeding control was achievedwith FEIBA, NovoSeven was started as a second-linebypassing therapy. UmanComplex D.I (containing FII,FIX, and FX) was added as a prothrombin complex con-centrate in order to supply a balanced coagulation factorcomposition.The aim of immunosuppressive therapy is to eradicatethe inhibitor suppressing its production by responsiblecell clone and to normalize the FVIII level [6]. Steroidsare the most commonly used drugs for this therapeuticgoal though several authors described their associationwith cyclophosphamide. To date, no definitive data sup-port combined steroids and cyclophosphamide therapy inAHA [2, 10]. Although remission rate seems to be higherwith combined immunosuppressive therapy, final out-come is not influenced by the initial immunosuppressiveregimen, possibly reflecting the higher morbidity (i.e.,infections, cytopenia) associated with the combinedimmunosuppressive therapy [10]. Moreover, advancedage and comorbidities may preclude an aggressiveimmunosuppressive treatment and influence the finaloutcome.ConclusionAlthough AHA is a rare disease, it should be taken intoaccount in the differential diagnosis of elderly patientswith a history of recent onset bleeding and a prolongedAPTT. Identifying a relationship between AHA and anassociated disease could be challenging and even in ourpatient’s case no definitive cause was found despite anaccurate review of old medical records and an extensiveinvestigation through imaging and laboratory tests. Asbypassing agents represent the first-line therapy, theyshould be promptly started after laboratory diagnosis con-firmation of AHA.Conflict of InterestNone declared.ª 2013 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd. 3A. Cortegiani et al. Perioperative Uncontrollable Bleeding and AHAReferences1. Franchini, M., and G. Lippi. 2008. Acquired factor VIIIinhibitors. Blood 112:250–255.2. Collins, P. W. 2012. Therapeutic challenges in acquiredfactor VIII deficiency. Hematology Am. Soc. Hematol.Educ. Program 2012:369–374.3. Franchini, M., G. Gandini, T. Di Paolantonio, and G.Mariani. 2005. Acquired hemophilia A: a concise review.Am. J. Hematol. 80:55–63.4. Levey, A. S., J. Coresh, E. Balk, A. T. Kausz, A. Levin, M.W. Steffes, et al. 2003. National Kidney Foundationpractice guidelines for chronic kidney disease: evaluation,classification, and stratification. Ann. Intern. Med.139:137–147.5. Knoebl, P., P. Marco, F. Baudo, P. Collins, A.Huth-Kuhne, L. Nemes, et al. 2012. Demographic andclinical data in acquired hemophilia A: results from theEuropean Acquired Haemophilia Registry (EACH2). J.Thromb. Haemost. 10:622–631.6. Delgado, J., V. Jimenez-Yuste, F. Hernandez-Navarro, andA. Villar. 2003. Acquired haemophilia: review andmeta-analysis focused on therapy and prognostic factors.Br. J. Haematol. 121:21–35.7. Huth-K€uhne, A., F. Baudo, P. Collins, J. Ingerslev, C. M.Kessler, H. Levesque, et al. 2009. Internationalrecommendations on the diagnosis and treatment ofpatients with acquired hemophilia A. Haematologica94:566–575.8. Hoffman, M., and Y. Dargaud. 2012. Mechanisms andmonitoring of bypassing agent therapy. J. Thromb.Haemost. 10:1478–1485.9. Hoffman, M., and D. M. Monroe III. 2001. A cell-basedmodel of hemostasis. Thromb. Haemost. 85:958–965.10. Collins, P., F. Baudo, P. Knoebl, H. Levesque, L. Nemes, F.Pellegrini, et al. 2012. Immunosuppression for acquiredhemophilia A: results from the European AcquiredHaemophilia Registry (EACH2). Blood 120:47–55.4 ª 2013 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.Perioperative Uncontrollable Bleeding and AHA A. Cortegiani et al.

A perioperative uncontrollable bleeding in an elderly patient with acquired hemophilia A: a case report

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