COVID-19-associated coagulopathy: a clinical case

Background. Comorbid patients with a new coronavirus disease (COVID-19) often have thrombosis or bleeding in different periods of the disease. Early diagnosis of these complications and adequate therapy of these patients are complicated due to the peculiarities of the disease in comorbidity. Anticoagulation regimens in patients with COVID-19 are still unclear. The protocol of ef ﬁ cacy and safety the intermediate or therapeutic dose of low-molecular-weight heparins is not clear and complete. It is very important to organize an individual approach for correction of the anticoagulants doses, taking into account the coagulation tests and the activity of in ﬂ am-matory markers. Clinical case description. We report a 71-year-old white male with COVID-19 pneumonia. Acute respiratory distress syndrome and atrial ﬁ brillation were diagnosed in ten days of the disease. Therapeutic anticoagulation was started upon the admission. As early as in the 20 th day of the disease a gluteal hematoma developed. Hence, prophylactic regimen of anticoagulation was started, but the worsening of dyspnea at rest, decreasing in SpO2 values to 82% according to pulse oximetry, and thrombelastographic hypercoagulability were observed after two days of such anticoagulation treatment. The patient has been receiving daily low-molecular-weight heparins injections in therapeutic doses for the following two weeks, and then the doctors have switched him to new oral anticoagulants. Patient was discharged to continue ambulatory anti-coagulant’s treatment. Conclusion. It is clear that the optimal choice of anticoagulation strategy in comorbid patients with concomitant COVID-19 remains challenging and requires randomized trials. Until the guidelines develop the effective anticoagulation strategy for various phenotypes of COVID-19 patients, the clinicians’ knowledge, experience and creative thinking will be apply to choose effective anticoagulant’s treatment on individual basis.


INTRODUCTION
Studies suggest that thrombosis and bleeding are complications of the novel coronavirus infection. Changes in coagulation tests are found in approximately 50% of patients with COVID-19. T. Jayakrishnan et al. demonstrated that the incidence of thrombotic and bleeding complications is higher among critically ill COVID-19 patients [1,2]. Many publications propose mechanisms of the coagulopathy. Coronavirus infection can cause activation of the coagulation cascade, fi brinolysis and, in some cases, disseminated intravascular coagulation.
Recent studies determined very high cumulative incidence of thrombotic complications in critically ill patients with COVID-19 pneumonia [3]. Several mechanisms have been considered to cause hypercoagulability in COVID-19 patients including the release of cytokines, causing the production of blood coagulation factors, high levels of fibrinogen, D-dimer, mild thrombocytopenia together with normal values of prothrombin time. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to angiotensin-converting enzyme-2 (ACE-2) receptor found in various pulmonary cells like type II alveolar cells, macrophages, endothelial, smooth muscle cells and perivascular pericytes. These changes cause uncontrolled inflammation, micro-thrombosis of small pulmonary vessels, endothelial dysfunction [4,5]. The cytokines and especially the interleukin family are known to play an important role in inflammation and have direct effect on the plasma molecules, on erythrocytes and platelets. Hypercoagulability and impaired fibrinolysis are usually the trademarks of several inflammatory conditions [6]. M. Levy et al. showed that COVID-19 coagulopathy mimics disseminated intravascular coagulation or thrombotic microangiopathy. The clinical and laboratory characteristics of the coagulation changes in COVID-19 are variable. Severe COVID-19 infection induce systemic inflammation, hypoxia, severe endothelial cell injury with release of von Willebrand factor and plasminogen activators resulted in coagulation abnormality and pulmonary microvascular thrombosis [7].
The indications for antiplatelet and anticoagulant use are guided by COVID-19 severity [8]. Hemorrhage is less common than thrombosis in patients with severe COVID-19, reaching a hospital mortality of 45.7%. The etiology of bleedings is multi-factorial -secondary to multi-system organ failure, iatrogenic use of anti-coagulants [9]. COVID-19 is associated with severe thrombosis in the early stages of the disease, but also with bleeding between the second and third weeks of the disease, especially in patients receiving therapeutic doses of anticoagulants T. Jayakrishnan et al. demonstrated that half of patients with major bleeding events were either without anticoagulation or only on the thrombo-prophylactic-doses. Meanwhile, two thirds of the major bleeding events occurred in patients receiving therapeutic anticoagulation. Different studies provide evidence that there are no indications for a full dose of anticoagulant in patients without clinical thrombosis, thromboembolism or absence of other standard indications for therapeutic anticoagulation (mechanical valve prosthesis, atrial fibrillation) [2,[10][11][12].

Patient information
The patient M., a 71-year-old white male, was admitted to Grodno Regional Infectious Clinical Hospital on March 5, 2021. He presented to the department with febrile fever, dry cough, and fatigue.
Due to the fact of persistent febrile fever during 2 days before hospitalization, intensifi ed not productive cough and dyspnea, bad control of blood pressure in spite of quadri-combination hypotensive therapy, admission to Grodno Regional Infectious Clinical Hospital was required in the patient.

Physical examination
Patient was admitted in moderate state. The color of skin was pink. Body mass index (BMI) was 30.2 kg/m 2 and waist circumference -110 cm. Body temperature was 39.2 °C. His respiratory rate was 19 breaths/min, the respiration was effective (SpO 2 94-96%) on room air. Auscultation reviled diminished vesicular breath sounds with crackles in the lower lung lobes bilaterally, small amount of the high-pitched wheezes in interscapular space; diminished S 1 , accentuated S 2 on aortic valve were revealed. Heart rhythm was irregular (single ventricular extrasystoles were revealed on ECG). Pulse was 93/min. Blood pressure was 180/110 mm Hg.

The time scale
The chronology of disease is on the Fig. 1.
Arterial blood gas analysis (05.03.2021) revealed a PaO 2 of 65 mm Hg and a SaO 2 of 94%, moderate hypocapnia.

Differential Diagnosis
Dyspnea is the most common symptom in patients with coronavirus infection both in the acute period of the disease and in long COVID-19. All the mechanisms of this symptom have not been clarifi ed, however, microthrombosis, destruction of the lungs parenchyma may be the causes of impaired perfusion of lung tissue. A number of authors present clinical reports about different mechanisms of pulmonary hypertension in severe COVID-19, observe a disturbances of lung perfusion within a year after infection. It is the sign of the lung damage, the mechanism of which is not clear [13].

01.03.2021
The rapid onset of disease (ambulatory treatment) The day of hospitalization Dyspnea in our case requires a differential diagnosis with many conditions such as pulmonary embolism, complications of pneumonia, including bacterial complications, acute coronary syndrome, and myocarditis in a comorbid patient with acute anemia.
Laboratory and instrumental diagnostic methods can be effective to clarify the causes of shortness of breath: the dynamics of the blood test, D-dimer levels, markers of myocardial damage (creatine kinase MB-fraction (CK-MB), troponin test, myoglobin), B-type natriuretic peptide levels, as well as the results of ECG and Echocardiography. In order to diagnose pulmonary embolism, ventilation-perfusion scanning, duplex ultrasonography, spiral CT can be performed. Today investigators can propose pulmonary dynamic contrast-enhanced magnetic resonance imaging.
We performed laboratory and noninvasive instrumental tests (blood test, levels of procalcitonin, markers of myocardial damage, ECG, echocardiography) and excluded complications such as sepsis, myocarditis and acute coronary syndrome.
Spontaneous gluteus muscle hematoma can be a common symptom of congenital (hemophilia) or acquired coagulation disorders (for example, disseminated intravascular coagulation), may be mistaken for thrombocytopenic purpura or as a manifestation of other cutaneous vasculitis. In addition to these causes anticoagulant or antiplatelet treatment, and also glucocorticosteroids treatment (it may inhibit platelet aggregation and cause spontaneous muscle hematoma) need to be considered by the physicians. It is established, that outside of COVID-19, the incidence of spontaneous hematomas in patients on anticoagulants is 0.6%, but in COVID-19 subjects the frequency of hematomas rise to 2.1% [14].
The spontaneous gluteus muscle hematoma was diagnosed based on ultrasonography (US) appearance: acute bleeds appear as focal areas of high attenuation that, over time, demonstrate decreasing attenuation due to clot lysis. In addition, diffuse parenchymal hemorrhage may present solely as isodense enlargement of the involved gluteus muscle. Our patient had no episodes of hemorrhagic syndrome in the anamnesis and in family history. Also the patient showed normal aPTT, the platelet level was normal essentially excluding hemophilia and thrombocytopenic purpura from the etiology of the spontaneous gluteus muscle hematoma.
Other laboratory tests, including fi brinogen and the D-dimers were found to be abnormal, thereby had possessed a challenge to exclude disseminated intravascular coagulation. The clinical report demonstrates confi rmed COVID-19-patient (lab-oratory-proven by IgG and IgM-based ELISA kit: SARS-CoV-2 "Ig M+", "IgG-"). The patient's bleeding tendency (occurrence of spontaneous hematoma) has pathogenic link with this infection and has been explained as possible consequence of imbalances in platelet production/disruption, endothelial dysfunction, coagulopathy, antithrombotic prophylaxis.
Endotelial injury is the sign of COVID-19. Endotelial injury can cause microvascular angiopathy and thrombosis. For the purpose of differential diagnosis (to exclude pulmonary embolism), it was necessary to perform visualization according to the clinical guidelines, however, there was no computed tomographer in the hospital where the patient was treated. The measurement of the risk/ benefi t of patient transportation were performed and it was made decision to refuse of visualization. The patient's dosage of LMWHs was increased, conservative hematoma treatment was continued. The response for treatment was good: we noticed clinical improvement.

Medical interventions
On the day of admission, after the diagnosis was made, the patient was prescribed dexamethasone 8 mg intravenously once daily, subcutaneously prophylactic dose of dalteparinum sodium (Fragmin®, Pfi zer, Belgium), 7500 МЕ, once daily. These were given in addition to the continuation of previous treatment of arterial hypertension and dyslipidemia. Also, initially, the insulin therapy was started. Since at home the patient had febrile temperature for 2 days in spite of high-dose paracetamol therapy, and wheezes were revealed during the auscultation, the decision for dexamethasone prescription was made.

Dynamics and results
Then 4 to 5 days later (the day 9 th -10 th of disease), the patient developed worsening of respiratory symptoms and laboratory parameters. He became tachypneic (≥30 breaths/min) and presented with PaO 2 /FiO 2 ratio ≤300 mm Hg, the oxygen saturation of 86% despite the escalation in non-invasive ventilation (the O 2 fl ow rate was increased from 5 l/min (the 9 th day of the disease) to 15 l/min (the 10 th day of the disease)). Blood tests showed progressive growth of CRP, fi brinogen, ferritin ( Table 1).
The patient developed hypotension, onset of atrial fi brillation and ventricular extrasystoles at the ECG. The state of patient was assessed as severe; the doctors suspected acute respiratory distress syndrome (ARDS). It was made a decision to administer 400 mg intravenous tocilizumab (Actemra™, Roche, Switzerland). The patient also received amiodarone (Borimed, Belarus) 1000 mg/daily, subcutaneously therapeutic doses (15000 МЕ) of low-molecu-lar-weight heparins (LMWHs). It was prescribed antibacterial treatment. Later, on day 12 th of the disease, the patient clinical condition gradually improved with decreasing the O 2 supply to 7 l/min, diminishing of infl ammatory biomarkers. ECG showed sinus rhythm. It was noted QTc prolongation (500 msec) requiring canceling of amiodarone and initiation of metoprolol succinate (Betaloc ZOK®, Astrazeneca, Sweden), 200 mg/day orally.
On the 20 th day of the disease the patient's oxygen saturation was 97-98% in non-invasive ventilation with a fl ow rate of O 2 5 l/min, but the patient presented with sudden acute pain in the gluteal region and loss of movement in his right leg. Blood tests showed a reduction in hemoglobin with a drop of its level from 163 g/L to 85 g/L. A surgeon examined the patient. There was a large ecchymosis on the skin of the gluteus and a hard tender mass was palpated. It was diagnosed spontaneous hematoma of the right gluteus muscle (120×150×46 mm, 270 cm 3 confi rmed by ultrasound) (Figure 2). The dynamic observation was recommended, and the patient was transferred to a surgical hospital. The dose of LMWHs was decreased to prophylactic (5000 ME) according to the patient's weight and glomerular fi ltration rate (GFR).
On the 22 d day of the disease it was noted progression of dyspnea at rest, the level of saturation decreased to 88-90%, the O 2 fl ow rate was increased to 10 l/min. Thromboelastography (TEG) was done at the 24 th day. The hemostatic condition was defi ned as hypercoaguable as were noted the following parameters: decreased R-time, tendency of decreasing K-time, increased alpha angle, and increased the maximum amplitude. The coagulation profi le, including the TEG is shown in the Table 2.
The TEG revealed that anti-Xa activity was 0,075 IU/mL with a prophylactic reference value of 0.1-0.3 IU/mL. Given the hypercoaguability observed in the patient ( Figure 3) the doctors switched him to therapeutic doses of dalteparinum sodium -10 000 ME.
The patient's condition improved gradually. By the 30 th day of the disease: the level of SpO 2 was 94%, off oxygen. The patient was discharged home with specifi c treatment (metoprolol succinate, 200 mg once daily; perindopril, 10 mg once daily; indapamide, 2.5 mg once daily; spironolactone, 25 mg once daily; amlodipine, 5 mg once daily; rosuvastatin, 20 mg once daily; rivaroxaban, 20 mg once daily; oral iron replacement therapy and folic acid; insulin therapy for diabetes mellitus treatment) with an outpatient follow-up.

Prognosis
Prognosis is positive. Patient M. continues to use all the treatment.

Patient's opinion
Patient thinks that complication of the disease (hematoma) was iatrogenic because of high doses of anticoagulants for treatment.

DISCUSSION
COVID-19 poses a clinical challenge due to the lack of a reliable protocol of anticoagulation therapy. The clinical course of the patient's disease is characterized by stages, which are confi rmed by both clinical and laboratory data. Early at the disease course the patient had typical symptoms of viral infection. Symptoms of ARDS, cytokine storm appeared on the 10 th day of the disease and were associated with progressive elevation in CRP (up to 170 mg/L), ferritin (up to 817 ng/mL), LDH (up to 651 U/l), IL-6 (up to 103.3 pg/mL), D-dimer (up to 990 ng/mL). Laboratory changes refl ected thromboinfl ammatory processes and were accompanied by a progression of respiratory failure, hypotension, and onset of atrial fi brillation. Clinical and laboratory improvement was noted after the administration of tocilizumab: dyspnea and oxygen demand decreased, IL-6, CRP, D-dimer values decreased. Pharmacological cardioversion was performed. Spontaneous muscle hematoma on therapeutic LMWH for atrial fi brillation appeared. The use of  therapeutic-dose LMWH manifested as a hematoma of the right gluteus muscle on the 3 d week of the disease. Such bleeding complication seems probable to be infl uenced by COVID-19 coagulopathy and vasculopathy. To date, none personalized treatment anticoagulant regimes are developed in COVID-19 patients.
N.Musoke et al. investigated the bleeding rates in patients (n = 355) with therapeutic, subtherapeutic and prophylactic doses of anticoagulation. Patients who received therapeutic anticoagulation treatment showed signifi cantly higher rates of major bleeding. Meanwhile, subtherapeutic dose of anticoagulation was associated with less bleeding compared to therapeutic regimen but the bleeding risk was higher compared to those without anticoagulation [12]. Analysis of anti-Xa activity may be useful for assessing the risk of unpredictable bleeding in patients receiving anticoagulants. Fibrinogen may be a useful biomarker for early detection of bleeding risk [15][16][17].
Endotelial injury is the sign of COVID-19. Endotelial injury can cause microvascular angiopathy and thrombosis. For the purpose of differential diagnosis (to exclude pulmonary embolism), it was necessary to perform visualization according to the clinical guidelines, however, there was no computed tomographer in the hospital where the patient was treated. The measurement of the risk/ benefi t of patient transportation were performed and it was made decision to refuse of visualization. The patient's dosage of LM-WHs was increased, conservative hematoma treat-ment was continued. The response for treatment was good: we noticed clinical improvement.

CONCLUSION
The optimal type, dose, duration and time of anticoagulant use have not yet been determined in literature. In this clinical case assessment of the bleeding risk and the risk of thrombotic events were made to prescribe adequate therapeutic doses of anticoagulants. Of particular importance is the progression of respiratory failure with an increase in oxygen support after the changes of anticoagulants doses. Low anti-factor Xa (anti-Xa) activity was the indication for therapeutic anticoagulation that improved the patient's saturation. Thromboprophylaxis should be adapted to the two-phases of COVID-19 with an individual assessment of the risk of bleeding / thrombosis for each patient (taking into account the dynamics of BMI, GFR; it is advisable to recalculate the dose of anticoagulant). After the infl ammatory phase with high prothrombotic risk, the second phase of bleeding risk is coming with diminished levels of D-dimer and fibrinogen. Evidently, the one-size-fi ts-all approach to anticoagulation will not work for COVID-19 patients. True medical mastery must be forged in the management of such patients.

INFORMED CONSENT
The patient provided a free written informed consent for the clinical case description and photograph publication in a medical journal, including its electronic version signed (15.05.2022).
Text preparation and editing -drafting of the manuscript and its fi nal version, contribution to the scientifi c layout.
Approval of the fi nal manuscript -acceptance of responsibility for all types of the work, integrity of all parts of the paper and its fi nal version.

Balabanovich T.I.
Conceptualization -development of key goals and objectives.
Conducting research -data analysis and interpretation.
Text preparation and editing -critical review of the manuscript draft with the introduction of valuable intellectual content; contribution to the scientifi c layout.
Approval of the fi nal manuscript -acceptance of responsibility for all types of the work, integrity of all parts of the paper and its fi nal version.
Conducting research -data collection.
Text preparation and editing -critical review of the manuscript draft with the introduction of valuable intellectual content; contribution to the scientifi c layout.
Approval of the fi nal manuscript -acceptance of responsibility for all types of the work, integrity of all parts of the paper and its fi nal version.