Introduction

Thrombophilia is a medical condition characterised by an increased tendency for blood to clot. This is also known as hypercoagulability. Clot formation is a vital part of the body’s defence mechanism to prevent excessive bleeding. However, in patients diagnosed with thrombophilia, clot formation is dysregulated, leading to a higher risk of venous thromboembolism (VTE). Thrombophilia can be broadly categorised into two main types: inherited (genetic/from parents) and acquired (arising due to external or physiological factors).

Differentiating between inherited and acquired thrombophilia is crucial for proper diagnosis, treatment planning, and long-term management. It plays a significant role in determining the risk of recurrence and identifying at-risk family members who may benefit from screening. Understanding the distinctions and classifications of thrombophilia not only aids clinicians in delivering personalised care but also helps patients make informed decisions regarding lifestyle, prevention, and therapy.

Inherited thrombophilia

Inherited thrombophilia refers to a genetic predisposition to develop abnormal blood clots. This may be attributed to inherited mutations or deficiencies in the body’s natural anticoagulant systems. These genetic abnormalities are passed down from parents to offspring. This can increase the risk of VTE, especially when combined with other risk factors (e.g. surgery, immobility, or pregnancy).

Common types and classifications

The common types of inherited thrombophilia include:

• Factor V Leiden mutation: The most common type of inherited thrombophilia, particularly in individuals of European descent. The mutation in the Factor V gene causes activated protein C resistance, leading to prolonged clotting activity
• Prothrombin G20210A mutation: The second most common type of inherited thrombophilia. The mutation in the Prothrombin gene causes elevated levels of prothrombin (Factor II), increasing the likelihood of clot formation
• Protein C deficiency: Protein C is a natural anticoagulant that inactivates Factors Va and VIIIa. Deficiency leads to uncontrolled clot formation
• Protein S deficiency: Protein S acts as a cofactor for Protein C; its deficiency reduces the effectiveness of the Protein C pathway
• Antithrombin III deficiency: Antithrombin inhibits several clotting factors, including thrombin and Factor Xa. Deficiency results in unchecked thrombin activity and clot propagation

Pathophysiology

Inherited thrombophilia involves genetic mutations that either enhance pro-coagulant activity or diminish the function of natural anticoagulants. This imbalance facilitates clot formation, especially in situations that promote stasis or vascular injury.

Inheritance patterns

Most inherited thrombophilias follow an autosomal dominant inheritance pattern. This means that a single copy of the defective gene can increase the risk of thrombosis. However, homozygous individuals or those with compound heterozygosity (e.g., having both Factor V Leiden and Prothrombin mutations) often have a higher risk of developing inherited thrombophilia and may experience earlier or more severe thrombotic events.

Diagnosis

Diagnosis for inherited thrombophilia involves laboratory testing. This includes genetic testing for Factor V Leiden and Prothrombin mutations, as well as functional assays to measure levels of Protein C, Protein S, and Antithrombin III.

Testing is recommended for individuals with:

• Unprovoked or recurrent VTE
• A family history of thrombosis
• Thrombosis at a young age or in unusual sites (e.g., cerebral, mesenteric veins)

Clinical significance

Not all individuals with inherited thrombophilia develop blood clots. However, they may increase in the presence of additional risk factors, such as surgery, pregnancy, oral contraceptive use, hormone replacement therapy, or prolonged immobility. Identifying inherited thrombophilia can guide preventive measures, decisions regarding anticoagulation treatment, and inform family members about potential risks and testing.

Acquired thrombophilia

Acquired thrombophilia refers to a hypercoagulable state that develops due to external factors or underlying medical conditions. Unlike inherited forms, acquired thrombophilia can arise at any point during a person’s life and may be temporary or persistent, depending on the cause.

Common types and classifications

The common types of acquired thrombophilia include:

• Antiphospholipid syndrome (APS)
  • An autoimmune disorder characterised by the presence of antiphospholipid antibodies (aPL), including lupus anticoagulant, anticardiolipin antibodies, and anti-β2 glycoprotein I antibodies
  • Leads to both venous and arterial thrombosis and pregnancy complications (e.g., recurrent miscarriages, preeclampsia)
  • It can occur as a primary disorder or secondary to autoimmune diseases (e.g., systemic lupus erythematosus).
• Malignancy-associated thrombophilia
  • Cancer increases thrombotic risk through tumour-related procoagulant release, inflammation, and compression of vessels
  • Common in pancreatic, lung, gastric, and brain cancers
  • Risk further increases with chemotherapy and immobilisation
• Hormone-related thrombophilia
  • Use of oral contraceptives, hormone replacement therapy (HRT), or selective estrogen receptor modulators (e.g., tamoxifen) can increase clotting risk
  • Estrogen promotes coagulation factor production and reduces natural anticoagulant levels
• Pregnancy and postpartum period
  • Natural hypercoagulable state to prevent postpartum bleeding
  • Increased levels of clotting factors, reduced fibrinolysis, and venous stasis
  • Risk is highest in the postpartum period
• Heparin-induced thrombocytopenia (HIT)
  • Immune-mediated adverse reaction to heparin therapy
  • Antibodies form against platelet factor 4 (PF4)-heparin complexes, which activate platelets and lead to paradoxical thrombosis despite low platelet counts
• Prolonged immobility, surgery, trauma
  • Physical inactivity slows venous return, predisposing to clot formation
  • Major surgeries (especially orthopaedic) and trauma increase clotting factor release and vessel wall injury

Pathophysiology

Acquired thrombophilia involves processes such as inflammation, immune system dysregulation, endothelial injury, and activation of the coagulation cascade. These factors disrupt the normal balance between clot formation and breakdown, leading to a higher risk of thrombus formation.

Diagnosis

Diagnosis for acquired thrombophilia is based on clinical history and laboratory tests.

• Testing for antiphospholipid antibodies is essential for persistent cases like APS
• In cancer-related thrombophilia, diagnosis focuses on identifying the malignancy and assessing thrombotic risk
• HIT diagnosis includes platelet count monitoring, clinical scoring systems (e.g., 4Ts score), and confirmatory tests (e.g., ELISA, serotonin release assay)

Clinical significance

Acquired thrombophilias often pose a higher thrombotic risk than inherited forms, especially when associated with systemic illnesses like cancer or autoimmune disease. These conditions may necessitate long-term or indefinite anticoagulation, particularly in APS or ongoing malignancy. Timely diagnosis is crucial to prevent and manage thrombotic risk.

Management

• Anticoagulation therapy tailored to the underlying cause (e.g., low molecular weight heparin in cancer, warfarin or direct oral anticoagulants in APS)
• Removal or treatment of the triggering factor (e.g., discontinuation of hormone therapy, cancer treatment)
• Preventive strategies in high-risk situations (e.g., thromboprophylaxis during hospitalisation or surgery)

Key differences between inherited and acquired thrombophilia

Understanding the distinctions between inherited and acquired thrombophilia is critical for accurate diagnosis, risk assessment, and clinical management. Below is a comparison of the key differences across various aspects:

Clinical implications

• Inherited thrombophilia is diagnosed by evaluating unexplained or recurrent VTE in patients with a family history
• Acquired thrombophilia has more severe or recurrent presentations, particularly in conditions like APS or malignancy-associated thrombosis
• Management strategies differ, with targeted treatment of underlying causes playing a larger role in acquired cases, whereas inherited thrombophilia requires risk mitigation during high-risk situations

Summary

• Thrombophilia, whether inherited or acquired, is a significant risk factor for venous and sometimes arterial thrombotic events
• Understanding their differences is crucial for accurate diagnosis, risk stratification, and personalised clinical management
• Inherited thrombophilias are lifelong genetic conditions that often remain asymptomatic until triggered by external factors
• Acquired thrombophilias develop in response to underlying medical conditions or environmental influences and often pose a more immediate and serious thrombotic risk
• Early recognition, appropriate testing, and targeted management strategies—ranging from short-term anticoagulation to lifelong therapy—can significantly reduce morbidity and mortality
• Individualised patient education and preventive measures are essential to minimise thrombotic risk and improve long-term outcomes
• As our understanding continues to evolve, ongoing research and updated clinical guidelines will enhance our ability to deliver effective and personalised care to patients with thrombophilia