A Case Series of Life-Threatening Hemorrhagic Events in Patients with COVID-19

Since venous microthrombotic and thromboembolic events in end organs have been pathophysiologically confirmed as a component of thrombo-inflammatory cascade in COVID-19 syndrome, anticoagulant prescription with prophylactic or therapeutic goal is recommended. Different guidelines for the above are introduced; however, there is no general consensus on any neither the type of anticoagulant nor for the dosage and duration of prescription. In our medical center, adopted internal guideline was considered for patients COVID-19. We consulted patients with COVID-19 who suffered from concurrent hematoma. Appropriate surgical approach was considered. Finally autopsy study was performed for patients. In this article, we presented a series of seven SARS-CoV-2 confirmed cases faced with bleeding complication following initiation of anticoagulation protocol. The rectus sheath hematoma with extension to pelvic and/or retroperitoneal space, even involving bowel mesentery was seen most commonly. Despite receiving appropriate surgical care, all seven cases died. Finally, in all cases, autopsy studies revealed no evidence for confirmation of DIC/SIC or organ failure as the reason of death although pulmonary involvement with SARS-CoV-2 and bleeding phenomena were approved. The nature of the COVID-19 syndrome makes patients vulnerable to hemorrhagic events following anticoagulant administration which relatively causes or accelerates patient’s expiration.


Introduction
From last December 2019, the novel beta corona virus  was introduced with respiratory symptoms until the March 2020 that the World Health Organization [WHO] announced a global viral pandemic [1,2]. The virus has diverse invasive behaviors and poor response to human immune system which leads to aggressive colonization, different organ involvement, recurrence, and death. Recent knowledge about pathophysiology of the disease revealed thromboinflammatory accidents at microvascular level of body systems including the lungs, central nervous system, heart, kidneys, liver, stomach, bowels, and etc. [3]. The virus binds to ACE-2 receptor at endothelial surface and activates infectious-related coagulopathy cascade [3]. Injured endothelium is then affected by blood flow stasis and thrombotic events. The primary result is microthrombosis formation that if it does't restrained would end to target organ failure. Systemic response to this thromboinflammatory reaction encounters the victim to venous thromboemboli [VTE], deep vein thrombosis [DVT], pulmonary thromboemboli [PTE], acute coronary syndrome [ACS], brain stroke, sepsis-induced coagulopathy [SIC], and disseminated intravascular coagulation [DIC] with increased fibrinogen, d-Dimer, IL-6, von-Willebrand factor, and decrease in antithrombin and lymphocyte count [1][2][3][4][5][6]. Regarding these data, anticoagulation therapies have became prominent among inpatient and particularly ICU admitted subjects with COVID-19 disease [1,3,5,6]. However, there is no general consensus yet about details of anticoagulation prescription. Unfractionated heparin [UFH], LMWH [enoxaparin], factor X inhibitor [fondaparinux, apixaban, rivaroxaban], direct thrombin inhibitor [dabigatran], antiplatelet (aspirin), and warfarin were utilized [1,3,5]. Although physicians insist on prescribing anticoagulants in medical centers based on presented guides, it is not clear that how these drugs would affect the patient to survive from thrombotic events. Hence, it seems important to not order anticoagulants for every SARS-CoV-2 positive while risk of hazardous complication including mortal hemorrhage could be relatively significant. Following toactivation of anticoagulation guideline for inpatient COVID-19 sufferer in our hospital we were called as general surgeon to consult some patients developed hematoma. Considering the latter we presented the cases with unpredictable course and outcome of the disease. Current article was written in lined with the SCARE 2020 guideline [7].

Diagnostic and Therapy Approach
Every patient who was suspicious for the SARS-CoV-2 initially admitted to particular ward equipped specifically for the clinical statusaccordingly. After receiving primary care, computed tomography [CT] scanning study of lungs and also polymerase chain reaction [PCR] test for SARS-CoV-2 from oropharyngeal secretion was performed individually. If the evaluations confirmed the COVID-19 pneumonia, patient then was transferred to COVID-19 ward/ICU and received proper therapy based on clinicaljudge for severity of the disease.

Anticoagulant Guideline
According to our center instruction for VTE prophylaxis/ treatment in patients with COVID-19, following guideline was ordered: As Table 1 shows, every patient who admitted in hospital because of involvement with SARS-CoV-2 underwent anticoagulant prophylaxis or therapy. In case of UFH prescription, dosage titration was accordingly conducted based on activated partial thrombin time [aPTT] measurement. For all categories of patient condition daily, Acetylsalicylic Acid [ASA] 80 mg was prescribed if no contraindication was identified including liver and/or renal failure (Crcl < 15 mL/min) and/or ongoing GI bleeding.

Case 1
A 26-year-old female with no past medical or surgical history, complained of a 3 days body pain, fever and chill, dyspnea of exertion, dry cough, and fever. diagnosis. Therefore, the UFH was held. The Hb level fell down 3.1 g dL −1 and was measured 9.8 g dL −1 . PTT and INR were85 and 1.5 respectively on the day of hematoma diagnosis and did not rise in following evaluation. Patient was closely observed without PBC infusion. She died after 18 days of admission when examination showed near normal abdominal exam but about 110 cc of remained hematoma in controlled US. Autopsy study was otherwise normal except for presence of pulmonary involvement and stated hemorrhage.

Case 3
A 58-year-old woman whose CT and PCR test for SARS-CoV-2 were positive underwent hospitalization in a non-ICU ward. She claimed that she had fever, cough, dyspnea of exertion, fatigue, and orthopnea from 2 days prior to admission. Registered data at her first visit was included of BP 150/90 mmHg, HR 83/min, RR 22/min, OT 38.2°C, SO 2 91%, and BMI 38.6 kg m −2 with no specific change for RS in lungs. Past medical and surgical history was unremarkable except for appendectomy. Her disease severity was considered moderate and underwent subcutaneous UFH 5000 IU TID in addition to daily oral ASA 80 mg tablet. On the 2nd day of admission, we were called for surgical consult for expanding hematoma and painful movement of right upper limb and axilla. We identified total right upper limb hematoma and ecchymosis from shoulder joint superiorly to the wrist and dorsum of the hand inferiorly. Ipsilateral axillary region ecchymosis with extension to lateral breast border anteriorly, ribs 7-8 interspace inferiorly, and medial border of the scapula posteriorly was observed. History of recent trauma was negative. The right arm was tender and the skin was in tension. Distal arterial pulses at the wrist were palpated and no evidence of compartment syndrome was signed. Active limb movement was painful. Focused regional US showed a heterogeneous hypoechoic 33 × 20 × 18 mm (about 40 cc) hematoma formation in biceps brachii muscle. Anticoagulants were held. Conservative management with elevation of the extremity and physical therapy was regarded. Normal range for either Hb or for PTT/INR level maintained. After 9 days of admission patient was expired with extension of both right sided hematoma to 130 cc in controlled US with the regional ecchymosis. Autopsy study was revealed pulmonary involvement with COVID-19 and aforementioned bleeding with no extra sign of any other organ failure.

Case 4
A 51-year-old woman suffered from generalized body pain, at rest dyspnea, productive cough, and fever from 2 days ago was admitted to the ICU.

Case Summary
A brief report of aforementioned study subjects is presented in below Table 2.

Discussion
Since the knowledge of COVID-19 pathophysiology has confirmed microthrombosis events in end organs therefore, concurrent anticoagulation prescription is recommended for patients to prevent or treat thromboembolic events. VTE, DVT, PTE, ACS, and stroke are reported to have association with SARS-CoV-2 [1,2]. Available scientific reports showed arteriovenous thromboemboli (6.6%), PTE (2.4-35%), isolated lower limbs DVT (0.9-54%), proximal DVT (0.5-25%), major bleeding (2.7%), and mortality (8.7-44%) in patients with SARS-CoV-2 who received anticoagulants [1]. Enoxaparin, UFH, fondaparinux, aspirin, and direct oral anticoagulants (DOAC) including rivoraxaban, apixaban, and dabigatran are prescribed in different guidelines [1][2][3][4][5][6]. However, there is no general consensus on any guideline for the therapy in moderate to severe disease [3]. For outpatient setting, if the risk of VTE is low, guidelines do not advise neither anticoagulant nor antiplatelet administration [3,5]. Unfortunately, it is neither clear that how is the incidence of hemorrhagic events among COVID-19 patients after recovery or discharge from hospital nor there is reliable knowledge on how long anticoagulant should be continued. Namely, studies generally implied on that just critically ill patients with SARS-CoV-2 are at high risk for bleeding event according to the IMPROVE hemorrhagic risk score [1]. Additionally, it seems attributed side effects of anticoagulation protocols are still neglected in patients with COVID-19. Prior studies among non-COVID patients showed clearly that the risk of VTE after hospital discharge remains high but this phenomenon has not confirmed for COVID-19 patients since now [8][9][10][11][12][13][14][15][16][17][18][19]. Nonetheless, some authors recommend continuation of antithrombotics extensively after recovery from the disease; however, neither duration nor dosage is explained [1,20]. Opponents point to that since association between COVID-19 and SIC and/or DIC is not exactly proven, any anticoagulation approach is uncertain [1].
Regarding previous medical data, UFH is preferred among SARS-CoV-2 positive with concurrent renal failure, instable hemodynamic status, and pleural effusion because physician is able to reverse the drug effect by antidote if needed; while among the others, the choice of anticoagulant is LMWH since it limits the staff exposure to patient for administration of the drug [1].
Analysis shows that total in-hospital mortality is similar between anticoagulant receivers and who do not receive but in intubated ICU admitted patients anticoagulants increases survival from 9 to 21 days when administered for at least 7 days [5,21,22]; although still 27% of ICU admitted COVID-19 patients manifest VTE while they receive anticoagulants [5]. Evidence noted that anticoagulation protocol occasionally also has no positive impact (6-16%) but makes additional complications [21].
In current case series neither the type of anticoagulant nor the administered dosage made safety window to prevent complication (bleeding and hematoma formation) in patients with COVID-19. The latter may be due to combination of anticoagulant and antiplatelet therapy; however, it seems the results are at least partially attributed to the nature of the disease because the guideline was safe previously in non-COVID patients that it was adopted from. Advocates of antiplatelet therapy implied on that it could decrease mortality while opponents considered antiplatelet therapy in critically or acutely ill hospitalized patients should be prevented [1,6]. Regarding current study results, it seems prescription of any adjuvant anticoagulation protocol in patients with COVID-19 should be limited to selected patient especially in patients with severe disease. It is not yet clear how the SARS-CoV-2 primarily disturbs coagulation pathway and how it interacts when anticoagulants administered secondarily. Anyhow, according to available data severe COVID-19 disease is accompanied with coagulopathy disorders, and critically ill patients who are susceptible for thrombotic events including VTE a n d m i c r o e m b o l i z a t i o n w o u l d b e n e f i t f r o m thromboprophylaxis [1]. In addition, there is no agreement on anticoagulation guideline considering the dose or the duration of prescription [1][2][3][4][5][6]. In this study, all cases died due to bleeding while expiration was not expected with such volume of hemorrhage if the patient was a non-COVID. We found no definite evidence for DIC or SIC confirmation and patients except for hemorrhage and primary pulmonary involvement with SARS-CoV-2 were otherwise normal in autopsy studies. We hypothesized that presence of SARS-CoV-2 is associated with susceptibility to remarkable organ intolerance to circulation upset following even moderate bleeding events. Regarding aforementioned and our findings due to the nature of the COVID-19 syndrome vulnerable hemorrhagic outcome is probable despite that thromboembolic events are expected. Therefore, firstly therapeutic dose of anticoagulants with/ without antiplatelet is not recommended in any patient with COVID-19 if no active thrombotic event is confirmed. Secondly, since there is no long-term prospective data available to clarify how hemorrhagic side effects would appear in patients with COVID-19 who receive prophylaxis regimen of anticoagulant it is advised to prescribe minimal sufficient dose of anticoagulant with no additional blood thinner agent.

Conclusions
Since the VTE is pathophysiologically confirmed as a component in acute phase of COVID-19 syndrome particularly in critically ill patients, antithrombotic prescription is of advantage. However, the latter is generally accepted but there is no consensus on details. Because of unknown nature of SARS-CoV-2, possibility of life-threatening hemorrhagic phenomena independently from presence of DIC/SIC, and also uncertainty of outcome following anticoagulation administration in patients with COVID-19 it is highly recommended to use anticoagulants cautiously in selected subjects with confirmed thromboembolic event. Additionally utilization of anticoagulant should be restricted to minimal sufficient dose without any adjuvant blood thinner. credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.