Introduction

Thrombophilia (also known as hypercoagulability) is a condition in which blood clots more easily. The SARS-CoV-2 virus (severe acute respiratory syndrome coronavirus 2) is also known to increase the risk of blood clots.¹ Does this mean patients with thrombophilia have a higher risk of blood clotting in COVID-19? The following article explores thrombophilia, COVID-19, and the potential relationship between the two. 

Blood clotting and thrombosis

Blood clotting is an essential part of the body’s repair mechanism. When a person has an injury which damages the walls of blood vessels, blood clots form to block any holes in the damaged walls, preventing excessive blood loss. Once the injury is healed, the blood clots are no longer required and naturally dissolve. 

However, clots can sometimes form inside the blood vessels without any injuries, or fail to dissolve after an injury is healed. This abnormal blood clotting is known as thrombosis. The clot can block the blood vessel where it is formed, stopping the blood flow. Parts of the blood clot can also break off and travel elsewhere in the body. When a blood clot blocks major arteries providing blood to the brain and heart, an ischaemic stroke or heart attack may occur. This can potentially be life-threatening unless immediate medical assistance is obtained.²

Symptoms

Symptoms of thrombosis differ according to the location of clotting:

Heart

Thrombosis may block the coronary arteries, which supply blood to the heart. This may cause angina (pain in the chest), shortness of breath and fatigue. If the coronary arteries are completely blocked, it may cause a heart attack. The pain in the chest may spread through the upper body. There may also be sweating, nausea, light-headedness and an overwhelming feeling of anxiety. If this occurs, emergency services must be called immediately. 

Brain

Blood vessels which supply blood to the brain include the carotid arteries (located at the sides of the neck) and vertebral arteries (located in the spinal column). Blood clots in these arteries interrupt blood supply to the brain, which may result in an ischaemic stroke. 

Symptoms and response to a stroke can be remembered through the acronym BE FAST:³

• Balance – a person having a stroke may have trouble standing upright
• Eyes – a person experiencing a stroke may have blurry vision or ‘see double’
• Face – ask the person to smile. A person experiencing a stroke may have one or both sides of their face droop when smiling
• Arms – ask the person to raise their arms. One or both of their arms may droop downwards
• Speech – a person with a stroke may have slurred speech or difficulty choosing their words
• Time – if someone is suspected of having a stroke, call the emergency services immediately. This allows them to receive treatment as soon as possible, improving their chances of survival

Transient ischaemic stroke may also occur. Known as a mini-stroke, the blood supply to the brain is temporarily disrupted by a blood clot before the blood clot dissolves, restoring blood flow. While shorter-lasting than a stroke, early symptoms of a mini-stroke are identical to a full stroke. Emergency services should still be called, with the patient evaluated at a hospital, even if the symptoms have disappeared. Transient ischaemic strokes are a warning sign of a full stroke occurring in the future. Therefore, their occurrence must not be disregarded. 

Arms and legs

Deep vein thrombosis occurs when abnormal clotting happens in the deep veins of the arms and legs, with the latter occurring more commonly. Symptoms include throbbing pain and swelling in the limb. The skin around the painful area may also be warm and red. While less urgent than thrombosis in the heart or brain, deep vein thrombosis should still be brought to a doctor’s attention as soon as possible. This is due to the potential for fragments of the clot to break off and block other blood vessels in the body, particularly in the lungs.

Lungs

Pulmonary embolism occurs when a blood clot breaks off from another area of the body to block the arteries transporting blood to the lungs (pulmonary arteries). The clot often originates from deep vein thrombosis in the legs, with deep vein thrombosis and pulmonary embolism jointly known as venous thromboembolism. Symptoms include chest pain, shortness of breath, and coughing up blood. These symptoms overlap with other cardiovascular and respiratory diseases, making diagnosis difficult. 

Thrombosis is a preventable and treatable condition, with drugs such as anticoagulants preventing blood clot formation and thrombolytics dissolving blood clots if a clot has formed inside a blood vessel. However, it can also be life-threatening if not identified and treated quickly. To reduce the risk of abnormal blood clotting, risk factors of thrombosis should be identified in patients and brought to the attention of healthcare providers, among them are thrombophilia and SARS-CoV-2 infections.

What is thrombophilia?

Thrombophilia is a blood disorder that causes an increased risk of thrombosis. It can be inherited (genetic/inherited thrombophilia) or caused later in life due to other medical conditions (acquired thrombophilia). However, people with thrombophilia do not necessarily experience thrombosis, particularly if risk factors are identified and managed early.⁴

Genetic thrombophilia

People with genetic thrombophilia inherit a gene causing abnormal blood clotting from one or both parents. The most common blood clotting disorder is Factor V Leiden, caused by a mutation in the coagulation factor F5 gene. The F5 gene produces the protein Factor V, which assists in blood clot formation. Mutations in the F5 gene increase the likelihood of deep vein thrombosis. Another common cause of genetic thrombophilia is mutations in the prothrombin gene. Also known as Factor II, prothrombin is a protein encoded by the coagulation factor F2 gene. Due to prothrombin’s role in blood clot formation, mutations in this gene increase the risk of deep vein thrombosis and pulmonary embolism. 

As genetic thrombophilia can be inherited from parents, patients with a family history of thrombophilia should inform their healthcare providers to discuss how to reduce the risk of thrombosis. 

Acquired thrombophilia

Acquired thrombophilia is more common than genetic thrombophilia. It can be caused by pre-existing medical conditions, including cancer, obesity, diabetes, high blood pressure, high blood cholesterol and atherosclerosis (buildup of fatty deposits leading to the narrowing of blood vessels). An increase in the levels of the hormone oestrogen, potentially due to birth control pills, pregnancy or hormone replacement therapy, may increase the risk of abnormal blood clotting. Behavioural factors such as smoking and prolonged periods of immobility also increase the risk of thrombosis. 

The most common acquired thrombophilia is antiphospholipid syndrome, also known as Hughes syndrome. It is an autoimmune disease in which the immune system mistakenly attacks proteins bound to fat molecules known as phospholipids. This increases the risk of blood clotting, which may lead to deep vein thrombosis, strokes, heart attacks, as well as miscarriages (a loss of pregnancy) if a clot blocks the blood flow to the placenta (a temporary organ providing nutrients to the foetus).

Effect of COVID-19 on blood clotting

COVID-19 is an infectious disease caused by the SARS-CoV-2 virus. While most patients experience mild to moderate symptoms and recover with minimal medical input, some patients may experience complications which result in serious illness. One complication includes abnormal blood clot formation. 

Severe COVID-19 may trigger a state of hyperinflammation in the body, which may damage organs and the walls of the blood vessels. Blood clots may form as part of the body’s immune response, leading to thrombosis. This often occurs in the form of pulmonary embolism or deep vein thrombosis, with reported incidence rates of thromboembolism in ICU (intensive care unit) patients ranging from 31% up to 79%.⁵ The risk of thrombosis increases up to 70 days after COVID-19 infection.⁶ The likelihood of ischaemic stroke is also high. Patients with thromboembolic complications are at a higher risk of death or disability after recovery. Hence, it is important to prevent and manage blood clotting due to COVID-19.

Diagnosis can be quite difficult, particularly for pulmonary embolism. Symptoms of pulmonary embolism include chest pain and shortness of breath, which are indistinguishable from symptoms caused by a worsening respiratory infection. Additionally, D-dimer tests are often used to diagnose thrombosis. D-dimers are protein fragments released during the dissolution of blood clots. Patients with venous thrombosis have high levels of D-dimers in their blood.⁷ However, patients with severe COVID-19 infection also have high levels of D-dimers, making this testing method unreliable. The additional difficulty of diagnosing blood clots in COVID-19 patients increases morbidity and mortality rates.

Does thrombophilia increase blood clotting in COVID-19 patients?

While a singular thrombophilia condition is unlikely to increase the risk of thrombosis in COVID-19 patients, there are cases in which patients experiencing thrombosis were later found to have multiple genetic thrombophilia disorders.⁸ However, another study indicates there is no significant difference in thrombosis incidence between patients with and without genetic thrombophilia.⁹ In a third study, the majority of patients with severe thrombophilia did not experience thrombosis during their COVID-19 infection, which may be due to adherence to a pre-existing treatment plan of anticoagulant drugs before and during their COVID-19 infection.¹⁰ Although most studies identify a weak correlation between thrombophilia and increased risk of thrombosis in COVID-19 patients, more research is required to understand the link between the two.

In terms of the significance of the above conclusion, one study suggests genes for thrombophilia should be identified in COVID-19 patients who possess other risk factors for COVID-19 complications.⁸ This will allow healthcare providers to better anticipate potential complications that patients may experience. Another study suggests that all COVID-19 patients with thrombophilia should be given preventative anticoagulant drugs to reduce the risk of thrombosis.⁹ Ultimately, further investigations are required for a definitive conclusion on the effect of thrombophilia on COVID-19 prognosis. 

Summary

Thrombosis is the formation of blood clots within blood vessels. This blocks blood flow, potentially leading to life-threatening conditions, including heart attacks and ischaemic stroke. Thrombophilia is a condition in which the risk of thrombosis is increased. It can be caused by genetic factors, as well as other medical conditions, medications and/or lifestyle choices. 

COVID-19, the infectious disease caused by the SARS-CoV-2 virus, also increases the risk of thrombosis. Although there is a weak correlation between thrombophilia and an increased risk of thrombosis in COVID-19 patients, more research is needed to completely understand the impact of thrombophilia on COVID-19 patients.