Clinical Drug Experience Knowledgebase

Efficacy and Safety Study to Evaluate the Use of Nebulized Heparin in Patients With Severe Acute Respiratory Syndrome Covid-19 (SARS-CoV-2)

The emergency of COVID-19 requires the urgent development of strategies to avoid the impact of the disease on our population, the saturation of the health system and the mortality of the disease.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in Wuhan, Hubei province, China and has subsequently spread to the world population. Factors associated with the development of SARS and its mortality include advanced age, lymphopenia, organ dysfunction, and bleeding disorders.

Different manifestations have been described (deep vein thrombosis, pulmonary thromboembolism, digital ischemia and cerebral infarcts), and different mechanisms, such as the presence of antiphospholipid antibodies in COVID-19. There is evidence of the presence of a hypercoagulable state in the majority of deaths from SARS associated with COVID -19.

Increased plasma D-dimer concentrations is a common finding and also appears to be an independent predictor of mortality. These patients and those who meet criteria for sepsis-induced coagulopathy (SIC) would benefit from anticoagulant therapy primarily with low molecular weight heparin (LMWH).

Antithrombotic therapies have been used in clinical practice for almost a century. In clinical practice, unfractionated heparin (UFH) and heparin derivatives remain the predominant antithrombotic therapies administered parenterally.

Heparin binds to antithrombin III (AT-III), a plasma glycoprotein, and to a small extent also to the heparin II cofactor. The result of this binding produces a conformational change and a strong increase in the inhibitory effect of thrombin, which becomes approximately 1000 times more potent than before. Other targets of heparin on coagulation are the inhibition or reduced activation of factors V, VIII and IX and the inhibition of thrombocyte function, due to a nonspecific binding of platelet factor IV.

However, heparin is a drug not only with anticoagulant properties, it has many other properties (interaction with growth factors, regulation of cell proliferation and angiogenesis, modulation of proteases and antiproteases), making it an interesting subject of research in the field of inflammation, allergy and immunology, interstitial lung fibrosis and oncology. Inhalation of heparin produces local anti-inflammatory and antifibrotic effects . In addition, possible effects have been described to prevent viral infection, including coronaviridae . It was describes the capacity of SARS-CoV-2 S1 RBD to bind heparin. Such binding capacity is an important prerequisite for research related to the development of SARS-CoV-2 unfractionated heparin therapeutic inhalation Experimental studies of inhaled UFH in healthy subjects showed that doses of less than 32,000 IU of UFH through the lower respiratory tract were safe. In a prospective cohort study in young adults, Harenberg determined that the inhaled dose of LMWH had to be 10 times greater than that administered subcutaneously to achieve similar levels of anti-factor Xa assay.

Considering the role of coagulopathy and inflammation in the induction of ventilator-induced lung injury, nebulized heparin improved lung function in ventilated patients, equivalent to the use of corticosteroids. It has also been compared with other interventions to stimulate the fibrinolysis or block coagulation to suppress the inflammatory response and reduce lung injury in adult acute respiratory distress syndrome .