COVID-19 and Anticoagulation

Abstract

With infection of SARS-CoV-2, a0, response in both hemostatic and immune systems begins. The mechanism of coagulopathy that SARS-CoV-2 virus cause is as a result of a complex order of initial effects promoting thrombosis both on microvascular and macrovascular scale. Starting from the pulmonary circulation, depending on the course of the disease, a simple inflammation can advance to acute pulmonary injury which threatens hemodynamics of the patient and can potentially create multisystemic dysfunctions. While the symptoms are only mild in the majority of patients, a distinguishing aspect of COVID-19 is that a certain percentage of individuals experience serious complications shortly after infection. These complications include adult respiratory syndrome (ARDS) or disseminated intravascular coagulation (DIC), sepsis leading to organ failure, and ultimately, death. The beneficial use of anticoagulants in COVID-19 patients has the potential of reducing the risk of thrombotic events like deep vein thrombosis and pulmonary embolism. This chapter compiles existing studies and presents recommendations for a better understanding of the disease and clinical approach.

1. Introduction

COVID-19 is attributed to a novel coronavirus called SARS-CoV-2 and is marked by an excessive inflammatory reaction that may result in severe outcomes for some patients, including adult respiratory syndrome, sepsis, coagulopathy, and mortality.

At the beginning of SARS-CoV-2 infection, the lungs serve as the primary site of entry, leading to the development of acute infection and subsequent local clot formation within the pulmonary microcirculation. This ultimately results in hypoxemia, disruptions in ventilation and perfusion. The virus primarily enters the cell by binding to the angiotensin-converting enzyme II (ACE-II) receptors of human cells. This binding process leads to the aggravation of an inflammatory reaction in the body and leads to the appearance of various symptoms and complications. One of these complications of COVID-19 is that it triggers the condition hypercoagulopathy, and increases the risk of thrombosis.

Among other factors and direct effects of the virus; the product peptide hormone of angiotensin-converting enzyme ll, angiotensin II, causes vasoconstriction and an increase in the blood pressure. Renowned for its potent vasoconstrictive properties, Angiotensin II induces hypercoagulability by upregulating the expression of tissue factors [1].

Up to 50% of the patients with severe clinic progression manifest COVID-19, coagulopathy and a significant increase of angiotensin II have been reported. Immunothrombosis is one of the pathological mechanisms of the COVID-19 virus, which is described by the interaction between the hemostatic response and the immune pathway. After the virus causes endocytosis in the infected cells, vascular damage occurs as an initial outcome, eventually progressing to a phase of programmed cell death that tends to cause inflammation. This type of cell death is known as “pyroptosis”, which promotes an increase of cytokines in the bloodstream and different damage-associated molecular patterns (DAMPs) that cause cell membrane rupture as a result (Figure 1) [2].

Figure 1.

Inflammation mechanism of SARS-CoV-2.

The prothrombotic chain appears to be caused by Virchow’s triad; which includes stasis and immune cell activation, hypercoagulation, and endothelial injury [3].

On the basis of the glycocalyx layer and antithrombin glycoprotein expression, endothelial cells have an anti-thrombogenic effect for healthy individuals. When endothelial cells get damaged, the glycocalyx layer is disorganized and, as a result, cells change their properties towards a procoagulant state [4].

In scientific articles, it has been observed that elevated levels of plasminogen activator inhibitor (PAI-1), a key inhibitor of fibrinolysis that interferes with tissue plasminogen activator (tPA) and urokinase, are associated with a heightened risk of thromboembolic events [5].

2. Coagulation & hypercoagulability

Evidence from multiple studies indicates that the implementation of prophylactic anticoagulation therapy among COVID-19 patients exerts a protective effect, resulting in a reduction of the possibility of thromboembolism in venous and arterial systems, and overall mortality. In cases where severe COVID-19 infection led to fatalities, the incidence of microthrombosis in alveolar capillaries was observed to be nine times higher compared to patients who succumbed to influenza. Moreover, a significant proportion of patients with severe COVID-19 infection, ranging from 15.2% up to 79%, exhibited thrombotic outcomes [6].

Yet it is likely that the virus itself does not have intrinsic procoagulant effects alone, while coagulopathy appears as a result of the exaggerated COVID-19 inflammatory response and endothelial cell activation/damage [7].

There are multiple elements that can accelerate the hypercoagulability in serum plasma of COVID-19 patients:

• Elevation in tissue-factor levels,

• Increased factor VII, fibrinogen (coagulation mediators)

• Anti-phospholipid antibodies,

• Protein C dysregulation

• Circulating prothrombotic microparticles

• Neutrophil extracellular traps

Severe COVID-19 complications are more prevalent among elderly patients with underlying health conditions, who also face an age-related heightened risk of thrombosis. Additionally, comorbidities like diabetes, hypertension, and cardiovascular diseases in COVID-19 pneumonia patients are associated with an increased risk of venous thromboembolism (VTE) and thrombotic events. These pre-existing conditions are known to elevate the likelihood of clotting events and can exacerbate the impact of COVID-19 (Table 1).

Individual factors	Pneumonia	SARS_CoV-2
Advanced age	Need of Intensive Care Unit	Cytokines / Cytokine storm
Male	Need of mechanical ventilation	High levels of plasminogen activator inhibitor-I
Immobility / prolonged; Hospitalization	High levels of Hypoxia inducible factor -I	Tissue factor increase
Cardiovascular morbidity	Central catheters	Angiotensin
Hypertension	Endotelial Damage
Obesity
Diabetes
Malignities

Table 1.

Patient-related, pneumonia-related, and SARSCoV2-related factors that increase the risk of thrombotic complications in COVID-19.

Moreover, the hypoxia-mediated condition evident in severe COVID-19 can intensify thrombotic occurrences, not solely through increased blood viscosity but also via the reaction of the hypoxia-inducible transcription factor-dependent signaling pathway [8, 9].

Hypoxia has been implicated as a key initiating factor in the prothrombotic state observed in patients with SARS-CoV-2 infection. It activates the production of a hypoxia-inducible transcription factor (HIF-1α), which, in turn, stimulates the endothelial cells to secrete PAI-1 and macrophages. Additionally, hypoxia induces the release of cytokines such as tumor necrosis factor-α (TNF-α) and IL-6 [10].

Obesity has emerged as a notable risk for human health, with research pointing out that individuals who are overweight have a greater susceptibility to thrombotic events compared to those within the normal weight range. Adipose tissue has been revealed as the source of one-third of total circulating concentrations of IL-6 [11].

In addition, immobility, often due to prolonged hospital administration, plays a significant part in developing thrombotic events in COVID patients [12].

Lastly, High D-dimer level was found to be the most notable coagulation parameter in severe COVID-19 patients, and progressively increasing values can be used as a prognostic parameter, pointing out the poor prognosis.

Elevated D-dimer levels, surpassing 2.0 ug/mL upon admission, or a subsequent increase of 3–4 times during hospitalization, have been linked to elevated rates of in-hospital mortality [13].

A prolonged prothrombin time, alongside elevated D-dimer levels, has been associated with reduced survival rates and an escalated need for critical care [14]. Approximately twenty to fifty percent of COVID-19 patients admitted to hospitals exhibit hematologic alterations in their coagulation profiles, such as elevated D-dimer levels, prolonged partial thromboplastin time (PT), decreased platelet counts, and/or reduced fibrinogen levels. This condition is characterized by an increased occurrence of thrombotic events, particularly associated with coagulopathy, notably venous thromboembolism (VTE) (Table 2).

Coagulation biomarkers
D-dimer
PT
aPTT
Fibrinogen

Table 2.

Increasing coagulation biomarkers in COVID-19.

Change in these parameters can occur seven to eleven days after the beginning of symptoms or four to ten days after the patient is ministered to the hospital. In hospitalized patients with severe COVID-19, it is recommended to conduct regular reevaluations of coagulopathy indicators (D-dimer, prothrombin time, and platelet count) at intervals of at least every two to three days [7, 15].

3. Beneficial use of anti-coagulants

AAnticoagulants are drugs used to treat or prevent blood clots by thinning the blood. For the treatment of venous thromboembolism (VTE) associated with COVID-19, several agents are used. These include heparins, direct oral anticoagulants (DOACs), platelet aggregation inhibitors, factor XII inhibitors, thrombolytics, complement inhibitors, neutrophil inhibitors, and IL-1 receptor antagonists.

Anticoagulants can be used to treat conditions such as PE or venous thrombosis or to prevent the formation of blood clots after deep vein thrombosis or post-operative or prolonged bed rest. Therapeutic anticoagulation plays a central role in the management of deep vein thrombosis (DVT) and pulmonary embolism (PE). In intensive care units, unfractionated heparin (UFH) is commonly favored for treating venous thromboembolism due to its rapid onset of action and lack of known interactions with any of the investigational drugs used for COVID-19 [16].

In moderate-to-severe COVID-19 patients, current knowledge of anticoagulant treatment has proven to be associated with better clinical outcomes. Increased biochemical coagulative parameters including elevated D-dimer, elevated fibrinogen, and low levels of anti-thrombin are targeted for anticoagulant treatment [17, 18].

The use of anticoagulants like Heparin and vitamin K antagonists in patients who have COVID-19 is a complex subject, depending on keeping the balance of the therapeutic income statement and avoiding the potential risks. The standard approach for prophylactic anticoagulation therapy in COVID-19 patients is the usage of low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) in general. LMWH is usually being administered via a subcutaneous route and dosage is arranged by the patient’s weight, while UFH dosing is guided by monitoring activated partial thromboplastin time (aPTT) levels. This strategy ensures the provision of appropriate anticoagulation therapy to patients while minimizing the risk of adverse events [19, 20].

At the beginning of the pandemia in Italy, the CORIST study was launched. This is aimed to be a large retrospective, multicentered, and observational study of patients hospitalized with laboratory-confirmed SARS-CoV-2 infection in 34 hospitals carried out between February 19th and May 23rd, 2020.

Studies showed that in hospitalized patients, daily treatment with heparin until discharge was related with lower mortality, particularly usage in heavily ill patients who have a strong response of coagulation activation [21].

Longer-acting agents, such as LMWH, may also be considered in anticoagulation of hospitalized patients. The clinical benefit of LMWH may arise from its ability to suppress the release of IL-6 while promoting an increase in lymphocytes, thereby potentially delaying or obstructing the inflammatory cytokine storm. Although there have been reports of thrombosis occurring despite the use of low-dose prophylactic LMWH, a plausible approach is to consider escalating the LMWH dosage either empirically or in response to increasing D-dimer values. Although oral Factor Xa therapy is not the preferred option for prophylaxis due to its higher bleeding risk, it can be a viable alternative when LMWH is unsuitable for routine anticoagulant therapy. Additionally, oral Factor Xa therapy can be administered subcutaneously once or twice daily without the need for frequent monitoring to ensure effective dosing.

In individuals categorized as having low or intermediate risk for thrombotic events, the application of prophylactic doses of LMWH has been observed to lead to a simultaneous decrease in the incidence of severe acute respiratory distress syndrome and venous thromboembolism (VTE). This effect may potentially reduce the requirement for mechanical ventilation and result in lower cardiovascular mortality rates [22].

Several non-anticoagulant features of LMWH have also been suggested, such as the reduction of the release and biological activity of IL-6. LMWH has been shown to bind to SARS-CoV-1 and inhibits replication of the virus.

The International Society on Thrombosis and Hemostasis (ISTH) and the American Society of Hematology (ASH) have both endorsed the use of prophylactic LMWH. However, the optimal and most effective dosage remains uncertain [15]. Prophylactic anticoagulation for one week or ten days is recommended in patients who are discharged but have additional risk factors creating a tendency for thrombosis [23].

Factor Xa inhibitor therapies have been already proven to have inflammatory and antiviral effects in addition to their anti-coagulant activity, and they have been suggested for a potential therapeutic role in coronavirus infections [24].

Moreover, anti-platelet agents have been investigated as potential anti-thrombotic therapy for COVID-19, although the rationale for aspirin usage in this context remains uncertain. A recent study suggests the adoption of a low-dose aspirin regimen for primary prevention of arterial thromboembolism in patients aged between forty and seventy, who possess moderate or high cardiovascular risk and a slight risk of bleeding. This alternative approach sheds light on the potential preventive role of acetylsalicylic acid in COVID-19-related respiratory disease and vascular thrombosis, even in individuals without a history of cardiovascular disease [25].

The effects of using anticoagulants in the long term can still differ according to the patient’s current state and prognosis. Usually, it is determined by the patient’s chronical co-morbidities, and adverse effects that are caused by chronic drug use.

The primary concern linked to this therapy is a heightened susceptibility to bleeding, necessitating meticulous evaluation and monitoring for each individual patient [19, 26, 27].

Potential adverse effects of heparin use are the development of heparin-induced thrombocytopenia (HIT), hemorrhages, excessive bleeding, and bleeding disorders in patients who have undergone major surgery. Still, in the majority of COVID-19 patients, anticoagulation treatment was shown to improve survival in severely ill patients, along with a reduction in thromboembolic complication rates.

4. Subsections

4.1 Anticoagulation in children

Children have better outcomes with COVID-19 because of their level of procoagulation factors, endothelial functions, and immune responses.

Moreover, children usually experience fewer adverse effects. However, some children’s immune systems can create hyperinflammatory responses that can cause endothelial injury and coagulopathy as a result. This particular response is similar to Kawasaki’s disease and it is called the multisystem inflammatory syndrome in children.

4.2 Anticoagulation in pregnancy

COVID-19 and pregnancy are both create a tendency for thrombosis.

Hypercoagulability is a physiologically adaptive mechanism that prevents bleeding from miscarriage, childbirth, and postpartum hemorrhage. Women in pregnancy or the postpartum period are at a four to five-fold higher risk of thromboembolism than non-pregnant women. Pregnancy is naturally followed by an increased concentration of factors VII, VIII, X, and von Willebrand factor and fibrinogen [28, 29].

The Centers for Disease Control and Prevention (CDC) has stated that pregnant women might face an elevated risk of COVID-19-associated complications, such as ICU admission and acute lung injury requiring mechanical ventilation, possibly attributable to their weakened immune system.

Although current data we have on the pregnant population are limited, their relative risk is low and mortality risk is similar compared with nonpregnant patients in the same age group.

5. Interpretation

It appears that therapeutic doses of anticoagulation did not yield any clinical benefit for hospitalized patients with moderate-severe COVID-19. Furthermore, the dosage of anticoagulants did not show a significant difference in the progression of organ failure. A previous study also reported no variance in the antithrombotic effect when administering low-dose unfractionated heparin two or three times a day. Although low-molecular-weight heparin offers the convenience of once-daily administration, its thrombotic prevention effect is nearly equivalent to that of prophylactic unfractionated heparin, with a lower risk of bleeding [12, 30].

Statistics on the long-term effects of anticoagulant use provide important information about the effectiveness of drugs in the treatment of COVID-19. However, more research and clinical studies are needed to understand these effects and consequences. These will help us to understand the effectiveness and reliability of the use of anticoagulants better for COVID-19. Comprehensive risk assessment and individualized treatment plans can improve the outcome of patient studies and prevent treatment-related complications.

6. Conclusions

The challenge for physicians is represented by the decision of whether, and how to start anticoagulant therapy. We should continue to focus on the mechanism of vascular endothelial injury and evaluate the potential therapeutic options that may create a balance between the risks and benefits of the treatment for each patient. They may also be of benefit for future microorganisms that can potentially generate similar thrombo-inflammatory responses.

According to the majority of guidelines, hospitalized patients should receive standard thromboprophylaxis treatment, with the option of individualized adjusted dosing based on specific objective parameters instead of standardized adjustments. However, it is crucial to take bleeding risks into account, as major bleeding events can be observed in 2.3% of all patients, even when using standard doses for VTE prevention [1].

The common agreement for thromboprophylaxis, anticoagulation, and additional deliberations for the management of coagulopathy and bleeding should be implemented in each health center following the most current recommendations.

Conflict of interest

The authors declare no conflict of interest.

Notes/thanks/other declarations

None.

Acronyms and abbreviations

ASH	American Society of Hematology
ACE-2	Angiotensin Converting Enzyme −2
COVID – 19	Corona Virus Disease −2019
DAMPs	Damage-associated molecular patterns
DOAKs	Direct oral anticoagulants
DIC	Disseminated intravascular coagulation
HIT	Heparin-induced Thrombocytopenia
HIF-1α	Hypoxia-inducible transcription factor
ICU	Intensive Care Unit
ISTH	International Society on Thrombosis and Hemostasis
LMWH	Low Molecular Weight Hepatin
CDC	The Centers for Disease Control and Prevention
PT	Partial thromboplastin
aPTT	Partial thromboplastin time
PAI-1	Plasminogen activator inhibitor
PE	Pulmonary Embolism
tPA	Tissue plasminogen activator
TNF-α	Tumor necrosis factor-α
UFH	Unfractionated heparin
VTE	Venous Thromboembolism