Hypercoagulability in COVID-19 and post-COVID patients - characteristics and current treatment guidelines

COVID-19 and the vascular system

Coronavirus-induced disease 2019 (COVID-19) is characterised by hypercoagulability that is incompletely understood [1,2]. The Virchow triad (endothelial dysfunction, venous stasis, and hypercoagulability) is at the core of COVID-19 [1,2]. Endothelial injury, with endothelial exocytosis in the presence of endotheliitis and microvascular inflammation play a major role in the severe clinical status of COVID-19 [1,2,3]. The hypercoagulability is verified by elevated factor VIII, elevated fibrinogen, circulating prothrombotic microparticles, hyperviscosity, and increased formation of neutrophil extracellular traps (NETs) [1,2].

COVID-19 is characterised by normal or prolonged prothrombin time (PT) and active partial thromboplastin time (aPTT), normal or elevated platelets, elevated D-dimer and elevated von Willebrand factor antigen [4]. A slight decrease in the values ​​of antithrombin and protein S, and a slight increase in protein C have also been demonstrated [4]. At hospital admission, all patients should have a baseline complete blood count, and PT, aPTT, fibrinogen, and D-dimer evaluated [1,2,3,4].

The issue of thromboprophylaxis has persisted from the beginning of the pandemic and requires careful consideration. Prophylaxis of patients who are not hospitalised is generally not recommended. However, based on considerable empirical knowledge thus far, ambulatory thromboprophylaxis may be appropriate for patients with COVID-19 who have risk factors such as previous venous thromboembolism (VTE) or recent surgery, trauma or immobilisation [4,5,6]. If this is indicated, the use of enoxaparin, or a different low-molecular-weight heparin (LMWH), at a dose of 40 mg daily, is recommended.

In patients who weigh >120 kg or have a body mass index (BMI) >35 kg/m², enoxaparin dosage can be 40 mg twice daily (Table 1, Table 2). In addition, a thromboprophylactic dose of one of the novel oral anticoagulants (NOACs) can be used. However, the use of NOACs, as an integral part of thromboprophylaxis protocol in COVID-19 patients, is still undergoing investigation in clinical trials. In patients with a previous diagnosis of thrombophilia, there is an increased risk of developing VTE, especially if a patient is hospitalised or on oxygen therapy, but the previous diagnosis of thrombophilia is not associated with a higher incidence of VTE in patients with COVID-19 [6].

Table 1. Characteristics of unfractionated and low-molecular-weight heparin.

aPTT: activated partial thromboplastin time; HIT: heparin-induced thrombocytopaenia

Table 2. Use of enoxaparin, dalteparin, nadroparin and reviparin in thromboprophylaxis of the VTE.

CrCl: creatinine clearance; IU: international units

In hospitalised patients, the use of a modified early warning score (MEWS) is recommended before starting therapy (which takes into account body temperature values, systolic blood pressure values and heart rate, a number of respirations, and a patient’s neurological status) and before taking the final decision regarding in- or out-of-hospital treatment of a patient [7].

VTE occurs in 13.6% of patients with COVID-19 in intensive care units (ICU), deep vein thrombosis (DVT) occurs in 9.4% of patients, while pulmonary embolism (PE) occurs in 6.2% of patients [8]. The VTE rate is approximately 3% of patients who were hospitalised in standard hospital wards [9]. The first option for thromboprophylaxis should be the use of enoxaparin (as an LMWH) in all patients except those with creatinine clearance <15 mL/min (or in those who require haemodialysis), when the use of unfractionated heparin, which is an alternative to LMWH, is required [10]. The use of enoxaparin at a thromboprophylactic dose of 40 mg daily did not prove to be inferior compared to an intermediate dose (1 mg/kg daily) or a therapeutic dose (1 mg/kg twice daily), as indicated in patients with verified VTEs. However, a number of experts are advocating the use of an intermediate or a therapeutic dose of enoxaparin in critically ill patients [10,11].

Development of VTE during COVID-19, despite therapeutic enoxaparin dosing, has led to a hypothesis of heparin resistance. This hypothesis lacks details of its molecular mechanism, although it seems not to be associated with elevated fibrinogen or factor VIII levels, or decreased antithrombin levels. Heparin resistance may be diagnosed due to a so-called pseudo resistance (characterised by therapeutic values ​​of anti-Xa activity, and a decreased aPTT), due to low heparin concentrations (characterised by subtherapeutic values ​​of anti-Xa activity, and aPTT) or due to antithrombin deficiency [12]. It was reported that 22 to 39% of COVID-19 patients who required ICU treatment developed VTE despite prophylactic anticoagulation [12]. Monitoring of anti-factor Xa activity is appropriate, if available, and the therapy itself may be titrated based on the values obtained. In the literature, lower values of anti-factor Xa activity have been reported in ICU patients.

It is hypothesised that they are associated with respiratory function, i.e., that higher doses of anticoagulant therapy will be required in these patients (this research is still ongoing). This has led to the opinion that all patients in the ICU should be on higher doses of anticoagulant therapy (in the therapeutic regimen), i.e., that the value of anti-factor Xa activity should be monitored in these patients [13,14,15]. It should be noted that monitoring of this activity has not been a routine diagnostic tool, when it comes to thromboprophylaxis; however, its value has been recognised during the COVID-19 pandemic, since case reports on heparin resistance and an increase in the occurrence of VTE despite thromboprophylaxis have begun to emerge.

In the case of anamnestic data on heparin-induced thrombocytopaenia (HIT), prophylaxis with fondaparinux is recommended [6,7,12]. If HIT is suspected (mandatory use of 4Ts score), the use of a NOAC, argatroban, bivalirudin, danaparoid, or fondaparinux, should be considered [16]. The use of extracorporeal membrane oxygenation (ECMO) requires continuous use of unfractionated heparin, with monitoring of aPTT values, where they tend to be 2-2.5 times higher than the reference value [11]. 

COVID-19 has similar diagnostic values to disseminated intravascular coagulation (DIC), which may raise doubts about treatment. The International Society on Thrombosis and Haemostasis (ISTH) diagnostic scoring system may be helpful in diagnosing DIC, but it must be kept in mind that this is based solely on laboratory findings and should be carefully interpreted [14]. For the treatment of such patients, experience and knowledge are necessary in order to differentiate blood biomarker changes that are associated with HIT and those associated with DIC. It should be borne in mind that DIC is related to low fibrinogen levels, due to consumable coagulopathy.

Patients who are undergoing treatment at home and are prescribed warfarin therapy are candidates for replacing warfarin with a NOAC, if it is not contraindicated (in indications where the use of a NOAC is contraindicated, warfarin therapy should be continued) [17].

The issue of cavernous sinus thrombosis is debatable, although the use of unfractionated heparin or LMWH is compulsory for a few weeks up to several months. The use of LMWH is also indicated after the occurrence of a venous sinus thrombosis during hospitalisation, and thereafter, if it was provoked by the use of oral anticoagulants, for 3 to 6 months, and, if it was not provoked, for 4 to 12 months.

Clear guidelines for routine thromboprophylaxis, following the SARS-CoV-2 infection, have not yet been established. The risk of post-discharge VTE appears to be the same as after other acute conditions [15]. Prolonged thromboprophylaxis is recommended if the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE-VTE) score is ≥4, in patients with D-dimer value 2x greater than the reference value, in patients with one of certain risk factors (prolonged immobilisation, previous venous thromboembolism, hormonal therapy, body weight >120 kg or BMI >35 kg/m²), or in patients with an ongoing oncological process.

Prolonged thromboprophylaxis should last for between 39 and 42 days, with an enoxaparin dose of 40 mg daily, an apixaban dose of 2x2.5 mg daily (off-label use), or a rivaroxaban dose of 10 mg daily (according to clinical studies) [18]. In case of hepatotoxicity arising due to previous pharmacological therapy, the Non-VKA after COVID-19 pNeumonia and Based on Abnormalities of Liver’s parameters (ANIBAL) protocol is a simple approach that considers liver and renal function and can be a tool for anticoagulation modality.

D-dimer value should not be decisive for initiating thromboprophylaxis, or for deciding on prolonged thromboprophylaxis. In addition, D-dimer values are not decisive for the diagnosis of PE and, if the patient is hypotensive, tachycardic, and with respiratory deterioration, computed tomography with pulmonary angiography is indicated. Making thromboprophylaxis-related decisions based on D-dimer values, without considering a patient's complete clinical status, is currently considered redundant.

In a study of 3,334 patients, of whom 829 were in ICUs and 2,505 in standard care wards, acute myocardial infarction showed an incidence rate of about 8.9%, while stroke occurred in 1.6% of patients [8]. There is no recommended antiplatelet therapy outside the standard indications. It should continue in the regime in which it was previously prescribed (necessary correlation with anamnestic data, and knowledge of the concepts of primary and secondary prevention). In case of the need for dual antiplatelet therapy, prasugrel will be used as a drug of choice (avoid CYP3A4 metabolism). Glycoprotein IIb/IIIa inhibitors or cangrelor can be used for the treatment of an acute myocardial infarction without ST-segment elevation, in accordance with the increase in the cardiac necrosis enzyme values and the clinical picture of an acute myocardial infarction (follow guidelines for the treatment of an acute coronary syndrome).

Post-COVID syndrome - what can we expect in daily practice

The following symptoms can occur in patients up to seven months after an acute COVID-19 episode and have been characterised as belonging to a post-COVID syndrome as, currently, they are not explained by an alternative diagnosis: presence of shortness of breath (dyspnoea, over two to three months, sometimes longer), cough, chest tightness, anosmia (altered taste and smell), ageusia, fatigue, myalgia, headache and difficulty to focus, tremor, problem with attention and concentration, cognitive blunting (“brain fog”), dysfunction in the peripheral nerves, changes in the menstrual cycle and mental health problems such as anxiety, mood changes, depression, post-traumatic stress disorder and decreased quality of life and economic and social concerns [17,19,20]. The exact mechanism of these symptoms is still unclear, but it is thought that it could be due to organ injury (primary, pulmonary fibrotic lung disease, bronchiectasis, and pulmonary vascular disease or any other organ), the presence of a chronic inflammatory process, the presence of viral particles in the body, non-specific effect of hospitalisation, sequelae of critical illness, post-intensive care syndrome (in 20% of patients re-hospitalisation is required within 30 to 60 days), complications related to a previous SARS-CoV-2 infection, comorbidities or adverse effects of medications [20].

In younger patients with mild COVID-19, clinical follow-up examination is not indicated. In older patients with mild to moderate COVID-19, who did not require hospitalisation, clinical follow-up examination is indicated three weeks following the onset of an illness. In patients with severe COVID-19, who did require hospitalisation, clinical follow-up examination is indicated within one week after discharge from the hospital (and no later than two to three weeks after discharge from the hospital).

Echocardiographic examination should be performed in order to analyse the dilation and kinetics of the heart cavities, the existence of pericardial separation (or effusion), to determine the degree of pulmonary hypertension and the volume status (diastolic dysfunction). The analysis of pericardial separation, which occurs after viral infection, must be in accordance with the literature, in order to exclude the haemodynamic effect of effusion and compression syndrome (cardiac tamponade, constrictive pericarditis) [19,20]. In patients with previous VTE, the parameters of the right ventricle should be monitored, as they can explain the clinical status of a patient. The use of 24-hour electrocardiogram (Holter) monitoring is indicated, especially in patients with previous cardiac pathology (also in patients with palpitations or symptoms of dysautonomia). In case of exaggerated symptoms with standing, a tilt table test is indicated. Ergometry (especially ergospirometry with a 6-minute walk test) can be a good option for assessment of a patient’s condition (it should be avoided in early post-COVID syndrome). In patients with palpitations or symptoms of dysautonomia, despite an unremarkable ECG, extended Holter monitoring should be performed. For patients who develop exaggerated symptoms associated with changes in posture, a tilt table test can be used for further assessment of changes in vital signs with a change to an upright posture.

It is reported that up to 50% of post-COVID patients suffer from fatigue [20]. Interstitial mononuclear cell infiltrate has been verified on autopsies, while the rate of myocarditis is unclear (as magnetic resonance imaging is not available on all sites). Many patients demonstrated elevated N-terminal pro-brain natriuretic peptide (NTpro-BNP) values and, therefore, based on the NTpro-BNP, myocarditis could be indicated (especially if symptoms such as dyspnoea, chest discomfort or oedema are present). The viral infection itself may have an effect on the myovasculature due to virus entry through the ACE2-receptors, and, thus, have an effect on myocardial ischaemia and ventricular dysfunction. This fact could explain the increase in troponin values, ​​that would favour myocardial injury, and the increase in NTpro-BNP, as a biomarker of volume load [20].

The most common arrhythmias that occur are sinus tachycardia, followed by pathological disorders such as atrial fibrillation or atrial flutter, or monomorphic or polymorphic ventricular tachycardia [20]. Cardiac complications are more common in patients with pre-existing cardiac pathology (e.g., hypertension, ischaemia, diabetic cardiomyopathy, valvular defect, or congenital heart anomalies), due to decreased cardiac reserve. The term “COVID-19 cardiomyopathy” has not yet been established, but microvascular dysfunction, inflammatory cytokine storm, and myocarditis have been suggested [20].

The choice of a specific angiotensin-converting enzyme (ACE) inhibitor should be made based on their cardioprotective and nephroprotective properties, as well as with regard to the effect on atherosclerosis. Lipid solubility should also be considered. Selective beta-blockers should be preferred (e.g., nebivolol, bisoprolol, metoprolol succinate). The use of dihydropyridines, due to peripheral vasodilation, is justified, and the use of non-dihydropyridines, due to relaxation of the muscular layer of the respiratory system, could have benefit, as in the pharmacological modality of vasospasm (use in heart failure or signs of myocarditis is not indicated). The use of dronedarone, which is a non-iodinated congener of amiodarone with a better safety profile, should be preferred in the case of an indication for amiodarone. Ranolazine and trimetazidine can be used because of the microvascular dysfunction. Caution should be exercised with nitro preparations due to the effect of the infection on the central nervous system. The use of statin therapy in the post COVID-19 phase is imperative, due to the proatherogenic potential of the virus.

For healthy, younger patients with mild COVID-19 who do not require medical intervention or hospitalisation, whose health status is rapidly improving, follow-up visits are not part of routine practice. For older patients or patients with comorbidities (e.g., hypertension, or diabetes), with mild to moderate acute disease not requiring hospitalisation, a follow-up is scheduled using telemedicine or an in-person visit approximately three weeks following the onset of the illness. For patients with more severe acute COVID-19 disease requiring hospitalisation (with or without the need for subsequent post-acute care such as inpatient rehabilitation), ideally a follow-up within one week, but no later than two to three weeks after discharge from hospital or a rehabilitation facility, is scheduled.

Conclusion

Endothelial disease underlies COVID-19. An understanding of this disease is essential for the successful treatment of COVID-19 patients. The indications are that pre-hospital, hospital, and post-hospital thromboprophylaxis is justified, with antiplatelet therapy indicated. When choosing the most appropriate pharmacological therapy, a knowledge of the pharmacokinetic and pharmacodynamic properties of a specific drug, as well as its interactions with antiviral drugs, is necessary. However, after the acute infection phase, it is worth remembering that a patient's treatment has not been completed. Post-COVID syndrome is a challenge for the cardiologist in everyday practice, and its treatment should be in accordance with the clinical characteristics of each individual patient.