Study of Coagulation Disorders and the Prevalence of Their Related Symptoms among COVID-19 Patients in Al-Jouf Region, Saudi Arabia during the COVID-19 Pandemic

Introduction: The coronavirus (COVID-19) has affected millions of people around the world. COVID-19 patients, particularly those with the critical illness, have coagulation abnormalities, thrombocytopenia, and a high prevalence of intravascular thrombosis. Objectives: This work aims to assess the prevalence of coagulation disorders and their related symptoms among COVID-19 patients in the Al-Jouf region of Saudi Arabia. Subjects and methods: We conducted a retrospective study on 160 COVID-19 patients. Data were collected from the medical records department of King Abdulaziz Specialist Hospital, Sakaka, Al-Jouf, Saudi Arabia. The socio-demographic data, risk factors, coagulation profile investigation results, symptom and sign data related to coagulation disorders, and disease morbidity and mortality for COVID-19 patients were extracted from medical records, and the data were stored confidentially. Results: Males represented the highest prevalence of COVID-19 infection at 65%; 29% were aged 60 or over; 28% were smokers; and 36% were suffering from chronic diseases, with diabetes mellitus representing the highest prevalence. Positive D-dimer results occurred in 29% of cases, with abnormal platelet counts in 26%. Conclusion: Our findings confirm that the dysregulation of the coagulation cascade and the subsequent occurrence of coagulation disorders are common in coronavirus infections. The results show absolute values, not increases over normal values; thus, it is hard to justify increased risk and presence based on the presented data.


Introduction
In December 2019, Chinese authorities in Wuhan identified atypical pneumonia clusters of unclear cause. On January 7, 2020, they identified a new Coronaviridae virus as the cause of the respiratory infection outbreak, naming it SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) [1]. COVID-19 has been a global health disaster, with almost 497,960,492 cases of COVID-19 and 6,181,850 deaths associated with COVID-19 documented globally [2].
Due to the abundance of viruses that bind to the angiotensin-converting enzyme 2 (ACE2) receptor in the human body, COVID-19 has the ability to impact several organs and systems in the body, including the pulmonary, central nervous, cardiovascular, hematological, urogenital, and gastrointestinal systems. In addition, lung fibrosis may indirectly injure other organs by impairing oxygen delivery and triggering a cytokine storm, which leads to the malfunctioning of immune responses, impaired coagulation, and inflammatory cell infiltration [3]. The severity of COVID-19-induced pneumonia was attributed to a number of factors, such as age, chronic obstructive pulmonary disease (COPD), smoking history, and respiratory failure [4]. COVID-19 patients who experience severe symptoms, especially those who have coexisting conditions such as chronic diseases, may quickly develop acute respiratory distress syndrome (ARDS) as well as pneumonia, with a higher mortality rate days after the disease first appears, suggesting that it may lead to a multisystem condition [1]. Fever, cough, dyspnea, wheezing, and excessive mucus production were the most prevalent symptoms of COVID-19 disease [5]. Death in severe COVID-19 infection is generally caused by the development of ARDS, sepsis, and multiple organ failure, all of which are a result of dysfunctional immunological, endothelial, and coagulation responses characterized by thrombocytopenia, leukopenia, hypercoagulation, and elevated D-dimer levels [6].
Neurological clinical manifestations of COVID-19 are generally non-specific for the SARS-CoV-2 virus. However, SARS-CoV-2 has the capability to gain direct access to the nervous system, increasing the risk for even more serious neurological complications, including ischemic stroke [7]. The most common neurologic manifestations of COVID-19 are alterations in taste and smell, headache, disorders of consciousness/cognition, and neuropsychiatric manifestations; rarer manifestations include seizures, transverse myelitis, Guillain-Barre syndrome, rhabdomyolysis, and cranial nerve palsy [8]. In individuals with pre-existing neurological disorders like Parkinson's disease or dementia, COVID-19 may raise the likelihood of exacerbating neurological complications and vice versa [9].
Severe COVID-19 seems to have a strong link with coagulopathy and platelet count abnormalities [10]. Many individuals have coagulation abnormalities that match those of other systemic coagulopathies associated with severe infections, such as disseminated intravascular coagulation (DIC), venous thromboembolism (VTE), and/or thrombotic microangiopathy [11]. Alterations caused by COVID-19 coagulopathy, such as increased blood coagulation, result in a reduction of platelets, which leads to DIC that rarely occurs [12]. The disruption in the synthesis of coagulation proteins may result in the formation of exhaustion factors, which can lead to bleeding. Even if DIC in certain individuals is uncommon, assessing sepsis-induced coagulopathy is extremely useful in predicting the severe consequences of COVID-19 [12].
The mechanisms that trigger coagulation and exacerbate coagulative disorders in association with COVID-19 infection have been connected to immune system responses, specifically the pro-inflammatory mediator release that interacts with platelets, activating tissue factor expression, and triggering stimulation of plasminogen activator inhibitor-1, which leads to the inhibition of the fibrinolytic system and leads to endothelial dysfunction, causing thrombogenesis. Elevated D-dimer levels have been identified as a reliable biomarker for poor prognosis [13].
The aim of this study is to assess the prevalence of coagulation disorders and their related symptoms among COVID-19 patients in the Al-Jouf region of Saudi Arabia.

Materials and Methods
The study design in this research was a retrospective study on COVID-19 patients, conducted in the Al-Jouf region of Saudi Arabia. Study duration and sample size were conducted (12/2021-02/2022), with samples comprised of the medical records of 160 COVID-19 patients previously admitted (01/2020-10/2021) to isolation and intensive care units in King Abdulaziz Specialist Hospital, Sakaka, Al-Jouf, Saudi Arabia. Exclusion criteria were pregnancy, recurrent miscarriage, history of stroke or deep venous thrombosis (DVT), long history of birth control pill use and/or hormone replacement therapy, family history of coagulation disorders, and recent surgery with prolonged bed rest. For data collection and ethical approval, data were collected from the medical records department in King Abdulaziz Specialist Hospital, Sakaka, Al-Jouf, Saudi Arabia, with confidentiality, and stored securely in accordance with the study protocol approved by the Research Ethics Committee, Qurayyat Health Affairs, Reg. No.: H-13-S-071.
Sociodemographic data and risk factor information, such as smoking and history of chronic diseases, were collected for COVID-19 patients, along with results for thrombosis risk, including platelet count, PT (prothrombin time), aPTT (activated partial thromboplastin time), INR (international normalized ratio), and D-dimer level. A control group was added to the analysis for coagulation values, platelet counts, and D-dimer using data gathered from 160 normal cases without COVID-19 infection.
Symptoms and signs for the 160 COVID-19 patients, related to coagulation disorders, disease morbidity, and mortality data, were also stored. The relative risk and odds ratio at 95% CI (confidence interval) for the thrombosis risk factor in COVID-19 patients were estimated.
Data analyses were carried out using SPSS 23 statistical software, and results were analyzed using the Chi-square test. Relative risk, odds ratio, and Fisher's exact test were used, and any differences were considered statistically significant at p < 0.05.

Discussion
COVID-19 surfaced in Wuhan, China, and rapidly spread across the globe, causing a pandemic that crippled life as we know it and put tremendous pressure on governments and individuals alike. The SARS-CoV-2 strain is incredibly contagious, and the hospitalization rate increases significantly in patients aged ≥50 and in those with underlying conditions such as hypertension or obesity [14]. Furthermore, hospitalized patients suffering from severe respiratory or systemic ailments are more susceptible to developing venous thromboembolism and thrombotic complications, which can be life-threatening [15]. Our study focused on the prevalence of coagulation abnormalities and symptoms associated with COVID-19 in patients in the Al-Jouf region.
The first COVID-19 case in Saudi Arabia was reported on March 2, 2020 [16]. There were 507,000 confirmed COVID-19 cases and 8048 fatalities as of July 19, 2021 [17]. In May 2021, Saudi Arabia documented the first case of the delta variant, and delta became the predominant variant of concern from May through June 2021. Sequenced samples revealed that delta was the most prevalent variant (at 40.9%), which, compared to the original strain, is more contagious and causes more serious symptoms [18]. Additionally, the second most abundant strains are beta (15.9%) and alpha (11.6%); this is consistent with transmission rates reported from other nations, such as the UK and France, the latter of which in June 2021 reported a rapid spread of delta [19]. Since our data were collected from January 2020 to October 2021, we speculate the aforementioned strains were circulating from May 2021 until the end of the study, in addition to the original strain that had been circulating in Saudi Arabia since the beginning of 2020.
This research found that the rate of COVID-19 infection in the Al-Jouf region was significantly higher in males (65%) than females (35%). Similarly, a study conducted in Saudi Arabia revealed that men constituted 71% of all cases [20]. On the other hand, Chinese research demonstrated that male and female patients exhibited similar susceptibility to the virus [21]. In addition, the gap in infection rates between sexes in Saudi Arabia does not comport with several studies from China, the USA, and Europe that showed a comparable number of cases in both men and women [22][23][24]. Moreover, during COVID-19 outbreaks, women in Saudi Arabia had better knowledge of infection control practices and were more compliant with the WHO prevention protocols [25]. This may explain the difference in gender infection rates in Saudi Arabia when compared with the rest of the world. Another possible explanation is that most women in Saudi Arabia tend to wear a cloth niqab, which works roughly as a mask and may prevent face touching and limit the spread of droplets.
Coughing is the most common symptom in our study, followed by fever, muscle ache, chest pain, dyspnea, sore throat, and epigastric pain. The highest prevalence of symptoms associated with (and possibly precipitating) thrombotic risk was found in pulmonary thrombosis (29%), followed by DVT, cerebral, and urinary tract thrombosis. Monitoring symptoms may assist clinicians in identifying individuals with bad prognoses, especially in high-risk patients. By promptly identifying risk factors, we can focus on high-risk groups to hopefully reduce the severity and mortality of the disease through timely diagnosis, isolation, and treatment. With this in mind, our study demonstrated that the most prevalent risk factor is diabetes mellitus (39%), followed by hypertension (30%), COPD (14%), chronic liver diseases, and chronic renal disorders. Additionally, 28% of all cases involved smokers, and 36% had chronic diseases. Other risk factors include unconsciousness, septic shock, susceptibility to bleeding, electrolyte imbalance, and renal failure. Finally, 76% of patients in this study required O2 therapy. These risk factors are associated with the progression of pneumonia in COVID-19 patients and may increase the severity of the disease [4].
We found that the most common morbidity associated with COVID-19 was pneumonia (30%), followed by thrombosis (12%). Similar findings have linked several morbidities to COVID-19, such as pneumonia with ARDS, thrombosis, renal failure, anorexia, and digestive issues [26]. Furthermore, we found that DVT was the most common type of thrombosis in COVID-19 patients, accounting for 53% of all cases, followed by pulmonary (26%), cerebral (16%), and cardiac thrombosis (5%). A study by Hanff and co-workers indicated that the most common thrombotic events in COVID-19 are pulmonary and DVT, followed by cerebral and cardiac thrombosis, which result in ischemic stroke [27]. These findings support our results that COVID-19 is highly prothrombotic. Finally, since COVID-19 infection is commonly associated with hypercoagulability, the chance of developing DVT or a potentially fatal pulmonary embolism is significantly higher as a result of small thrombus migration [28,29].
In this study, about one out of five patients (21%) was admitted to the ICU. Of these, 7% required artificial ventilation for respiratory system failure. Additional complications found in the ICU included shock and organ failure. Although ICU admissions are at 21% in Al-Jouf, the mortality rate is only 2%. This finding is in line with the global mortality rate of around 2% [30]. Numerous variables, such as age, smoking, and illness, have a significant impact on the death rate [31]. The fatality rate raises significantly in adults above the age of 50; patients above 80 years of age have a mortality rate of 14.8%; and those between ages of 70 and 79 have a mortality rate of 8%. Finally, the mortality rate at 60-69 years of age is 3.6% [32].
In our study, the risk of thrombosis substantially increased in the presence of chronic diseases, old age, positive D-dimer, thrombocytopenia, and smoking. Our coagulation panel revealed that COVID-19 patients exhibited elevated D-dimer levels in 29% of cases, elevated PT and INR in 34% of cases, and 28% had high aPTT. Both low and high platelet counts were noted. These findings are in line with the findings of other studies, which reported that coagulopathy was a common symptom of SARS-CoV-2 infection, with an increase in D-dimer, fibrinogen, PT, aPTT, and moderate thrombocytopenia [28,33]. As we have previously demonstrated, the levels of PT were significantly higher in COVID-19 patients, and this can be used as a key coagulation marker that may help us better predict the outcome of the disease, as higher PT results have been associated with an increased ICU admission rate as well as increased mortality [5]. Additionally, Zhang et al. discovered that elevated D-dimer levels above 2.0 mg/L might predict mortality with a sensitivity of 92.3% and a specificity of 83.3% [34]. Similarly, Poudel et al. found that D-dimer levels exceeding 1.5 µg/mL predict mortality in COVID-19 patients with high specificity and sensitivity [35]. Tang et al. demonstrated that elevated D-dimer, thrombocytopenia, and delayed prothrombin time have been linked to poor prognosis in patients with COVID-19 [28]. Yet, if a substantial thrombus develops in the body but is not cleared (a far more severe situation for the body), the spike in D-dimer could be moderate. In particular, even in extreme situations such as death, the rise in D-dimer is relatively moderate in suppressedfibrinolytic-type DIC induced by sepsis [36]. Thus, to properly identify and forecast the outcome of COVID-19-associated coagulopathies, we should not depend exclusively on D-dimer as a coagulation indicator; other coagulation makers should be included.
Our analysis of COVID-19 patient data showed significantly higher (8%) and, in some cases, lower (18%) levels of platelet count. This finding may suggest that platelet abnormalities may be predictive of poor prognosis since low platelet count is associated with a fivefold increase in the risk of disease severity, which could be attributed to secondary infections [37,38]. Furthermore, only 8% of ICU patients had platelet counts of less than 100 × 10 9 /L when they were admitted, according to Wu et al. [5]. Other studies have observed the reduction and elevation of platelet count in COVID-19 patients; this phenomenon may point to an increased inflammatory state, with a low platelet count suggesting excessive platelet consumption via thrombi formation but an increase in platelet count suggesting a cytokine storm [39]. Different mechanisms can dictate viral-platelet interactions depending on the virus type; these interactions may change platelet number and function. For example, suppressing platelet production or enhancing platelet destruction, anti-viral antibodies that cross-react with platelet surface integrins, inducing systemic inflammation, and clearing of activated platelets via splenic/liver macrophages and/or phagocytosis by neutrophils may increase platelet counts in COVID-19 patients, and activated platelets may, in turn, contribute to lung injury [40].
Long-term COVID is a chronic, frequently disabling illness that affects many organ systems and is present in at least 10% of severe COVID-19 infections. It has more than 200 known manifestations. Furthermore, numerous pathogenic theories have been put forth, such as SARS-CoV-2 reservoirs remaining in tissues, immunological dysregulation, effects of SARS-CoV-2 on the microbiota (i.e., the virome, autoimmune responses, and immune system priming caused by molecular mimicry), microvascular blood clotting with endothelial dysfunction, and dysfunctional signaling in the brainstem and/or vagus nerve. Its symptoms include postural orthostatic tachycardia syndrome, dysautonomia, and myalgic encephalomyelitis/chronic fatigue syndrome [41]. The contradictory presence of both lymphopaenia and an autoimmune state in long-term COVID is puzzling; autoantibodies are directed against ACE2, ACE1, beta-adrenergic receptors, muscarinic cholinergic receptors, and a variety of self-antigens. The presence of CD4+ T-cell lymphopenia was found to be a reliable predictor of severity and hospitalization in COVID-19 individuals. This phenomenon suggests that the effects of SARS-CoV-2 may be selectively targeting CD8-expressing T lymphocytes while leaving the B lymphocytic system unaffected [42].
Coagulopathies resulting from a COVID-19 infection are possibly caused by numerous underlying mechanisms. Firstly, viral infections induce a systemic inflammatory response that alters the homeostatic balance between procoagulant and anticoagulant activities through various mechanisms, for example, endothelial dysfunction, increased von Willebrand factor, TLR (Toll-like receptor) activation, and tissue-factor pathway activation. These pathways can lead to excessive activation of the coagulation cascade, increasing D-dimer levels [43]. Additionally, during infection, levels of pro-inflammatory cytokines such as IL-1 (interleukin) and IL-6 increase as a result of the virus binding to TLR, which eventually leads to inflammation, fever, and lung fibrosis [44]. Furthermore, because of the strong expression of the virus-binding ACE2 receptor, it is widely established that the gastrointestinal system is actively involved in COVID-19 pathogenesis. The intestinal invasion of SARS-CoV-2 could disturb intestinal homeostasis and host immunological homeostasis, which were responsible for COVID-19 s adverse consequences [45,46]. The dispersion of the gut microbiota and bacteria, which is associated with socioeconomic status and could correlate with viral invasion and the severity of COVID-19 illness. During a COVID-19 infection, antibiotics are administered to treat secondary infections; this could potentially worsen the prognosis due to the decline in human microbiota that promotes the host's immune system as a result of excessive antibiotic consumption [47]. The capacity of microbial pathogenic components to translocate via the leaky gut into the circulatory system allows inflammatory cytokines to be secreted by triggering pattern recognition receptor-like TLRs and NOD-like receptors, resulting in systemic inflammation. Moreover, the amounts of various microbial species varied in tandem with the course of COVID-19 and were linked to biomarkers of host immunology and inflammation [48]. An additional possibility for the increased inflammation in COVID-19 patients is the glycolysis pathway enrichment, which has been linked to greater SRAS-Cov-2 activity. Due to the TLR involvement and subsequent activation of the PI3K/Akt pathway, the primary energy metabolism shifts from lipid to glycolysis to create ATP amidst viral and bacterial infections, particularly following macrophage polarization and dendritic cell activation [49].
Cytokines such as IL-6, TNF, and IL-1 have a vital role in the down-regulation of crucial physiological coagulant pathways, as well as the hyper-activation of platelets that can result in an aberrant clot formation [50]. TLR activation mediated by a COVID infection is responsible for the initiation of extrinsic coagulation pathways and inflammatory signaling in endothelial cells, leukocyte infiltration, neutrophil granule leakage, platelet aggregation, and fibrin deposition that cause thrombosis [51]. Thrombosis caused by a cytokine storm, antiphospholipid antibody syndrome, macrophage activation syndrome, complement cascade, and RAS dysregulation are only a few of the thrombogenic processes that may be involved in the COVID-19 thrombosis. Although cytokine storm and IL-6, in particular, are substantially increased in COVID-19 patients compared to other septic etiologies, and these are mechanistically upstream of numerous thrombogenic pathways, it is currently unclear which set of pathways are prominent in COVID-19. Further studies are needed to better understand how these pathways could potentially help us develop novel, pathway-guided treatment strategies for the disease [52].

Conclusions
Our findings confirm that coagulation cascade dysregulation and subsequent disorders are common in COVID-19 infections and that thrombosis risk increases with chronic disease, old age, a positive D-dimer, unconsciousness, an increased coagulation profile, thrombocytopenia, and smoking. In addition, coagulation disorders cause intravascular clots in deep veins and in the pulmonary, cerebral, and cardiac circulations. Considering the high prevalence of coagulation disorders in COVID-19 patients in Al-Jouf, a national strategy for prevention and management is urgently needed and could provide public education programs for awareness focused on prevention of transmission modes, spread risk factors, signs, and symptoms.

Informed Consent Statement:
Our study is retrospective, thus the patient consent was waived.
Data Availability Statement: All data supporting the reported findings are available upon request from the first and second co-authors.

Conflicts of Interest:
The authors declare no conflict of interest.