Overview

Thrombophilia, also known as hypercoagulability, is a condition characterised by an increased tendency for the blood to clot due to abnormalities in the clotting process. The clotting is referred to as thrombosis. This abnormality can lead to serious complications such as deep vein thrombosis (DVT) and pulmonary embolism (PE), which are potentially life-threatening. Thrombophilia can be inherited or acquired; in some cases, the causes may not be identified.¹

The identification and understanding of the clinical presentation of thrombophilia is critical for early diagnosis, effective management and prevention of complications. The recognition of symptoms, including leg swelling, pain or shortness of breath, can help initiate timely medical intervention.

Inherited thrombophilia affects up to 10% of the population. Acquired risk factors, such as obesity and hormonal therapy, are frequent in the community. The most defined heritable thrombophilias are Factor V Leiden, protein C (PC) deficiency, protein S (PS) deficiency, and antithrombin (AT) deficiency, which are associated with hypercoagulability.² Key acquired thrombophilias include the antiphospholipid syndrome (APS), paroxysmal nocturnal haemoglobinuria (PNH), myeloproliferative neoplasms (MPN) and the presence of a JAK2 mutation in the absence of an MPN phenotype. Pregnancy is a hypercoagulable state because of physiological changes in both the coagulation and fibrinolytic systems.³ The interaction between heritable and acquired thermophilias can increase the risk of thrombosis, for example, during pregnancy and the puerperium. As there is evidence that some thrombophilias may be associated with pregnancy failure and complications, testing for this purpose is included.⁴

Symptoms of thrombophilia

Thrombophilia often remains asymptomatic until a blood clot forms. The clinical manifestations depend on the location and size of the clot.​

Symptoms associated with venous thromboembolism (VTE)

Inherited thrombophilia is a hereditary predisposition to venous thromboembolism (VTE) and genetic defects, which include the lack of endogenous anticoagulants antithrombin, protein C, and protein S and gain-of-function polymorphisms in factor V (Factor V Leiden) and prothrombin ¹.  Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), represents a major health problem. 

The risk of any VTE in the general population is 0.1%–0.2% per year, and the risk increases with age. VTE is an important and preventable cause of morbidity and mortality, with a third of survivors experiencing long-term effects. Obesity is a well-known risk factor for VTE. The extent of the effects of obesity on VTE depends not only on total body fat but also on the distribution of adipose tissue (e.g., central obesity) and the interplay among risk factors for VTE, such as genetic mutations, and other risk factors.⁵

Deep vein thrombosis (DVT) is a blood clot that typically forms in deep veins within the legs; however can occur in the arms and the mesenteric and cerebral veins. It is a common venous thromboembolic (VTE) disorder with an incidence of 1.6 per 1000 annually. The most common symptoms include leg pain and swelling, redness and warm skin in the affected area. Approximately 30% of individuals have ongoing issues, including leg pain/swelling, recurrent skin breakdown, and ulcers, along with an increased risk of future DVT, even after treatment in some cases.⁶       

A pulmonary embolism (PE) occurs when a blood clot blocks a blood vessel in the lungs. This typically happens when a clot that originally formed in another part of the body, such as the leg or arm, travels through the bloodstream to the lungs. PE disrupts normal blood flow, reduces oxygen levels in the lungs, and increases pressure in the pulmonary arteries.⁷

This is a serious medical emergency that requires immediate treatment. If left untreated, a pulmonary embolism can lead to severe lung or heart damage and may be fatal. Alarmingly, around one-third of individuals with a pulmonary embolism do not survive because they are diagnosed too late or do not receive timely medical care.  

Symptoms of arterial thrombosis

Arterial thrombosis can present as an acute stroke, myocardial infarction, or both acute and chronic peripheral arterial disease. Renal arteries, mesenteric arteries, and retinal arteries are less affected.  In addition to acute management, secondary prevention focuses on reducing cardiovascular risk factors such as obesity, high cholesterol, diabetes, and high blood pressure and encouraging lifestyle modification such as stopping smoking.⁸

^{Figure 1: Anatomic sites of unexplained acute arterial thrombosis with citations for relevant comprehensive reviews.6-14  *Organ infarctions can occur due to arterial thrombosis, but also venous thrombosis, low flow states, and other causes. Determining if the end-organ infarction is caused by arterial thrombosis is a key step in determining further diagnosis and best management.9 Credit: May et al.,2021.}

Thrombophilia can increase the risk of stroke and arterial thrombosis, where blood clots block arteries supplying oxygen to the brain or other organs. A stroke occurs when a clot disrupts blood flow to the brain, leading to symptoms like sudden weakness, slurred speech, or vision loss. In younger adults, an unexplained stroke may indicate an underlying clotting disorder like antiphospholipid syndrome (APS). Arterial thrombosis can also cause heart attacks or limb ischemia (reduced blood supply to limbs). Blood thinners, lifestyle changes, and monitoring help manage risks in people with thrombophilia to prevent life-threatening complications.

Antiphospholipid syndrome (APS) is a condition where the immune system mistakenly produces antibodies that increase the risk of blood clots. This can cause pregnancy complications, including recurrent miscarriages, pre-eclampsia, stillbirth, and poor baby growth. APS affects the placenta by reducing blood flow, leading to pregnancy risks. A key protein, Annexin A5, helps prevent clotting, but APS reduces its levels, making blood clots more likely. Doctors diagnose APS through blood tests and may recommend aspirin or heparin to improve pregnancy outcomes. Early detection and treatment can help women with APS have safer pregnancies and reduce the risk of complications.¹⁰

Common complications of thrombophilia

Venous thromboembolism (VTE)

Recurrent episodes of DVT and PE are significant concerns in patients with venous thromboembolism (VTE). The National Institute for Health and Care Excellence (NICE) recommends a minimum of 3 months of anticoagulation therapy for confirmed VTE, regardless of whether it is provoked or unprovoked. For unprovoked VTE, extending anticoagulation beyond 3 months should be considered after evaluating the individual's risk of recurrence and bleeding. Some patients, such as those with active cancer or a known thrombophilia, may require extended or indefinite anticoagulation.¹¹

​Post-Thrombotic syndrome (PTS)

PTS is a chronic complication that can develop after DVT, characterised by symptoms such as leg pain, swelling, and, in severe cases, skin changes or ulcers. NICE guidelines advise against the routine use of elastic graduated compression stockings to prevent PTS or VTE recurrence following a DVT. Management strategies focus on early mobilisation and individualised care to alleviate symptoms and improve quality of life.¹²

Arterial thrombosis

Both ischemic stroke and heart attack (myocardial infarction) can lead to serious long-term health issues. Understanding these complications helps in managing risks and improving recovery.

Ischemic stroke complications

A stroke happens when a blood clot blocks an artery in the brain, cutting off oxygen. This can lead to lasting difficulties, such as trouble with movement, speech, memory, and even emotional changes like depression. Stroke survivors are also more likely to develop heart disease. Research shows that about one in three stroke patients without previous heart problems have signs of heart disease, and some may suffer a heart attack within a year ¹³.

Heart attack complications

A heart attack occurs when a clot blocks blood flow to the heart. This can weaken the heart, increasing the risk of heart failure (where the heart struggles to pump blood properly) or irregular heartbeats (arrhythmias), which can be life-threatening. Heart attack survivors are also at a higher risk of stroke, especially if their heart’s pumping ability is reduced ¹⁴ . 

Why are these conditions linked?

A heart attack can create clots that travel to the brain, causing a stroke. Likewise, a stroke can stress the heart, leading to complications. This cycle highlights the importance of lifestyle changes, medication, and regular check-ups to reduce risks ¹⁵. 

Summary

• Thrombophilia is a hidden but serious risk. Many people are unaware they have a clotting disorder until they experience a life-threatening event like deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, or heart attack. Early detection is crucial to prevent complications
• Pregnancy increases clotting risks – Women with thrombophilia are at higher risk of miscarriage, pre-eclampsia, stillbirth, and other pregnancy complications. Screening and preventive treatment can significantly improve outcomes
• Recurrent blood clots are common and dangerous. Without proper management, thrombophilia can lead to repeated DVT and PE, increasing the likelihood of long-term damage, disability, or death. Post-thrombotic syndrome (PTS) affects up to 30% of DVT survivors, causing chronic leg pain, swelling, and ulcers
• Acquired thrombophilia, like antiphospholipid syndrome (APS), is often overlooked – APS is a major cause of recurrent pregnancy loss and unexplained strokes, especially in younger adults, yet it is frequently underdiagnosed and untreated
• Lifestyle and medical management are key to prevention. Factors like obesity, smoking, immobility, and hormonal therapy increase clotting risks. Regular monitoring, blood thinners, and lifestyle changes can help prevent severe complications and improve quality of life