Introduction

Thrombophilia is a serious medical condition in which your body forms blood clots more than the normal amount and develops thrombosis in the veins and arteries. This abnormal clotting increases the risk of developing deep vein thrombosis and pulmonary embolism. It is important to break down the clots with anticoagulants such as heparin because if left untreated, they can lead to other serious complications such as ischemic stroke, heart attack, or recurrent miscarriage in pregnancy. 

Thrombophilia is likely to be diagnosed in individuals who suffer from recurrent thrombosis or have inherited mutated genes. The drugs used are anticoagulants such as warfarin, heparin, and direct oral anticoagulants. They are mostly safe to use, but they can cause some side effects such as thrombocytopenia and haemorrhage.

Thrombophilia

When you accidentally cut your finger with a knife or get a paper cut, you start to bleed instantly. After a few minutes, the bleeding stops, and the area is now red and slightly painful. This bleeding is stopped by the formation of clots—a natural life-saving process that prevents the body from losing too much blood. But what happens when there is no bleeding and your body continues to make excessive clots inside the vessels? Well, you are likely to have thrombophilia, a condition characterised by abnormal and excessive blood clots (thrombosis) in the arteries and veins.¹

These clot formations inside the arteries and veins cause blockage in the vessels, which interrupts the normal blood circulation around the body. The vessels become narrow, decreasing the blood flow to the affected area and increasing the peripheral resistance, which in turn, increases blood pressure, leading to complications such as angina or stroke.²

Thrombophilia may develop deep venous thrombosis (DVT), pulmonary embolism (PE), and venous thromboembolism. They are all serious medical conditions that must be treated urgently.

Causes of thrombophilia

Primary (inherited) thrombophilia

• Factor V Leiden mutation: Factor V gene is involved in the clotting process; mutation in this gene causes excessively abnormal clotting³
• Mutation in Prothrombin G20210A: Prothrombin is a protein also involved in the clotting process in the final stage of the clotting cascade

Secondary (acquired) thrombophilia

Other causes may include: 

• Diet
• Obesity
• Stress 
• Tobacco usage
• Cancer
• Atherosclerosis
• Heparin-induced thrombocytopenia 
• Antiphospholipid syndrome

Indications for anticoagulant therapy

Anticoagulants are a class of drugs that prevent blood clot formation in vessels. They prolong the clotting time and reduce the risk of developing serious medical conditions. The indications for using anticoagulants are as follows.

Deep vein thrombosis (DVT)

When a blood clot is formed in the deep veins of the body, particularly the veins of the calf or legs, it is called deep vein thrombosis. It may occur due to an injury to the hip or legs, or damage within the veins leading to the formation of thrombosis. It is a serious medical condition because the blood clot may break down and settle in other parts of the body and form thromboembolism.⁴

Signs and symptoms 

• Pain in the legs, calves, or the affected area
• Swelling and redness
• Firm or thickened vein
• Distended vein
• Numbness or tingling

Pulmonary embolism (PE)

It is a more serious and life-threatening condition where the blood clot developed in DVT breaks down and the embolus (small pieces of clot) move through the blood vessels and get stuck in the lungs, forming an embolism called pulmonary embolism. It blocks the artery in the lungs and stops the blood flow either partially or fully. It is a hazardous situation as it can stop the oxygenation of the blood and lead to instant breathing problems and chest pain.

Signs and symptoms

• Sudden chest pain
• Inability to breathe
• Dizziness
• Fainting
• Palpitations
• Sudden anxiety
• Coughing up blood
• Rapid heartbeat
• Low blood pressure

Stroke

A stroke is a sudden interruption of the blood flow to the brain, called an Ischemic stroke. This may also occur due to the formation of a clot, which may be an embolus that has travelled from the legs or calf. It is a serious condition and may be life-threatening if not promptly treated.

Signs and symptoms

• Confusion
• Troubled speaking
• Disorganised thoughts
• Severe headache
• Inability to walk
• Face paralysis

Commonly used anticoagulant drugs

Vitamin K antagonists, direct oral anticoagulants (factor Xa and direct thrombin inhibitors), and heparin are used as anticoagulants. Below is an image that shows the coagulation pathway and how these drugs stop this pathway.

Vitamin K antagonists (VKAs)

Vitamin K antagonists, including warfarin, acenocoumarol, and phenprocoumon, are used in the treatment of thromboembolic disorders. These are anticoagulants that prevent the formation of blood clots and slow the growth of existing ones. Vitamin K is a crucial substance taking part in the coagulation cascade; therefore, inhibition of it can result in a decrease in blood clotting.

Dosage

The dose of warfarin varies from individual to individual due to differences in BMI, body index, muscle mass, age, and gender, so a physician should be consulted.

You first need a blood test to determine INR, which shows how the blood clots. Depending on this result, the doctor prescribes the medicine along with directions. Venous thromboembolism: The dose must be adjusted in such a way as to achieve 2.5 INR.⁵

Side effects of warfarin

Some side effects associated with warfarin include:

• Excessive bleeding
• Bloody gums
• Blood in urine
• Hematemesis
• Severe bruising
• Severe chest pain and difficulty in breathing
• Warfarin-induced skin necrosis

Direct oral anticoagulants

Direct oral anticoagulants (DOACs) are newer alternatives to warfarin as they have a high safety profile, require less monitoring, less frequent doses, and a faster onset of action. They reduce the complications associated with thrombophilia and inhibit or slow the clot formation. There are two classes of direct oral anticoagulants:⁶

Direct factor Xa inhibitors

Factor Xa is a crucial protease protein, which plays a huge role in the coagulation cascade pathway as it converts prothrombin to thrombin, which converts fibrinogen to fibrin and forms clots (shown in the illustration provided above). The inhibition of factor Xa prevents the formation of blood clots and treats thromboembolism. The drugs used for this are 

• Rivaroxaban
• Apixaban
• Edoxaban

Direct thrombin inhibitors

Thrombin is also a crucial protein that activates fibrinogen to fibrin and forms blood clots. This class of DOAC directly acts on thrombin, thrombin stops its function. Without thrombin, blood clots cannot be formed. The commercially available direct oral anticoagulants are

• Dabigatran
• Ximelagatran

Side effects of DOACs

• Increased risk of bleeding
• Abdominal pain
• Heartburn
• Nausea
• Rash
• Anemia
• Intracranial haemorrhage (very rare)

Heparin

Low molecular weight heparin is the choice of drug for treating thrombophilia, especially in cases of pregnancy and obesity. It works as a blood thinner and blocks the clot formation by inhibiting the clotting factors IIa and Xa instantly after administration. It has a short half-life, so it may require frequent doses.

Dose 

The dose for heparin is determined based on body weight. It may be administered through the intravenous or subcutaneous route, depending on the condition. In toxicity, an antidote, protamine, can be used to reverse the action.⁸

Safe in pregnancy

Heparin is safe in pregnancy and a preferred option to warfarin because heparin does not cross the placental barrier, so it does not harm the fetus, ensuring protection to the fetus. However, it is crucial to ensure proper monitoring and look out for any side effects.

Caution

Before initiation of heparin, you must inform your doctor if you are taking aspirin, clopidogrel, or any NSAIDS because if you take heparin along with these medications, you are at severe risk for heavy bleeding due to their blood-thinning properties.⁷

Side effects of heparin

• Heparin-Induced Thrombocytopenia (HIT): In rare cases, heparin can induce an immune response that results in the production of antibodies, causing thrombocytopenia and paradoxical thrombosis. It is quite intriguing that heparin, which prevents clot formation, may accidentally cause more clot formation and put patients suffering from DVT and PE in a life-threatening condition.
• Loss of bone strength and weakness
• Elevated liver enzymes
• Increased risk of bleeding (most severe)
• Headache
• Easy bruising

Summary

Thrombophilia is a medical condition where the body tends to abnormally form blood clots (thrombosis) excessively. It is a defence mechanism against cuts and bruises to prevent blood loss, but excessive clotting can disrupt the normal blood circulation throughout the body. Thrombosis in the calves or legs can cause deep vein thrombosis, and the clots formed at the lower extremities may break into smaller pieces and travel to the lungs (pulmonary embolism) and brain (stroke), requiring urgent medical attention.

Luckily, they can be treated and managed with anticoagulants, including vitamin K antagonists such as warfarin, direct oral anticoagulants such as dabigatran and apixaban, and heparin. These medications prevent the formation and facilitate the breakdown of blood clots, ensuring proper blood circulation. Pregnant women can take heparin as it is considered safe; however, you must consult a physician or local pharmacist before administration.

Excessive bleeding is the most common side effect is common among all the anticoagulants. It is advised to consult with your doctor and describe your medical history, condition, and family history to the doctor before administering the medications. Heparin is considered safe; however, it is advised to consult a physician or local pharmacist before administration.