10.4081/btvb.2023.88
Acquired von Willebrand syndrome (AVWS) is a relatively infrequent but often overlooked finding when testing for von Willebrand factor (VWF) levels in a patient with mucocutaneous bleeding. Known causes include cardiovascular disorders, hematologic and solid tumors, autoimmune disorders, hypothyroidism, and drugs. An incoercible oral bleeding after a two-teeth removal in a patient with a mechanical aortic valve eventually raised suspicion about an AVWS that was confirmed through laboratory testing. Substitution therapy with an exogenous VWF factor was required to control the bleeding. Known causes of AVWS, including Heyde’s syndrome, were ruled out. VWF levels finally normalized two days after suspension of allopurinol, which the patient received for symptomatic hyperuricemia, leading to his complete recovery and early discharge without any other complications. AVWS is an underdiagnosed entity due to a lack of testing. Allopurinol has never been postured before as a possible etiology and should be evaluated when reaching a diagnosis.
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Bleeding, Thrombosis and Vascular Biology
case report
Allopurinol-induced acquired von Willebrand syndrome
Text.Serial.Journal
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Case Reports
2023-10-25
2023-06-20
2023-10-01
2023-10-30
Bleed Thromb Vascul Biol
Santiago Bonanad
2023/10/25
10.4081/btvb.2023.88
Unit of Hemostasis and Thrombosis, Department of Hematology, La Fe Polytechnic and University Hospital, Valencia
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case report
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Parida S. Clinical causality assessment for adverse drug reactions. Indian J Anaesth 2013;57:325-6.
Allopurinol-induced acquired von Willebrand syndrome
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                                                                                                                       CASE REPORT

Allopurinol-induced acquired von Willebrand syndrome
Juan Eirís, Marina Suárez-Terrón, Pablo Granados, David Martínez-Campuzano, Ana Rosa Cid, Saturnino Haya,
Santiago Bonanad

Unit of Hemostasis and Thrombosis, Department of Hematology, La Fe Polytechnic and University Hospital, Valencia, Spain



                                                                            ABSTRACT
                                                                                 Acquired von Willebrand syndrome (AVWS) is a relatively
  Correspondence: Juan Eirís, Avinguda de Fernando Abril                    infrequent but often overlooked finding when testing for von
  Martorell, 106 Hospital La Fe., 46026 Valencia, Spain.                    Willebrand factor (VWF) levels in a patient with mucocutaneous
  Tel.: +34.961244866 - Fax: +34.961246201.                                 bleeding. Known causes include cardiovascular disorders, hema-
  E-mail: eiris_jua@gva.es                                                  tologic and solid tumors, autoimmune disorders, hypothyroidism,
                                                                            and drugs. An incoercible oral bleeding after a two-teeth removal
  Citation: Eirís J, Suárez-Terrón M, Granados P, et al. Allopurinol-
                                                                            in a patient with a mechanical aortic valve eventually raised sus-
  induced acquired von Willebrand syndrome. Bleeding, Thrombosis,
  and Vascular Biology 2023;2:88.                                           picion about an AVWS that was confirmed through laboratory




                                                                                                        ly
                                                                            testing. Substitution therapy with an exogenous VWF factor was
  Key words: acquired von Willebrand syndrome, von Willebrand               required to control the bleeding. Known causes of AVWS, includ-




                                                                                                on
  factor, allopurinol, bleeding disorders, case reports.                    ing Heyde’s syndrome, were ruled out. VWF levels finally nor-
                                                                            malized two days after suspension of allopurinol, which the
  Contributions: JE, wrote the case report and participated in the pa-      patient received for symptomatic hyperuricemia, leading to his




                                                                                         e
  tient’s care; MST, PG, DMC, revised the manuscript and suggested          complete recovery and early discharge without any other compli-
  improvements; SB, SH, ARC, were the main caregivers of the pa-
  tient and approved the final article contributing with their expertise.
  All the authors approved the final version to be published.
                                                                                 us
                                                                            cations. AVWS is an underdiagnosed entity due to a lack of test-
                                                                            ing. Allopurinol has never been postured before as a possible
                                                                            etiology and should be evaluated when reaching a diagnosis.
                                                                            al
  Conflict of interest: the authors declare no potential conflict of in-
  terest.
                                                                  ci

  Funding: none.                                                            Introduction
                                                                er



  Ethical approval and consent to participate: the patient gave written         Von Willebrand factor (VWF) is a large multifunctional gly-
                                                               m



  informed consent for the publication of this case report.                 coprotein whose role in hemostasis is critical, as it acts as a bridg-
                                                                            ing molecule for platelet adhesion and aggregation, as well as a
                                                    om




  Availability of data and material: the data that support the findings     carrier for factor VIII in the circulation.1-3 Deficiency or dysfunc-
  of this study are available from the corresponding author, JE, upon       tion of VWF results in a bleeding susceptibility condition known
  reasonable request.                                                       as von Willebrand syndrome (VWS), which can either be con-
                                             -c




                                                                            genital, resulting from mutations in the VWF gene, or acquired.1-
  Conference presentation: a poster will be presented at the Spanish
  Society of Hematology and Hemotherapy and the Spanish Society
                                                                            3
                                                                              Acquired von Willebrand syndrome (AVWS) is a rare disorder
                                    on




  of Transfusion and Hemostasis annual congress, taking place in            with a diverse and not yet fully understood pathophysiology. Sev-
  October 2023.                                                             eral mechanisms have been proposed, which could be summa-
                                                                            rized in four: antibody-mediated clearance, adsorption onto the
                              N




  Acknowledgments: the authors would like to thank the patient for          surface of cells or drugs, proteolytic degradation caused by shear
  his permission to use his clinical data for the benefit of science.       stress, and a decrease in its synthesis or secretion.2-4 The etiology
                                                                            of AVWS is broad, with various associated pathologies reported,
  Received: 19 June 2023.
                                                                            including lymphoproliferative and myeloproliferative disorders,
  Accepted: 6 October 2023.
                                                                            solid tumors, autoimmune diseases, cardiac disorders, hypothy-
  Publisher’s note: all claims expressed in this article are solely those   roidism, and drug-induced cases.2-4
  of the authors and do not necessarily represent those of their affili-        Allopurinol is a xanthine oxidase inhibitor used to lower
  ated organizations, or those of the publisher, the editors and the re-    serum levels of uric acid by diminishing its production. Common
  viewers. Any product that may be evaluated in this article or claim       indications are symptomatic hyperuricemia, in order to prevent
  that may be made by its manufacturer is not guaranteed or endorsed        new episodes of gout, and hyperuricemia coexisting with renal
  by the publisher.                                                         insufficiency. The drug is typically initiated orally at a dose of
                                                                            100 mg per day and then increased gradually at weekly intervals
  ©
   Copyright: the Author(s), 2023                                           until the target uric acid level is reached.4
  Licensee PAGEPress, Italy
  Bleeding, Thrombosis and Vascular Biology 2023; 2:88
  doi:10.4081/btvb.2023.88
                                                                            Case report
  This work is licensed under a Creative Commons Attribution-
  NonCommercial 4.0 International License (CC BY-NC 4.0).                       We report the case of a Caucasian 73-year-old male patient
                                                                            with multiple medical priors, from which a mechanical aortic


                                              Bleeding, Thrombosis and Vascular Biology 2023; 2:88
                                           Allopurinol-induced acquired von Willebrand syndrome                                                   59



valve (implanted to address severe stenosis) on oral anticoagula-              IMWM, and peaks >7 as HMWM according to the manufacturer's
tion therapy with acenocoumarol stood out. He also had multiple                recommendations; those with supranormal levels were catego-
cardiovascular risk factors (hypertension, dyslipidemia, a past                rized as VHMWM. A normal plasma was included on each gel as
smoking and drinking habit, and symptomatic hyperuricemia, for                 a control.
which he received allopurinol), a sinus node dysfunction for                        These findings suggested an acquired type 2A von Willebrand
which he carried a pacemaker and a radiotherapy-treated prostate               syndrome. Amoxicillin-clavulanate was suspended and proper re-
cancer (in remission at the time of the events).                               placement therapy with exogenous VWF was initiated. VWF lev-
     The patient was admitted to the emergency department fol-                 els were monitored before and three hours after the administration
lowing incoercible oral bleeding after the removal of two teeth on             of a 50 IU per kg dose, excluding the possibility of a a rapid clear-
the right maxillary hemiarch. Hemifacial edema on his ipsilateral              ance pattern as the recovery rate was nearly normal (VWF: GPIb
cheek was also present (Figure 1). He had suspended aceno-                     increased from 4.2 to 57.7 IU/dL). Trough levels were also satis-
coumarol and started bridge therapy with low-molecular-weight                  factory, with VWF: GPIb remaining at 31.8 IU/dL nine hours after
heparin before the intervention. Heparin dose was lowered and                  administering a 25 IU per kg dose.
antibiotic therapy with amoxicillin-clavulanate was initiated on                    Multiple tests were performed throughout the patient’s hos-
admission.                                                                     pitalization to determine the underlying cause of the disease. Valve
     The patient showed no response to local hemostatic interven-              function was evaluated through echocardiography, revealing no
tions throughout the initial six days of hospitalization, as mild but          notable abnormalities. The levels of thyroid-stimulating hormone,
persisting bleeding kept troubling the postoperative period. The               prostate-specific antigen, and beta-2 microglobulin levels were




                                                                                                   ly
cessation of heparin treatment failed to alleviate the bleeding.




                                                                                            on
VWF was finally measured on the seventh day of hospitalization,
showcasing a significant decrease in antigen levels (VWF:Ag 35.2
IU/dL). This decrease was further evident in the assessment of




                                                                                    e
VWF activity (VWF: RCo 12.1 IU/dL, VWF: GPIb <4 IU/dL).
The propeptide ratio was sightly incremented (VWF: pp/VWF:
Ag 3.55; reference value <2.60). Multimeric analysis revealed a
decrease in intermediate and high molecular weight FVW multi-
                                                                            us
                                                                    al
mers and an increase in low and very high molecular weight FVW
multimers [IMWM, HMWM, LMWM, and VHMWM, respec-
                                                     ci

tively (Table 1)]. Analysis of VWF multimers was performed with
the Hydragel 11 VWF multimers kit (H5VWM; Sebia Hispania,
                                                   er


Barcelona, Spain). Agarose gel electrophoresis was performed
with the Hydrasys 2 Scan instrumentation, using preformed 2%
                                                  m




agarose gels, direct immunofixation, visualization with peroxi-
                                       om




dase-labelled antibody, and densitometry according to the manu-
facturer’s recommendations. Samples were diluted according to
their VWF: Ag levels as follows: <20%: 1/4; 20-50%: 1/6; 150-                  Figure 1. Axial contrast-enhanced computed tomography on ad-
300%: 1/10; >300%: 1/20. The percentage of LMWM, IMWM,                         mission. Right hemifacial subcutaneous tissue thickening (ar-
                                 -c




                                                                               rows). Postoperative changes on the right maxillary hemiarch
HMWM and VHMWM were assessed using Phoresis software                           (asterisk in panel B).
                         on




(Sebia) with peaks 1-3 designated as LMWM, peaks 4-7 as
                   N




Table 1. Multimer von Willebrand factor pattern before (1st measurement) and after (2nd measurement) the cessation of allopurinol.
                                1st measurement, %                          2nd measurement, %                            Reference values
LMWM                                     34.1                                        14.0                                     (8.48-15.20)
IMWM                                     14.6                                        18.3                                    (16.65-21.11)
HMWM                                     17.7                                        49.2                                    (48.49-55.21)
VHMWM                                    33.6                                        18.5                                    (14.28-20.58)
Electrophoresis




LMWM, low molecular weight multimer; IMWM, intermediate molecular weight multimer; HMWM, high molecular weight multimers; VHMWM, very high molecular
weight multimers.


                                           Bleeding, Thrombosis and Vascular Biology 2023; 2:88
60                                                               J. Eirís et al.




within normal range. The autoantibody screening panel yielded                tiple case reports and revisions.4 This prior helped raise suspicion
negative results. Serum biomarkers did not suggest the presence              on the possibility of an AVWS in our patient, after ruling out the
of liver dysfunction. Hematologic neoplasms commonly associ-                 possibility of an anticoagulation excess but was not its ultimate
ated with the condition were ruled out through examinations of               cause. Clinicians should also test for the presence of hypothy-
the blood smear, lymphocyte populations, proteinogram, im-                   roidism, autoimmune diseases, and hematologic and solid tumors
munoglobulin levels, and molecular testing for V617F JAK-2 mu-               at diagnosis.4
tation and BCR::ABL rearrangement. No positive findings for von                   There are several drugs known to be involved in the decrease
Willebrand disease-related genetic mutations were detected                   in VWF levels. Valproic acid, ciprofloxacin, griseofulvin, tetra-
through next-generation sequencing. A computed tomography                    cyclines, thrombolytic agents, hydroxyethyl starch (HES), high-
scan was conducted, revealing no liver alterations or solid tumors,          dose recombinant factor VIII, and pesticides have been previously
except for a small polyp in the cecum, which was successfully re-            reported.2-3 No clear pathogenic mechanisms have been proposed
moved endoscopically and showed no signs of malignancy.                      except for HES (absorption of multimers of VWF into its large
     Having exhausted every complementary testing that could                 molecules) and ciprofloxacin (increased proteolysis of the FVW
lead to a diagnosis, the possibility of a drug-induced condition             by specific proteases). Causality was established based on the nor-
was considered. Amoxicillin-clavulanate was ruled out, as it was             malization of all hemostatic parameters after suspension of the
initiated when the bleeding was already present, and then sus-               medicine.3
pended and reintroduced during the patient’s hospitalization, with                AVWS type 2A is the most commonly described form of the
no changes in his clinical status. Allopurinol was suspended on




                                                                                                        ly
                                                                             disease when associated with drug toxicity,3 which was consis-
day 17 after admission. VWF levels improved significantly two                tent with our patient’s antigen levels and VWF activity along




                                                                                                on
days later, allowing termination of substitution treatment and clin-         with the loss of IMWM and HMWM. However, VHMWM were
ical and analytical stabilization (VWF: Ag and VWF: GPIb                     paradoxically incremented. This has been described in some
reached 168 IU/dL and 109 IU/dL respectively within 24 hours                 cases of congenital type 1 VWD, associated with an increment




                                                                                          e
after stopping exogenous VWF; Figure 2). Multimer levels were                of FVW synthesis trying to compensate for its rapid clearance.6
also normalized (Table 1). During immediate follow-up after dis-
charge, alternative therapy with febuxostat was initiated and reg-
ular anticoagulation was restarted. The patient did not develop
                                                                                   us
                                                                             The latter mechanism could explain the phenomenon observed
                                                                             in our patient. The administered exogenous VWF molecule do
                                                                             not seem to have been affected by the possible proteolysis,
any other complications on this matter and remained in complete
                                                                           al
                                                                             which could account for the normal recovery pattern we ob-
response.
                                                                             served when testing for post-administration efficacy, but this is
                                                            ci

                                                                             only speculation.
                                                                                  Allopurinol has not previously been associated with the oc-
                                                          er


Discussion                                                                   currence of AVWS. The Naranjo adverse drug reaction probability
                                                         m



     AVWS is an often overlooked and relatively infrequent find-             scale yielded a low grade (four points),7 indicating a possible ad-
ing when testing for VWF levels in a patient with mucocutaneous              verse event, although this score may be influenced by the predom-
                                               om




bleeding.1,2 Its association with aortic stenosis, and more particu-         inant role of pharmacodynamics in its calculation. To prevent
larly with mechanical valves, is well-known and described in mul-            iatrogenic effects, the drug was not reintroduced, which repre-
                                                                             sented the main limitation in establishing causality. According to
                                         -c




                                                                             the WHO-UMC categorization,7 this association would be more
                                                                             accurately described as a probable or likely adverse event of the
                                 on




                                                                             medication.
                            N




                                                                             Conclusions
                                                                                 AVWS is an underdiagnosed entity. Its diagnostic workup re-
                                                                             quires a high level of suspicion and well-designed labs or a com-
                                                                             prehensive network of facilities. Multimeric analysis is crucial
                                                                             when diagnosing AVWS to determine its potential underlying
                                                                             physiopathology mechanism. The possibility of a drug-induced
                                                                             AVWS must always be considered in our differential diagnosis
                                                                             and alopurinol should be ruled out as a possible cause.


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levels; Rco, ristocetin cofactor activit.
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                                     Bleeding, Thrombosis and Vascular Biology 2023; 2:88
