What are the causes of unprovoked pulmonary embolism?

From the Guidelines

Unprovoked pulmonary embolism is primarily caused by inherited or acquired thrombophilia disorders, occult cancer, and other factors such as chronic inflammatory conditions, certain medications, and prolonged immobility. The causes of unprovoked pulmonary embolism can be complex and multifactorial. According to the 2016 guidance from the SSC of ISTH 1, unprovoked VTE is defined as having no provoking risk factor, either transient or persistent. Some of the key causes of unprovoked pulmonary embolism include:

• Inherited or acquired thrombophilia disorders, such as Factor V Leiden mutation, prothrombin gene mutation, protein C or S deficiency, antithrombin deficiency, and antiphospholipid syndrome
• Occult cancer, particularly cancers of the pancreas, lung, and blood
• Chronic inflammatory conditions, such as inflammatory bowel disease
• Certain medications, such as hormone replacement therapy or oral contraceptives
• Prolonged immobility that may not be immediately apparent
• Age-related changes in blood vessels and clotting factors, which increase risk in older adults It is essential to note that idiopathic cases can occur when no specific cause can be identified despite thorough investigation. Patients with unprovoked pulmonary embolism typically require anticoagulation therapy for at least 3-6 months, often with direct oral anticoagulants like apixaban (5mg twice daily) or rivaroxaban (20mg daily with food), and may need extended or lifelong treatment depending on risk factors, as suggested by the 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism 1. Comprehensive testing for underlying thrombophilia and occult malignancy is often recommended, especially in younger patients or those with recurrent events.

From the FDA Drug Label

Approximately 90% of patients enrolled in AMPLIFY had an unprovoked DVT or PE at baseline. The remaining 10% of patients with a provoked DVT or PE were required to have an additional ongoing risk factor in order to be randomized, which included previous episode of DVT or PE, immobilization, history of cancer, active cancer, and known prothrombotic genotype The causes of unprovoked pulmonary embolism are not explicitly stated in the provided text, but it mentions that unprovoked DVT or PE were present in approximately 90% of patients enrolled in the AMPLIFY study.

• Some possible causes or risk factors associated with provoked DVT or PE include:
  • Previous episode of DVT or PE
  • Immobilization
  • History of cancer
  • Active cancer
  • Known prothrombotic genotype 2

From the Research

Causes of Unprovoked Pulmonary Embolism

The causes of unprovoked pulmonary embolism can be attributed to various factors, including:

• Genetic thrombophilic factors, such as factor V Leiden, prothrombin gene mutation, and methylentetrahydrofolate reductase (MTHFR) genetic variant 3
• Antiphospholipid syndrome (APS), which can increase the risk of recurrent pulmonary embolism despite inferior vena cava (IVC) filter placement 4, 5
• Hereditary thromboembolism, which can be caused by genetic mutations such as 4G/4G polymorphism of the PAI-1 gene and C677T/A1298C polymorphism of the MTHFR gene 6
• Other genetic factors, such as protein C, protein S, and antithrombin III deficiencies, which can increase the risk of thrombosis and pulmonary embolism 7

Genetic Predisposition

Genetic predisposition plays a significant role in the development of unprovoked pulmonary embolism, with certain genetic variants increasing the risk of early onset and recurrent incidents. For example:

• Factor V Leiden (FVL) is found in 23.5% of patients with pulmonary embolism, compared to 7.1% of controls 3
• The PlA2 polymorphism in platelet glycoprotein IIb/IIIa is found in 35.3% of patients with pulmonary embolism, compared to 14.3% of controls 3
• Patients with recurrent pulmonary embolism have a high prevalence of genetic factors, with 70.4% of patients having at least one genetic variant 3

Hypercoagulable States

Hypercoagulable states, such as antiphospholipid syndrome, can increase the risk of unprovoked pulmonary embolism. These states can be caused by genetic or acquired factors, and can increase the risk of thrombosis and pulmonary embolism 4, 5