In December 2019, the SARS-COV2 outbreak began in Wuhan, China, shaking the entire medical world, causing over 6 million deaths [1]. The novel virus called Severe Acute Respiratory Syndrome Coronavirus 2-SARS-COV-2 belongs to the subfamily Orthocoronavirinae of the family Coronaviridae (order Nidovirales) and causes viral pneumonia associated with acute respiratory failure and a vascular component such as micro-lesions/micro-thromboses in pulmonary, coronary or cerebral vessels, as well as thromboses in the arterial and venous systems [2,3,4]. The cause of this condition is endothelial damage and hypercoagulability caused by SARS-COV2.

Hemostasis is an ancestral system that serves as a defense mechanism to stop bleeding from blood vessels [5]. Triggered by endothelial damage, hemostasis consists of platelet activation and the coagulation cascade controlled by natural anticoagulants and the fibrinolytic system [5]. The whole phenomenon leads to microvascular and macrovascular thrombosis [6]. Even if it is a physiological process, in certain situations it can become a pathological process leading to thrombosis [7].

By definition, the disseminated intravascular coagulation (DIC) is a syndrome characterized by the activation of the coagulation cascade leading to formation of intravascular thrombi and the depletion of platelets and clotting factors. Classically, DIC is characterized by increased D-dimer levels, prolonged Activated Partial Thromboplastin Time (APTT) and decreased fibrinogen and platelet levels. Usually, schistocytes can be found on the blood smear. [8] There are several causes of DIC, including sepsis, trauma, malignancies and even severe SARS-COV2 infection - to name a few [9].

We hereby report a challenging case of a 73-year-old Caucasian male, former smoker, with a history of myocardial infarction in 2017, an aneurysm at the apex of the left ventricle of 72/76/82 mm, and atrial fibrillation (AFib) on treatment with anticoagulant therapy-antivitamin K (AVK), laryngeal cancer treated with 33 sessions of radiotherapy in 2018, which suffered of severe Covid-19 infection complicated with hydropneumothorax and DIC.

On December 3, 2020, the patient presented to the Emergency Department because of shortness of breath, dry cough and pain in the right hemithorax, with an oxygen saturation of 77%, associating edema of the lower limbs.

Laboratory investigations were performed and revealed severe lymphopenia - 370/mm³, normal renal and hepatic function, but an International Normalized Rate (INR) of. 5.60- Table 1. The thoracic Computed Tomography scan showed a right-sided hydropneumothorax with a fluid component of 32 mm and an air component of 53 mm, as well as basal bilateral ground-glass opacities.

Table 1: Evolution of laboratory investigation during first admission.

Hgb- Hemoglobin; Htc- Hematocrit; WBC- White Blood Cells; Neut- Neutrophiles; Lymph- Lymphocytes; PLT-Platelets; AST- Aspartate Aminotransferase; ALT- Alanine Aminotransferase; LDH- Lactate Dehydrogenase; CRP- C-Reactive Protein; POS- Positive

Based on the CT description and the severe lymphopenia, the patient was tested RT-PCR for Covid-19, with a positive result, and subsequently admitted to the Covid Department of Emergency

Clinical County Hospital Targu Mures.

Given the overdose of acenocoumarol, plasma transfusion was required to lower the INR from 5.6 to 1.58 so as the surgical team to be able to intervene in fitting a chest drain for the right-sided hydropneumothorax.  An amount of ~800 ml of sero-hemorrhagic liquid was drained. Given the presence of atrial fibrillation and the aneurysm, anticoagulant therapy was required, acenocoumarol was replaced with enoxaparin in a therapeutic dose also the chronic cardiac treatment was continued. Covid-19 treatment was also given according to the guidelines available at that time associated with antibiotics, but without antiviral therapy.

Considering the patient's cardiac history, we decide to perform a transthoracic echocardiography, which shows an EF of 40% and aneurysm at the apex of the left ventricle, with no visible thrombus, but with spontaneous contrast in the left ventricle.

As the respiratory status did not improve, the thoracic CT scan was repeated on the 7th day of admission. The scan revealed multiple bilateral ground-glass opacities occupying almost the entire lung surface, an image of the right upper lobe suggestive of bacterial infection, and a minimal bilateral pleural effusion. The surgical team decided to suppress the chest drainage, adjust the antibiotic therapy, and start corticosteroid therapy with dexamethasone 16 mg/day, it was started with laboratory monitoring.

On the 12^th day, the laboratory investigation revealed a change in the coagulation parameters: INR 1.61, fibrinogen 89 mg/dl, platelets 97.000/µL - Table 2. The following day, on the 13^th day of hospitalization the laboratory tests were repeated and showed INR 1.69, platelets 84.000/µL, fibrinogen was tested four times with two different devices but there was no result. At that time we interpreted that the fibrinogen level was too low to achieve a result. On the peripheral smear ovalocytes and schistocytes were described. Considering all of the above we interpreted the result as disseminated intravascular coagulation and started treatment with 10-15 ml/kg of fresh frozen plasma transfusions and a low dose of enoxaparin due to the cardiac associated pathology (AFib and the left ventricle aneurysm). There were no signs of bleeding, hemoglobin levels were normal throughout hospitalization.

Table 2. Coagulation parameters in evolution during first admission.

Hosp. day- Hospitalization day, INR – International Normalized Rate; FIB – Fibrinogen, APTT - Activated Partial Thromboplastin Time; PT -Prothrombin Time

*The sample was tested 4 times on 2 different devices but there was no result of fibrinogen. At that time we interpret the value of fibrinogen was too low to achieve a result.

After 1 day, the coagulation parameters and platelets began to improve, and after 5 days they were normal: INR 0.98, Fibrinogen 205.87 mg/dl, Platelets 155.000/µL- Figure 1.

Figure 1: The evolution of Fibrinogen (Fib) and Platelets (PLT) during first admission.

Fib- Fibrinogen; PLT- Platelets

After the bleeding risk had decreased, the anticoagulant treatment was adjusted to a full dose of enoxaparin.

Along with the decrease in fibrinogen, we observed increases in lactate dehydrogenase (LDH) and AST and ALT levels-Figure 2.

Figure 2: The evolution of Fibrinogen (Fib) and Lactate Dehydrogenase (LDH) during the first admission.

Throughout the admission, the patient required continuous oxygen therapy, initially even requiring an oxygen flow of 17 l/min via the facial mask to maintain saturation above 90%. Slowly, with the help of respiratory therapy, we were able to replace the face mask with a nasal cannula and maintain oxygen saturation at 91-93% with a flow of 5 l/min on an oxygen concentrator, with improvement in clinical and paraclinical status.

During admission, the patient was tested RT-PCR six times for SARS-COV2, with a positive result each time. At that time, performing Ct (Cycle Thresholds) was not available.

On December 31, 2020, after 29 days of hospitalization, the patient required to be discharged upon request although he still required oxygen therapy.

We discharged the patient with a recommendation for a home oxygen concentrator and a prescription of antibiotics and corticosteroid therapy with gradually decreasing doses, due to the long period of corticosteroid therapy during hospitalization. Regarding anticoagulation, considering the overdose of acenocoumarol on admission and the recent DIC, we decided to prescribe apixaban 2x 2.5 mg daily.

After almost a month, the patient presented again to the Emergency Department for worsening dyspnea. The patient was tested RT-PCR for SARS-COV2, the result being still positive. The Thoracic Computer Tomography scan showed ground-glass opacities on the superior left lobe and inferior right lobe. Also, the scan showed infected bronchiectasis on the left lung. This time laboratory investigation didn’t reveal modification in coagulation parameters, but sepsis has been proven (Procalcitonin 10 µg/L)-Table 3.

Table 3: Coagulation and Inflammatory Parameters at the second admission.

Fib-Fibrinogen; INR-International Normalized Rate, ESR- Erythrocyte Sedimentation Rate; CRP-C-Reactive Protein; LDH- Lactate Dehydrogenase; PCT-Procalcitonin

The patient was admitted to the Covid Department of another Hospital from Targu Mures where, to our knowledge, he died of sepsis and related complications.

In recent years, humanity has been forced to deal with COVID-19 and with all its consequences. COVID -19 poses a significant threat to global health as it is not just a respiratory infection but a systemic disease associated with multiple symptoms in the cardiovascular, gastrointestinal, neurological, immunological, and hematopoietic systems. Actually, it is closely related to the hematopoietic system and hemostasis [10].

The initial COVID -19 coagulopathy was characterized by elevated D-dimers and fibrinogen or fibrin degradation products, but also by abnormalities of prothrombin time, acute partial thromboplastin time and platelet counts [11]. 

According to Gomez-Mesa et al, a percentage of 20 to 50% of patients hospitalized for Covid-19 infections have altered coagulation parameters that can lead to thrombotic and hemorrhagic complications. Furthermore, they describe that a change in coagulation parameters can occur 7-11 days after the onset of symptoms or 4-10 days after hospitalization and recommend monitoring these parameters every 2-3 days [12].

Similar to the literature, in our case the patient showed changes in coagulation parameters on day 12 of hospitalization as follows: INR 1.61, Fibrinogen 89 mg/dl and decreasing platelet count to 97.000/µL. As outlined in the case description, our patient was on permanent treatment with acenocoumarol for AFib and the huge aneurysm of the left ventricle, which is why we interpreted the high INR value of the admission day as an overdose of acenocoumarol. Due to the cardiac diseases, anticoagulant therapy was required, so acenocoumarol was initially replaced with enoxaparin at full dose. Later, during the DIC episode, the enoxaparin dose was reduced and combined with Fresh Frozen Plasma transfusions. It is known that in DIC, a state of hypercoagulability occurs initially, causing micro- and macro-thrombosis, but after clotting factors are consumed and platelet counts decrease, the risk of bleeding increases [9].

DIC usually occurs as an acute complication in patients with severe underlying diseases and usually has a severe outcome, but according to Costello et al, it is difficult to determine mortality due to associated comorbidities [9,13]. Our patient had multiple risk factors for developing DIC, including severe Covid-19 infection, laryngeal cancer, and probably a bacterial infection which has not been proved but this could be influenced by the prophylactic antibiotic therapy initiated at the admission by the surgical team for fitting the drainage tub. Table 1 shows the evolution of the complete blood count (CBC) along with the inflammatory markers. We can note that on day 12 when the DIC probably started, the leukocyte levels were slightly elevated compared to the previous days, which was accompanied by high levels of LDH and ferritin. On the same day, interleukin-6 (IL-6) was determinate, which also showed an elevated value (26.46 pg/ml). Clearly, the patient had a severe inflammatory state contributing to DIC.

Regarding the laryngeal cancer (diagnosed in 2018, 33 radiotherapy sessions until admission to our department), we had no data about the remission status at that time. As we do not know whether the cancer was in remission or not, we cannot exclude that the cancer contributed to the DIC. On the other hand, given the fact that the DIC episode lasted only five days and the coagulation parameters were normal at the second presentation to the Emergency Department, most likely the severe inflammatory status had the biggest contribution to the DIC. Zhou et al conducted a meta-analysis that included 14 studies and evaluate the prevalence of DIC in Covid-19 patients. The meta-analysis found that 3% of Covid-19 patients developed DIC, which was associated with severity and poor prognosis [14].

In our case, the thoracic CT scan showed multiple bilateral ground-glass opacities occupying almost the entire lung surface, the persistent acute respiratory failure even after the drainage of the hydropneumothorax and the persistent inflammatory markers were signs of a severe form of Covid-19 infection.

Hydropneumothorax is defined as abnormal accumulation of air and fluid in the pleural space [15]. To the best of our knowledge, only a few cases of hydropneumothorax were reported in non-ventilated Covid-19 patients. In contrast, pneumothorax has been reported more frequently compared to hydropneumothorax, but again the incidence is low. Considering that our patient was a former smoker and had undergone radiotherapy for laryngeal cancer, we might consider that the hydropneumothorax could be a complication of pre-existing chronic pulmonary disease. On the other hand, it could also be a mechanical complication caused by cough.

However, another factor for poor prognosis in Covid-19 infection is lymphopenia. In 2022, Jianli Niu et al conducted a retrospective study including 4485 patients, which demonstrated that even if lymphopenia is common in Covid-19 patients it is associated with a poor prognosis [16]. In our case, the lymphocyte count was low (persistently below 400/mm³) throughout the admission period and even at the second presentation to the Emergency Department. A meta-analysis conducted by Zhao et al. showed that Covid-19 patients with lymphopenia have a three times higher risk of exacerbation [17].

Interleukin-6 (IL-6) is a proinflammatory cytokine produced in response to damaged tissue and infection. Back in 2014, Tanaka et al. described it as a "soluble mediator with a pleiotropic effect on inflammation, immune response and hematopoiesis"[18]. Among other effects, IL-6 increases C-reactive protein (CRP), serum amyloid A (SAA) and fibrinogen, but decreases albumin and fibronectin and also lowers serum iron levels by inducing hepcidin production, which is also responsible for the anemia associated with chronic inflammation [18,19,20]. In a meta-analysis, Aziz et al. showed that an elevated level of IL-6 is associated with a high mortality rate [21]. As mentioned earlier, in our case IL-6 was significantly elevated - 26.46 pg/ml, associated with an increased ferritin level of 1235 and a decreased serum iron level of 14.35 mmol/L, but no anemia - hemoglobin 12.6 g/dl. Albumin levels were also low, but we interpreted this in the context of neoplasia given the history of laryngeal cancer and radiotherapy.

Long Covid Syndrome or Post-acute Covid-19 Syndrome is defined as the persistence of clinical symptoms more than four weeks after the acute onset of symptoms [22]. Regarding the prevalence of Long Covid Syndrome, O'Mahoney et al. conducted a meta-analysis including 194 studies and a total of 735.006 participants, concluding that 45% of Covid-19 survivors were experiencing symptoms consisting with Long Covid after~4 months [23]. There are several manifestations of Long Covid Syndrome, including fatigue, dyspnea, chest pain and joint pain - to name a few [24,25]. According to Ho Cheng Koc et al., the most common symptom of Long Covid Syndrome is fatigue [24]. In our case, the main symptom that determined the patient to present to the emergency department for the second time was fatigue along with worsening dyspnea. Considering the symptomatology and the persistent positive RT-PCR SARS-COV2 test and the persistent ground-glass opacities on the thoracic CT scan, we considered the case as Long Covid associated with sepsis (Procalcitonin 10 µg/L) in an immunocompromised patient.

The frequently described severe acute respiratory syndrome can lead to medical divergences, but especially Covid-19 coagulopathy, which, although analyzed and re-analyzed, does not answer all the question marks. The literature is not clear about the CID in Covid-19, some authors speak about it, others consider it a CID -like phenomenon.  The association of cardiac pathology -giant left ventricle aneurysm, AFib forced the indication for anticoagulation, an indication that became dangerous in the context of DIC.  The management of this case being a challenge for the entire medical team.

Funding: This research received no external funding.

Conflicts Of Interest: The authors declare no conflicts of interest.

Institutional Review Board Statement: The study was conducted according to the guidelines of the Declaration of Helsinki, and was approved by the Ethics Committee, protocol code 6195/15.03.2023, 15 March 2023.

Informed Consent Statement: The patients signed an informed consent on admission regarding anonymous data collection for scientific purposes. Data handling and publication respected the Declaration of Helsinki, and approval of the Ethical Committee of Mures, Emergency County Clinical Hospital of Targu Mures was attained.

Author Contributions: Conceptualization, MGR and ZAS; Methodology, ZAS and SD; Software, MGR.; Validation, MC, LAB and SD.; Formal Analysis, AMM; Investigation, MGR.; Resources, ZAS.; Writing- Original Draft Preparation, MGR and ZAS.; Writing-Review & Editing MGR, ZAS and SD; Visualization, MC; Supervision, LAB, AMM.; Project Administration, AMM. All authors have read and agreed to the published version of the manuscript.

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