Introduction

Pulmonary embolism is a type of venous thromboembolism (VTE)—a life-threatening occurs when blood clots form in vessels outside the lungs (mostly in the legs or arms) and break off, forming an embolus. The embolus travels and obstructs the pulmonary arteries.¹

This disrupts blood flow in the circulation and can lead to fatal complications.¹ It is also one of the leading causes of mortality, morbidity and hospitalisation worldwide, with about 100,000 to 200,000 deaths in the United States each year and 8.3 (8.1–8.5) per 100,000 people in the UK.^2,3

People who have a pulmonary embolism can show a varying number of symptoms and develop problems that need to be identified and treated quickly. Some common but nonspecific symptoms are shortness of breath, chest pain, cough and syncope.¹ Conditions like thrombophilia, being immobile for a long time, surgery, and cancer are all things that can put you at risk for PE.

Our body’s ability to form blood clots from a series of events known as the clotting system. This enables us to stop bleeding after an injury and quicken recovery and wound healing.⁴ A problem with the clotting system, which causes the increased likelihood of forming a thrombus in blood vessels, is a group of disorders known as thrombophilia.⁵ It can be acquired or genetic. Individuals with thrombophilic disorders are more prone to developing a PE, which makes risk assessment and timely management very important.

This article provides a simple and comprehensive guide on the risk assessment and management of PE in individuals with thrombophilia.

How does PE develop in individuals with Thrombophilia?

The relationship between thrombophilia and pulmonary embolism is caused by a complex interplay between an individual's genes, environmental factors and the way blood clots.⁶ Since thrombophilia can be acquired or inherited, the way it causes a PE depends on the type of thrombophilia a person has. Let's break this down:

Hereditary thrombophilia and PE

Thrombophilia that runs in families is often caused by the lack of natural blood thinners like antithrombin III, protein C, and protein S, or by genetic changes like factor V Leiden, hyperhomocysteinemia and prothrombin G20210A.^7,8,9 These changes and defects disrupt different areas involved in the blood clotting sequence and hence may lead to a PE.¹⁰ 

Acquired thrombophilia and PE 

Acquired thrombophilia arises from environmental or physiological factors. Antiphospholipid syndrome (APS), heparin-induced thrombocytopenia (HIT), and situations that cause a lack of active protein C, like using oral contraceptives, being pregnant, or having cancer, can cause acquired thrombophilia that can lead to a hypercoagulable state.¹¹ In the general population, APS is said to cause lots of thrombus formation and is the most common type of acquired thrombophilia.¹²

Although acute PE is mainly caused by both environmental and acquired risks like trauma and other comorbidities, it is noteworthy that about 20-50% of unexplained cases of sudden PE can be explained by a genetic tendency to clot easily.¹³

What are the methods of risk assessment for thrombophilia-related PE?

Many genetic, clinical, and serologic tests can be used to determine the risk of thrombophilia-related pulmonary embolism (PE). PE can be fatal, with a 90-day fatality rate of 15-20%.¹⁴ Therefore, risk assessment is paramount, and we will simplify it under three broad umbrellas:

Identifying risk factors

A thorough history of the presenting person is required to identify risk factors.¹³ In individuals with thrombophilia, one of the most recognised risks for PE is the existence of at least one component of Virchow's triad.¹⁵ This means your history has to be taken at your healthcare facility to determine if you are susceptible to the formation of clots as described in the triad.

Your doctor will want to know if you have had:^16,17

• Personal and family history of clotting disorders
• Lifestyle factors like smoking, obesity, and a sedentary daily routine
• Previous VTE
• Hospitalisation for heart failure/atrial fibrillation in the last 3 months
• Pregnancy
• Cancer
• Autoimmune disorders 

The risk factors, either inherited or acquired, can each be classified into weak, moderate, and strong.¹⁵

Risk assessment tools

Clinicians can use several scoring systems and laboratory tests to assign people into specific risk groups.

Risk scores

The most common are the Wells or Geneva scoring. In the Wells scoring system, a score of ≤4/>4 indicates a low or high chance of PE, respectively; see Wells score table. While in the Geneva score table, a score of ≤5/>5 indicates a low or high chance of PE, respectively.²

Besides, PE Rule-Out Criteria (PERC) can help rule out PE in low-risk emergency department patients. The mentioned scoring tools and PERC are only used if you are stable presenting in the emergency room. They may not be reliable for inpatients and the critically ill.²

Another risk-assessing tool is the European Society of Cardiology (ESC) Pulmonary Embolism Severity Risk Score (PESI/sPESI). It is used to divide PE patients in order of severity, from very low to very high risk (1-5). If you have a PESI score of 1-2 or sPESI <1, this is very low and can be managed in the outpatient setting.¹⁸ The PESI score of 3-5 or sPESI >1 is very high and will require more evaluation.

Laboratory evaluations

Serologic factors

Similarly, only one blood marker can't tell you about haemodynamic instability in PE or suspected PE; it needs to be looked at along with your medical history, initial conditions, physical exam, and imaging results.¹⁹

Some important non-specific markers are plasma troponin (T or I), B-type natriuretic peptide (BNP) and N-terminal (NT)-BNP for assessing heart muscle injury, right ventricular dysfunction due to muscle stretch and increased pressure in the heart caused by a PE.¹⁷ 

Another blood marker is D-dimer (a substance formed from broken pieces of a blood clot). It can rule out a PE or DVT in people with low or intermediate clinical risk. But, increased D-dimer level alone is not enough to confirm PE because it can also be increased in other conditions like cancer, infections, and inflammation.²⁰

These markers can give your physician an idea of how your body responds and may identify low-risk PE events and individuals at a higher risk for PE.

Imaging techniques/modalities

Various imaging techniques may be employed for risk assessment that depend on your symptoms and the provider's evaluation. Some include:²⁰

• Electrocardiography (ECG) is quick and may be very suggestive of a PE, but can only reinforce your providers’ clinical suspicion
• Chest X-ray is important in ruling out other causes of acute dyspnea and chest pain in assessing the risk of a PE
• CT pulmonary angiography (CTPA) is the most preferred diagnostic tool if you are suspected of having PE. It can also determine how severe the PE is by assessing the heart’s right ventricle (RV) widening, which is linked to a higher risk of a bad outcome
• Echocardiography is currently thought to be the best way to check for acute PE. In addition to a physical exam, it is also important for emergency risk evaluation to assess the heart’s chambers
• Ventilation-Perfusion V/Q Scintigraphy is useful for ruling out whether there is a presence of low or intermediate risk of PE

Genetic testing and screening

Testing should be done at the right time so that results aren't affected by severe PE or anticoagulation use. This is because clotting may lower protein S and antithrombin levels, making them hard to interpret.¹⁵ So take the test:²¹

• outside the acute PE window, which is 3 months after you have taken your anticoagulant drug
• when you can stop using blood thinners
• 48 hours after direct oral anticoagulants (DOACs) and two weeks before vitamin K antagonists

For some PE cases, routine testing for thrombophilia is NOT a good idea, like when one is young, the clot is in an odd site, the individual is pregnant, or worried about the risk to their family.¹⁵

Please make decisions based on your preference, the clinical situation, physician advice and the risk of recurrence.

How are individuals with thrombophilia diagnosed with a PE?

Different methods are used in a certain way to diagnose PE. 

A quick evaluation is very important, especially in cases of severe PE that show signs of shock or unstable blood flow.²² It is advised to follow a standardised testing route as it lowers the risk of complications. To do this, individuals must be put into groups based on how likely they are to have a PE.

The diagnosis for suspected PE in patients with thrombophilia involves the combination of clinical workup, serologic tests, genetic evaluation, and imaging like CTPAs, V/Q scans and supplementary imaging techniques.¹⁵

What are the management strategies?

Because of PE’s complexity and the need to be individualised for treatment, a multidisciplinary team of clinicians with expertise in PE diagnosis, medical, surgical, and interventional management has emerged to improve patient care.²³

This is called the PERT, pulmonary embolism response team, and every healthcare facility should have one. Using the PERT treatment algorithm table, PE management is as follows:²³

Acute management of PE

Initiation of anticoagulation therapy 

Heparin, also known as unfractionated or low molecular weight heparin (UFH), is used to stop bleeding right away, especially in high-risk situations. 

Direct Oral Anticoagulants (DOACs) are preferred in low-risk PE because they are fast acting, have a specific dosage, and don't need as much monitoring. 

Considerations for thrombolytic therapy in severe cases

1. Systemic Thrombolysis (ST) - for high-risk PE with hemodynamic instability (e.g., cardiac arrest, severe hypotension) to dissolve clots rapidly
2. Reduced-Dose ST - for those with a reason to avoid the full-dose thrombolysis or those with intermediate-high-risk PE showing signs of deterioration
3. Catheter-Directed Thrombolysis (CDL) - individuals with high risk of bleeding or intermediate-high-risk PE with right heart failure
4. Surgical Embolectomy (SPE) - this is like a last resort for cases where thrombolysis is contraindicated or has failed 

Supportive care

When an individual is critical, oxygen therapy, vasopressors, and ECMO may be considered for haemodynamic support.

Long-term management and secondary prevention

The duration of anticoagulation treatment is based on risk assessment:

• Provoked PE (e.g., surgery, trauma)- anticoagulation therapy is prescribed for about 3–6 months
• Unprovoked PE—Indefinite anticoagulation is mostly used due to the high risk of recurrence
• Recurrent PE or persistent risk factors — Incorporated long-term or indefinite anticoagulation

Summary

These are the takeaways:

• Risk assessment is crucial for the treatment and management of thrombophilia-related PE
• Genetic thrombophilia is more likely to cause PE 
• Risk scores and ESC guidelines should be sought by physicians for proper diagnosis and effective care
• Various treatments are available for PE, like anticoagulants alone, catheter-directed thrombolysis, systemic thrombolysis, catheter embolectomy, surgical embolectomy, and/or external cardiac support devices
• Management needs the incorporation of a multidisciplinary PERT team for individualised care