“Prevalence, Predictors and Outcomes of Surgical and Gastrointestinal Bleeding Events in Patients with COVID-19 Infection on Anticoagulation”

Background: This study aims to examine risk factors and complications associated with bleeding events in patients with coronavirus 19 (COVID-19) who are on anticoagulation. Method: We conducted retrospective review of a prospectively maintained database of all patients who were admitted with COVID-19 and developed bleeding events. Results: Of 122 bleeds, there were 67 (28%) non-gastrointestinal (GI) and 55 (28%) GI bleeds. Overall mortality was 59% (n= 72), 34 (28%) and 38 (31%) following non-GI and GI bleeds respectively. The prevalence of therapeutic invasive interventions was 7.5% and 16.3% in non-GI and GI bleeds respectively and all were successful in resolving the bleeding event. We found that having a GI bleeds was associated with higher risk of mortality compared to non-GI bleeds (p= 0.04) and having occult bleeds to be associated with 15 times increased risk of mortality. Furthermore, patients who were on therapeutic dose of anticoagulation were more likely to die compared to patients who were on none (odds ratio (OR) 0.1, 95%CI 0.01-0.86), on prophylactic (OR 0.07,95%CI 0.02-0.28) or intermediate (OR 0.36,95%CI 0.09-1.34) anticoagulation doses. Conclusions: Routine prescription of supra-prophylactic dose anticoagulation should be revisited as it appears to be associated with increased of mortality and so more individualized approach to prescription should be the norm. Regardless of the cause of bleeding event it appears that the majority of bleeding events resolve with noninvasive interventions, correction and optimization sepsis therapies. However, when invasive interventions were necessary, they were associated with high success rate despite the delay.


Background
The rapid emergence of the novel coronavirus 19 (COVID-19) has brought the world to a standstill. The transmissibility and associated morbidity and mortality of this virus have overwhelmed many worldwide healthcare systems, resulting in an urgent need to understand this virus and its associated effects better.
It appears that the principal cause of death is acute respiratory failure complicated by a concomitant coagulation disorder that can induce disseminated intravascular coagulation (DIC) (1). In light of this, anticoagulation therapy has been introduced recently as an adjuvant treatment, showing promising results in term of reducing mortality rate in several small retrospective studies (2). As a result, many organizations including the international society of thrombosis and hemostasis (ISTH) are recommending speci c anticoagulation regimens for COVID-19 patients (3). Recommendations included the use of low molecular weight heparin (LMWH) at various doses or unfractionated heparin (UFH) infusions in COVID-19 patients with elevated D-dimer levels but no known thrombotic complications (4)(5). However, others have argued against empiric escalation of anticoagulation due to fears of a potential still unquanti ed increased risk of bleeding (6). Furthermore, COVID-19 induced thrombocytopenia and DIC has been hypothesis to contribute to further increased risk of bleeding as a direct or a sepsis induced effect (7).
Because of these changes in practice, we predicted an increase in inpatients' surgical and gastrointestinal consults to manage patients with bleeding and hence it was imperative to appropriately identify high risk patients for bleeding so that we can mitigate potential bleeding episodes and the associated morbidities and mortality. To date there is a lack in studies evaluating risk factors associated with increased risk of gastrointestinal (GI) and non GI bleeding events, as well as factors associated with the resolution of bleeding episodes after interventions and the risk of mortality following bleeding events in patients with COVID-19 on anticoagulation. Our study aims to be the rst to investigate these.

Methods
The study was approved by Kuwait Ministry of Health Ethical Review Board.The study was approved by Kuwait Ministry of Health Ethical Review Board. All patients admitted to Jaber Al-Ahmad Al-Sabah hospital in Kuwait, with a diagnosis of COVID-19, based on the World Health Organization (WHO) interim guidance (8) and have been con rmed by laboratory testing using polymerase chain reaction (PCR) testing, between March 2020 and June 2020 were included. Patients who had equivocal PCR tests were excluded from the study.

Data collection
Data regarding patients' demographics, baseline characteristics, inpatient therapies, complications, at time of consultations symptoms, laboratory values and interventions were collected retrospectively from the hospital electronic medical record system. These data were entered by the admitting resident prospectively.
as PaO2/FiO2 ratio of 200-300, and normal as PaO2/FiO2 over 300. World health organization bleeding scale was used to classify bleeding severity. Grade 0 was de ned as no bleeding, grade 1 was de ned as minor bleeding such as petechial or mucosal bleeding, vaginal spotting and nasopharyngeal bleeding lasting less than 30 minutes. Grade 2 was de ned as mild blood loss (clinically signi cant) such as having hematemesis, melena, gross hematuria and persistent nasopharyngeal bleeding. Grade 3 was de ned as gross blood loss severe enough to require blood transfusion. Grade 4 was de ned as debilitating blood loss associated with hemodynamic instability and or associated with fatality. Occult bleeding was de ned as failure to identify the source of bleeding after dropping over 2 grams of hemoglobin. Patient was deemed to have sepsis if they were found to have systemic in ammatory response syndrome in response to an infectious process. We have also calculated the quick sequential organ failure assessment score (qSOFA) (value 0 to 3) and charlson comorbidity index (CCI) (value 0 to 9) scores for all patients. All patients diagnosed with COVID-19 stayed in the hospital until they had resolution of symptoms; de ned as being afebrile for more than 72 hours and having oxygen saturations equal to or above 94%, Discharge occurred after two consecutive negative PCR tests for COVID-19, more than 24 hours apart. Patients' mortality was tracked up to 30 days after bleeding event consultation.

Outcome measured
Data were analyzed in accordance with three major outcomes. First was mortality within 30 days of bleeding episode. Second was resolution of the bleeding event after consultation. Third was bleeding event outcome which was de ned as either developing a GI or non-GI bleeding event. Gastrointestinal bleeding included bleeding from the upper or lower GI systems. Non-GI bleeding included all bleeding events other than GI bleeds such as retroperitoneal bleeding, intraperitoneal bleeding, abdominal wall hematoma, genitourinary bleed, nasopharyngeal (NPA) bleed, and central nervous system bleeds.
Interventions were de ned as invasive, noninvasive or hemostatic. Noninvasive intervention was de ned as withholding anticoagulation/antiplatelet therapies, reducing the dose of anticoagulation, transfusion of blood products, nasal packing, bladder continuous irrigation, and or instigating medications such as proton pump inhibitors. Invasive interventions included upper endoscopy (gastroscopy, laryngoscopy and bronchoscopy), lower GI endoscopy and traditional angiography. Hemostatic interventions included a surgical operation to control the bleeding, angioembolization, use of gold probe, epinephrine injection, argon positron coagulation (APC) and hemoclips to control an active GI bleed.

Statistical analysis
Qualitative variables were expressed as numbers and percentages while quantitative variables were expressed as means and standard deviations and/or medians and interquartile ranges (IQR). We performed univariate and multivariate analyses using R statistical software package (9). We imputed the missing data using the random forest algorithm implemented in MissForest R package (10). We used the univariate analyses, which included the chi-square test, two-sample t-tests and Mann-Whitney U test, to assess the degree of statistical signi cance between the risk factors and the three selected outcomes, described above. We set a p-value equal or less than 0.1 as a threshold for selecting the risk factors for the subsequent multivariate analyses. Our multivariate analyses include three independent logistic regression models for each of the selected outcomes. We used a backward elimination approach and selected the nal models based on the largest pseudo R 2 as well as the smallest Akaike information criterion. Confounding by the demographic characteristics of the patients was assessed using the 10% threshold change in the regression coe cient approach. Finally, we evaluated how well the nal models t the data using the Hosmer -Lemeshow goodness-of-t statistic.
Of all 67 non-GI bleeds 5 patients (7.5%) required invasive interventions to control the bleeding with 100% success rate to resolve the bleeding event ( We identi ed 9 cases of retroperitoneal bleeding (7.3%). Three patients were on prophylactic anticoagulation, ve were on therapeutic dose and one was on none. Only one patient was on antiplatelet (aspirin) as well as anticoagulation. Two patients (both were on prophylactic dose) required angioembolization to control the bleeding and both were resolved. The rest resolved with no intervention. Of the 7 patients who did not require interventions 3 died within 30 days of consultation from sepsis.
We identi ed 2 intraperitoneal bleeding. Both patients were on therapeutic dose anticoagulation and both required angioembolization to successfully control the bleeding. However, one of the two patients died later within 30 days from sepsis.

GI BLEEDING
Out of 55 patients who had signs of GI bleed at initial presentation 47 patients were managed with full dose proton pump inhibitors (PPI) and active observation, of whom 6 failed this approach and required endoscopic intervention, ve EGD and 1 colonoscopy.
Of the 19 patients who had endoscopic procedures 18 EGDs and 5 colonoscopies were performed. Nine patients (16.3%) required an endoscopic hemostatic intervention to control the bleeding, all were successful. Eight patients required upper GI hemostatic intervention and 1 lower GI hemostatic intervention. The upper GI interventions included gold probe, epinephrine injection, APC and hemoclips applications for bleeding ulcers. Bleeding resolved for all cases. Etiology for bleeding events were duodenal & gastric ulcers in 10 patients (55.5%), esophagitis and Roux-en-Y anastomosis ulcer in 1 patient, and gastritis in 5 patients (27.7%). Three patients died within 30 days of consultation. The only lower GI endoscopic intervention was for large colonic ulcer in the cecum which was treated with APC. Bleeding resolved but patient later died from sepsis. Other colonoscopies done without interventions were for; small rectal ulcer with piles for 1 patient, ischemic colitis for 1 patient, piles for 1 patient, and one colonoscopy was essentially normal.
Overall, of 55 patients with signs of GI bleed, 38 (69.1%) expired within 30 days of consultation. Two patients had unclear source of bleeding and died while still bleeding, both were on Plavix and therapeutic anticoagulation at the time of consultation. The rest died after resolution of the bleeding episode from COVID-19 complications.
2) Demographics and baseline characteristics by primary outcomes, Univariate analysis (1) - Table 2 Mortality outcome Male patients (80.56%) were signi cantly more likely to die than female patients. The mean age for patients who died was 60 years old. They were also signi cantly more likely to be admitted to intensive care unit (ICU) and had shorter hospital stay compared to patients who survived. Medical comorbidities at the time of admission did not have signi cant implication on the risk of mortality. These included having a history of hypertension requiring medications, asthma or chronic obstructive pulmonary disease (COPD), having complicated diabetes, remote history of myocardial infarction, or being on antiplatelets (single or dual) at the time of admission. Moreover, admission baseline hemoglobin level, before the onset of bleeding episode, did not affect the risk of mortality.

Resolution of bleeding event & having GI bleed outcomes
Gender appears to have a signi cant association with bleeding resolution outcome, but it did not appear to in uence the risk of having a GI bleeding compared to a non-GI bleed. ICU patients were more likely to have a GI bleed than non-GI bleed.
3) Inpatient therapies and complications developed during patient's admission by primary outcomes, Univariate analysis (2) - Table 2 Mortality, resolution of bleeding event, & having GI bleed outcomes The use of PPI, vasopressors, and inotropes appears to be signi cantly associated with the risk of death.
We also found GI bleeds to be signi cantly associated with the need to use PPI and inotropes but not vasopressors. Furthermore, the dose but not the type of anticoagulation at the time of admission was signi cantly associated with risk of death following the bleeding episode. The dose of anticoagulation however did not in uence bleeding event resolution or the type of bleeding.
Being on systemic steroids appears to be signi cantly associated with increased risk of death but not the bleeding resolution or the type of bleeding. Furthermore, being on invasive ventilation was associated with increased risk of mortality and having a GI bleed rather than a non-GI bleed. Moreover, severe ARDS was associated with higher risk of mortality, but it did not affect the bleeding resolution or the type of bleeding event. With regard to mortality outcome, having a cardiac injury, liver injury, acute kidney injury, Glasgow coma scale (GCS) less than 15, systolic blood pressure less than 100 and sepsis and high qSOFA score were associated with higher risk of death. However, the CCI score and the WHO bleeding grade did not affect the risk of death. Furthermore, having cardiac injury, liver injury, being on renal replacement therapy, having a respiratory rate over 22, systolic blood pressure less that 100, and sepsis appears to signi cantly in uence the type of bleeding event. Also, the qSOFA and WHO bleeding grade but not CCI score signi cantly affected the type of bleeding event. With regard to resolution of bleeding event outcome, there was a signi cant association with the WHO bleeding grade. None of the complications the patients developed during admission affected bleeding resolution chance. Table 2 Mortality

4) At consultation symptoms, laboratory values and interventions by primary outcomes; Univariate analysis (3) -
Having an occult source of bleeding rather than a speci c symptoms and signs indicative of a source of bleeding was signi cantly associated with the risk of death. Furthermore, hemoglobin level, white blood cell (WBC) count, platelet, international normalized ratio (INR), D-dimer level, e-glomerular ltration rate (eGFR) level, urea, creatinine, and C reactive protein (CRP) were signi cantly associated with the risk of death. There was no relationship between the type of intervention (invasive, noninvasive or hemostatic) and the risk of death within 30 days.

Resolution of bleeding event
We did not identify a signi cant relationship between any coagulation pro le derangements and the ability to control bleeding episode. However, CRP and Procalcitonin (PCT) were signi cantly associated with bleeding resolution.

Having GI bleed outcome
Having an occult bleed appeared to be signi cantly associated with having a GI bleed. Also, having high urea but not deranged coagulation pro le was signi cantly associated with having a GI bleed. Furthermore, there was a signi cant relationship between the type of intervention (invasive, noninvasive or hemostatic) and the type of bleeding event. Table 3 We found having a GI bleeding event was signi cantly associated with the risk of death (P = 0.04). The prevalence of death following bleeding event was higher following a GI bleed compared to a non-GI bleed, 52.7% vs. 48.3% respectively.

6) Risk factors predictors of primary outcomes
Mortality -Multivariate logistic regression (1) - Table 4 Patient who had longer hospital stay appeared to be less likely to die, odds ratio (OR) 0.95 (95% CI, 0.92-0.98, p= 0.003). We also found that patients who were on therapeutic dose of anticoagulation were more likely to die compared to patients who were on none, on prophylactic or intermediate anticoagulation Resolution of bleeding event -multivariate logistic regression (2) - Table 5 Patients who were on PPI were more likely to have resolution of bleeding event compared to patients who were not. Out of all GI symptoms and signs melena appeared to be signi cantly associated with lower odds of bleeding resolution, OR 0.03 (95%CI 0.01-0.18, p < 0.00). C-reactive protein appeared as well to be signi cantly associated with lower odd of bleeding resolution, OR 0.98 (95% CI 0.97-0.99, p < 0.00).
Type of bleeding event -multivariate logistic regression (3)- Table 6 The risk of GI bleeding increased when patient was on inotropes (OR 7.

Discussion
To our knowledge, this is the largest and rst study to evaluate the risk factors associated with GI and surgical bleeding events in patients with COVID-19.
In our population WHO grade, which is representative of the volume of blood lost and thus indirectly blood transfusion requirements, did not affect the risk of mortality. The majority of the bleeding events encountered in our population were WHO 2 or 3 (78.6%). This moderate degree of bleeding likely did not lead to hemodynamic instability and thus did not generate enough force to tip the patient toward shock when they were not or worsened an existing shock. Furthermore, we found newly developed, in hospital, medical comorbidities rather than pre-existing ones before admission to carry more weight on increasing the risk of mortality following a bleeding event. Charlson score, contains both pre-existing and newly developed medical comorbidities, and qSOFA score contains only acute ones. We found CCI score did not to affect the risk of mortality, but qSOFA score, acute cardiac injury, acute liver injury, acute kidney injury, in hospital GCS less than 15, in hospital systolic blood pressure less than 100, and sepsis, were signi cantly associated with increased risk of mortality.
Due to the hypothesized hemostatic derangement observed with COVID-19 which causes a microthrombosis induced multiorgan failure and death (11)  were found to have ICH on concurrent neuroimaging, of whom the majority of these patients were on therapeutic anticoagulants. These are all indications that being on "supra-prophylactic" dose anticoagulation can put patient at increased risk of fatal head and neck bleeds. In our population, with regards to brain bleeds, it appears to be associated with high risk of mortality because by the time it happened intervention seems too late in typical patient with limited physiological reserve in context of COVID-19 sepsis. With regards to NPA bleeds, despite bleeding resolution in all events, signi cant proportion of patients eventually expired. This might be because the progressive "lingering" COVID-19 associated platelet dysfunction and DIC rather than the acute bleeding event itself are the major contributors to the eventual death of patient with COVID-19 and so NPA bleeds should be considered red ags for aggressive persistent COVID-19 coagulopathy, multiorgan failure and eventual death. Thus, efforts should be focused on correction and optimization of COVID-19 sepsis therapies and anticoagulation should be administered with caution in head neck bleeds subpopulation.
We are the rst to identify a signi cant association between the dose of anticoagulation in the setting of bleeding event and risk of death. Speci cally, we found patients who were on prophylactic dose or no anticoagulation appeared to be on lower risk of death compared to patient on therapeutic anticoagulation by 7%, and 10% respectively. When therapeutic dose was compared to intermediate dose, there was no signi cant difference in the risk of death. These ndings put into question the routine unopposed practice of prescribing "supra-prophylactic dose" anticoagulation to newly admitted COVID-19 patients and probably these doses should be prescribed in selective cases only.
Moreover, we found that the dose of anticoagulation did not in uence the risk of bleeding resolution nor the type of bleeding. This might suggest that regardless of the dose of anticoagulation patient is on, noninvasive interventions such as withholding anticoagulation following bleed event, rather than an invasive or hemostatic intervention are the major determinants of bleeding resolution, and so should always be considered as rst and primary line of intervention. This approach will save valuable resources and spare health care professionals unnecessary exposure.
Samkari et. al. (5) retrospective study of 400 admitted COVID-19 patients who were primarily receiving prophylactic dose of anticoagulation reported thrombocytopenia at initial presentation to be signi cant predictor of bleeding. In our study, we found, "chemical thrombocytopenia", being on antiplatelets therapy (single, dual or even the novel ones), did not affect the risk of mortality, resolution of bleeding events nor the type of bleeding. This might indicate that sepsis induced platelet dysfunction and eventually shock rather than thrombocytopenia itself signi cantly interact with bleeding events variables.
In general, in acute GI bleeding events, endoscopy remains the rst line intervention within 24 hours of patient stabilization. However, with the era of COVID-19, the risk bene ts equation got more complex by concerns for provider safety and a need to preserve personal protective equipment. Moreover, there are limited data on the diagnostic and therapeutic bene ts of endoscopy in this cohort, leaving endoscopist with inadequate information and algorithms to guide their decision of when the risk of endoscopy outweigh the bene ts. In our population the prevalence of instigating diagnostic or therapeutic endoscopic is relatively low. However, this does not appear to be unique to our center. Salerno et. al. (15) looked at the impact of COVID-19 on urgent endoscopy in Italy. They reported a signi cant reduction in the number of urgent upper and lower GI endoscopy by 80% and 55% respectively. This reduction in endoscopy use was replicated in a Belgium study which reported 40% reduction in upper GI bleeding events requiring endoscopy (16). Salerno et. al also reported that the signi cant reduction in endoscopy use was associated with increase in diagnostic yield by over 10% in the upper GI endoscopy group. This correlate well with our ndings. Where even though our use of endoscopy to investigate our GI bleeding events was relatively low, as endoscopy was preserved for patients with clinically signi cant GI bleed and those who failed conservative therapy, our diagnostic yield was relatively high for both upper and lower GI endoscopy, 88.8% and 60% respectively.
Martin et. al. (17) conducted a match case control study of 41 patients with COVID-19 who had bleeding events (31 upper GI and 10 lower GI bleeds) compared to 82 COVID-19 patients who did not have GI bleeds. They found no difference in presenting symptoms and signs, no difference in severity of COVID-19 manifestations, and no difference in anticoagulation use. They reported most common cause of upper GI bleed was duodenal ulcer (80%), ours was 55.5% duodenal & gastric ulcers. For lower GI bleeding event they reported rectal tube insertions to be the most common cause (60%), our hospital does not use rectal tubes routinely. In their study, hemostatic interventions where successful in all cases who required intervention (n = 7), with no immediate postprocedural complications happened, and no interventional radiology or surgical procedures were required. We had similar experience with 100% successful interventions for both non-GI and GI bleeds for all hemostatic interventions attempts. On multivariate analysis they found having a previous history of upper GI bleed to be the only predictor of upper GI bleeding. We found being on inotropes, having liver injury, high qSOFA score, having hematemesis, and occult bleeding to be signi cant predictor of having a GI bleed. Furthermore, they found trends toward higher risk of upper and lower bleeding events with being on anticoagulation, but this was not statically signi cant. We as well did not nd a signi cant relationship between the dose of anticoagulation and the risk of having a GI bleed. Similar to Martin et. al. the majority of our study bleeding events ultimately had cessation of bleeding without the need for hemostatic intervention. Furthermore, our GI bleeding population had high mortality rate (69%) despite bleeding resolution in the majority of cases. Based on all that, in COVID-19 era it appears to be safe to delay instigating endoscopic an intervention for GI bleeds, contrary to most guidelines which recommends early intervention for bleeding events. This will help alleviate concerns toward patient's respiratory status or illness severity, provider safety, PPE conservation, and the preservation of ventilators and avoiding procedural related intubations.
Finally, we found having a GI bleed was signi cantly associated with increased risk of mortality (p = 0.04), despite bleeding event resolution in the majority of cases. We also found having an occult bleed was associated with 15 times increased risk of death. This suggests that slow non profound bleeding as a consequence of COVID-19 coagulopathy might be a more signi cant contributor to increased risk of mortality rather an acute bleeding episode which is normally associated with hard signs of bleeding such as hematemesis and melena. Based on that, efforts probably should be focused on correction of coagulopathy and sepsis rather than none targeted invasive GI interventions in patient with COVID-19, since most of these patients do not have identi able source of bleeding amendable to invasive hemostatic intervention.

Limitations
One major limitation of the present study was that it was derived from a single institutional crosssectional study with inherent selection and information bias, hence generalizability of the ndings to larger populations might not be representative. Further, our study had a limited sample size which led to the in ation of the ORs 95% CI, rendering them notably less precise. However, our inferences were based on all available data on rare outcomes that were collected within a short time during the current pandemic. Therefore, future studies should be focused on collecting more data to additionally validate our results.

Conclusions
As COVID-19 pandemic evolves, surgeons and gastroenterologists are being confronted with unique challenges, particularly understanding the bleeding sequala of this novel virus. With the increasing use of supra-prophylactic doses of anticoagulation in this subpopulation the incidence of bleeding events, both surgical and GI, will be on the increase. We are the rst to identify a signi cant association between the dose of anticoagulation and risk of mortality. The previously unchallenged recommendation to prescribe therapeutic and or intermediate doses of anticoagulation to all newly admitted patients with COVID-19 should be revisited and more individualized approach to prescription should be the norm.
Gastrointestinal bleeds appear to be associated with increased risk of mortality compared to non-GI bleeds, however, regardless of the source of bleeds the majority of bleeding events in COVID-19 patients appear to resolve with noninvasive interventions and when hemostatic interventions were necessary it had high success rate, despite the delay. This means that conservative management at the time of consultation seems to be a reasonable initial approach managing these complex cases, as most cases will resolve without the need for intervention. This alleviates concerns regarding provider safety, and the need to preserve personal protective equipment without jeopardizing patient safety and outcomes.
With regards to GI bleeds, endoscopic intervention should be limited to patients with hard signs of GI bleeds, such as hematemesis or melena. In patients with occult bleed efforts might be better geared toward optimizing therapies that manage COVID-19 sepsis induced coagulopathy, DIC and shock rather than none target low yield endoscopic interventions. The Ministry of Health of Kuwait which is the government branch at the state of Kuwait which manage Jabir AL-Ahmad Hospital (our study center) approved the study.
Since the this is a retrospective review of prospectively maintained database, patient consent was not required to get ethical approval. To ensure patient con dentiality patient identi cation data were anonymized.

Consent for publication section:
The ethics committee approved publication of this manuscript Availability of data and material:   Hosmer -Lemeshow goodness-of-t p-value = 0.612  Hosmer -Lemeshow goodness-of-t p-value = 0.99