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\begin{document}

\title{Rapid response to mycophenolate mofetil in combination with romiplostim
in a case of severe refractory immune thrombocytopenia post COVID-19
vaccination}



\author[1]{snigdha nutalapati}%
\author[1]{gerhard hildebrandt}%
\affil[1]{University of Kentucky}%


\vspace{-1em}



  
  \date{May 21, 2024}


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\begin{abstract}
Vaccine mediated immune mediated thrombocytopenia (ITP) is an
exceedingly rare. We present a 25-year-old female who developed severe
refractory ITP with multiple active bleeding sites post second dose of
COVID vaccination. She was treated with a combination of Romiplostim and
Mycophenolate mofetil that resulted in rapid platelet count recovery.%
\end{abstract}%



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\textbf{TITLE PAGE}

\textbf{Title:} \textbf{Rapid response to mycophenolate mofetil in
combination with romiplostim in a case of severe refractory immune
thrombocytopenia post COVID-19 vaccination}

Snigdha Nutalapati, Gerhard C. Hildebrandt

Snigdha Nutalapati, MD (snutalapati@uky.edu)

University of Kentucky College of Medicine, Division of Hematology and
Oncology, Lexington, KY, USA

Gerhard C. Hildebrandt, MD (gerhard.hildebrandt@uky.edu)

University of Kentucky College of Medicine, Division of Hematology and
Oncology, Lexington, KY, USA

Key Words: Immune thrombocytopenia, SARS -CoV2 vaccination, Romiplostim,
Mycophenolate mofetil

Key Clinical Message: Though it could not entirely be determined if ITP
post COVID vaccination is truly causative or mere coincidence, it should
be reported and considered as a differential in all patients who present
with thrombocytopenia post COVID vaccination.

Contributions:

Snigdha Nutalapati contributed to the case management and manuscript
writing.

Gerhard C. Hildebrandt contributed to the case management, manuscript
writing and final approval.

Conflict of Interest disclosure statements:

The authors report no conflict of interest.

Data availability statement:

Data sharing not applicable - no new data generated.

\subsection*{Corresponding Author:}

{\label{corresponding-author}}

Gerhard C. Hildebrandt, MD FACP

Professor of Medicine

Division Chief, Hematology and Blood \& Marrow Transplantation

University of Kentucky College of Medicine

Lexington, KY, USA

Email:~gerhard.hildebrandt@uky.edu

predisposed patients. It is advisable to warn patients with CAD or other
immune cytopenias

and monitor the occurrence of these phenomena when they receive the
vaccine. It would be

useful to explore possible immunosuppressive therapy regimens to control
flares, as well as to

estimate the impact of these drugs on the vaccine serological response.

References

{[}1{]} W. Barcellini, J. A. Giannotta, and B. Fattizzo, ``Are Patients
With Autoimmune

Cytopenias at Higher Risk of COVID-19 Pneumonia? The Experience of a
Reference

Center in Northern Italy and Review of the Literature,'' Front.
Immunol., vol. 11, no.

January, pp. 1--9, 2021, doi: 10.3389/fimmu.2020.609198.

{[}2{]} D. Kanduc and Y. Shoenfeld, ``Molecular mimicry between
SARS-CoV-2 spike

glycoprotein and mammalian proteomes: implications for the vaccine,''
Immunol. Res.,

vol. 68, no. 5, pp. 310--313, 2020, doi: 10.1007/s12026-020-09152-6.

{[}3{]} K. A. Downes, R. E. Domen, K. F. McCarron, and K. A. Bringelsen,
``Acute autoimmune

hemolytic anemia following dtp vaccination: Report of a fatal case and
review of the

literature,'' Clin. Pediatr. (Phila)., vol. 40, no. 6, pp. 355--358,
2001, doi:

10.1177/000992280104000610.

{[}4{]} M. Akbik, D. Naddeh, A. A. Ashour, and A. Ashour, ``Severe
immune thrombocytopenia

following MMR vaccination with rapid recovery: A case report and review
of literature,''

Int. Med. Case Rep. J., vol. 13, pp. 697--699, 2020, doi:
10.2147/IMCRJ.S286335.

{[}5{]} D. B. Cines and J. B. Bussel, ``SARS-CoV-2 Vaccine--Induced
Immune Thrombotic

Thrombocytopenia,'' N. Engl. J. Med., p. NEJMe2106315, Apr. 2021, doi:

10.1056/NEJMe2106315.

{[}6{]} A. Greinacher, K. Selleng, and T. E. Warkentin, ``Autoimmune
heparin-induced

thrombocytopenia,'' J. Thromb. Haemost., vol. 15, no. 11, pp.
2099--2114, 2017, doi:

10.1111/jth.13813.

Ethics declaration: verbal consent was obtained from the patient for the
publication of this

report.

Data availability: Other laboratory or clinical data is available from
the corresponding author

on reasonable request.

Author contributions:

M.J.G is the consultant hematologist responsible for the patient, P.L.L
and M.J.G did the

bibliographic research, wrote the clinical case and its discussion.
V.K.K, T.N.MC, J.M.A and

V.C.A provided technical guidance and advice. J.C.C, A.M.B and N.T.C
were involved in critical

revision of the report. L.J.FJ and G.G.V helped with the literature
review and provided overall

\textbf{Introduction:}

Immune mediated thrombocytopenia (ITP) is a autoimmune condition
characterized by low platelet counts and wide range of clinical
manifestations from asymptomatic presentation to major bleeding
manifestations. Vaccine mediated secondary ITP is rare and is associated
with influenza, measles mumps rubella (MMR), hepatitis A and B
vaccination. Most patients respond with steroids and intravenous
immunoglobulin.\textsuperscript{1} We hereby report a case of a
26-year-old female with severe refractory ITP who presented with
multiple active bleeding sites leading to a significant drop in
hemoglobin post second dose of COVID vaccination. She was refractory to
treatment with steroids and intravenous immunoglobulin(IVIG) and was
eventually treated with combination of romiplostim and mycophenolate
mofetil with which her counts improved dramatically.

\textbf{Case discussion:}

A 25-year-old Caucasian female with no significant past medical history
except for well controlled bronchial asthma presented to us with two-day
history of worsening petechiae that initially started on her face and
lower extremities and eventually spread to back, chest, abdomen and
upper extremities. She also complained of intermittent epistaxis.

Vital signs on initial presentation including blood pressure, heart rate
and oxygen saturation were normal. Physical examination revealed
extensive bruising over her back, chest and extremities along with
scattered petechiae all over the body. Laboratory findings on
presentation include WBC of 11x10\textsuperscript{9}/L, hemoglobin (Hb)
of 11g/dl and severe thrombocytopenia with a platelet count of
1x10\textsuperscript{9}/L. Prothrombin time (PT/INR), activated partial
thromboplastin time (aPTT), fibrinogen, Lactate dehydrogenase (LDH),
absolute reticulocyte count and haptoglobin levels resulted normal.
Peripheral blood smear showed profound thrombocytopenia with no evidence
of schistocytes. RT-PCR testing for SARS CoV-2 infection was negative.
Autoimmune and infectious workup including antinuclear antibody (ANA)
screening, coombs testing, HIV ELISA and serology for hepatitis B, and C
were negative. Ultrasound of the abdomen did not show evidence of
splenomegaly or liver parenchymal changes.

Her most recent hematological labs including Hb, platelet count from
three months ago during routine primary care visit were within normal
limits. She neither reported personal or family history of bleeding
disorders nor required blood transfusions prior to this presentation. 26
days prior to this presentation she had received her second dose of
Moderna mRNA vaccination.

Given her clinical presentation, negative infectious and autoimmune
workup, normal hemolysis and coagulation studies along with absence of
other identifiable underlying etiology, she was presumed to be having
immune mediated thrombocytopenic purpura (ITP) and was initiated on
dexamethasone 40mg daily for four days along with intravenous
immunoglobulin (IVIG) 1g/kg for two days\emph{.} She continued to have
clinical worsening during the second and third day of hospitalization
and developed multiple bleeding sites including gross hematuria,
hematochezia, subconjunctival hemorrhage. Her hemoglobin dropped from
11g/dl on presentation to 6.4g/dl. She was initiated on tranexamic acid
for bleeding control and supportive care with platelet transfusions. Her
platelet counts continued to remain low (5x10\textsuperscript{9}/L)
despite receiving 4 days of dexamethasone, 2 days of IVIG and platelet
transfusion support. She continued to have intermittent epistaxis
however hematuria and rectal bleeding started improving with Tranexamic
acid initiation.

As there was no improvement in platelet counts with IVIG and
dexamethasone, on day 7 she was initiated on mycophenolate mofetil (MMF)
1 gram twice daily and Romiplostim 1 mcg/kg weekly. On day 12 her
platelet counts for the first time improved to
13x10\textsuperscript{9}/L. Hb remained stable around 11g/dl. She was
discharged after receiving second dose of Romiplostim 3mcg/kg on day 14.
During her first outpatient visit on day 21 her platelet counts improved
to 140x10\textsuperscript{9}/L. She went on to receive third dose of
Romiplostim at 3mcg/kg. She continued to have no active sites of
bleeding. During fourth week follow up, platelet count recovered to
268x10\textsuperscript{9}/L and MMF was tapered down to 500mg twice
daily and Romiplostim to 2mcg/kg. By fifth week, her platelet counts
continued to improve to 324x10\textsuperscript{9}/L and MMF was tapered
to 250mg twice daily and Romiplostim to 1mcg/kg. She continued to have
normal and stable platelet counts and eventually MMF and Romiplostim
were discontinued.

\textbf{Discussion:}

ITP is an autoimmune entity characterized by autoantibodies directed
against platelet antigens leading to platelet destruction and
thrombocytopenia. Clinical manifestations range from asymptomatic
presentation, spontaneous petechiae and purpura, mucocutaneous
hemorrhage to fatal complications such as gastrointestinal bleeding or
intracranial hemorrhage which usually occur when platelet count is below
10x10\textsuperscript{9}/L.\textsuperscript{2}

Vaccination as an etiology for secondary ITP was previously reported
with influenza, hepatitis A and B, measles, mumps and rubella (MMR) and
diphtheria tetanus acellular pertussis (DTaP) vaccines. It is
hypothesized that pathogenesis of ITP is mainly secondary to molecular
mimicry, a phenomenon in which antigens of host are recognized as
antigens of immunization, provoking the development of autoantibodies.
These antibody-coated platelets may undergo reticuloendothelial
phagocytosis resulting in reduced platelet survival. It is also proposed
that vaccine associated autoimmunity can stem not only form antigen
mediated responses but also contributed by constituents of vaccine such
as adjuvants, preservatives or diluents.\textsuperscript{1,3}

Lee et al described 20 patients who developed thrombocytopenia after
receiving COVID vaccination with either Moderna or Pfizer vaccine.
Sixteen of these patients did not report history of thrombocytopenia
prior to their vaccination. Onset of symptoms from the date of
vaccination ranged from 1-23 days. Similarly, our patient had normal
platelet counts prior to this presentation however ITP developed on day
26 after the second vaccine was given which differs from cases reported
by Lee et al. \textsuperscript{4} It is not clear how the immunologic
mimicry happens after SARS-CoV2 vaccination, nor what the immunologic
target is. Immune response to vaccines are highly variable between
different individuals and populations, and there may be other factors
implicated such as the microbiome impact on vaccine
immunity.\textsuperscript{5} Most common treatments received in these
patients were corticosteroids, IVIG along with platelet transfusions.
Outcomes were reported in 16 patients of which 13 responded to initial
treatment with IVIG, steroids or platelet transfusion, one patient
received Rituximab, thrombopoietin receptor agonist, vincristine along
with steroids and IVIG and one patient developed severe thrombocytopenia
and intracranial hemorrhage despite receiving corticosteroids, IVIG and
Rituximab. In our case thrombocytopenia was refractory to initial
treatment with dexamethasone and IVIG. Due to her presentation with
massive and multi-site bleeding, there was concern for imminent
intracranial hemorrhage in this young and otherwise healthy female, and
a rapid response to treatment of her refractory ITP seemed critical.
Commonly used options for refractory ITP, such as rituximab, single
agent thrombopoietin stimulating agent (TSA), spleen tyrosine kinase
inhibitor fostamatinib seemed either to be too delayed or insufficient
in their response rates for this case. Splenectomy was prohibited due to
bleeding risk and would increase lifelong susceptibility to encapsulated
bacteria. \textsuperscript{6}

Promising activity for MMF in the treatment of de novo and refractory
ITP has emerged over the recent years, and after careful consideration
and in detail discussion with the patient and her family, we decided to
combine MMF with the TSA Romiplostim. The combination of
immunosuppressants with IVIG and TSA has been reported in a small series
to be efficacious and safe.\textsuperscript{7,8} The response to this
combination was rapid and vigorous.

As COVID 19 pandemic persists concerns for vaccine related side effects
remain both among care givers and general population. As of June 26,2021
around 46.4\% of United states population received full vaccination
against COVID 19 and the risk of serious adverse events remains
extremely low. Like primary ITP, vaccine related ITP can have a broad
spectrum of presentation ranging from mild bleeding and petechiae to
fatal bleeding manifestations. When patients present with ITP, a
thorough vaccination history is needed. ITP after COVID 19 vaccination
is rare and the potential association is often overlooked and missed.
With neither of the clinical trials studying Moderna or Pfizer
vaccination had documented cases of
thrombocytopenia,\textsuperscript{9}it is worthwhile to note that
possibility of reported thrombocytopenia post vaccination could be
merely a coincidence rather than causative factor. Nevertheless, we are
probably just now only at the beginning of our understanding of the
plethora and complexity of side effects and immunological impact of the
SARS-CoV 2 directed vaccination and the virus itself. Continued
vigilance and reporting of the possible side effects with vaccinations
is needed, and we believe this should not preclude individuals from
getting vaccinated given rarity of these events and the proven
effectiveness of vaccine in mitigating this horrendous pandemic.

Further studies on the aggressive management with combination regimens
including immunosuppressants and thrombopoietin agonist, especially
among patient's refractory thrombocytopenia and bleeding complications
is warranted.

\textbf{References:}

\begin{enumerate}
\tightlist
\item
  Perricone, C., Ceccarelli, F., Nesher, G.~et al.~Immune
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\item
  Rodeghiero F, Stasi R, Gernsheimer T, et al. Standardization of
  terminology, definitions and outcome criteria in immune
  thrombocytopenic purpura of adults and children: report from an
  international working group. Blood 2009; 113:2386.
\item
  Rinaldi M, Perricone C, Ortega-Hernandez OD, Perricone R, Shoenfeld Y.
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\item
  Lee EJ, Cines DB, Gernsheimer T, Kessler C, Michel M, Tarantino MD,
  Semple JW, Arnold DM, Godeau B, Lambert MP, Bussel JB.
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  American Journal of Hematology. 2021 Feb 19.
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\item
  Cuker A, Prak ET, Cines DB. Can immune thrombocytopenia be cured with
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\item
  Gudbrandsdottir, S., Leven, E., Imahiyerobo, A., Lee, C.S. and Bussel,
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  severe refractory immune thrombocytopenia in adults and children. Br J
  Haematol, 189: e37-e40.
\item
  Charlotte A Bradbury, Rosemary Greenwood,Julie Pell, Katie
  Breheny,Rebecca Kandiyali,Jenny Ingram,Ian Thomas,Catherine Bagot,
  Quentin Hill,Nichola Cooper. A multicentre randomised trial of first
  line treatment pathways for newly diagnosed immune thrombocytopenia:
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  the Flight Trial.Blood\emph{~} (2020) 136 (Supplement\_2): LBA-2.
\item
  Walsh EE,~Frenck RW Jr,~Falsey AR, et al.~Safety and immunogenicity of
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\end{enumerate}

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