D dimer 4

Introduction

1. The Corona virus pandemic
One of the greatest threats to global health in the 21st century is the corona virus
pandemic that emerged in December 2019 in China, and which rapidly transmitted to other
areas of the world. Of recent, the total number of individuals that have contracted the corona
virus is estimated at more than 392,612,632 individuals worldwide with more than 5 million
deaths being recorded as well (Fauci et al., 2020). The novel corona virus can be described
as a virus that shows similarity to the SARS-2 and the MERS-2 virus and is composed
principally of an outer nuclear capsid (N), a spike protein (S), a membrane (M), an envelope
(E) and tightly packed viral RNA.
The principal infectious agent of this virus is the spike protein (S) this protein is
consisted of an extracellular domain, a transmembrane domain, and an intracellular
domain. The way by which coronavirus gain access into the host cell is one of the
determining factors in terms of the infectious nature of the virus and its pathogenesis. The
virus get access to the human cells by the spike protein that bind the angiotensin-converting
enzyme 2 receptors through its receptor-binding domain. This then causes the
internalization of the viral particles which then replicate into millions of virions that infect
other neighboring cells leading to increased infectiousness of the hosts by these viral
particles (Naqvi et al., 2020).

2. Viral transmission of the corona virus
Several modes of transmission of the novel COVID-19 virus have been identified of
which are the following:

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2.1. Respiratory transmission through aerosols and droplets
The primary route of viral transmission is through droplets and aerosols from coughing
and sneezing of an infected individual that comes into contact with the nose, mouth and
eyes of an uninfected individual. Transmission occurs when individuals that are infected
with the virus are within a 1m radius of other non-infected individuals (Zhou et al., 2021).

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Figure 1. viral pathogenesis and infectious pathway of the corona virus (Naqvi et al.,
2020)

2.2. Fomite transmission
Direct contact with fomites has been posited as another method of transmission of
COVID-19. This occurs when aerosols or droplets from an infected mucosa are located on
inert surfaces and are then touched by an uninfected individual leading to entry of the virus
into mucosal surfaces such as the mouth eyes and nose thus causing transmission of the
virus (Cevik et al., 2020).

3. Coronavirus diseases -19 in the Kingdom of Saudi Arabia
Several epidemiology studies have been conducted to report on the incidence and
epidemiology of the novel COVID 19 virus in the Kingdom of Saudi Arabia. The status of
the rate of infection of the novel COVID-19 in the country was in the order of 392 infections
at the beginning of March 2020 and had increased exponentially to about 549,518 cases by
the end of 2021 thus demonstrating a rapid spread of the virus in the population of more
than 53 million individuals. Daily infections in June 2020 were recorded at more than 4,757
daily with net reductions to about 39 daily as from November 2021 thus indicating a
significant decrease in the mode of transmissibility of the virus due to enhanced vaccination
against the virus and a mortality rate of 8,826 has been recorded so far in the Kingdom of
Saudi Arabia (Salam et al., 2022).

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4. Clinical manifestations of COVID-19
Different clinical presentations of the novel COVID-19 virus have been recorded in
patients that have been diagnosed with this disease. Symptoms such as severe headache
and high fever, loss of sense of taste and smell, cough, fatigue, anorexia, dyspnea and
myalgia. A significant proportion of individuals do not present with fever and other
radiological abnormalities that is frequently encountered in some individuals that have been
infected by the virus (Kordzadeh-Kermani et al., 2020). Other clinical manifestations of the
disease are the presence of microthrombi or blood clots. Laboratory findings on
immunological parameters have shown changes in clotting factors such as increased
prothrombin, prolonged or partial activation of thromboplastin time and elevated D-dimer
levels which is a principal factor that is responsible for coagulopathy in these patients that
is one of the major causes of mortality in patients that have been afflicted by this disease
(Pourbagheri-Sigaroodi et al., 2020). It has additionally been observed that more than 80%
of patients that have been with COVID-19 have been diagnosed with mild respiratory
illness with about 15% of patients in need of in hospital admission due to moderate to
severe pneumonia. Disease progression may show a rapid deterioration of the patient due
to multiple organ failure and death. The management of complex cases might require
patient ventilation due to severe hypoxemic respiratory failure and hypotension which
progress rapidly to acute respiratory distress syndrome (ARDS), septic shock, blood
clotting dysfunction even death (Tsai et al., 2021).

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5. The comorbidity of COVID-19
Given the relative novelty of the COVID-19 virus, there exist a relative paucity in data
on the correlation between comorbidities and the severity of disease. It has since emerged
that the presence of comorbidities not only increases the chances of infections but the
severity of infection as well (Guan et al., 2020). Based on current epidemiological studies,
the elderly as well as those with compromised immune systems are at a greater risk of
infection by the virus. The elderly that has been diagnosed with chronic conditions such as
diabetes, cardiovascular disease is at an increased risk of a more severe outcome of the
disease. Several systematic reviews have been conducted to determine if there exist a
correlation between the severity of disease and the presence of comorbidities in patients
that have been infected with the disease (Elezkurtaj et al., 2021). It has been found that the
patients with the most COVID-19 related severe disease were patients that had
comorbidities such as cardiovascular disease and diabetes. In terms of diabetes mellitus, it
was observed that poor glucose control had a direct effect on the increased mortality rate
in patients that had been diagnosed with the disease, in comparison to patients that had a
better glucose control thus demonstrating a direct correlation between disease severity and
this comorbidity (Sanyaolu et al., 2020).

6. Correlation between COVI-19 disease severity and host factors.
Several studies have been carried out to determine if there is a correlation between
COVID-19 severity and factors such as age, gender, pregnancy, and differences in patient
blood group. In terms of gender, in a study that was conducted by .a comparison of various
parameters such as viral mRNA between males and females was carried out to determine

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if there existed differences in viral load between these two subgroups. It was observed that
there were no differences in terms of viral load, as quantitated by the amount of circulating
viral mRNA that was recorded in the blood of these various subgroups. Anti-SARS-CoV2
antibodies (IgG and IgM) were at comparable levels between the two groups as well
(Takahashi et al., 2020). In terms of differences in age and disease severity, in the beginning
of the pandemic, the elderly (>55 years of age) was observed to have developed a more
serious disease and this was principally due to the fact that there was an increased
prevalence of comorbidities in the elderly such as suppressed immune system,
cardiovascular dysfunctions, diabetes mellitus and other comorbidities that are known to
increase disease severity in the elderly (Gallo Marin et al., 2021). Several studies have been
carried out to determine if disease severity could be increased in pregnant women that had
been diagnosed with COVID-19. In a study that was carried out by, a review of the current
evidence in a study on 8207 pregnant women that had been infected with the virus showed
that pregnant women were at an increased risk of more severe disease which requires the
need for hospitalization, ICU admission and possibility of mechanical ventilation. This was
due to greater immune tolerance to accommodate the fetus during pregnancy leading to an
increase in the susceptibility of pregnant women towards viral infections and most
respiratory pathogens such as the COVID-19 virus (Kucirka et al., 2020). Other factors
such as cardiopulmonary changes have been known to increase the susceptibility of
pregnant women towards infection and severe disease thus rendering them more at risk to
severe disease in terms of COVID-19. Lastly, hematological changes in terms of increased
procoagulant factors and increased indicators such as D-dimer could contribute to a more
rapid disease morbidity and a faster development of severe disease in pregnant women

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leading to the elevated number of deceased pregnant women that had been afflicted by the
disease (Vlachodimitropoulou Koumoutsea et al., 2020).
7. D-dimer level and relation to COVID-19 .
D-dimer can be described as a fibrin degradation byproduct that has been previously
utilized as a biomarker in the diagnosis of several thrombotic disorders. D-dimer levels can
be used as a prognostic biomarker for fibrin turnover in the plasma and can be utilized as
an assessment criterion for fibrinolytic status. DD assays are used for the detection of DDimer in the whole blood or plasma mediated fibrin degradation products that might
contain elevated levels of cross-linked D fragments. The fibrinolytic system breaks down
the fibrin mesh following the formation of a blot clot. The D-dimer fragment is formed
from two fibrin fibers following the activation of the plasmin enzyme. As such, the levels
of D-dimer in the serum are a representation of the systemic activation of the coagulation
pathway as well as fibrinolysis (Rostami & Mansouritorghabeh, 2020). Elevated levels of
D-Dimer have been correlated to the onset of several coagulopathies of which are the
following:

7.1. Pulmonary embolism
Pulmonary embolism is a coagulopathy that is one of the major causes of deaths in the
elderly. Pulmonary embolisms are characterized by an obstruction of the main pulmonary
artery or its branches by an embolus that occurs in the deep veins. Previous researches had
reported elevated D-Dimer in patients with clinically suspected pulmonary embolism.
However, the diagnostic levels of D-Dimer for acute pulmonary embolism is still subject
to controversy given the fact that studies have proven inconclusive as to the accurate levels

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of this biomarker that can aid in the identification of patients that might present with a
pulmonary embolism (Gao et al., 2018).

7.2. Deep venous thrombosis
Deep vein thrombosis is one of the leading causes of mortality in hospitalized patients and
D-dimer is one of the biomarkers that is used for the screening of patients that are at risk
of venous thromboembolism and it has been detected in patients that have been diagnosed
with deep vein thrombosis given the fact that it can be used as a marker for endogenous
fibrinolysis. Several retrospective analysis have been done to determine the prognostic
significance of D-Dimer level in patients with suspected deep vein thrombosis. In studies
conducted by, it was observed that high D-Dimer levels were positively correlated to the
diagnosis of distal versus proximal deep vein thrombosis (DVT) of the lower limb (Hochuli
et al., 2007).

8. D-dimer and COVID-19 pathogenesis
Since the start of the pandemic, one of the major causes of mortality of the coronavirus
is hyper coagulopathy and an increased risk for venous thromboembolism events which
causes a series of inflammatory processes that most often results in multiple organ failure
and ultimately the death of the patient. Several biomarkers for disease severity in patients
that have been infected with the virus have been identified of which is D-Dimer, which is
a byproduct of fibrinolysis. Clinical studies have been carried out to determine the
prognostic importance between D-dimer levels and disease severity in patients that have
been diagnosed with the novel coronavirus. In a systematic review that was done by (Zhan

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et al., 2021), the diagnostic sensitivity for D-dimer in terms of COVID-19 severity was
variable ranging from 43% to 100% with a variable specificity also( 57 – 89% ). In another
review conducted by, the prognostic significance for D-dimer in terms of disease severity
was conducted in pediatric patients as well as in adults that had been infected with the virus.
It was observed that in pediatric patients, D-Dimer levels were significantly linked to
severe coagulopathy and disease severity in pediatric patients but not with age. In adults,
similar results were obtained with increased levels of D-Dimer being correlated to disease
severity in this patient demographic . Additionally, a correlation between D-dimer levels
and patients with co-morbidities such as diabetes was also investigated. It was observed
that infected patients with co-morbidities such as diabetes had higher plasma levels of Ddimer in comparison to patients that were not diagnosed with diabetes but had tested
positive for the COVID-19 virus (Rostami & Mansouritorghabeh, 2020). These results
clearly demonstrated that diabetes might further exacerbate the severity of COVID-19 in
patients that have been diagnosed with this disease (Wang et al., 2020).
This project aims at determining if there exists a correlation between D-dimer levels
and COVID-19 severity in a cohort of 451 patients, of which half of this cohort have been
diagnosed with the novel COVID-19 virus. As such, owing to the significant coagulopathy
in patients that have been diagnosed with coronavirus, we hypothesize that elevated levels
of D-dimer will be correlated to the patient cohort that has been included in this
retrospective study.

9. Mechanism of elevated D-dimer
Fibrin degradation by plasmin, thrombin, factor XIIIa, give rise to D-dimer which is used
as a marker of fibrinolysis. thrombin converts fibrinogen into fibrin monomers, that
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polymerize by factor XIIIa which is active transglutaminase. Finally, plasmin breaks down
the fibrin polymers , releasing fibrin split products and revealing the D-dimer. Before it is
incorporated into a fibrin gel or after the fibrin clot has been dissolved by plasmin, D-dimer
antigen can be found on fibrin degradation products produced from soluble fibrin.

Aim of the study
This study aimed at:
1. Estimate the level of D-dimer in the plasma of confirmed COVID-19 patients.
2. Investigate the relation between D-dimer level in COVID-19 patients and their
outcome.

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Material and Method

1. Study design and participants
For this retrospective study, the electronic medical record of 310 patients after
excluding 141 patients with no D-dimer result was reviewed on the diagnosis of COVID19 for clinical data, disease severity and laboratory findings, parameters for inflammation,
and D-dimer plasma level. The diagnostic criteria for COVID-19 were as follows: the
detection of a high homology for the spike protein of the virus using real-time PCR, and
D-dimer levels were also obtained using the DD assays. The study proposal was accepted
by Medical Services General Directorate (REC-22-008).

2. Data collection
The age, sex, patients history, laboratory tests results , treatment protocols , and patients
outcome were extracted from the electronic medical files for each of the patients. All
information obtained were inputted into a data management form for better management.
To ensure data accuracy, two independent researchers assessed the data that was collected
individually. For the detection of COVID-19, all nasopharyngeal swabs were collected
from patients from the Al Medina General Hospital, Ouhd Hospital and Prince Sultan
Armed Forces Hospital in the Al Medina region and the test results were thus obtained from
the electronic medical records of the patients. Blood samples were also collected for further
laboratory analysis to detect biochemistry parameters levels and D-dimer levels as well in
the patients.

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3. Inclusion criteria
For patients to be included in this study, they had to have received a positive diagnosis
of infection with the novel COVID-19 virus, had to have been hospitalized either in the Al
Medina General Hospital, Ouhd Hospital and Prince Sultan Armed Forces Hospital or
treated as an outpatient in any of these hospitals. Informed consent from each of the patients
had to have been received prior to the researchers gaining access to the patient electronic
medical records.
4. Exclusion criteria
Patients that had been diagnosed with other upper or lower respiratory illnesses caused
by other viruses than corona viruses or bacteria were excluded from the study.

5. Statistical analysis
The collected data was analyzed using SPSS program version 26 and Excel 20. mean ±
SD or median (min – max) were used to express quantitative data For p-value to be
statistically significant 13

Result

Table 1. Age, gender, and nationality distribution in COVID-19 patients
Parameters

N=310

%

Meal

178

57.42%

Female

132

42.58%

Saudi

219

70.65%

non- Saudi

91

29.35%

under 18

3

0.97%

18-35

15

4.84%

35-50

40

12.90%

50-70

134

43.23%

70+

118

38.06%

P value

Gender

Nationality

Age groups

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*Significant P1. D-Dimer distribution
D-dimer level was generally high elevated in most of the studied patients (74.51%).
The numbers of males with abnormal D-dimer levels (above 583 ug/l) were 132 (42.59%)
and in the normal range (below 583 ug/l) was 46 (14.84%). In contrast, the numbers of
females with abnormal D-dimer levels (above 583 ug/l) were 99 (31.93%), while the
number of females with normal D-dimer levels (below 583 ug/l) was 33 (10.64%) (Figure
2). No statistically significant difference between both male and female were noticed .The
entire data set is listed in Tables 2 and 3.

Table 2. D-dimer distribution
Parameters
Abnormal

N=310

%

231

74.51%

D-dimer
Normal

79

Mean

SD

P value

15584.9

±21884.9

0.045*

25.48%

*Significant PD-

25414.31
Female

99 (31.93%)

±21344.02

0.093

33 (10.64%)

dimer

140
120

100
80
60
40
20
0
Normal

abnormal

Normal

Male

abnormal
Female

Figure 3. D-dimer distribution based on gender

2. D-dimer level and severity in COVID-19 patients
The mean value of D-dimer of all patients was 23245.95 ug/l (standard deviation SD,
13735.78), 51957.06 ug/l (SD, 36515.48) for patients in ICU, and 6006.78 ug/l (SD,
658.11) for patients in Ward. Differences in the mean value of D-dimer between ICU and
ward was 28757.16 ug/l (95% confidence interval CI, 65796–7832, pTable 4. D-dimer level in severity COVID-19 patients
Number
Patients

of
Mean value of D-dimer

SD

P value

95% CI

patients
Overall

310 (100%)

23245.95 ug/l

±13735.78 0.0916

In ward

193 (62.26%)

6006.78 ug/l

±658.11

In ICU

117 (37.74%)

51957.06 ug/l

±36515.48 0.1593

-3768 to 50113

0.0001* 4769 to 7358
-20783 to 125152

*Significant P583 ug/l had the highest risk of mortality (PTable 5. relation between D-dimer level and mortality .
Patients

Number of patients Mean value of D-dimer

SD

Overall

310 (100%)

23245.95 ug/l

±13735.78 0.0916

-3768 to 50113

Death

54 (17.42%)

17157 ug/l

±19907

Discussion

It has been proven that the higher the D-dimer level, the more severe is contributes to
the advancement of Sars-cov-2. Regarding this work, we investigated the relation amid
increased D-dimer level, clinical severity and outcome of COVID infection. D-dimer levels
were considerably greater in individuals suffering from symptomatic COVID-19 and nonsurvivors in this study. D-dimer concentrations larger than 0.5 ug/ml were linked to more
severe disease and poor patients’ outcome, as verified by previous research (Han et al.,
2020).
D-dimer tests are routinely applied in medical care to rule out coagulopathy, peripheral
arterial disease, and DIC. A high D-dimer level suggests a higher risk of irregular blood
coagulation. It was also shown that high D-dimer concentration were related to higher death
rates in some illnesses, such as severe pneumonia (Querol et al., 2004). Pneumonia in the
community people with acute clinical illness had higher D-dimer levels, whereas those with
conventional D-dimer levels had better health conditions (Sneijders et al., 2012). In our
research, severely affected COVID-19 patients were shown to have higher levels of Ddimer. Presumably, coagulation dysfunction is also linked with the severity of COVID-19.
Recent research has demonstrated that increased D-Dimer levels in COVID-19
individuals are associated with more severe clinical symptoms and disease progression
(Huang et al., 2020). It was revealed that the concentration of D-dimer in ICU individuals
who were suffering from COVID-19 was significantly elevated (Huang et al., 2020).
Particular attention should be addressed to the dangers of venous thromboembolism among
individuals with acute COVID-19 who are bedbound and exhibit impaired congealing
symptoms. During the elaboration of the disease, those with considerably elevated D-dimer
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showed rapid deterioration (Huang et al., 2020; Chen et al., 2020). In this case, arterial
infarction atop of venous thrombosis must be treated as soon as possible, notably if
individuals exhibit clinical signs including a quick decrease in blood pressure, a significant
loss in oxygen saturation, and breathing difficulties (Nasif et al., 2022).
On top of coagulation and pulmonary intercalation, D-dimer could indicate a serious
viral infection. Infection with a virus can lead to sepsis and coagulation malfunction, which
is typical in the course of serious diseases. In addition, the rise in D-dimer could also be
seen in inflammatory reaction, since inflammatory cytokines may produce an dysregulated
clotting and fibrinolysis in the air sac, and this has high possibilities of stimulating the
fibrinolysis and hence enhance the echelon of D-dimer (Tang et al., 2019; Li et al., 2020).
D-dimer levels more than 1 g/ml were identified as a considerable danger for a poor results
in people affected by COVID-19 (Zhou et al., 2020).
In our research, amid the 310 hospitalized individuals suffering from COVID-19 the
mortality mean for D-dimer was (17157 [SD, 19907]; [95% CI, 11724 to 22591]; PLimitation
Our research has some limitations. Exclude missing D-dimer concentrations from
gathered data. When comparing D-dimer score variations amongst acute and asymptomatic
patients, transforming non-normally distributed information (median and variance) to
regularly distributed data (average and standard deviations) may cause bias. The odds ratio
could not calculate because there was no control group. The observed relationships between
D-dimer and outcomes are confounded by as-yet-unidentified factors; nevertheless, we
adjusted our analyses for well-established and novel risk factors.

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Conclusion

Independent of previously recognized risk variables, D-dimer echelons were autonomously
related with an amplified danger of critical illness, thrombosis, acute renal injury, and all-cause
death among COVID-19 patients. This work provides more evidence that COVID-19 is a
coagulopathy, with D-dimer serving as a direct link between COVID-19 infection and poor
outcomes. An overall of 310 individuals suffering from COVID-19 were encompassed in the
analysis after excluding 141 with no D-dimer. Briefly, 42.58% of them were ladies, and 57.42%
of the overall number were men with an average of sixty five years (IQR; 53.0-78.0). The average
D-dimer distribution between ICU and ward equaled 28757.16 ug/l (95% confidence interval CI,
65796–7832, p

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