\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[greek,english]{babel}



\usepackage{float}








\begin{document}

\title{COVID19 Associated Thrombotic Angiopathy Improved After Plasma Exchange}



\author[1]{Natalie Elkayam}%
\author[1]{Gagan Raju}%
\author[2]{Martin Bluth}%
\author[2]{Yiwu Huang}%
\author[2]{Jay Lipshitz}%
\author[2]{Stephen Peeke}%
\affil[1]{Maimonides Cancer Center}%
\affil[2]{Maimonides Medical Center}%


\vspace{-1em}



  
  \date{May 24, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Woman admitted for COVID-19 respiratory failure requiring intubation,
renal failure and rising bilirubin, requiring CVVHD. Due to dropping
hemoglobin and platelets, TTP was suspected and empiric plasma exchange
initiated. Platelets normalized; she improved; ADAMTS13 level resulted
50.7\%, indicating possible benefit of plasma exchange for COVID19
thrombotic microangiopathy despite normal ADAMTS13.%
\end{abstract}%



\sloppy


\textbf{COVID19 Associated Thrombotic Angiopathy Improved After Plasma
Exchange}

Natalie Elkayam, M.D.\textsuperscript{1}; Gagan Raju,
M.D.\textsuperscript{1}; Bluth, Martin, M.D. Ph.D.\textsuperscript{2};
Huang, Yiwu, M.D.\textsuperscript{1}; Lipshitz, Jay,
M.D.\textsuperscript{1}; Peeke, Stephen, M.D. \textsuperscript{1}

\textsuperscript{1}Department of Hematology and Oncology, Maimonides
Medical Center, Brooklyn, NY, USA

\textsuperscript{2}Department of Pathology, Maimonides Medical Center,
Brooklyn, NY, USA

Corresponding author: Gagan Raju, MD (gagan.raju@gmail.com)

Case presentation:

A 44-year-old Chinese woman with no known medical history presented to
the emergency department for evaluation of shortness of breath. The
patient reported fevers, chills and a dry cough which had progressively
worsened during the preceding week. Her husband was also sick at home
with similar symptoms. Upon arrival to the emergency room, she was
afebrile (36.4) with a blood pressure of 132/87 mmHg, tachycardic (122
beats/minute) and tachypneic (25 breaths/minute). Her oxygen saturation
was 80\% on 6 L of oxygen via nasal cannula requiring escalation to a
non-rebreather mask on which her oxygen saturation declined to 75\%. Due
to progressive dyspnea and hypoxia refractory to oxygen supplementation,
she was endotracheally intubated and mechanically ventilated on account
of acute respiratory failure. Initial laboratory studies demonstrated
creatinine of 1.0 mg/dL, lactate dehydrogenase (LDH) was 2334IU/L and
liver function tests (LFT) were aspartate transaminase (AST)/alanine
transaminase (ALT) 79/63 IU/L with bilirubin levels within normal
limits. Coronavirus-2019 (COVID19) PCR was reactive. C-reactive protein
(CRP) was 38.6mg/dL and ferritin was found to be 297.9 ng/ml. Her
complete blood count (CBC) on presentation demonstrated the following:
white blood cell (WBC) 13.4 cells/L, hemoglobin (Hgb) of 11.7 g/dL and
platelet count of 243k/uL. Coagulation profile including international
normalized ratio (INR), activated partial thromboplastin time (aPTT) and
fibrinogen were all in normal range. Patient was admitted to the medical
intensive care unit for management of septic shock and acute respiratory
failure secondary to acute COVID19 infection. She underwent CT
angiography of the chest, which demonstrated no pulmonary embolism and
bilateral, predominantly ground glass opacities consistent with COVID19
infection changes.

The patient received dexamethasone therapy as indicated in the standard
of care for management of severe COVID19 infection. Within one day of
her hospitalization, her laboratory findings demonstrated worsening
renal function (blood urea nitrogen (BUN)/creatinine 45/2.2 mg/dL), and
worsening total bilirubin up to 4.0 mL/dL within 3 days of her
admission. The patient underwent continuous venovenous hemodiafiltration
(CVVHD) for acute renal failure. Her troponin trended up to 1.41 ng/mL,
which was attributed to demand ischemia due to underlying infectious
process. Her WBC count remained stable throughout her admission. Her
hemoglobin decreased to 6.8 g/dL and she received PRBC transfusion. Her
platelet count within one day of admission dropped from 243 to 65k/\selectlanguage{greek}µ\selectlanguage{english}L
and further decreased to 23k/\selectlanguage{greek}µ\selectlanguage{english}L. Poly Coombs test was negative. Heparin
induced thrombocytopenia (HIT) antibody was negative.

Due to dropping hemoglobin and platelet values, hematology evaluation
was obtained for assessment of possible thrombotic thrombocytopenic
purpura (TTP). Peripheral smear demonstrated normochromic red blood
cells (RBC) with some polychromasia, numerous nucleated RBCs, occasional
basophilic stippling with many schistocytes identified (approximately
5-6/high power field). No platelet clumps were identified though some
large platelets were observed and manual platelet count estimated around
30-50k. Polymorphonuclear cells with toxic granules, many band cells and
some large activated lymphocytes were identified. ADAMTS13 testing was
sent.

On account of high clinical suspicion for thrombotic angiopathy, a
decision was made to commence empiric plasma exchange in advance of
receipt of ADAMTS13 level. The patient underwent plasma exchange with
one blood volume of fresh frozen plasma (FFP) for five consecutive days.

After initiation of plasma exchange, the patient's laboratory values
demonstrated significant improvement: LDH level improved from 3802 to
945 within one day of plasma exchange initiation. Total bilirubin levels
improved from 4.0 to 2.9 within one day of plasma exchange. After the
initial plasma volume exchange, her platelet count increased from 18k to
68k and continued to increase and eventually normalize thereafter,
concurrent with daily plasma exchange. The patient also showed
significant clinical improvement with declining vasopressor requirement
after the second day of plasma exchange and subsequently required
antihypertensives due to elevated blood pressure on the third day of
plasma exchange. Peripheral smear on the fourth day of plasma exchange
demonstrated a significant decrease in schistocytes per high power
field. The presumption was that the rapid clinical improvement
concurrent with plasma exchange was consistent with the diagnosis of
TTP. However after five consecutive plasma exchanges, the ADAMTS13 level
(drawn before initiation of plasma exchange) resulted at 50.7\%,
subsequently plasma exchange was discontinued. The patient no longer
required renal replacement therapy.

\textbf{Hosted file}

\verb`image1.emf`  available at \url{https://authorea.com/users/400277/articles/512609-covid19-associated-thrombotic-angiopathy-improved-after-plasma-exchange}

\textbf{Figure 1.} Peripheral smear with numerous schistocytes seen.

Differential Diagnosis

The patient initially presented with normal platelet count and with
normal mentation. The rapid onset of thrombocytopenia and renal failure
in the context of severe COVID19 infection raised the concern for
possible thrombocytopenia induced by consumptive process due to her
underlying infection. In addition, COVID19-induced thrombotic angiopathy
without TTP was also considered on account of the patient's
coagulopathic and inflammatory changes. The presence of a significant
number of schistocytes on peripheral smear raised the concern for
thrombotic thrombocytopenic purpura (TTP), despite initial presentation
with normal platelet count and concurrent COVID19 infection. Due to a
high clinical and laboratory suspicion for TTP, plasma exchange with FFP
was initiated with pending ADAMTS13 results. The patient experienced a
significant improvement in her clinical status, biochemically, by
laboratory values and with significant decrease in schistocyte per high
power field. The patient's coagulation profile was not consistent with
disseminated intravascular coagulation (DIC). On account of normal
ADAMTS13 levels, yet clear laboratory and pathologic evidence of a
thrombotic microangiopathy, our patient was diagnosed with
COVID19-induced thrombotic angiopathy, which responded briskly to plasma
exchange intervention.

Discussion

Patients with COVID19 infection have been found to exhibit a wide array
of symptoms and complications, as published in the literature in 2020.
There is a known association with COVID19 infection and a unique
coagulopathy. It is postulated that this coagulopathy may be related to
endothelial activation and microvascular thrombosis/hemolysis. There is
evidence that viruses play an important role as a trigger in the
pathogenesis of thrombotic angiopathies. The mechanism of this remains
unclear; it has been suggested that direct endothelial injury by
cytokine storm and immune complex mediated events along with ADAMTS13
inhibitors are implicated as underlying triggers of viral activated
thrombotic microangiopathy {[}1{]}.

A study evaluating secondary thrombotic microangiopathy in
COVID19-infected patients found that patients with low ADAMTS13 levels,
elevated LDH, presence of schistocytes and elevated von Willebrand
factor levels were more likely to indicate severe infection and high
likelihood of death {[}2{]}.

There are case reports of secondary TTP due to COVID19 infection. There
is also a report by Albiol et al. of a 57-year-old woman diagnosed with
acquired autoimmune TTP following the diagnosis of Covid-19 {[}3{]}.
Another case is reported by Hindilerden et al. of a case of TTP which
was diagnosed following COVID19 infection {[}4{]}.

Martinelli et. al carried out a retrospective study on 50 admitted
patients with COVID19 infection in which they evaluated various
laboratory values. They found that about 2-4\% of patients had
documentation of schistocytes on peripheral smears. They also found a
mild decrease in ADAMTS13 level in most of the subjects (47\% with 95\%
CI 40--55). This was the first study suggesting ADAMTS13 impairment in
COVID19 infection {[}5{]}.

Our patient had a COVID-19-associated thrombotic microangiopathy that
exhibited a dramatic response to plasma exchange. The current report
adds to a growing body of literature reporting improvement with plasma
exchange in severely ill patients with COVID19 infection {[}6{]}{[}7{]}.
It is conceivable that plasma exchange accounts for cytokine removal of
inflammatory mediators in the plasma and reinstitution of immune
homeostasis. While employing plasma exchange as a therapeutic modality
for COVID-19 is sure to pose significant challenges, the emerging
evidence warrants further scientific consideration. Plasma exchange used
on a limited scale, particularly for patients with COVID-19
microangiopathy, may represent a useful treatment for a particularly
devastating manifestation of COVID-19.

References:

\begin{enumerate}
\tightlist
\item
  Lopes da Silva R. Viral-associated thrombotic
  microangiopathies.~Hematol. Oncol. Stem Cell Ther.~2011;4(2):51--59.
  doi: 10.5144/1658-3876.2011.51.
\item
  Sweeney JM, Barouqa M, Krause GJ, Gonzalez-Lugo JD, Rahman S, Gil MR.
  Evidence for secondary thrombotic microangiopathy in COVID-19.
  Preprint. \emph{medRxiv} . 2020;2020.10.20.20215608. Published 2020
  Oct 23. doi:10.1101/2020.10.20.20215608
\item
  Albiol N., Awol R., Martino R. Autoimmune thrombotic thrombocytopenic
  purpura (TTP) associated with COVID-19. Ann. Hematol. 2020 May
  28:1--2. doi: 10.1007/s00277-020-04097-0.
\item
  Hindilerden, Fehmi et al. ``Covid-19 associated autoimmune thrombotic
  thrombocytopenic purpura: Report of a case.'' Thrombosis research vol.
  195 (2020): 136-138. doi:10.1016/j.thromres.2020.07.005
\item
  Martinelli, N., Montagnana, M., Pizzolo, F., Friso, S., Salvagno, G.,
  Forni, G., Luca et al. (2020). A relative ADAMTS13 deficiency supports
  the presence of a secondary microangiopathy in COVID 19. Thrombosis
  Research. 193. . 2020 Sep; 193: 170--172
\item
  Shi H., Zhou C., He P. Successful treatment of plasma exchange
  followed by intravenous immunoglobin in a critically ill patient with
  2019 novel coronavirus infection. Int J Antimicrob Agents.
  2020:105974. doi: 10.1016/j.ijantimicag.2020.105974.
\item
  Zhang L., Zhai H., Ma S., Chen J., Gao Y. Efficacy of therapeutic
  plasma exchange in severe COVID-19 patients.~Br J Haematol.~2020 doi:
  10.1111/bjh.16890
\end{enumerate}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/schistocytes-covid-TTP/schistocytes-covid-TTP}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

