Abbal, Claire

Angelillo-Scherrer, Anne

Gavillet, Mathilde

Lambert, Jean-François

Nötzli, Jasmine

Schmidt, Sabine

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Life-threatening bleeding under vitamin K antagonists in spiteof an INR in the therapeutic rangeMathilde Gavillet • Claire Abbal • Sabine Schmidt •Jasmine No¨tzli • Jean-Franc¸ois Lambert •Anne Angelillo-ScherrerPublished online: 18 March 2011 Springer Science+Business Media, LLC 2011Keywords Oral anticoagulation  Factor IX  Propeptidemutation  Vitamin K antagonists  Prosthetic heart valveThe major risk associated with the use of vitamin Kantagonists (VKA) is haemorrhage, which might be severeor even life-threatening. In clinical studies where antico-agulation intensity was carefully monitored, treatment withVKA increases the risk of major bleeding by 0.3–0.5% peryear when compared to controls [1]. In randomized trialsincluding patients with mechanical heart valves, VKAtreatment was associated with a risk of major bleedingranging between 1 and 8.3% [1]. However, in clinicalpractice, the rates are less consistent [1]. The majordeterminants of VKA-induced bleeding are the intensity ofthe anticoagulant effect, the patient characteristics, theconcomitant use of drugs that interfere with hemostasis,and the length of therapy [1].Here, we report a case of a rare hypersensitivity to VKAdue to a mutation of factor IX (FIX) propeptide in thecontext of a prosthetic mechanical heart valve.In November, 2008, a 62-year-old man presented with anobstructive laryngeal hematoma (Fig. 1a, b) after tonguebiting requiring intratracheal intubation. His medical historyrevealed prosthetic mechanical aortic valve replacement inJuly 2008 (Bentall procedure, Cardiomedic prosthesis). Oralanticoagulation with VKA (acenocoumarol) was initiatedpost-operatively. When the laryngeal hematoma appeared,the patient’s International Normalized Ratio (INR) was 3.5.In December, 2008, the patient was admitted to the intensivecare unit with a massive hemothorax (Fig. 1c) occurring10 days after a reintervention to cure a paraprosthetic leak,and requiring surgical drainage. INR was 1.3. The patient’sand his relatives reported no history of bleeding. Aspirin, theonly patient’s medication favoring bleeding, had beenstopped 4 days before the first bleeding episode. Before theintroduction of acenocoumarol, blood count, prothrombintime (PT) and activated partial thromboplastin time (APTT)were within the normal range.Coagulation tests are listed in Fig. 1d. Both majorbleeding episodes were accompanied by INR values withinor even below the therapeutic range (therapeutic range for amechanical valve carrier: 2.5–3.5) [2]. However, APTTwas abnormally prolonged because FIX was exaggeratedlylower than the other vitamin K dependant factors (II, VII,X). Factor V, VIII, XI and XII were within the normalrange during both bleeding episodes. APTT and FIX bothnormalized after vitamin K supplementation and bleedingdid not recur.Genomic DNA was purified from the patient wholeblood, and FIX exon 2 was amplified using the forwardprimer 50-catgccctaaagagaaattggct-30 and the reverse pri-mer 50-tgcatctgaagggtattatgtgg-30. The thermocycling con-ditions of the PCR were 30 s 94C, 1 min 53C, and 1 min72C, for 40 cycles. Direct sequencing of the PCR productshowed a single guanosine-to-adenosine transition atnucleotide 109 (numbered from genBank accessiongi180552) causing the substitution of alanine at locus-10(Ala-10) by threonine in the FIX propeptide (Fig. 2a).M. Gavillet  C. Abbal  J. No¨tzli  J.-F. Lambert A. Angelillo-Scherrer (&)Service and Central Laboratory of Hematology, CentreHospitalier Universitaire Vaudois and University of Lausanne,rue du Bugnon 46, CH-1011 Lausanne, Switzerlande-mail: Anne.Angelillo-Scherrer@chuv.chS. SchmidtDepartment of Radiology, Centre Hospitalier UniversitaireVaudois and University of Lausanne, rue du Bugnon 46,CH-1011 Lausanne, Switzerland123J Thromb Thrombolysis (2011) 32:232–237DOI 10.1007/s11239-011-0580-yFig. 1 a (axial) and b (sagittal) CT of the neck, showing an obstructive laryngeal hematoma (arrow heads). c CT of the chest showing a righthemothorax (arrow heads). d Table including coagulation testsFig. 2 a Schematicrepresentations of, upper line,FIX gene (accession numberM11309), and, lower line, FIXpropeptide. The mutation isindicated by an arrow line [6].Exons are numbered.G guanosine, A adenosine, GLAVitamin K-dependentcarboxylation/gamma-carboxyglutamic domain, EGFEpidermal growth factor-likedomain, B family pedigree.Affected males in black, femalecarriers in stripes, wild typephenotype in white, unknownphenotype in grey, deductedphenotypes circled with grey.Arrow head indicates the indexpatientLife-threatening bleeding under vitamin K antagonists 233123Table1Summaryofallsimilarcasespublished#ReferenceDateOriginAgeat DnAnticoagulationindicationBleedingsitesBasalFIXlevel(%)FIXLevelunderanticoagulation(%)OthercoagulationtestsunderanticoagulationMutationtypeAlternativetherapyproposed/used131996USA49MechanicalprostheticaorticvalvereplacementHemothorax,hematuria,andecchymosesoverthearms,legs,andtrunk120–148\lPT23.7%,APTT[l50s,FVII42%,FVIII[200%Ala-l0?ThrLowdosewarfarin,withtarget:noPTprolongation(FIX16%,FVII80%,FX43%).C:freeofthromboticandhemorrhagiccomplications.24,13l997Germany66MechanicalprostheticaorticvalvereplacementSeveremusclebleeding55\lPT45%,APTT70.9s,FII50%,FVII31%,FX22%Ala-l0?ValLongtermheparin.34l997Germany38MechanicalprostheticaorticvalvereplacementBleedinginscrotumandmuscle55\lPT50%,APTT59.1s,FII66%,FVII44%,FX46%Ala-l0?ThrLongtermheparin.44,13l997Germany30DeepveinthrombosisSeveremusclebleeding1251PT29%,APTT106s,FII35%,FVII19%,FX13%Ala-l0?ValLongtermheparin.514,13l997Germany66MechanicprostheticaorticvalvereplacementMajorepistaxis,severemusclebleeding803INR1.6,APTT70.9s,FV92%,FVII31%,FVIII260%,FX22%,FXI79%,FXII122%n.a.Longtermheparin.614,13l997Germany38MechanicprostheticaorticvalvereplacementMuscleandscrotalbleeding482INR1.4,APTT59.1s,FV69%,FVII44%,FVIII112%,FX46%,FXI75%,FXII66%n.a.Longtermheparin.C:nocomplication.78l99SGermany29Deepveinthrombosis,aspartofanantipholpholipid-antibodysyndromSeveremusclebleeding1201PT29%,APTT106s,FV94%,FVII19%,FVIII69%,FX13%,FXI138%,FXII87%Ala-10?ValAspirin100mg/dpluslowmolecularweightheparin5000lU/d.87,132000UK56DeepveinthrombosissecondarytocarcinomaofthestomachSeveremusclebleeding65\lINR2.2,APTT104–170s,FVII20%Ala-10?ThrLowmolecularweightheparin.9122001Germany66MechanicalprostheticaorticvalvereplacementSeveremusclebleeding882APTT[140s,othervitaminKdependantfactors20–50%Ala-10?ValReplacementoftheprostheticmechanicalvalvewithabiologicaldevice.10132001Germany45PulmonaryembolismEpistaxis,hematuria,musclebleedingandatraumatichaemarthrosisNormal\5APTT[150s,FII18%,FVII11%,FX6%Ala-10?ValAlternativeanticoagulationtherapy.234 M. Gavillet et al.123Table1continued#ReferenceDateOriginAgeat DnAnticoagulationindicationBleedingsitesBasalFIXlevel(%)FIXLevelunderanticoagulation(%)OthercoagulationtestsunderanticoagulationMutationtypeAlternativetherapyproposed/used11132001Germany66MechanicalprostheticaorticvalvereplacementMuscleandsofttissuebleedingNormal\lAPTT[l20sec,FII34%,FVII64%Ala-10?ValAlternativeanticoagulationtherapy.12132001Switzerland77MechanicalprostheticaorticvalvereplacementMuscleandretroperitonealbleedingNormal3INR1.9,APTT80sAla-10?ThrAlternativeanticoagulationtherapy.13132001USAl3Mechanicalprostheticaorticvalvereplacementn.a.Normal6‘‘disproportional’’APTTAla-10?ThrAlternativeanticoagulationtherapy.14102002Denmark62MechanicalprostheticaorticvalvereplacementSeveremusclebleedingn.a.4INR1.9,APTT128sAla-10?Thr(1)Aspirin100mg/d.C:cerebralthrombosis,acutemyocardialinfarction,andatransientischemicattack.(2)Aspirin100mg/2d?lowdosewarfarinwithFIXmonitoring(target10–20%)C:4episodesofgastrointestinalbleedings.(3)LowdosewarfarinwithFIXmonitoring(target8–16%).C:neitherbleedingsnorthromboses.156,11,132001Switzerland58MechanicalprostheticaorticvalvereplacementMusclebleeding,heamarthrosis,intestinalwallbleeding,laryngealhematoma953INR1.5,APTT77.3s,FII56%,FV90%,FVII78%,FVIII187%,FX27%,FXI102%Ala-10?Val(1)Fulldoselowmolecularweightheparin.C:thrombusontheartificialheartvalvewithrecurrentcerebralischemiaepisodes.(2)Aspirin100mg/dadded.C:idem.(3)Aorticvalvereplacementwithbiologicalprosthesis.C:nofurthercomplication.166,132001Switzerland63Thrombosisprophylaxisafterhipreplacementsurgery(severeheparinallergy)Majorsubcutaneoushematoman.a.2INR2.8,APTT164s,FVIII270%Ala-l0?ThrStopanticoagulation(prophylaxis).C:nofurtherbleedingcomplication.Life-threatening bleeding under vitamin K antagonists 235123Screening of patient’s relatives allowed to identify sevenfurther asymptomatic carriers (two males, five females)(Fig. 2b).Because of the severe bleeding complications presentedby our patient, the oral anticoagulation was replaced bylow molecular weight heparin at therapeutic dose moni-tored by anti-Xa activity in order to be sure that anti-Xaactivity levels were maintained within the therapeuticrange. 15 months later no recurrence of bleeding northrombotic complication were observed.In the literature, two point mutations causing Ala-10substitution by either a valine (Ala-10Val) or a threonine(Ala-10Thr) have been described [3, 4]. Ala-10 is locatedat the essential recognition site for the c-carboxylase [5]and is highly conserved in all vitamin K-dependent coag-ulation factors [6]. Ala-10Val and Ala-10Thr FIX variantsdisplay a more than 30-fold lower affinity for the c-car-boxylase than the wild type propeptide [3]. The affinity ofthe mutated enzymatic peptide complex for reduced vita-min K is decreased when compared to the enzymaticcomplex comprising the wild type peptide [3]. Consi-stantly, the c-carboxylation of these FIX variants is lessefficient and becomes dramatically impaired in patientswith VKA medication [3].Male patients have a normal or slightly lowered basalFIX level. However, under VKA therapy, they display adramatic decrease of FIX activity that is out of proportionwith the other vitamin K dependant coagulation factors(II, VII, X). APTT is thus abnormally prolonged, while PTand INR remain within, or even below, the therapeuticrange; and patients exibit severe and sometimes life-threatening soft tissue and muscle bleeding [3, 4, 7–16].From time to time misdiagnosed for mild hemophilia B,patients carrying a FIX propeptide mutation can be dis-tinguished by an absence of self or family bleeding historyas well as normalization of APTT and FIX level aftervitamin K administration. Because FIX gene is located onchromosome X, males are more affected than females.One female patient carrier of the Ala-10Val mutation wastreated by VKA [17]. When INR was 2.3, FIX level was16%. This patient did not develop bleeding complications[17].So far 18 similar cases have been reported in the litera-ture worldwide [3, 4, 7–16] (Table 1). Systematic screeningin 4039 individuals yielded no further case [4, 18–20].Therefore, prevalence of Ala-10Thr or Ala-10Val variantsin the population is estimated to range from 1/1,000 to1/10,000 and systematic screening prior to initiating oralanticoagulation is not indicated. However it is worthnoticing that about one-third of these patients (6/19) origi-nate from Switzerland including our current reported case.Although selection bias is possible, one study using hap-lotype analysis revealed a founder effect in the five GermanTable1continued#ReferenceDateOriginAgeat DnAnticoagulationindicationBleedingsitesBasalFIXlevel(%)FIXLevelunderanticoagulation(%)OthercoagulationtestsunderanticoagulationMutationtypeAlternativetherapyproposed/usedl7l52008Switzerland70BiologicalprostheticaorticvalvereplacementSofttissue,muscleandjointbleedingn.a.2INR2.1,APTT78s,FII46%,FVII29%Ala-l0?ThrStopanticoagulation.1892010Switzerland53MechanicalprostheticmitralvalvereplacementSubcutaneousbleeding,hemarthrosisandhaematomaoftheepiglottisn.a.\lINR2.9,APTT76s,FII30%,FV112%,FVII16%,FVIII263%,FX8%,FXI135%Ala-l0?ThrLowdosephenprocoumonwithmonitoringofFIXlevel(target5–15%).19Presentcase2011Switzerland62MechanicalprostheticaorticvalvereplacementLaryngealhematomaandpostoperativehemothorax801INR3.5,APTT142s,FII20%,FV145%,FVII11%,FX11%,FVIII185%,FXI110%,FXII110%Ala-l0?ThrFulldoselowmolecularweightheparin.Whenpublicationmentionsawholefamily,onlytheindexcaseislisted.Dndiagnosis,Ccommentontheoutcome,INRinternationalnormalizedratio,PTprothrombintime,APTTactivatedpartialthromboplastintime,FIIfactorII,FVfactorV,FVII,factorVII,FVIIIfactorVIII,FIXfactorIX,FXfactorX,FXIfactorXI,FXIIfactorXII.Ala-10?Thralanineresidueatposition-10tothreoninesubstitution.Ala-10?Valalanineresidueatposition-10tovalinesubstitution.n.a.Informationnotavailable236 M. Gavillet et al.123and Swiss patients carrying a FIX variant (1 Ala-10Val andand 4 Ala-10Thr) derived from a common founder [14].We postulate that the prevalence of this genetic variant maybe higher in the Swiss population. APTT screening is cer-tainly of interest in any bleeding patient with INR valueswithin the therapeutic range, especially in male patients. Ifabnormally prolonged, quantitative determination of FIXlevel can lead to the diagnosis. Further use of VKA is notrecommended. For the present being, low molecular weightheparins represent an inconvenient but safe alternative. Analternative could be to monitor FIX activity targeting a levelof 5–15%, as previously described [3, 10, 11]. We did notchoose this therapeutic option for our patient as he pre-sented a severe bleeding episode with a FIX level at 10%(Fig. 1d). The replacement of the prosthetic mechanicalvalve by a biological graft in order to avoid anticoagulationwas discussed but the risk of morbidity and mortalityassociated with cardiac surgery was considered to be toohigh. In the future, patients with FIX propeptide mutationmay benefit from the novel oral anti-thrombin and anti-Xainhibitors, yet further validation studies are needed.Acknowledgments We thank Drs. M. Wicki, B. Portmann andZimerli for participating in the screening part of the study.References1. Schulman S, Beyth RJ, Kearon C, Levine MN (2008) Hemor-rhagic complications of anticoagulant and thrombolytic treat-ment: American college of chest physicians evidence-basedclinical practice guidelines (8th Edition). Chest 133(6 Suppl):257S–298S. doi:10.1378/chest.08-06742. Salem DN, O’Gara PT, Madias C, Pauker SG (2008) Valvularand structural heart disease: American college of chest physiciansevidence-based clinical practice guidelines (8th Edition). 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Blood Coagul Fibrinolysis16(8):563–56620. van der Meer FJ, Vos HL, Rosendaal FR (1999) No indication forAPTT screening in patients on oral anticoagulant therapy.Thromb Haemost 81(3):364–366Life-threatening bleeding under vitamin K antagonists 237123

Life-threatening bleeding under vitamin K antagonists in spite of an INR in the therapeutic range

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Life-threatening bleeding under vitamin K antagonists in spite of an INR in the therapeutic range

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