10.4081/btvb.2022.40
Coronavirus disease 2019 (COVID-19) following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection called for a specific and massive vaccination campaign. Acquired hemophilia A (AHA) is a potential life-threatening coagulopathy. Hematological- targeted autoimmune conditions including immune thrombocytopenia, vaccine-induced thrombotic thrombocytopenia and AHA emerged during large-scale vaccination against SARS-CoV-2 and contributed to vaccination hesitation. The aim of the present study was to evaluate the putative recurrence of AHA after vaccination against SARS-CoV-2 with mRNA vaccines (BNT162b2 and mRNA- 1273) in patients with relatively recent history of AHA. Thirteen patients (8 women and 5 men, mean age = 63.1±16.6 years) with AHA in the previous two-to-five years were enrolled in the study. Platelet count, prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen and Factor VIII levels were evaluated 48 hours prior to each vaccine dose and 10 days post-vaccination. Clinical self-assessment and remote video visits were performed in the presence of even minor hemorrhagic signs. No major bleeding events were detected at any time-point, including evaluation at 30 days after the 3rd vaccine dose. No significant hemorrhagic changes were observed, in particular no thrombocytopenia and/or significant alterations in PTT and Factor VIII emerged across subjects. Patients with a previous history of AHA of various etiology do not seem to have an increased recurrence risk after a COVID-19 vaccination course of 3 doses with either mRNA vaccine. This finding supports this specific safety aspect in the face of the possible continuation of the vaccination campaign based on the trend of the COVID-19 pandemic.
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Monica Bocchia
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Bleeding, Thrombosis and Vascular Biology
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Safety of COVID-19 mRNA vaccination in patients with history of acquired hemophilia A: a case series
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Brief Reports
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Bleed Thromb Vascul Biol
Monica Bocchia
2022/10/17
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Puccetti L, Bacchiarri F, Calzoni P,et al. A fatal unsuspected case of acquired A hemophilia. Misleading role of therapy with acetylsalicylic acid? Intern Emerg Med. 2021 Nov;16(8):2339-2340.
Safety of COVID-19 mRNA vaccination in patients with history of acquired hemophilia A: a case series
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1
                                                                                                                  BRIEF REPORT

Safety of COVID-19 mRNA vaccination in patients with history of acquired
hemophilia A: a case series
Luca Puccetti,1 Vincenzo Sammartano,2 Federico Caroni,2 Margherita Malchiodi,2 Paola Calzoni,3 Eleonora Franceschini,3
Lucrezia Galasso,3 Monica Bocchia2
1
Hemostasis and Thrombosis Unit, “Santa Maria alle Scotte” University Teaching Hospital of Siena, University of Siena, Siena, Italy;
2
Hemathology Unit, “Santa Maria alle Scotte” University Teaching Hospital of Siena, University of Siena, Siena, Italy; 3Coagulative
Disorders Laboratory Unit, Santa Maria alle Scotte” University Teaching Hospital of Siena, Siena, Italy



ABSTRACT
     Coronavirus disease 2019 (COVID-19) following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection called
for a specific and massive vaccination campaign. Acquired hemophilia A (AHA) is a potential life-threatening coagulopathy. Hemato-
logical-targeted autoimmune conditions including immune thrombocytopenia, vaccine-induced thrombotic thrombocytopenia and AHA
emerged during large-scale vaccination against SARS-CoV-2 and contributed to vaccination hesitation. The aim of the present study
was to evaluate the putative recurrence of AHA after vaccination against SARS-CoV-2 with mRNA vaccines (BNT162b2 and mRNA-




                                                                                                       ly
1273) in patients with relatively recent history of AHA. Thirteen patients (8 women and 5 men, mean age = 63.1±16.6 years) with AHA
in the previous two-to-five years were enrolled in the study. Platelet count, prothrombin time (PT), partial thromboplastin time (PTT),




                                                                                               on
fibrinogen and Factor VIII levels were evaluated 48 hours prior to each vaccine dose and 10 days post-vaccination. Clinical self-assess-
                                                                         ment and remote video visits were performed in the presence of
                                                                         even minor hemorrhagic signs. No major bleeding events were




                                                                                         e
                                                                         detected at any time-point, including evaluation at 30 days after
   Correspondence: Luca Puccetti, Hemostasis and Thrombosis Unit,
   “Santa Maria alle Scotte” University Teaching Hospital of Siena,
   University of Siena, Viale Bracci 16, 53100, Siena, Italy.
                                                                                   us
                                                                         the 3rd vaccine dose. No significant hemorrhagic changes were
                                                                         observed, in particular no thrombocytopenia and/or significant
                                                                         alterations in PTT and Factor VIII emerged across subjects. Pa-
                                                                              al
   Fax: +39.0577586185.                                                  tients with a previous history of AHA of various etiology do not
   E-mail: luca.puccetti@unisi.it
                                                                         seem to have an increased recurrence risk after a COVID-19
                                                                    ci

   Key words: COVID-19; acquired hemophilia A; bleeding; mRNA            vaccination course of 3 doses with either mRNA vaccine. This
                                                                  er


   vaccine; vaccination.                                                 finding supports this specific safety aspect in the face of the pos-
                                                                         sible continuation of the vaccination campaign based on the
                                                                 m



   Contributions: LP conceived and wrote the manuscript; FC and          trend of the COVID-19 pandemic.
    MM collected clinical data and provided follow-up; PC, EF and
                                                      om




    LG performed laboratory analysis; LP, VS and MB revised and fi-
    nally approved the manuscript. All authors approved the final man-
    uscript.                                                                  INTRODUCTION
                                               -c




    Conflict of interest: The author declares no potential conflict of in-         Coronavirus disease 2019 (COVID-19) following se-
    terest.
                                      on




                                                                              vere acute respiratory syndrome coronavirus 2 (SARS-
    Funding: None.                                                            CoV-2) infection was declared a pandemic by the World
                                                                              Health Organization (WHO) on March the 11th, 2020.1
                                N




    Availability of data and materials: All data generated or analyzed        Large-scale vaccination of at-risk groups and later of the
    during this study are included in this published article.
                                                                              general population is the most effective public health
    Received for publication: 24 May 2022.                                    measure for the mitigation of the COVID-19 pandemic.2
    Accepted for publication: 5 September 2022.                                    Infection with SARS-CoV-2 has been strongly asso-
                                                                              ciated with immune-mediated reactions, including the de-
    Publisher’s note: All claims expressed in this article are solely those
                                                                              velopment of autoimmune disorders.3
    of the authors and do not necessarily represent those of their affili-
    ated organizations, or those of the publisher, the editors and the re-         Emerging data also suggest a link between COVID-19
    viewers. Any product that may be evaluated in this article or claim       vaccination and the development of various hematologi-
    that may be made by its manufacturer is not guaranteed or endorsed        cal-targeted autoimmune conditions including immune
    by the publisher.                                                         thrombocytopenia (ITP).4 Acquired hemophilia A (AHA)
    ©
     Copyright: the Author(s), 2022                                           is a rare but potentially life-threatening autoimmune hemo-
    Licensee PAGEPress, Italy                                                 static disorder where autoantibodies against Factor VIII are
    Bleeding, Thrombosis and Vascular Biology 2022; 1:40                      present in the blood due to a failure in immune tolerance.5
    doi:10.4081/btvb.2022.40
                                                                                   AHA due to either SARS-CoV-2 infection or post-
    This work is licensed under a Creative Commons Attribution-               COVID-19 vaccination has been reported. In particular,
    NonCommercial 4.0 International License (CC BY-NC 4.0).                   the post-vaccine forms may range from asymptomatic to
                                                                              severe, requiring the treatment provided for AHA.6-10 Fur-

                                                Bleeding, Thrombosis and Vascular Biology 2022; 1:40
                       Safety of COVID-19 mRNA vaccination in patients with history of acquired hemophilia A                                      11



thermore, relapses may characteristically occur in AHA                             to-four years and still in follow-up at our center were en-
and indeed, even after remission, whatever the cause, a                            rolled in the study. Each patient gave a specific further in-
prolonged follow-up is indicated to prevent the recurrence                         formed consent to participate in the study beyond that
of serious clinical forms.5                                                        spontaneously provided for the vaccination course accord-
    In our Italian experience, vaccination hesitancy was                           ing to the Italian regulation for the vaccination campaign
not uncommon in various population groups and subjects                             (2nd dose 21-28 days after the 1st and 3rd dose 4-5 months
with previous hematological and/or autoimmune and/or                               after the 2nd). The assessment schedule included platelet
coagulative disorders were often referred to a specific                            count, prothrombin time (PT), partial thromboplastin time
consultation on this matter. In such a context, also the                           (PTT), fibrinogen, and Factor VIII levels in the 48 hours
vaccine-induced thrombotic thrombocytopenia (VITT),                                prior to each vaccine dose and 10 days post-vaccination.
an extremely rare condition that may develop after vacci-                          Each patient received homologue vaccine for the three
nation with the recombinant adenoviral vector encoding                             doses (10 patients BNT162b2 and 3 mRNA-1273).
the spike protein antigen of SARS-CoV-2 (ChAdOx1                                       Clinical self-assessment was strongly recommended
nCov-19, AstraZeneca, Cambridge, UK)11 has signifi-                                in presence of even minor hemorrhagic signs (Interna-
cantly contributed to the vaccination hesitancy.                                   tional Society on Thrombosis and Haemostasias [ISTH]
    Therefore, given the confusion generated above all by




                                                                                                      ly
                                                                                   classification)12 with immediate reporting to the center and
unscientific disclosure regarding general coagulation                              consequent rapid clinical-laboratory evaluation. The pa-




                                                                                              on
problems and vaccination risk, the aim of our study was                            tient was directly contacted and managed by the center in
to evaluate over time, after each dose of COVID-19                                 case of significant alterations in the laboratory tests. Fort-
mRNA vaccines, patients previously affected by AHA of                              nightly remote video visits were performed as a follow-




                                                                                        e
different origins regarding, in particular, the possible re-                       up even in the absence of patient reports or alterations in
currence of the condition.                                                       usblood chemistry tests. The last remote video visit of the
                                                                                   study was performed 30 days after the 3rd dose of COVID-
                                                                      al
                                                                                   19 vaccine and considered as study closure in the absence
MATERIALS AND METHODS
                                                                                   of clinical bleeding or laboratory abnormalities.
                                                      ci

    Between June 2021 and January 2022, thirteen pa-                                   Patient characteristics, including AHA history, are
                                                    er


tients (8 females and 5 males, mean age = 63.1±16.6                                shown in Table 1. All patients had negative swab for
years, range 34-81 years) with AHA in the previous two-                            SARS-CoV-2 throughout the study.
                                                   m
                                         om




Table 1. Patient characteristics, including acquired hemophilia A (AHA) history.
      M/F    Age at     PTT       Hb at Factor      Inhibitor      Type of AHA                     Bleeding Site               Therapy    Relapse
                                  -c




            diagnosis ratio at diagnosis VIII at     title at         (year of
                         on




                      diagnosis   (g/dl) diagnosis diagnosis         diagnosis)
                                         (% activity)(Bethesda
                    N




                                                      Units)
1      F       59        3.5       6.6       0.9       25           R.A. (2017)                 Cutaneous, Muscular         rVIIa, PDN, CY    0
2      F       67        3.5       7.7       0.3       35           LES (2019)                  Cutaneous, Muscular         rVIIa, PDN, CY    0
3      F       31        2.4       6.3       0.4       20       post-pregnacy (2018)       Cutaneous, Muscular, Mocular     rVIIa, PDN, CY    0
4      M       74        2.5       6.2       0.6       35          Sepsis (2018)        Cutaneous,Muscular, Abdominal, Psoas rVIIa, PDN, CY   1
5      M       84        2.4      11.4       1.6       20         Pemfigo (2019)                Cutaneous, Muscular              PDN          0
6      M       77        3.4       6.3       0.3       50       gastric cancer (2019)     Cutaneous, Muscular, Abdominal    rVIIa, PDN, CY    0
7      F       85        3.4       6.2       0.2       40          Sepsis (2020)             Cutaneous, Muscular, Joint       aPCC, PDN       0
8      F       75        3.2       6.2       0.1       40        Idiophatic (2017) Cutaneous, Muscular, Abdominal, Psoas aPCC, PDNCY          1
9      F       76        3.5       6.3       0.3       50        Idiophatic (2019)              Cutaneous, Muscular         rVIIa, PDN, CY    0
10     M       69        3.2       7.8       0.4       35        Idiophatic (2018)        Cutaneous, Muscular, Abdominal    rVIIa, PDN, CY    0
11     M       73        2.2      10.1       1.2       15        Idiophatic (2017)                  Cutaneous                    PDN          0
12     F       62        3.6       7.9       0.3       40        Idiophatic (2019)           Cutaneous, Muscular, Joint     aPCC, PDN, CY,    0
                                                                                                                              Rituximab
13     F       60        2.2       9.1        2        10        Idiophatic (2019)                  Cutaneous                    PDN          0
M: male, F: female, PTT: partial thromboplastin time, H: hemoglobin, AHA: acquired hemophilia A, rVIIa: recombinant activated factor VII, aPCC:
activated prothrombin complex, PDN: prednisone, CY: cyclofosfamide.


                                            Bleeding, Thrombosis and Vascular Biology 2022; 1:40
12                                                        L. Puccetti et al.




    Hemoglobin level and platelet count were measured                   ulation at each time-point of the observation period. A p-
on a DXH 800 Beckman Coulter Counter (Brea, USA).                       value <0.05 was considered as statistically significant. All
Measurement of PT, PTT, fibrinogen (Clauss); and Factor                 analyses were performed using the software SPSS v27
VIII were performed on an ACL TOP 750 Analyzer and                      (IBM, Armonk, USA).
specific diagnostic kit according to manufacturer instruc-
tions (all by Instrumentation Laboratory Werfen,
Barcelona, Spain). The possible presence of inhibitors,                 RESULTS AND DISCUSSION
expressed in Bethesda Units, would have been evaluated
                                                                            No major bleeding events were detected during the
in the presence of hemorrhagic alterations of the coagu-
                                                                        study at any time-point, including evaluation at 30 days
lation tests according to specific indications.13
                                                                        after the 3rd vaccine dose. Three patients showed local
                                                                        pain, which resolved after 48 hours (two after the 1st dose,
Statistical analysis
                                                                        one after the 2nd dose) while a fourth patient presented a
    Bleeding incidence, except eventually self-limiting                 local hematoma at the injection site, less than 3 cm in di-
bleeding at the injection site if less than 3 cm in diameter,           ameter, which developed four days after injection of the
was recorded and described in detail. Repeated measures                 2nd dose and resolved spontaneously in a few days without




                                                                                                ly
analysis of variance (ANOVA) was used to assess putative                detectable thrombocytopenia and/or PTT and Factor VIII
differences in measurable variables across the study pop-               changes (patient number 7 in Table 2).




                                                                                            on
                                                                                    e
Table 2. Laboratory parameters in each patient throughout the study.
Patient and type of vaccine                           Baseline          I dose
                                                                       +10 days
                                                                                 us
                                                                                  Pre-II dose   II dose
                                                                                                +10 days
                                                                                                           Pre-III dose
                                                                                                            +10 days
                                                                                                                          III dose
                                                                       al
1 F 63y                       INR                       1.06            0.99         1.05         1.09        1.03          1.04
BNT162b2                      PTT ratio                 1.02            0.95         1.04          1          1.03          1.01
                                                        ci

                              VIII (%)                  109              116         104          114         100           104
                              Fibrinogen (mg/dl)        342             420*         351          402         360           395
                                                      er


                              PLT (x103/µL)             303             316          299          305         296           293
                              Hb (g/dl)                 14.3            14.5         14.2         14.1        14.5          14.2
                                                     m



2 F 69y                       INR                       1.1             1.02         1.04         1.06        1.05           1
BNT162b2                      PTT ratio                 1.04            0.98         1.01         0.95        1.03           1
                                             om




                              VIII (%)                   98             107          102          109         101           104
                              Fibrinogen (mg/dl)        338             436*         367          438         350           399
                              PLT (x103/µL)             234             218          229          216         228           210
                                       -c




                              Hb (g/dl)                 12.7            12.8         12.6         12.7        12.7          12.8
3 F 34y                       INR                       0.99             0.98        1.03          1          0.98          1.04
                               on




mRNA-1273                     PTT ratio                 1.01             0.94         1.1         1.02        1.06          0.96
                              VIII (%)                  121              130         117          120         112           116
                              Fibrinogen (mg/dl)        295              368         324          370         316           348
                              N




                              PLT (x103/µL)             267              258         276          280         257           260
                              Hb (g/dl)                 12.3             12.2        12.5         12.2        12.4          12.2
4 M 77y                       INR                       1.07             1            1.1           1         1.06          1.01
BNT162b2                      PTT ratio                 0.96            0.92         0.99         0.96        1.01          0.96
                              VIII (%)                  127             133          130          134         120           123
                              Fibrinogen (mg/dl)        316             408*         352          390         328           356
                              PLT (x103/µL)             219             208          232          220         229           218
                              Hb (g/dl)                 14.7             15          14.8         14.6        14.4          14.3
5 M 86y                       INR                       1.11            1.08         1.07         1.05        1.1           1.06
BNT162b2                      PTT ratio                 1.16             1.1         1.12         1.05        1.13          1.09
                              VIII (%)                   97              111         100          104         108           105
                              Fibrinogen (mg/dl)        307             394*         328          352         326           344
                              PLT (x103/µL)             249             230          233          228         226           230
                              Hb (g/dl)                 13.8            13.9         13.6         13.5        13.7          13.8
6 M 79y                       INR                       1.12             1.1         1.08         1.04        1.07          1.09
BNT162b2                      PTT ratio                 1.08            1.01         1.04         1.01        1.05          1.04
                              VIII (%)                  134             140          128          136         135           130
                              Fibrinogen (mg/dl)        307             404*         338          374         346           350
                              PLT (x103/µL)             224             209          216          211         208           205
                              Hb (g/dl)                 12.3            12.1         12.4         12.2        12.1          12.2
                                                                                                           To be continued on next page


                                        Bleeding, Thrombosis and Vascular Biology 2022; 1:40
                        Safety of COVID-19 mRNA vaccination in patients with history of acquired hemophilia A                                        13



    No significant hemorrhagic alteration of the study pa-                      pro-inflammatory state induced by COVID-19 vaccine
rameters was observed, in particular no thrombocytopenia                        binding to pattern recognition receptors (PRR).14
and/or significant changes in PTT and Factor VIII ap-                                Therefore, our data show that in patients with previous
peared across subjects (Table 2). Significant hyperfibrino-                     AHA of various origins (Table 1), immunization with
genemia (p<0.05) was found after the 1st dose but not after                     mRNA vaccines is safe and does not induce clinical
the 2nd or 3rd dose in the whole cohort (Table 3). No sig-                      and/or laboratory relapses of AHA following 3 doses of
nificant changes were observed in hemoglobin levels and                         vaccine.
platelet count (Table 2, Table 3). Furthermore, no throm-                            This finding may be relevant, considering that the in-
botic events occurred despite the transient increase in fib-                    cidence of new post-vaccination AHA cases is already in
rinogen especially after the 1st dose of vaccine. In this                       its rarity difficult to understand whether induced by direct
setting, increased fibrinogen may be due to a temporary                         mechanism or by association of probability.10


Tab. 2. Continued from previous page.
Patient and type of vaccine                                   Baseline         I dose       Pre-II dose      II dose     Pre-III dose     III dose




                                                                                                       ly
                                                                              +10 days                      +10 days       +10 days




                                                                                            on
7 F 88y                         INR                             1.16             1.2            1.14           1.13          1.15           1.17
BNT162b2                        PTT ratio                       1.13             1.1            1.07           1.09          1.06           1.04
                                VIII (%)                        106             102             111            114           115            118
                                Fibrinogen (mg/dl)              348             436*            388            412           390            398




                                                                                       e
                                PLT (x103/µL)                   198             188             195            190           188            190

8 F 79y
BNT162b2
                                Hb (g/dl)
                                INR
                                PTT ratio
                                                                13.8
                                                                1.06
                                                                1.02
                                                                             us 13.7
                                                                                0.99
                                                                                0.93
                                                                                                13.8
                                                                                                1.06
                                                                                                0.97
                                                                                                               13.6
                                                                                                               1.01
                                                                                                               0.94
                                                                                                                             13.5
                                                                                                                             1.05
                                                                                                                             0.99
                                                                                                                                            13.3
                                                                                                                                            1.01
                                                                                                                                            1.06
                                                                       al
                                VIII (%)                        116             122             120            123           121            113
                                Fibrinogen (mg/dl)              295             364             340            348           332            329
                                                      ci

                                PLT (x103/µL)                   277             260             268            279           260            268
                                Hb (g/dl)                       13.1            12.9            13.1            13           12.8           12.7
                                                    er


9 F 78y                         INR                             1.05            1.01            1.02           1.06          1.01           1.04
BNT162b2                        PTT ratio                       1.05            0.97            0.99           1.11          1.09           1.06
                                                   m



                                VIII (%)                        119             128             125            110           114            119
                                Fibrinogen (mg/dl)              316             420*            402            390           364            348
                                        om




                                PLT (x103/µL)                   211             220             233            220           218            210
                                Hb (g/dl)                       12.8            12.9            12.7           12.5          12.4           12.5
10 M 72y                        INR                             1.08            1.02            1.03           1.06          1.04           1.1
                                  -c




BNT162b2                        PTT ratio                       1.11            1.06            1.08            1.1          1.09           1.12
                                VIII (%)                         95             101              99             92            92             90
                          on




                                Fibrinogen (mg/dl)              366             438             430            402           390            385
                                PLT (x103/µL)                   370             391             352            360           364            351
                                Hb (g/dl)                       15.8            16.2             16            15.8          16.1           15.9
                    N




11 M 77y                        INR                             1.03            1.01            1.06           1.03          1.08           0.99
BNT162b2                        PTT ratio                       0.96            0.91            0.94           0.93          0.96           0.92
                                VIII (%)                        129             137             130            135           131            132
                                Fibrinogen (mg/dl)              337             427*            388            420           416            410
                                PLT (x103/µL)                   360             348             356            349           338            353
                                Hb (g/dl)                       16.1            16.3            15.8           15.9          15.9           16.2
12 F 64y                        INR                             1.02            0.95            0.96           0.99          1.04           0.97
mRNA-1273                       PTT ratio                       1.01            0.96            1.01           0.98          0.99           1.03
                                VIII (%)                        108              116            104            106           102             99
                                Fibrinogen (mg/dl)              245             339*            301            278           280            265
                                PLT (x103/µL)                   199             190             188            184           190            189
                                Hb (g/dl)                       13.5            13.6            13.3           13.2          13.4           13.2
13 F 62y                        INR                             1.06            1.01            1.06           1.02          1.08           1.01
mRNA-1273                       PTT ratio                        1.1            1.02            1.06            1.1          1.09           1.11
                                VIII (%)                         95              99              96             93            93             91
                                Fibrinogen (mg/dl)              307             412*            348            370           329            338
                                PLT (x103/µL)                   266             280             259            254           248            260
                                Hb (g/dl)                       12.9            12.8            12.5           12.9          12.6           12.8
M, male; F, female; BNT162b2 and mRNA-1273, type of mRNA vaccine against SARS-CoV-2; INR, International Normalized Ratio; PTT, partial
thromboplastin time; PLT, platelet count; Hb, Hemoglobin. II dose 21-28 days after I dose: III dose 4-5 months after II dose. Repeated measures analysis
of variance (ANOVA): *p-value <0.05.


                                            Bleeding, Thrombosis and Vascular Biology 2022; 1:40
14                                                               L. Puccetti et al.




Table 3. Laboratory parameters in the whole cohort throughout the study.
                              Baseline              I dose           Pre-II dose              II dose          Pre-III dose         III dose
                                                  +10 days                                   +10 days                              +10 days
INR                           1.03±0.08           1.01±0.09           1.05±0.08              1.08±0.11          1.04±0.09          1.02±.011
PTT ratio                     1.04±0.12           0.96±0.11           1.02±0.11             1.01±0.12           1.01±0.11          0.98±0.01
VIII (%)                     103.2±18.4          111.6±21.2          102.2±19.3             109.9±20.1          99.8±18.6          106.8±20.1
Fibrinogen (mg/dl)           306.2±26.8         398.8±34.6*          334.3±25.1             369.8±28.3         328.1±21.2          350.6±23.4
PLT (x103/µL)                  287±38              296±36              281±32                 283±30             281±32             290±33
Hb (g/dl)                     14.1±1.8            14.4±1.9            13.9±1.8               13.9±2.1           13.8±2.2            13.9±2.1
INR, International Normalized Ratio; PTT, partial thromboplastin time; PLT, platelet count; Hb, Hemoglobin. II dose 21-28 days after I dose: III dose
4-5 months after II dose. Repeated measures analysis of variance (ANOVA): * p-value <0.05.




    In fact, the specific evaluation of the cases found in                            dations on the diagnosis and treatment of acquired hemo-
the Swiss registry showed a possible mechanism linked                                 philia A. Haematologica 2020;105:1791-801.




                                                                                                             ly
to a subjective predisposition to the development of AHA                         6.   Wang KY, Shah P, Roarke DT, Shakil SA. Severe acquired




                                                                                                     on
and not to a direct mechanism induced by the vaccine in                               haemophilia associated with asymptomatic SARS- CoV-2
                                                                                      infection. BMJ Case Rep 2021;14:e242884.
forming antibodies against factor VIII.15
                                                                                 7.   Franchini M, Glingani C, De Donno G, et al. The first case
    Given the putative lethality of AHA,16 any possible re-




                                                                                               e
                                                                                      of acquired hemophilia A associated with SARS- CoV-2 in-
currence might contribute to the vaccination hesitancy due                            fection. Am J Hematol 2020;95:E197-8.
to fear of serious coagulation disorders as also emerged
for VITT. In this context, our data suggest that already in
                                                                                 8.    us
                                                                                      Radwi M, Farsi S. A case report of acquired hemophilia fol-
                                                                                      lowing COVID-19 vaccine. J Thromb Haemost 2021;19:
the extreme rarity of new AHA cases possibly linked to
                                                                             al
                                                                                      1515-8.
anti-SARS-CoV-2 vaccination with mRNA vaccines,10                                9.   Farley S, Ousley R, Van Wagoner N, Bril F. Autoimmunity after
                                                                ci

even safety, in terms of no recurrence, in subjects with a                            Coronavirus Disease2019 (COVID-19) vaccine: a case of ac-
previous pre-vaccination event is of relevant importance.                             quired hemophilia A. Thromb Haemost 2021;121:1674-6.
                                                              er


                                                                              10.     Cittone MG, Battegay R, Condoluci A, et al. The statistical
                                                                                      risk of diagnosing coincidental acquired hemophilia A fol-
                                                             m




CONCLUSIONS                                                                           lowing anti-SARS-CoV-2 vaccination. J Thromb Haemost
                                                om




                                                                                      2021;19:2360-2.
    In conclusion, our data suggest that patients with a pre-                 11.     Greinacher A, Thiele T, Warkentin TE, et al. Thrombotic
vious AHA of various etiology do not seem to have an in-                              Thrombocytopenia after ChAdOx1 nCov-19 Vaccination. N
                                          -c




creased risk of recurrence after a complete vaccination                               Engl J Med 2021;384:2092-101.
course (3 doses) with either mRNA BNT162b2 and                                12.     Schulman S, Kearon C. Subcommittee on Control of Anti-
                                  on




mRNA-1273 vaccine. This finding supports specific safety                              coagulation of the Scientific and Standardization Committee
in the face of the possible continuation of the vaccination                           of the International Society on Thrombosis and Haemostasis.
                                                                                      Definition of major bleeding in clinical investigations of an-
                            N




campaign based on the trend of the COVID-19 pandemic.
                                                                                      tihemostatic medicinal products in non-surgical patients. J
                                                                                      Thromb Haemost 2005;3:692-4.
                                                                              13.     Franchini M, Castaman G, Coppola A. Acquired inhibitors
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