Antonella Tufano

Ciro Miele

Cristina Mazzaccara

Ernesto Cimino

Filomena Capasso

Francesca D'Auria

Luca Manfredi

Marcella Savoia

Matteo Nicola Dario Di Minno

Olga Scudiero

Paolo Conca

Rosaria Mormile

Sabrina De Simone

English

Archivio della ricerca - Università degli studi di Napoli Federico II

HaemophiliaLETTER TO THE EDITORPharmacokinetic Studies, Assessing the Efficiency ofFVIII/VWF Concentrates and Intravenous HumanImmunoglobulin, Revealed the Etiopathogenesis ofAcquired vonWillebrand Disease in Patient With MGUSCiro Miele1,2,3 Francesca D’Auria1 Luca Manfredi1 Paolo Conca4 Ernesto Cimino4 Rosaria Mormile5Sabrina De Simone1 Olga Scudiero1,2,3 Marcella Savoia1,2,3 Antonella Tufano4 Matteo Nicola Dario Di Minno4Filomena Capasso3 Cristina Mazzaccara1,2,31Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, Naples, Italy 2CEINGE Advanced Biotechnologies FrancoSalvatore, Naples, Italy 3Department of Integrated Activity of Laboratory Medicine and Transfusion, University of Naples “Federico II”, Naples, Italy4Department of Clinical Medicine and Surgery, University of Naples “Federico II”, Naples, Italy 5Hematology, Department of Translation and PrecisionMedicine, Sapienza University, Rome, ItalyCorrespondence: Cristina Mazzaccara (cristina.mazzaccara@unina.it)Funding: The authors received no specific funding for this work.To the Editor,Acquired von Willebrand Syndrome (AVWS) is a rare disordercharacterized by a bleeding diathesis, with symptoms rang-ing from mild to severe. It differs from the congenital vonWillebrand disease (vWD) due to the absence of personal andfamily history of haemorrhagic disorders, a late-onset bleed-ing tendency and the frequent association with haematologicalmalignancies, autoimmune or cardiovascular diseases [1, 2].Amongst lymphoproliferative disorders, monoclonal gammopa-thy of undetermined significance (MGUS) is the most frequentlyreported condition associatedwithAVWS, accounting for approx-imately 23% of all cases, according to the International Registryof the Subcommittee on von Willebrand factor [3]. In thisregard, clinical attention should be given to most haemato-logic, malignant, and autoimmune disorders, with serum proteinelectrophoresis and a complete blood count being crucial toscreen for monoclonal gammopathy and other haematologicdisorders, respectively [4]. Despite the multiple pathophysio-logical mechanism involved, treatments for AVWS are focusedon the eradication of the underlying disease, control of acuteepisodes and prevention of bleeding events, especially in high-risk situations, such as during surgery. Desmopressin (DDAVP),plasma-derived FVIII/VWF concentrates, antifibrinolytic, high-dose IVIG (Intravenous Immunoglobulin) and plasmapheresisare some of the therapeutic measures taken for this purpose[4]. Despite the multiple pathophysiological mechanisms thatinterfere with the normal functionality of the VWF moleculein AVWS, patients with MGUS can exhibit the presence ofcirculating autoantibodies directed against both functional andnon-functional domains of VWF [5]. The pathogenesis of theseantibodies encompasses: the presence of circulating antibodiesneutralizing platelet-related domains of VWF (Inhibitors) or anti-bodies forming immuno-complexes with VWF, that are rapidlycleared from the circulation by the reticulo-endothelial systems(non-neutralizing antibodies) [6]. Since the presence of inhibitorsis often associated with a more severe haemorrhagic phenotype,laboratory investigations can be challenging trying to distinguishbetween the two immunological mechanisms [6, 7]. Mixing stud-ies and enzyme-linked immunosorbent assays (ELISA) are bothsuitable methods to identify the etiopathogenetic mechanism ofthese antibodies. However, since ELISA test is intricate and hasnot yet been adequately standardized, it is an option not yet fullyutilized in haemostasis laboratories [6]; at the same time, the soleuse of the mixing test can only confirm or exclude the presence ofneutralizing antibodies, but does not allow the identification ofantibodies increasing the clearance of the VWF. Here we reporta case of AVWS secondary to MGUS IgG λ associated to thepresence of non-neutralizing antibodies, whose etiopathogenicmechanism was identified with the help of pharmacokinetic© 2024 John Wiley & Sons Ltd.Haemophilia, 2024; 0:1–3https://doi.org/10.1111/hae.151371 of 3TABLE 1 Admission coagulative profile.Coagulative profileParameters ResultPT ratio (0.8–1.20) 0.95aPTT ratio (0.8–1.20)§ 1.49Fibrinogen (160–350 mg/dL) 236FVIII:C (50%–130%) 17.0FIX:C (50%–120%) 60.0FXI:C (50–120%) 72.0FXII:C (50%–120%) 56.0VWF:Ag (Blood type 0: 44%–116%; non-0 Bloodtype: 63%–159%)15.5VWF:RiCof (Blood type 0: 44%–116% non-0 Bloodtype: 63%–159%)9.6VWF:CB (Blood type 0: 44%–116%; non-0 Bloodtype: 63%–159%)11.1Note: Reference values are defined based on healthy population laboratoryassessment.Abbreviations: aPTT, activated Partial Thromboplastin Time; FIX:C, Coag-ulative Factor IX; FVIII:C, Coagulative Factor VIII; FXI:C, CoagulativeFactor XI; FXII:C, Coagulative Factor XII; PT, Prothrombin Time; VWF:Ag,von Willebrand Factor Antigen; VWF:CB, von Willebrand Factor CollagenBinding; VWF:RiCof, von Willebrand Factor Ristocetin Cofactor Activity.and mixing studies. Our patient was a 73-year-old woman whoreferred to Regional Reference Center of Coagulation Disordersof Federico II University Hospital, Naples (Italy), following amassive post-operative haemorrhage embroiling the surgery siteof a robotic cholecystectomy procedure due to cholelithiasis.No relevant haemorrhagic events were reported in family orpersonal medical history, apart from a recent haemothoraxarisen after tracheal intubation subsequent to a hysterectomywith bilateral salpingo-oophorectomy procedure. Given her olderage, the recent history of two bleeding events and the lack ofprevious bleeding diathesis, we suspected an acquired bleedingsyndrome. In agreement with this hypothesis, we researchedfor a possible underlying pathology that triggered this bleedingepisode. Serum protein electrophoresis studies revealed a peakin the gamma zone of the IgG λ type, probably associatedto an underlying monoclonal gammopathy (data not showed).The complete blood count showed low levels of erythrocytes(3.46 × 106/µL; r.v.), haemoglobin (10.80 g/dL; r.v. 12.0–15.5) andhaematocrit (31.10 %; r.v. 4.0–5.0) while leukocyte and plateletcounts were within the normal range. As showed in Table 1, firstlevel haemostasis assays, highlighted a prolongation of activatedPartial Thromboplastin Time (aPTT), with normal ProthrombinTime (PT) and Fibrinogen levels. Mixing study using an equalvolume of citrated patient plasma with a normal pool plasma,showed an aPTT value within the normal range, suggesting afactor deficiency as a cause of the prolonged aPTT, thus acquiredhaemophilia A (AHA) and antiphospholipid antibody syndrome(APS) were ruled out. Subsequently, factors VIII, IX, XI andXII were measured, displaying results within reference range,except for low FVIII levels (Table 1). Following these resultsand the patient’s clinical history, the AVWS was strongly sus-pected and the specific VWD tests, such as VWF:Ag, VWF:RiCofTABLE 2 Mixing tests measured after 2 h incubation at 37◦C.Mixing studiesParameters ResultaPTT ratio (0.8–1.20) 1.12FVIII:C (50%–130 %) 52VWF:Ag (Blood type 0: 44%–116%; non-0 Bloodtype: 63%–159%)62.1VWF:RiCof (Blood type 0: 44–116% non-0 Bloodtype: 63%–159%)61.7VWF:CB (Blood type 0: 44%–116%; non-0 Bloodtype: 63%–159%)53.3Note: Reference values are defined based on healthy population laboratoryassessment.Abbreviations: aPTT, activated Partial Thromboplastin Time; FVIII:C, Coag-ulative Factor VIII; VWF:Ag, von Willebrand Factor Antigen; VWF:CB, vonWillebrand Factor Collagen Binding; VWF:RiCof, von Willebrand FactorRistocetin Cofactor Activity.and VWF:CB were measured, showing a substantial reduction(Table 1). To elucidate the pathogenetic mechanism underlyingthe VWF defect affecting our patient, both mixing studies at 37◦Cfor 2 h and pharmacokinetic analysis were performed to confirmthe nature of anti-VWF antibodies. In our patient, we demon-strate non-neutralizing antibody-mediated VWF clearance as themechanism accountable for AVWS. Mixing studies showed noinhibitory effect on normal plasma for VWF:RiCof, VWF:CB andFVIII:C levels, consistent probably with antibodies against non-functional VWF domains, enabling us to rule out the presenceof neutralizing antibodies (inhibitors) (Table 2). Pharmacokineticstudies with FVIII/von Willebrand factor concentrate and IVIG,confirmed the suspicion of an acquired formof vWD, highlightingthe incomplete recovery of FVIII:C, VWF:Ag, VWF:RiCof, andVWF:CB levels, after the administration of FVIII/VWF concen-trates with a short-lived increase in plasma VWF levels relatedto the presence of anti-VWF antibodies (Figure S1A). On theother hand, 1 g/kg high-dose IVIG for 2 days demonstrated asignificant improvement in all parameters related to VWF levelsafter both the first and second infusions (Figure S1B), confirmingthe presence of non-neutralizing autoantibodies acceleratingthe clearance of circulating VWF due to the formation ofimmunocomplexes and their elimination through the reticu-loendothelial system. This corroborates what is already widelyreported about IVIG being an essential therapeutic instrumentfor the management of AVWS, particularly for IgGMGUS relatedcases [8, 9]. The exact mechanisms of action through which IVIGreduces the clearance of circulating VWF in IgG MGUS are notfully understood; however, they may involve the inhibition ofpathogenic VWFantibodies or B-cell receptors by transfused anti-idiotype antibodies, the blocking of macrophage Fc receptors,and/or the activation of the complement system [10]. The aimof this study was to demonstrate how, by utilizing the mixingtest and pharmacokinetic studies, it is possible to define theetiopathogenesis of anti-VWF antibodies and thus confirm thepresence of non-neutralizing antibodies even when the ELISAtest is not available. This approach has been crucial because,in the absence of a standardized ELISA assay, able to identifynon-neutralizing VWF antibodies, relying only onmixing studies2 of 3 Haemophilia, 2024 13652516, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/hae.15137 by Uni Federico Ii Di Napoli, Wiley Online Library on [20/12/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons Licensecould fail to recognize an AVWS, given the normalization ofaPTT, FVIII:C, VWF:Ag, VWF:RiCof and VWF:CB, especially ina routine laboratory. In this scenario, personal and family history,along with pharmacokinetic studies involving FVIII/VWF andhigh-dose IVIG, were found to be an excellent diagnostic tool fordistinguishing between the two types of antibodies. The studylimitation was the inability to evaluate vWF plasma clearancethrough the analysis of vWF multimers and the vWF propeptide,the latter being uncommon assays in haemostasis routine labora-tory. In conclusion, our work confirmed that patients with AVWSassociated with MGUS do not have a great recovery when usingplasma-derived concentrates compared to IVIG. Even thoughthey have different pharmacokinetic responses and effectiveness,the use of these medications played a pivotal role along withcoagulation assay for framing the right etiopathogenesis andhighlighted how the conversation between haematologists andlaboratory experts is key for a proper diagnosis, given thechallenging diagnostic workup in AVWS.Author ContributionsCiro Miele, Cristina Mazzaccara and Filomena Capasso conceived,designed and wrote the study; Francesca D’Auria, Sabrina De Simone,Luca Manfredi, Olga Scudiero and Marcella Savoia contributed to themanagement and collection of data; Rosaria Mormile, Paolo Conca,Ernesto Cimino, Antonella Tufano and Matteo Nicola Dario Di Minnoprovided advice on the study design and content. Cristina Mazzaccara,Ciro Miele, Antonella Tufano, Paolo Conca, Matteo Nicola Dario DiMinno and Filomena Capasso reviewed and edited the manuscript. Allauthors have read and agreed to the published version of the manuscript.Agreement to be accountable for all aspects of the work in ensuring thatquestions related to the accuracy or integrity of any part of the work areappropriately investigated and resolved.AcknowledgementsThe authors have no competing interests.Ethics StatementAll investigations were conducted according to the Declaration ofHelsinki principles.ConsentInformed consent was obtained from patient included in this study.Conflicts of InterestThe authors state no conflict of interest.Data Availability StatementThe data that support the findings of this study are available from thecorresponding author upon reasonable request.Ciro MieleFrancesca D’AuriaLuca ManfrediPaolo ConcaErnesto CiminoRosaria MormileSabrina De SimoneOlga ScudieroMarcella SavoiaAntonella TufanoMatteo Nicola Dario Di MinnoFilomena CapassoCristina MazzaccaraReferences1. A. L. Langer and N. T. Connell, “Acquired vonWillebrand Syndrome,”Hematology Oncology Clinics of North America 35, no. 6 (2021): 1103–1116,https://doi.org/10.1016/j.hoc.2021.07.005.2. C. Miele, P. Consorti, R. Mormile, et al., “Contribution of RotationalThromboelastometry (ROTEM) Research Parameters for the Evaluationof Hypercoagulability in PatientsWithMultipleMyeloma. A Pilot Study,”Biochimica Clinica 47, no. 4 (2023): 346–354.3. M. Y. Abou-Ismail, G. M. Rodgers, P. F. Bray, and M. Y. Lim,“Acquired von Willebrand Syndrome in Monoclonal Gammopathy—AScoping Review on Hemostatic Management,” Research and Practice inThrombosis and Haemostasis 5, (2021): 356–365.4. A. Tiede, J. H. Rand, U. Budde, A. Ganser, and A. B. Federici, “HowI Treat the Acquired von Willebrand Syndrome,” Blood 117, (2011): 6777–6785.5. M. Franchini and G. Lippi, “Acquired von Willebrand Syndrome: AnUpdate,” American Journal of Hematology 82, no. 5 (2007 May): 368–375,https://doi.org/10.1002/ajh.20830.6. M. Franchini and P. M. Mannucci, “Acquired von Willebrand Syn-drome: Focused for Hematologists,” Haematologica 105, (2020): 2032–2037.7. H. Mohri, S. Motomura, H. Kanamori, et al., “Clinical Significance ofInhibitors in Acquired vonWillebrand Syndrome,” Blood 91, (1998): 3623–3629.8. G. Jeryczynski, H. Agis, S. Eichinger-Hasenauer, and M. T. Krauth,“Successful Treatment of Acquired vonWillebrand Syndrome AssociatedWith Monoclonal Gammopathy: Breaking a Dangerous Bond,” WienerKlinische Wochenschrift 134, no. 11-12 (2022): 478–482, https://doi.org/10.1007/s00508-022-02012-3.9. A. Green, Y. P. Shen, A. T. Nelson, et al., “Successful Use of Lenalido-mide to Treat Refractory Acquired von Willebrand Disease AssociatedWith Monoclonal Gammopathy,” Annal of Hematology 101, no. 12 (2022):2627–2631, https://doi.org/10.1007/s00277-022-04991-9.10. C. Dicke, S. Schneppenheim, K. Holstein, et al., “Distinct Mecha-nisms Account for Acquired von Willebrand Syndrome in Plasma CellDyscrasias,” Annal of Hematology 95, (2016): 945–957.Supporting InformationAdditional supporting information can be found online in the SupportingInformation section.3 of 3 13652516, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/hae.15137 by Uni Federico Ii Di Napoli, Wiley Online Library on [20/12/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

Pharmacokinetic Studies, Assessing the Efficiency of FVIII/VWF Concentrates and Intravenous Human Immunoglobulin, Revealed the Etiopathogenesis of Acquired von Willebrand Disease in Patient With MGUS

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Pharmacokinetic Studies, Assessing the Efficiency of FVIII/VWF Concentrates and Intravenous Human Immunoglobulin, Revealed the Etiopathogenesis of Acquired von Willebrand Disease in Patient With MGUS

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