A Rare Case With Arterial and Venous Thrombotic Complications After COVID-19

Recently, it complications associated with severe COVID-19 disease. Studies have revealed the denition of COVID-19-associated coagulopathy as the underlying cause of these complications. With the emergence of hypercoagulability, systemic anticoagulant therapy was required at variable doses and durations in COVID-19 patients. We present the case of a 79-year-old female patient who developed ischemic stroke, deep vein thrombosis, and acute pulmonary embolism, respectively, despite the use of anticoagulants since hospitalization for severe COVID-19 disease.


Conclusion
The most important message to be taken from this case is that even in patients using anticoagulants, there is still a higher risk of thrombotic complications. Unfortunately, there are no speci c suggestions about the timing or dosing of these drugs. COVID-19associated coagulopathy (CAC) underlying pathophysiological processes can be summarized as excessive in ammation, hypoxia, immobilization, and diffuse intravascular coagulation (DIC). 1 In patients with severe COVID-19 symptoms; the frequency of clinical presentations associated with hypercoagulability was higher due to comorbid diseases, profound hypoxemia, and systemic hyperin ammation. 3,4 In this report, we present a patient who developed arterial thrombosis (ischemic stroke) in the acute period and venous thromboembolic processes (DVT and PE) in the mid and long term of the COVID-19 infection.

Case Presentation
A 79-year-old female patient with a history of hypertension applied to the emergency department with complaints of fatigue and dry cough for 4-5 days. The patient had normal vital signs and was in good general condition, cooperative, orientated and had a normal level of consciousness, and there was no signi cant nding except for the right basilar rales on lung auscultation. Basic laboratory ndings demonstrated an elevated white blood cell count (11.3 k/uL) with neutrophilic predominance (79.1%) and lymphopenia (9.8%), with anemia (11.7 gm/dL), and preserved platelet count (204 k/uL). Pathological values in the metabolic panel were mild hyponatremia (132 mmol/L), elevated LDH (311 U/L), and hypoalbuminemia (3.3 g/dL). When in ammatory markers are scanned; it was noteworthy that the CRP (152 mg/L) and D-dimer (1.5 mcg/mL) levels were high despite the mildly elevated procalcitonin (0.06 ng/mL) and preserved ferritin (62 ng/mL). The SARS-CoV2 nasopharyngeal PCR test was positive and Computed tomography (CT) of the chest showed that peripherally located consolidation in the lateral basal segment of the right lung lower lobe (Fig. 1).
The patient was consulted by the departments of infection and chest diseases and was hospitalized.
During the follow-up, the patient had low blood oxygen saturation and chest radiography showed patchy in ltrations on the right lung's middle and lower lobes ( Fig. 1). She received ve doses of hydroxychloroquine, ten days of azithromycin. Aspirin 100 mg once a day orally as antiplatelet therapy and enoxaparin 40 mg twice daily by subcutaneous (sc) injection as antithrombotic therapy was applied. Repeated SARS-CoV2 tests during her hospitalization were twice negative. Upon the developing clinical observations of dysarthria, left central facial paralysis, and left-sided weakness detected on the morning of the 11th day of hospitalization, cranial CT represented hypodense appearance compatible with acute infarction in the right middle cerebral artery (MCA) territory and the right basal ganglia.
Further, MR-DWI consisted of a well-de ned area of low T1 signal / high T2 signal with diffusion restriction in the right MCA territory (Fig. 1). The patient who was diagnosed with ischemic stroke was transferred to the neurology service. No atrial brillation, cardiac thrombus focus, and carotid or vertebrobasilar artery stenosis were observed. After seven days of hospitalization in the neurology service, where her treatment was updated to clopidogrel 75mg orally once a day and enoxaparin 40mg sc twice a day, the patient was transferred to the physical medicine and rehabilitation (PM&R) inpatient clinic for neurological rehabilitation.
She has left-sided hemiplegia, a sequel of ischemic stroke. The patient's Brunnstrom stages were stage 2 for lower extremity, stage 1 for upper extremity, and stage 1 for hand. Although there were no clinical symptoms, no pathological condition was detected in the venous Doppler ultrasound (VDUS) examination performed for control. The patient was immobile for about 15 days when rehabilitation started under close monitoring. In the 50th session of her rehabilitation (in the 3rd month of hospitalization), the patient developed sudden onset of shortness of breath, tachypnea, and tachycardia.
She had elevated D-dimer (5.4 mcg/mL) in the laboratory ndings, and her lower extremity VDUS ndings were consistent with thrombus in the left common femoral vein and super cial femoral vein lumen. CT pulmonary angiography (CTPA) showed a lling defect compatible with embolism in the lobar and segmental branches on the left (Fig. 1) and subsegmental branches on the right in the pulmonary artery. The pulmonologist quickly evaluated the patient, and the treatment was arranged as enoxaparin 60mg twice a day and clopidogrel 75mg once a day. By dint of the neurological rehabilitation program that continues after pulmonary recovery, which lasted a total of 90 sessions in PM&R inpatient clinic and was including intramuscular administration of 200 units botulinum toxin type A for spasticity in the left biceps, brachialis, pronator, gastrocnemius, and soleus muscles, the degree of ambulation of the patient has reached the level of the community.

Discussion
COVID-19 is associated with thrombotic complications in both arterial and venous systems and caused sudden deaths resulting from the complications in many previous studies. Initially, CAC was de ned as DIC-like consumptive coagulopathy due to increased D-dimer levels, decreased platelet count, and brinogen level in a study investigating the causes and risk factors of mortality. 5 However, in contrast to D-dimer progression, laboratory ndings showing variability in platelet count, clotting times, and brinogen levels revealed marked differences between CAC and DIC and led to an alternative etiology coagulopathy associated with excessive in ammation. 6 Later in another study, CAC was de ned as a combination of low-grade DIC and localized pulmonary thrombotic microangiopathy. 7 The major mechanisms in pathophysiology are direct endothelial cell damage, diffuse in ammation with immune system dysregulation, followed by cytokine storm, hypoxia-induced thrombosis, and increased levels of antiphospholipid antibodies. 6,8 In a retrospective observational study, acute ischemic stroke was speci ed in 5% of 221 patients. 9 In a related case series of young patients with ischemic stroke secondary to COVID-19 disease in New York; CAC is the most important cause of strokes in this population. 10 However, the transthoracic echo and DUS for the carotid and vertebrobasilar systems should be performed to determine the possible causes.
Demonstrating high D-dimer concentration and thrombotic microangiopathy in the pulmonary vessels by autopsies was suggested that pulmonary embolism may be a signi cant cause of acute respiratory failure in COVID-19 patients. 11 A review examining thrombotic complications in COVID-19 patients; the overall incidence of VTE was determined to be 21.9%. 4 Although the incidence of acute PE in patients hospitalized for COVID-19 varies between studies, the highest rate was determined in patients with severe disease who were treated in the intensive care unit. 12 Looking at the literature; studies on the incidence of DVT in COVID-19 patients are more limited. In a study, DVT was found in 46.1% of the COVID-19 patients through DUS scanning of the lower extremities. 13 The high heterogeneity observed between studies causes inconsistencies in PE with or without DVT. Principally, close clinical and ultrasonographic followup should be important in the early diagnosis of DVT, especially if there are additional risk factors such as a history of stroke and immobilization during patients' rehabilitation process with a history of severe SARS-CoV2 infection.
The International Thrombosis and Hemostasis Association recommends a prophylactic dose of LMWH for all hospitalized patients with SARSCoV2. Prophylaxis with LMWH or direct oral anticoagulants until 45 days after discharge was accepted, although not unanimously, in patients with risk factors for VTE and with a D-dimer height more than twice the upper value. 14 Notwithstanding the initiation of anticoagulation, sustained assessment for the progress of de novo thrombosis is recommended. 15 In this case, who was under anticoagulant treatment due to ischemic stroke associated with severe COVID-19 disease and was closely monitored in the neurological rehabilitation program, was rapidly treated after the diagnosis of PE because of sudden dyspnea.
In a patient who had one of the complications mentioned before; the likelihood of relapse of the same complication and other new thrombotic processes has increased. As in this case, the anticoagulant used in prophylactic doses in a patient with a history of CAC-related ischemic stroke may be insu cient to prevent new thrombotic complications. Perhaps it would be better to use higher doses of systemic anticoagulant drugs used in such cases. It is also necessary to reveal how long the anticoagulant treatment will last and what should be the combination options with other anticoagulant drugs in future studies. We believe that all clinicians should be prepared for possible COVID-19 related thrombotic complications, even with prophylactic anticoagulant dosing.
One of the limitations of this case was the inability to obtain antiphospholipid antibodies associated with hypercoagulability in COVID-19 patients.

Conclusion
In summary, COVID-19 is an infectious disease that causes both arterial and venous micro-macrovascular thrombotic circumstances leading to a hyperin ammatory and prothrombotic state. Accordingly, early identi cation and close monitoring of the thrombotic complication of COVID-19 can be lifesaving. Please note that clinical conditions caused by arterial and venous thrombotic complications associated with COVID-19 may also occur even when they are under anticoagulant therapy, especially in the long-term follow-up of these patients.