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\begin{document}

\title{Do We Need To Evaluate Patients With Spontaneous Subconjunctival
Hemorrhage For Bleeding Disorders?}



\author[1]{Selim Sayın}%
\author[2]{Arif Ülkü Yener}%
\affil[1]{Ankara Gülhane Eğitim ve Araştırma Hastanesi}%
\affil[2]{Ankara Keçiören Eğitim ve Araştırma Hastanesi}%


\vspace{-1em}



  
  \date{May 26, 2024}


\begingroup
\let\center\flushleft
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\maketitle
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\selectlanguage{english}
\begin{abstract}
Aim of the study: Subconjunctival hemorrage (SCH) is a frequent bleeding
manifestation and a common cause of visits to the primary care. Trauma
in young patients and vascular damage such as hypertension in the
elderly are the most common causes of SCH and the prevalence of
hematological diseases is less than 1\%. We aimed to evaluate the
prevalence of congenital or acquired bleeding disorders in patients with
once or recurrent SCH. Methods used to conduct the study: It is a
retrospective study and included fifty-two patients with SCH whose
etiologic factor was not detected. Hemostatic tests were studied in 52
patients (25 male and 27 females). All patients included were evaluated
for congenital or acquired bleeding disorder and SCH with once and those
with 2 or more were compared for the laboratory results. Results of the
study: Type I von Willebrand disease (vWD) was diagnosed in one patient
with recurrent SCH and one patient with single SCH (3.8\%). The
prevalence of patients with type 1 vWD in the study was not
statistically significant when compared with the frequency of vWD in the
normal population. Fibrinogen level was found to be statistically higher
in patients who had SCH once than those who had recurrent SCH. But
fibrinogen level was in normal range in all patients. Conclusions drawn
from the study and clinical implications: There was no increase in the
incidence of congenital or acquired bleeding disorder in SCH compared to
normal population. For this reason it was thought that there was no need
for evaluation for bleeding disorders in spontaneous SCH.%
\end{abstract}%



\sloppy


\textbf{Do We Need To Evaluate Patients With Spontaneous Subconjunctival
Hemorrhage}

\textbf{For Bleeding Disorders?}

\textbf{Abstract}

\textbf{Aim of the study:} Subconjunctival hemorrage (SCH) is a frequent
bleeding manifestation and a common cause of visits to the primary care.
Trauma in young patients and vascular damage such as hypertension in the
elderly are the most common causes of SCH and the prevalence of
hematological diseases is less than 1\%.

We aimed to evaluate the prevalence of congenital or acquired bleeding
disorders in patients with once or recurrent SCH.

\textbf{Methods used to conduct the study:} It is a retrospective study
and included fifty-two patients with SCH whose etiologic factor was not
detected. Hemostatic tests were studied in 52 patients (25 male and 27
females). All patients included were evaluated for congenital or
acquired bleeding disorder and SCH with once and those with 2 or more
were compared for the laboratory results.

\textbf{Results of the study:} Type I von Willebrand disease (vWD) was
diagnosed in one patient with recurrent SCH and one patient with single
SCH (3.8\%). The prevalence of patients with type 1 vWD in the study was
not statistically significant when compared with the frequency of vWD in
the normal population. Fibrinogen level was found to be statistically
higher in patients who had SCH once than those who had recurrent SCH.
But fibrinogen level was in normal range in all patients.

\textbf{Conclusions drawn from the study and clinical
implications:~}There was no increase in the incidence of congenital or
acquired bleeding disorder in SCH compared to normal population. For
this reason it was thought that there was no need for evaluation for
bleeding disorders in spontaneous SCH.

\textbf{Keywords:} bleeding disorder, screening, subconjunctival
hemorrhage, von Willebrand disease

\textbf{What' known?}

The first referral center of patients with spontaneous subconjunctival
hemorrhage is usually family medicine and the correct management of
these patient is very important. Bleeding disorders are frequently
reported to play a role in the etiology of SCH, but few studies have
investigated the prevalence and clinical significance. The most
important question to be answered in these patients is who should we
screen for bleeding disorders or should we refer tertiary centers?

\textbf{What' new?}

In this study patients who were not found to have an etiological factor
such as trauma, eye infection, hypertension, diabetes and drugs, that
would cause SCH were evaluated for bleeding disorder. We also firstly
evaluated for congenital or acquired bleeding disorder and spontaneous
subconjunctival hemorrhage with once and those with two or more. We
found no increased incidence of congenital or acquired bleeding
disorders in SCH patients compared to the normal population. In terms of
bleeding history in two patients with vWD, they reported more bleeding
findings in other patients. It was concluded that only SCH patients with
a history of other systemic bleeding such as recurrent epistaxis, skin
and mucosal, minor post-traumatic bleeding, hematuria, gastrointestinal
bleeding, tooth extraction, post-operative bleeding, hemarthrosis,
menorrhagia should be screened for congenital bleeding disorder.

\textbf{Introduction}

Subconjunctival hemorrhage (SCH) is acute bleeding with sharp borders
underneath the conjunctiva. It is often a cause of concern in patients
and is therefore one of the most common reasons for referral to
ophthalmology clinics from primary care\textsubscript{{[}1,2{]}}. It is
usually unilateral and the region and size of the bleeding vary
according to the etiology. Fukuyama et al reported the incidence of SCH
as 2.9\%\textsubscript{{[}3{]}}. Although the most common cause for SCH
is trauma and contact lens-induced injury in younger patients, among
older patients it is mostly associated with hypertension, diabetes
mellitus and anticoagulant usage~\textsubscript{{[}4,5{]}}. Despite all
these reasons, the cause of most cases remains unexplained. Bleeding
disorders are frequently reported to play a role in the etiology of SCH,
but few studies have investigated the prevalence and clinical
significance\textsubscript{{[}3{]}}. In addition to anticoagulant and
antiaggregant usage, immune thrombocytopenia and congenital bleeding
disorders have been reported in a few studies as hemostatic alterations
at the etiology of SCH~\textsubscript{{[}6-9{]}}.

The aim of this study was to evaluate the prevalence of congenital or
acquired bleeding disorders in patients with once or recurrent SCH and
to investigate the clinical characteristics of patients with SCH
presenting to Ophthalmology Division.

\textbf{Methods}

In this retrospective study, the patients admitted to Ophthalmology and
Hematology Division were enrolled between February 1, 2018, and November
30, 2019. The patients who admitted to the ophthalmology outpatient
clinic due to once or recurrent SCH, underwent a complete ophthalmologic
examination, including the best corrected visual acuity level, slit-lamp
biomicroscopy, intraocular pressure measurement with Goldmann
applanation tonometer and dilated fundoscopy. Patients who didn't have
any etiological reasons for bleeding such as conjunctivitis,
episcleritis, keratitis, corneal ulcer, glaucoma, dry eye and
blepharitis, were referred to the hematology outpatient clinic for
evaluation of bleeding disorders. ~ ~

All patients were questioned for ocular trauma (including the usage of
lenses), systemic hypertension, diabetes, cardiovascular abnormalities,
fever and medications affecting platelet function or blood clotting,
such as nonsteroidal anti-inflammatory drugs, aspirin, antiplatelet
agents, heparin, oral anticoagulants, anti-vitamin K or non-vitamin K
oral anticoagulants (NOACs), steroids, antiepileptics or antidepressants
and if any, they were excluded from the study. Patients' bleeding
histories were also evaluated using a standardized bleeding assessment
tool (BAT) created by International Society on Thrombosis and Hemostasis
(ISTH).

Complete blood count (CBC), prothrombin time (PT), activated partial
thromboplastin time (aPTT), fibrinogen, factor VIII, von Willebrand
factor antigen (vWF Ag), von Willebrand factor ristocetin cofactor (vWF
Rco) and factor XIII antigen levels were tested from all patients
meeting inclusion criterias. PFA-100 (collagen / epinephrine (C / Epi),
collagen / ADP (C / ADP) and closure time (CT) were studied in available
patients. Thrombin time was studied in a small number of patients.
According to these laboratory results, the patients with the hemorrhagic
disorders were determined and SCH with once and those with 2 or more
were compared for the laboratory results.

Statistical Package for the Social Sciences (SPSS) version 15.0 was used
for the analysis. The distribution of the datas were assessed using a
one-sample Kolmogorov-Smirnov test. Normally distributed continuous
variables were expressed as the mean\selectlanguage{ngerman}±SD, skew-distributed continuous
variables were expressed as the median (minimum-maximum), and
categorical variables were expressed as the number and percentage. For
comparison of categorical variables, Fisher's exact test or a chi-square
test was used. Differences between numeric variables were tested with
Student's t-test or a Mann-Whitney U-test, where appropriate. A p-value
of less than 0.05 was considered as statistically significant.

All procedures performed in studies involving human participants were in
accordance with the ethical standards of the institutional and/or
national research committee and with the 1964 Helsinki declaration and
its later amendments or comparable ethical standards. (Kecioren
Educational and Research Hospital-08.01.2020/2027)

\textbf{Results}

A total of 52 SCH patients were included in the study. Mean age of the
patients was 50.86 ±13.11 years (18--75). 25 were male and 27 were
females. 35 patients have once SCH and 17 patients have more than two
(Table 1). The mean and standard deviation of laboratory results of all
patients, and patients who have SCH once and two or more were given at
the table 2. One patient with once and one patient with recurrent SCH
(3.8\%) were diagnosed a type I vWD (table 3). The prevalence of type 1
vWD in the study was not statistically significant when compared with
the frequency of vWD in the Turkish population.

Fibrinogen level was found to be statistically higher in patients who
had SCH once than those who had recurrent SCH (p=0.048). But fibrinogen
level was in normal range in all patients. Thrombin time was studied in
a small number of patients and all results were in normal range.
Dysfibrinogenemia was not considered clinically in any patient.

There were 12 patients who reported a previous history of bleeding. The
most frequently reported symptoms, in order of frequency, are recurrent
skin and mucosal bleeding, minor post-traumatic bleeding, menorrhagia
and recurrent epistaxis.

\textbf{Discussion}

The first presentation of patients with SCH is usually to the family
medicine and there are few studies on whether these patients should be
evaluated for bleeding disorder. SCH is a mucosal hemorrhage and is
expected in the qualitative deficiency of platelets or in platelet
function disorders and coagulation factor deficiencies. In most of the
non-traumatic SCH cases, the etiological causes are hypertension,
diabetes mellitus and drugs. In addition, coagulation factor deficiency
was detected in less than 1\% of patients \textsubscript{(10)}. During
anticoagulant and antiaggregant usage, and hemostatic alterations as
immune thrombocytopenia, congenital bleeding disorders and hematologic
malignancy as leukemia, SCH was reported in previous
cases\textsubscript{{[}3, 9-11{]}}. However, in these cases SCH is
considered to be a part of other mucocutaneous bleeding, and patients
often apply to the hematology outpatient clinic.

Hypertension, diabetes mellitus and other systemic vascular disorders
play a major role in the etiology of subconjunctival hemorrhage and
their prevalence increases with age. Because of this, the number of
patients with SCH increases markedly over 50 years of
age\textsubscript{{[}12,13{]}}. Although only spontaneous SCH were
included in our study, the mean age of patients was found to be over 50
years as in previous studies. The frequency of non-traumatic SCH was
reported to be more common in women in previous
studies~\textsubscript{{[}4,6{]}}. In our study, although SCH was seen
more frequently in women, it was found to be close in frequency to each
other in both sexes. In 32.7 \% of cases, spontaneous SCH was recurrent
in the absence of any identifiable causes or risk factors. This rate was
higher than some previous studies~\textsubscript{{[}7{]}}. Lens usage is
an exclusion criteria in our study since it may lead to traumatic SCH.
Although the usage of glasses was not considered to be a risk factor for
SCH, it was determined that approximately one third of the cases were
wearing glasses. The incidence of SCH is similar in both eyes.

In our country patients pay attention to the SCH rather than cutaneous
bleeding. Therefore, patients may consult a doctor when they first
underwent SCH despite previous recurrent other mucocutaneous bleeding.
From this point we thought that the first finding of congenital bleeding
disorders such as vWD may be SCH and we expected increased frequency of
congenital or acquired bleeding disorders in patients with spontaneous
SCH. However we showed that the prevalence of hemostatic alterations in
patients with once or recurrent, spontaneous SCH is not different from
that in the general population. There was also no difference between
coagulation factor levels and hemostasis tests between those who had
once SCH and recurrent SCH.

In few studies, no difference was found in platelet count or coagulation
factor levels in recurrent SCH patients from that in the general
population as in our study~\textsubscript{{[}6,7,10{]}}. Although few
studies have shown that homozygosity and heterozygosity for the Val
34Leu mutation of blood clotting factor FXIII is more frequent detected
in SCH cases, factor XIII antigen levels were within the normal limits
in all patients in our study~\textsubscript{{[}8,14{]}.~}Likewise in a
study, there were no correlation between factor XIII antigen/activity
levels and SCH\textsubscript{{[}6{]}}.

40 (76.9\%) of the patients included in our study had a ISTH-BAT score
of 0 and no bleeding disorder was detected. When the other bleeding
findings of 2 patients with type 1 vWD were evaluated, it was learned
that they had bleeding attacks as epistaxis, cutaneous bleeding,
menorrhagia, bleeding after tooth extraction and bleeding from minor
wounds. The ISTH-BAT score of these two cases was 3 and 4, respectively.
Although there seems to be a strong relationship between ISTH-BAT scores
and vWD, there is no statistcal sample size to demonstrate this in our
study. The necessity of evaluating patients with spontaneous SCH for
bleeding disorder is stil a confusing. Although few studies suggest that
spontaneous SCH should be evaluated for bleeding disorder, the
conclusion to be drawn from our study is that, it is a more accurate
approach to investigate bleeding disorder only in SCH patients with a
history of bleeding~\textsubscript{{[}1,5{]}}. It is also more cost
effective.

In addition, fibrinogen level was the only statistically significant
parameter in the comparison between patients with once SCH and recurrent
SCH and it was lower in patients with recurrent SCH. Thrombin time was
studied in five patients and all results were in normal range. Although
it was statistically significant, fibrinogen levels in all patients were
within normal limits and it was considered to have no clinical
significance. Dysfibrinogenemia was also not considered clinically in
any patient.

The first limitation of our study was the fact that the PFA-100 test was
performed by appointment, and therefore the PFA-100 test could be
performed at 2-3 weeks after subconjunctival hemorrhage in all patients.
The second, although factor XIII antigen levels were studied in all
patients, none of them had laboratory examination of factor XIII
activity and Light transmission aggregometry. However, according to the
data from previous studies, it is considered that this situation has no
effect on the results of our study.

Patients presenting with SCH should be questioned and examined in
details for common etiological risk factors such as hypertension,
diabetes mellitus, fever, trauma, drug use, conjunctivitis, blepharitis,
episcleritis, and corneal ulcer. If diseases such as dry eye or glaucoma
are suspected, the patient should be referred to an ophthalmologist for
eye examination.

In addition, in terms of other systemic bleeding findings such as
recurrent epistaxis, skin and mucosal, minor post-traumatic bleeding,
hematuria, gastrointestinal system bleeding, tooth extraction,
post-surgical bleeding, hemarthrosis, menorrhagia, intramuscular,
postpartum and central nervous system bleeding should be questioned. It
should be known that acutely developing hematological diseases such as
leukemias and thrombocytopenia may rarely present with SCH as a single
mucosal site. It should be kept in mind that it is often associated with
skin and other system bleeding. In congenital bleeding disorders,
patients often have a history of previous skin and mucosal bleeding, and
a history of prolonged bleeding after surgical procedures. Patients with
a history of bleeding should be referred to a hematologist. However, it
should be known that less than 1\% of SCH patients will develop due to
hematological reasons.

In conclusion, we suggest not to examine patients with spontaneous SCH
for bleeding disorder, according to the data obtained from our study.
Patients with spontaneous SCH should be evaluated with ISTH-BAT score
instead of directly laboratory examination for bleeding disorder and
evaluation for the congenital bleeding disorders of patients with other
bleeding histories and high bleeding score would be more accurate.

\textbf{Declaration}

No funding and financial support was received for this submission.

The authors declare that they have no conflict of interest.

All the datas and materials are available for checking.

\textbf{References}

\begin{enumerate}
\tightlist
\item
  Cronau H, Kankanala RR, Mauger T. (2010) Diagnosis and management of
  red eye in primary care. Am Fam Physician 81:137--144.
\item
  Tarlan B, Kiratli H. (2013) Subconjunctival hemorrhage: risk factors
  and potential indicators. Clin Ophthalmol 7:1163-1170. doi:
  10.2147/OPTH.S35062
\item
  Fukuyama J, Hayasaka S, Yamada K et al. (1990) Causes of
  subconjunctival hemorrhage. Ophthalmologica 200:63--67. doi:
  10.1159/000310079
\item
  Mimura T, Yamagami S, Usui T et al. (2010) Location and extent of
  subconjunctival hemorrhage. Ophthalmologica. 224(2):90--95. ~doi:
  10.1159/000235798
\item
  Sahinoglu-Keskek N, Cevher S, Ergin A. (2013) Analysis of
  subconjunctival hemorrhage. Pak J Med Sci. 29:132-134. doi:
  10.12669/pjms.291.2802
\item
  Fierro T, Bartolini A, Mezzasoma AM et al. (2016) Prevalence of
  hemostatic alterations in patients with recurrent spontaneous
  subconjunctival hemorrhage. Clin Chem Lab Med.97-103. doi:
  10.1515/cclm-2015-0274
\item
  Cagini C, Iannone A, Bartolini A et al. (2016) Reasons for visits to
  an emergency center and hemostatic alterations in patients with
  recurrent spontaneous subconjunctival hemorrhage. Eur J Ophthalmol 26
  (2):188-192. doi: 10.5301/ejo.5000692
\item
  Incorvaia C, Costagliola C, Parmeggiani F et al. (2002) Recurrent
  episodes of spontaneous subconjunctival hemorrhage in patients with
  factor XIII Val34Leu mutation. Am J Ophthalmol. 134:927--929. doi :
  10.1016/s0002-9394(02)01812-3
\item
  Sodhi PK, Jose R. (2003) Subconjunctival hemorrhage: the first
  presenting clinical feature of idiopathic thrombocytopenic purpura.
  Jpn J Ophthalmol. 47: 316--318. doi :10.1016/s0021-5155(03)00017-0
\item
  Hu DN, Mou CH, Chao SC et al. (2015) Incidence of Non-Traumatic
  Subconjunctival Hemorrhage in a Nationwide Study in Taiwan from 2000
  to 2011. Plos One 10(7) 1-10. doi: 10.1371/journal.pone.0132762
\item
  Taamallah-Malek I, Chebbi A, Bouladi M et al. (2013) Massive bilateral
  subconjunctival hemorrhage revealing acute lymphoblastic leukemia. J
  Fr Ophtalmol 36:45-48. doi: 10.1016/j.jfo.2012.03.013
\item
  Wilson RJ. (1986) Subconjunctival hemorrhage: overview and management.
  J Am Optom Assoc. 57:376-380.
\item
  Mimura T, Usui T, Yamagami S et al. (2010) Recent causes of
  subconjunctival hemorrhage. Ophthalmologica 224(3):133--137. doi:
  10.1159/000236038
\item
  Parmeggiani F, Costagliola C, Incorvaia C et al. (2004) Prevalence of
  factor XIII Val34Leu polymorphism in patients affected by spontaneous
  subconjunctival hemorrhage. Am J Ophthalmol 138:481-484. doi:
  10.1016/j.ajo.2004.03.017
\end{enumerate}

\textbf{Table 1:}~\textbf{Characteristics of the patient with
subconjunctival hemorrhage}

\par\null\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{Variables{}}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{~}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{Age (years)}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
50.8 \selectlanguage{ngerman}±13.1\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{Sex{}}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{Male}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{Female}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
27 (52\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{Glasses usage}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{Yes}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{No}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
33(63.5\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{Frequency of SCH}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{1}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{[?]2}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
17 (32.7\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{Eye involvement}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{Right eye}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{Left eye}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
27 (51.9\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\emph{\textbf{ISTH-BAT score}}\textbf{{}}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{0}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{1}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
5 (9.6\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{2}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
4 (7.7\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{[?]3}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
3 (5.8\%)\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}





Abbreviation: SCH= subconjunctival hemorrage, ISTH-BAT= bleeding
assessment tool created by International Society on Thrombosis and
Hemostasis.

\textbf{Table 2: The mean and standard deviation of laboratory results}\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{Laboratory Test (Normal Range)}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{Laboratory Test (Normal Range)}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\selectlanguage{ngerman}\textbf{Mean ± SD}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\selectlanguage{ngerman}\textbf{Mean ± SD}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\selectlanguage{ngerman}\textbf{Mean ± SD}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{All cases}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Frequency of SCH=1}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Frequency of SCH=[?]2}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{P value}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Platelet (/mm\textsuperscript{3})}
\textbf{(150000-450000)}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Platelet (/mm\textsuperscript{3})}
\textbf{(150000-450000)}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
241326.92 (\selectlanguage{ngerman}±49384.33)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
238000 (\selectlanguage{ngerman}±50048.21)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
248176 (\selectlanguage{ngerman}±48753.50)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textgreater{}0.05\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{PT (sec) (10-15)}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{PT (sec) (10-15)}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
11.29 (\selectlanguage{ngerman}±0.91)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
11.44 (\selectlanguage{ngerman}±0.94)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
10.98 (\selectlanguage{ngerman}±0.79)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textgreater{}0.05\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{INR}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{INR}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.97 (\selectlanguage{ngerman}±0.07)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.99 (\selectlanguage{ngerman}±0.07)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.94 (\selectlanguage{ngerman}±0.04)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textgreater{}0.05\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{aPTT (sec) (22.1-38)}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{aPTT (sec) (22.1-38)}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
25.77 (\selectlanguage{ngerman}±2.45)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
26.07 (\selectlanguage{ngerman}±2.24)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
25.77 (\selectlanguage{ngerman}±3.59)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textgreater{}0.05\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Fibrinogen (mg/dL) (180-350)}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Fibrinogen (mg/dL) (180-350)}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
273.80 (\selectlanguage{ngerman}±68.72)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
285.50 (\selectlanguage{ngerman}±73.71)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
250.42 (\selectlanguage{ngerman}±51.77)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textless{}0.05\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Factor VIII Level (\%) (50-120)}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Factor VIII Level (\%) (50-120)}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
82.53 (\selectlanguage{ngerman}±29.92)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
82.74 (\selectlanguage{ngerman}±31.54)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
82.11 (\selectlanguage{ngerman}±27.21)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textgreater{}0.05\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Factor XIII Level (\%) (60-192)}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Factor XIII Level (\%) (60-192)}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
94.78 (\selectlanguage{ngerman}±32.68)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
94.22 (\selectlanguage{ngerman}±33.77)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
95.94 (\selectlanguage{ngerman}±31.30)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textgreater{}0.05\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{vWF Ag (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{AB Group (47-197)}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
91.80 (\selectlanguage{ngerman}±34.20)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
90.80 (\selectlanguage{ngerman}±36.42)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
94.09 (\selectlanguage{ngerman}±30.02)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textgreater{}0.05\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{O Group (30-197)}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
65.81 (\selectlanguage{ngerman}±13.60)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
67.50 (\selectlanguage{ngerman}±9.67)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
63.00 (\selectlanguage{ngerman}±19.26)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textgreater{}0.05\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{vWF Rco (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{AB Group (51-215)}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
94.63 (\selectlanguage{ngerman}±36.76)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
96.80 (\selectlanguage{ngerman}±39.27)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
89.72 (\selectlanguage{ngerman}±31.46)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textgreater{}0.05\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{O Group (30-215)}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
66.62 (\selectlanguage{ngerman}±23.29)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
75.20 (\selectlanguage{ngerman}±20.77)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
52.33 (\selectlanguage{ngerman}±21.43)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textgreater{}0.05\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{PFA-100}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{C/Epi (\%) (\textgreater{}60)}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
97.05 (\selectlanguage{ngerman}±23.09)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
103.87 (\selectlanguage{ngerman}±14.87)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
93,87 (\selectlanguage{ngerman}±25.91)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textgreater{}0.05\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{C/ADP (\%) (\textgreater{}60)}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
86.01 (\selectlanguage{ngerman}±9.50)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
86.38 (\selectlanguage{ngerman}±10.72)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
85.87 (\selectlanguage{ngerman}±9.37)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textgreater{}0.05\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{CT (sec) (0-60)}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
13.76 (\selectlanguage{ngerman}±14.62)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
16.4 (\selectlanguage{ngerman}±14.53)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
13.04 (\selectlanguage{ngerman}±15.26)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textgreater{}0.05\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Abbreviation: PT=prothrombin time, aPTT=activated partial thromboplastin
time, vWF Ag=von Willebrand factor antigen, vWF Rco=von Willebrand
factor ristocetin cofactor, PFA-100 C/Epi= collagen/epinephrine,
C/ADP=collagen/ADP, CT=closure time.

\textbf{Table 3:} \textbf{Characteristics of two cases with vWD.}\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
& \textbf{Case-1} & \textbf{Case-2}\tabularnewline
\midrule
\endhead
\textbf{Gender} & Female & Male\tabularnewline
\textbf{Age} & 49 & 65\tabularnewline
\textbf{Frequency of SCH} & 2 & 1\tabularnewline
\textbf{ISTH-BAT score} & 4 & 3\tabularnewline
\textbf{Platelet (/mm\textsuperscript{3})} & 282000 &
237000\tabularnewline
\textbf{Blood group} & O Rh (+) & B Rh (+)\tabularnewline
\textbf{aPTT (sec)} & 34.5 & 27.9\tabularnewline
\textbf{Factor VIII Level (\%)} & 49 & 45\tabularnewline
\textbf{vWF Ag (\%)} & 28 & 41\tabularnewline
\textbf{vWF Rco (\%)} & 16 & 44\tabularnewline
\bottomrule
\end{longtable}

Abbreviation: SCH= subconjunctival hemorrage, ISTH-BAT= bleeding
assessment tool created by International Society on Thrombosis and
Hemostasis, aPTT=activated partial thromboplastin time, vWF Ag=von
Willebrand factor antigen, vWF Rco=von Willebrand factor ristocetin
cofactor,

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

