Pulmonary Embolism

Acquired MONDO:0005279 Pathograph 22 Show in embeddings browser pulmonary artery disease venous thromboembolism

Acute obstruction of the pulmonary arterial circulation by embolic material, in the great majority of cases a thrombus that formed in the deep veins and then dislodged. The organising fact of the disease is that the embolus is not what kills. Death in the first hours comes from the right ventricle, which is a thin-walled chamber built for a low-pressure circuit and has no reserve for an afterload that appears in minutes. Everything clinically decisive about acute pulmonary embolism follows from that: severity tracks right ventricular function rather than clot burden, risk stratification is built on right ventricular imaging and myocardial biomarkers rather than on the size of the filling defect, and reperfusion is offered to the patients whose right ventricle is failing rather than to those with the most extensive disease. A second consequence of the anatomy runs the other way. The lung is supplied twice, by the pulmonary and the bronchial arteries, so occluding a pulmonary artery usually does not infarct the tissue it supplies. That is the opposite of what happens in the coronary or cerebral circulation, and it is why infarction is the wrong default model for this disease even though the word survives in its older names.

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10
Pathophys.
13
Phenotypes
3
Gaps
22
Pathograph
5
Genes
9
Medical Actions
3
Subtypes
4
Differentials
1
Models
1
Deep Research
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Classifications

Harrison's Part
CARDIOVASCULAR
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Subtypes

3
High-risk pulmonary embolism
Pulmonary embolism with haemodynamic instability. This is the stratum in which right ventricular failure has already progressed to systemic hypotension or arrest, and the one in which reperfusion is offered without further stratification. It is defined by the patient's circulation rather than by the anatomy of the clot.
Intermediate-risk pulmonary embolism
Normotensive pulmonary embolism with imaging evidence of right ventricular dysfunction and with myocardial biomarker elevation. Mechanistically this is the interesting stratum, because the right ventricle is demonstrably injured while the systemic circulation is still being maintained. It is the population in which fibrinolysis was formally tested and found to trade prevented decompensation for bleeding.
Low-risk pulmonary embolism
Normotensive pulmonary embolism without right ventricular dysfunction or biomarker elevation. Anticoagulation alone, and increasingly outpatient management, on the reasoning that the mechanism which causes early death is absent.
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Discussions and Knowledge Gaps

3
Why do some deep venous thrombi embolise while most do not, and can that propensity be predicted or modified?
KNOWLEDGE GAP OPEN what_makes_a_thrombus_embolise
Attached to
pathophysiology#Embolization to the pulmonary arterial tree
Every treatment in this disease acts either on thrombus formation or on the consequences of an embolus that has already lodged. Nothing acts on embolisation itself, and the step is treated clinically as a stochastic event. There is evidence that it is not purely stochastic, since two inherited thrombophilias with comparable effects on thrombosis risk are distributed differently between embolic and non-embolic presentations, which implies thrombus properties or location influence the propensity. What those determinants are is not established, and the model systems that could address it are precisely the ones that fail, since rodent venous thrombosis models do not embolise and the porcine models that reproduce the haemodynamics deliver emboli directly and so bypass the question.
Proposed experiments
Thrombus composition and embolic propensity
exp_embolic_propensity_thrombus_composition
Compare the composition, age, and anatomical origin of retrieved thrombi from patients undergoing mechanical thrombectomy for pulmonary embolism against thrombi retrieved or imaged in patients with deep vein thrombosis that did not embolise, testing whether fibrin content, platelet content, or degree of organisation predicts embolisation.
Show evidence (1 reference)
PMID:11583312 SUPPORT Human Clinical
"we also confirmed that the frequency of factor V Leiden was lower in patients with pulmonary embolism than in patients with deep vein thrombosis without PE (odds ratio 0.69)."
Establishes that embolic propensity is not a simple function of thrombotic tendency, which is what makes this a gap rather than an already-answered question.
Should thrombophilia risk be assessed as a polygenic quantity rather than as carrier status for a small number of named variants?
OPEN QUESTION OPEN polygenic_background_modifies_monogenic_thrombophilia
Attached to
pathophysiology#Prothrombotic venous context
Thrombophilia testing in practice asks whether a patient carries one of a handful of variants. A large genome-wide meta-analysis found that the extremes of a polygenic score reach the risk conferred by those variants, and, more consequentially, that carriers of the classical variants who sit in the low tail of the polygenic distribution have risk indistinguishable from the general population. If that is confirmed prospectively it means carrier status alone is not the right unit of risk, and that some patients currently counselled as thrombophilic are not. The open question is whether this changes management decisions, principally the duration of anticoagulation, rather than merely improving risk estimation.
Show evidence (2 references)
PMID:36658437 SUPPORT Human Clinical
"We also document that F2 and F5 mutation carriers in the bottom 10% of the PRS distribution had a risk similar to that of the general population."
This is the specific finding that makes carrier status an incomplete description of risk, and therefore the basis of the question.
PMID:36658437 SUPPORT Human Clinical
"Individuals within the top 0.1% of PRS distribution had a VTE risk similar to homozygous or compound heterozygous carriers of the variants G20210A"
Establishes the other half of the argument, that common-variant background alone can reach monogenic-equivalent risk.
Which patients with a strained but compensating right ventricle should have the obstruction removed?
CONTROVERSY OPEN reperfusion_in_intermediate_risk_disease
Attached to
pathophysiology#Right ventricular afterload mismatch and dilation pathophysiology#Ventricular interdependence and impaired left ventricular filling
The intermediate-risk stratum is defined by demonstrable right ventricular injury without systemic hypotension, so by the mechanistic account in this entry it is the group in which intervening before the cascade becomes self-reinforcing should pay off most. The randomised test of systemic fibrinolysis in exactly this group found the expected benefit and an offsetting harm, leaving no net mortality difference. Catheter-directed approaches are proposed as the way to get the mechanical benefit without the systemic bleeding, and the haemodynamic evidence that they reverse ventricular interdependence is encouraging, but it comes from small uncontrolled series. The controversy is therefore not about the mechanism, which is well supported, but about whether any currently available way of acting on it improves outcomes.
Proposed experiments
Randomised outcome trial of catheter-directed reperfusion
exp_catheter_reperfusion_randomised_outcome
Randomise normotensive patients with right ventricular dysfunction and biomarker elevation to catheter-directed reperfusion plus anticoagulation versus anticoagulation alone, powered for death or haemodynamic decompensation with bleeding as a co-primary safety outcome, to test whether the mechanical benefit demonstrated haemodynamically translates into outcome benefit without the bleeding cost of systemic lysis.
Show evidence (1 reference)
PMID:24716681 SUPPORT Human Clinical
"By day 30, a total of 12 patients (2.4%) in the tenecteplase group and 16 patients (3.2%) in the placebo group had died (P=0.42)."
Shows the absence of a mortality difference at thirty days despite the reduction in haemodynamic decompensation, which is the core of the controversy.
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Pathophysiology

10
Prothrombotic venous context
Stasis, endothelial injury, and a hypercoagulable state, singly or together, create the conditions in which a venous thrombus forms. In pulmonary embolism these are usually acquired and transient, such as surgery, immobilisation, pregnancy, oestrogen exposure, or malignancy, and they are frequently layered on an inherited thrombophilic background. The node is placed first because it is the only part of the causal chain that prophylaxis can act on, and because it is what distinguishes a provoked from an unprovoked event, which in turn determines how long anticoagulation continues.
Downstream
Deep venous thrombus formation The prothrombotic conditions are what permit a thrombus to nucleate and propagate rather than being cleared.
Deep venous thrombus formation
Platelet adhesion and coagulation-cascade activation build a fibrin-platelet thrombus, most often beginning in a valve pocket of a lower-limb or pelvic deep vein. This node is the disease of deep vein thrombosis, and pulmonary embolism only becomes a separate clinical entity at the next step. Curating it here rather than treating it as an external precondition is deliberate, because anticoagulation acts on this node and not on any node downstream of it.
platelet CL:0000233 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves platelet (CL:0000233). CL:0000233 is a cell type from the Cell Ontology. endothelial cell CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endothelial cell (CL:0000115). CL:0000115 is a cell type from the Cell Ontology.
blood coagulation, fibrin clot formation GO:0072378 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased blood coagulation, fibrin clot formation (GO:0072378). GO:0072378 is a biological process from the Gene Ontology. ↑ INCREASED regulation of blood coagulation GO:0030193 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased regulation of blood coagulation (GO:0030193). GO:0030193 is a biological process from the Gene Ontology. ↓ DECREASED
deep vein UBERON:0035552 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in deep vein (UBERON:0035552). UBERON:0035552 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Embolization to the pulmonary arterial tree A formed venous thrombus is the material that embolises. Most venous thrombi never do, so this edge describes a possible fate of the thrombus rather than an obligatory one.
Embolization to the pulmonary arterial tree
A thrombus fragment detaches and travels through the inferior vena cava, right atrium, and right ventricle to lodge in the pulmonary arteries, at a level determined by its size. This is the step that converts a limb disease into a cardiopulmonary emergency, and it is mechanistically distinct from thrombus formation rather than a continuation of it. Which thrombi embolise is not simply a function of how prothrombotic the patient is, and one pooled analysis found the commonest inherited thrombophilia to be relatively less frequent among patients presenting with pulmonary embolism than among those with deep vein thrombosis alone.
pulmonary artery UBERON:0002012 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in pulmonary artery (UBERON:0002012). UBERON:0002012 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Acute rise in pulmonary vascular resistance Lodged embolic material physically removes cross-sectional area from the pulmonary arterial bed.
Ventilation-perfusion mismatch and increased dead space Segments that remain ventilated but lose perfusion become dead space at the moment of occlusion.
Pulmonary infarction Occlusion causes tissue necrosis only in the minority of cases where the bronchial arterial supply cannot compensate, so the intervening determinant is the adequacy of that second circulation rather than the occlusion itself.
Show evidence (1 reference)
PMID:11583312 SUPPORT Human Clinical
"we also confirmed that the frequency of factor V Leiden was lower in patients with pulmonary embolism than in patients with deep vein thrombosis without PE (odds ratio 0.69). Conversely, factor II G20210A mutation was equally balanced in both patient groups."
Supports the claim that embolization is a step with its own determinants rather than a simple function of thrombotic tendency, since two thrombophilias with similar effects on thrombosis risk are distributed differently between embolic and non-embolic presentations. Graded PARTIAL because the observation establishes that the propensities differ without identifying what makes a thrombus embolise.
Acute rise in pulmonary vascular resistance
Loss of pulmonary arterial cross-sectional area raises pulmonary arterial pressure immediately. Pressure and resistance do not rise together, which matters because they are often treated as interchangeable. In a controlled porcine model of successive emboli, pulmonary pressure rose after the very first embolus while pulmonary vascular resistance and right ventricular arterial elastance did not rise until the third, so early pressure elevation reflects obstruction being absorbed by a still-compensating circuit rather than the afterload burden the right ventricle ultimately faces. A humoral contribution from platelet-derived vasoconstrictors is widely proposed as an amplifier of the mechanical obstruction. This entry does not cite evidence for that component and does not assert it.
pulmonary artery UBERON:0002012 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in pulmonary artery (UBERON:0002012). UBERON:0002012 is an anatomical location from the Uberon multi-species anatomy ontology.
Experimental models
Porcine consecutive pulmonary embolism model OTHER Serial embolisation reproduces the rise in pulmonary pressure and, with greater burden, in pulmonary vascular resistance.
Downstream
Right ventricular afterload mismatch and dilation Sustained elevation of the resistance the right ventricle pumps against is what the chamber must then accommodate.
Show evidence (2 references)
PMID:38745282 SUPPORT Model Organism
"Pulmonary pressures increased after the initial PE administration"
Establishes that pulmonary arterial pressure rises from the first embolic insult. Evidence source is MODEL_ORGANISM because the measurements are from an anaesthetised porcine preparation with catheter-delivered emboli.
PMID:38745282 SUPPORT Model Organism
"Conversely, RV arterial elastance and pulmonary vascular resistance was not increased after the first PE, but after three PEs an increase was observed (p = 0.0103 and p = 0.0015, respectively)."
Separates the pressure response from the resistance and afterload response, which is the basis for modelling this node distinctly from the right ventricular afterload node downstream of it.
Right ventricular afterload mismatch and dilation
The right ventricle is a thin-walled chamber adapted to a low-resistance circuit, and it cannot acutely generate the pressures a hypertrophied chamber can. Faced with an afterload that appears over minutes it dilates, and wall stress rises. Dilation is a compensatory response before it is a failure state, and the same porcine model shows the sequence directly. Dilation occurs from the earliest emboli while ejection fraction is preserved, and only with further embolic burden does contractile performance fall. This is why a dilated right ventricle on imaging is a risk marker rather than a diagnosis of shock.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
heart right ventricle UBERON:0002080 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart right ventricle (UBERON:0002080). UBERON:0002080 is an anatomical location from the Uberon multi-species anatomy ontology.
Experimental models
Porcine consecutive pulmonary embolism model OTHER The model reproduces right ventricular dilation and the later decline in ejection fraction.
Downstream
Right ventricular ischaemia and contractile failure Raised wall stress increases myocardial oxygen demand while dilation and systemic hypotension reduce the perfusion gradient that supplies it.
Ventricular interdependence and impaired left ventricular filling A dilated, pressure-loaded right ventricle displaces the interventricular septum into the left ventricle within the shared pericardial space.
Show evidence (1 reference)
PMID:38745282 SUPPORT Model Organism
"RV dilatation occurred following initial PEs, while RV ejection fraction declined after the third PE (p = 0.004)."
Directly separates dilation from contractile failure in time, supporting dilation as the earlier, compensatory event modelled at this node. Evidence source is MODEL_ORGANISM because this is a porcine experimental preparation.
Right ventricular ischaemia and contractile failure
Right ventricular myocardium becomes ischaemic in the absence of any coronary disease. Demand rises with wall stress while supply falls, because right coronary perfusion depends on the gradient between systemic pressure and right ventricular cavity pressure, and pulmonary embolism moves both in the wrong direction. The resulting myocardial injury is measurable as troponin release, which is why a biomarker of myocyte necrosis is a risk-stratification tool in a disease of the lungs. Once contractile failure is established the cascade is self-reinforcing, and this is the mechanism behind the observation that a large share of deaths occur within the first hour.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
heart right ventricle UBERON:0002080 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart right ventricle (UBERON:0002080). UBERON:0002080 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Ventricular interdependence and impaired left ventricular filling A failing right ventricle delivers less blood to the pulmonary circulation and therefore less to the left heart.
Show evidence (1 reference)
PMID:11888976 SUPPORT Human Clinical
"In either case, the presence of shock defines a threefold to sevenfold increase in mortality, with a majority of deaths occurring within 1 h of presentation."
Establishes that mortality is concentrated in the first hour once the circulation has failed, which is the clinical signature of a self-reinforcing haemodynamic cascade rather than of progressive respiratory failure.
Ventricular interdependence and impaired left ventricular filling
The two ventricles share a septum and a pericardium, so right ventricular dilation and pressure overload bow the septum leftwards and physically restrict left ventricular diastolic filling. Cardiac output falls even though the left ventricle is contracting normally, producing obstructive shock. The causal direction has been demonstrated by intervention rather than only inferred from imaging. Relieving the pulmonary arterial obstruction mechanically reduces septal bowing and simultaneously increases left ventricular volume and improves transmitral filling, and septal curvature tracks both pulmonary pressure and left ventricular filling pressure.
heart right ventricle UBERON:0002080 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart right ventricle (UBERON:0002080). UBERON:0002080 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (2 references)
PMID:41984155 SUPPORT Human Clinical
"Right ventricular (RV) volumes and septal bowing decreased, whereas left ventricular (LV) volumes and transmitral filling parameters improved (E/e', p = 0.0002)."
Shows the interdependence relationship reversing when the upstream obstruction is removed, which is stronger evidence for the causal direction than a cross-sectional association between septal position and low output.
PMID:41984155 SUPPORT Human Clinical
"Septal curvature strongly correlated with sPAP (r = 0.84) and LV filling pressure (r = - 0.51 with E/e'), indicating its potential as a surrogate marker linking RV pressure overload to impaired LV diastolic filling."
Quantifies the septum as the mechanical link between right-sided pressure overload and left-sided filling impairment, which is the specific claim this node makes.
Ventilation-perfusion mismatch and increased dead space
Occluded segments continue to be ventilated but are no longer perfused, so they become alveolar dead space, while blood is redistributed to the remaining vasculature at higher flow per unit of alveolus. The result is hypoxaemia with hypocapnia, since the patient hyperventilates in response. This arm runs in parallel with the haemodynamic arm rather than downstream of it, and it is the source of the presenting symptoms. It is not, however, what determines survival, which is the central asymmetry of the disease.
lung UBERON:0002048 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in lung (UBERON:0002048). UBERON:0002048 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (2 references)
PMID:38745282 SUPPORT Model Organism
"Acute pulmonary embolism (PE) induces ventilation-perfusion mismatch and hypoxia and increases pulmonary pressure and right ventricular (RV) afterload, entailing potentially fatal RV failure within a short timeframe."
States the parallel gas-exchange and haemodynamic consequences of the same embolic event, which is the structure this node and the afterload node together represent.
PMID:38745282 SUPPORT Model Organism
"Ventilatory variables exhibited a more direct association with clot burden."
Supports the gas-exchange arm scaling with embolic burden more directly than the haemodynamic arm does, which is why symptom severity is a poor guide to haemodynamic risk.
Pulmonary infarction
Necrosis of lung distal to an occluded pulmonary artery. It is the exception rather than the rule, because the lung receives a second arterial supply from the bronchial circulation that can sustain the tissue when the pulmonary supply is lost. Infarction is accordingly associated with smaller, more distal emboli and with conditions that limit bronchial collateral flow, and it produces the pleuritic pain and haemoptysis that the classical description of the disease was built around. Its true frequency is uncertain, and is higher in post-mortem series than in series of survivors, which is itself informative about ascertainment.
lung UBERON:0002048 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in lung (UBERON:0002048). UBERON:0002048 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (1 reference)
PMID:36013155 SUPPORT Human Clinical
"The real incidence of PI could be underestimated considering only non-fatal PE presentation. However, following postmortem examination, the prevalence of PI is considerably higher."
Supports the statement that the frequency of infarction is ascertainment-dependent and higher at autopsy, which is why this entry does not attach a single frequency figure to the node.
Thrombus resolution versus fibrotic organization
Most emboli resolve. Endogenous fibrinolysis, assisted by anticoagulation preventing further accretion, clears the pulmonary arterial bed over weeks to months. In a minority the material is not cleared but organises into fibrotic tissue incorporated into the vessel wall, giving fixed obstruction and chronic thromboembolic pulmonary hypertension. The risk is concentrated early and is higher after an unprovoked event, and it does not accumulate indefinitely.
fibrinolysis GO:0042730 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased fibrinolysis (GO:0042730). GO:0042730 is a biological process from the Gene Ontology. ↓ DECREASED
pulmonary artery UBERON:0002012 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in pulmonary artery (UBERON:0002012). UBERON:0002012 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (2 references)
PMID:15163775 SUPPORT Human Clinical
"No cases occurred after two years among the patients with more than two years of follow-up data."
Supports the claim that the risk of chronic thromboembolic pulmonary hypertension is front-loaded rather than cumulative, which is what a failure of early resolution rather than a progressive arteriopathy predicts.
PMID:15163775 SUPPORT Human Clinical
"The following increased the risk of CTPH: a previous pulmonary embolism (odds ratio, 19.0), younger age (odds ratio, 1.79 per decade), a larger perfusion defect (odds ratio, 2.22 per decile decrement in perfusion), and idiopathic pulmonary embolism at presentation (odds ratio, 5.70)."
Identifies embolic burden and recurrence as the dominant risk factors, consistent with failure of clearance of thromboembolic material as the mechanism at this node.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Pulmonary Embolism Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

13
Blood 1
Concurrent deep venous thrombosis HP:0002625 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Deep venous thrombosis (HP:0002625). HP:0002625 is a phenotype from the Human Phenotype Ontology.
Cardiovascular 4
Tachycardia HP:0001649 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tachycardia (HP:0001649). HP:0001649 is a phenotype from the Human Phenotype Ontology.
Syncope HP:0001279 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Syncope (HP:0001279). HP:0001279 is a phenotype from the Human Phenotype Ontology.
Hypotension and obstructive shock HP:0002615 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotension (HP:0002615), qualified as severity severe. HP:0002615 is a phenotype from the Human Phenotype Ontology.
Severity: SEVERE
Show evidence (1 reference)
PMID:11888976 SUPPORT Human Clinical
"In either case, the presence of shock defines a threefold to sevenfold increase in mortality, with a majority of deaths occurring within 1 h of presentation."
Establishes shock as the prognostically decisive phenotype and quantifies the mortality difference it marks.
Chronic thromboembolic pulmonary hypertension Pulmonary arterial hypertension HP:0002092 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary arterial hypertension (HP:0002092), qualified as course progressive. HP:0002092 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
The HPO term bound here is Pulmonary arterial hypertension, which is a broader concept than the chronic thromboembolic form and does not encode the thromboembolic aetiology. HPO has no term specific to chronic thromboembolic pulmonary hypertension, so the aetiology is carried by the phenotype name and description rather than by the binding.
Show evidence (1 reference)
PMID:15163775 SUPPORT Human Clinical
"The cumulative incidence of symptomatic CTPH was 1.0 percent (95 percent confidence interval, 0.0 to 2.4) at six months, 3.1 percent (95 percent confidence interval, 0.7 to 5.5) at one year, and 3.8 percent (95 percent confidence interval, 1.1 to 6.5) at two years."
Quantifies the cumulative incidence after an index pulmonary embolism in a prospective cohort.
Respiratory 5
Dyspnoea Dyspnea HP:0002094 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dyspnea (HP:0002094), qualified as temporality acute. HP:0002094 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Show evidence (2 references)
PMID:17904458 SUPPORT Human Clinical
"In patients with pulmonary embolism in the main or lobar pulmonary arteries, dyspnea or tachypnea occurred in 92%, but the largest pulmonary embolism was in the segmental pulmonary arteries in only 65%."
Quantifies how often the symptom is present and shows that it becomes markedly less reliable with more distal emboli. No frequency band is assigned to this phenotype because the figure is for dyspnoea or tachypnoea together and is stratified by embolus location.
PMID:17904458 SUPPORT Human Clinical
"Dyspnea may be absent even in patients with circulatory collapse."
Records the counterintuitive dissociation between the presenting symptom and haemodynamic severity. Graded PARTIAL because it qualifies the phenotype rather than establishing it.
Tachypnoea Tachypnea HP:0002789 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tachypnea (HP:0002789). HP:0002789 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:17904458 SUPPORT Human Clinical
"In patients with pulmonary embolism in the main or lobar pulmonary arteries, dyspnea or tachypnea occurred in 92%, but the largest pulmonary embolism was in the segmental pulmonary arteries in only 65%."
The same combined figure supports tachypnoea as a common presenting sign in proximal disease. No frequency band is assigned, because the number is a composite.
Hypoxaemia Hypoxemia HP:0012418 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoxemia (HP:0012418). HP:0012418 is a phenotype from the Human Phenotype Ontology.
Haemoptysis Hemoptysis HP:0002105 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hemoptysis (HP:0002105). HP:0002105 is a phenotype from the Human Phenotype Ontology.
Post-pulmonary embolism syndrome Dyspnea HP:0002094 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dyspnea (HP:0002094), qualified as temporality chronic. HP:0002094 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
The binding is to Dyspnea with a CHRONIC qualifier. HPO has no term for post-pulmonary embolism syndrome as an entity, and the syndrome is a composite of persistent breathlessness, exercise intolerance, and psychological impairment that no single HPO term covers, so the dominant symptom carries the binding and the composite is described in prose.
Show evidence (2 references)
PMID:41765088 SUPPORT Human Clinical
"Post-pulmonary embolism syndrome (PPES) describes the spectrum of long-term sequelae following acute pulmonary embolism (PE), including persistent dyspnea, exercise intolerance, and psychological impairment, often in the absence of pulmonary hypertension (PH) or right ventricular (RV) abnormalities."
Defines the syndrome and makes explicit that it usually occurs without the haemodynamic abnormality one would expect to find, which is what distinguishes it from chronic thromboembolic pulmonary hypertension.
PMID:41765088 SUPPORT Human Clinical
"Persistent RV dysfunction occurs in up to 18% of patients beyond three months and is associated with recurrent venous thromboembolism (VTE) and PE-related mortality."
Quantifies the measurable subset and shows it is prognostically meaningful rather than an incidental finding. No frequency band is assigned, since the figure is an upper bound.
Constitutional 1
Pleuritic chest pain HP:0033771 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pleuritic chest pain (HP:0033771). HP:0033771 is a phenotype from the Human Phenotype Ontology.
Other 2
Elevated jugular venous pressure HP:0030848 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated jugular venous pressure (HP:0030848). HP:0030848 is a phenotype from the Human Phenotype Ontology.
Right ventricular failure HP:0001708 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Right ventricular failure (HP:0001708), qualified as temporality acute. HP:0001708 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Show evidence (1 reference)
PMID:40312123 SUPPORT Human Clinical
"Pulmonary embolism (PE) has a significant impact on right-sided heart function. Clinical presentation can range from no involvement of the right ventricle to right ventricular dysfunction, cardiogenic shock, and even cardiac arrest."
States the spectrum of right ventricular involvement, from none to arrest, which is the range this phenotype covers.
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Genetic Associations

5
F5
Gene: F5 hgnc:3542 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is F5 (hgnc:3542). hgnc:3542 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE
Show evidence (2 references)
PMID:11583312 SUPPORT Human Clinical
"Odds ratios for VTE were 4.9 (95% CI; 4.1-5.9) for the factor V Leiden and 3.8 (3.0-4.9) for the factor II G20210A mutation."
Quantifies the effect size for venous thromboembolism in a pooled analysis of eight case-control studies.
PMID:11583312 SUPPORT Human Clinical
"In factor V Leiden carriers using OC, the odds ratio for VTE was 10.25 (5.69-1 8.45)."
Quantifies the gene-environment interaction with combined oral contraceptive use, which is the clinically important consequence of carrier status.
F2
Gene: F2 hgnc:3535 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is F2 (hgnc:3535). hgnc:3535 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE
Show evidence (1 reference)
PMID:11583312 SUPPORT Human Clinical
"The odds ratio for venous thrombosis in double heterozygotes was 20.0 (11.1-36.1)."
Quantifies the combined effect with factor V Leiden, showing that the two variants compound rather than merely coexist.
PROC
Gene: PROC hgnc:9451 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PROC (hgnc:9451). hgnc:9451 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE
PROS1
Gene: PROS1 hgnc:9456 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PROS1 (hgnc:9456). hgnc:9456 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE
SERPINC1
Gene: SERPINC1 hgnc:775 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SERPINC1 (hgnc:775). hgnc:775 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE
💊

Medical Actions

9
Pharmacological thromboprophylaxis
Action: Anticoagulation TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Anticoagulation Therapy (NCIT:C63341). NCIT:C63341 is a clinical intervention from the NCI Thesaurus. NCIT:C63341
Low-dose anticoagulation given to patients at risk who do not have the disease, in hospital, after surgery, and in other high-risk settings. It is the only intervention in this entry that acts on the prothrombotic context node, which is the only part of the causal chain that exists before the disease does. That makes it the sole primary-prevention lever, and its effect on venous thromboembolism in hospitalised medical patients was roughly a two-thirds relative reduction against placebo.
Mechanism Target:
INHIBITS Prothrombotic venous context — Prophylactic anticoagulation offsets the hypercoagulable component of the prothrombotic context so that a thrombus does not form in the first place.
Show evidence (2 references)
PMID:10477777 SUPPORT Human Clinical
"The incidence of venous thromboembolism was significantly lower in the group that received 40 mg of enoxaparin"
Establishes the effect in hospitalised medical patients against placebo, which is the cleanest available demonstration that acting on the prothrombotic context prevents the disease rather than treating it.
PMID:10477777 SUPPORT Human Clinical
"There was no significant difference in the incidence of venous thromboembolism between the group that received 20 mg of enoxaparin"
The dose-response arm, which matters mechanistically because it shows the benefit is not a general property of receiving an anticoagulant. Graded PARTIAL because it qualifies rather than establishes the treatment.
Therapeutic anticoagulation
Action: Anticoagulation TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Anticoagulation Therapy (NCIT:C63341). NCIT:C63341 is a clinical intervention from the NCI Thesaurus. NCIT:C63341
The mainstay of treatment in every risk stratum. Anticoagulation does not dissolve the embolus. It prevents further thrombus accretion and recurrent embolisation while endogenous fibrinolysis clears what is already there, which is the reason the treatment works despite acting on a node upstream of the one causing the symptoms.
Mechanism Target:
INHIBITS Deep venous thrombus formation — Suppressing thrombin generation stops propagation of the source thrombus and formation of new thrombus, which is what prevents further embolisation.
Direct oral anticoagulant therapy
Action: Anticoagulation TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Anticoagulation Therapy (NCIT:C63341). NCIT:C63341 is a clinical intervention from the NCI Thesaurus. NCIT:C63341
Agent: rivaroxaban CHEBI:68579 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses rivaroxaban (CHEBI:68579). CHEBI:68579 is a therapeutic agent from Chemical Entities of Biological Interest. apixaban CHEBI:72296 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses apixaban (CHEBI:72296). CHEBI:72296 is a therapeutic agent from Chemical Entities of Biological Interest.
Fixed-dose oral factor Xa inhibitors, now preferred over vitamin K antagonists for most patients. Their advantage over the older standard is not greater efficacy but less bleeding at equivalent efficacy, which was demonstrated separately for rivaroxaban in a pulmonary-embolism-specific trial and for apixaban across venous thromboembolism.
Mechanism Target:
INHIBITS Deep venous thrombus formation — Direct factor Xa inhibition reduces thrombin generation at the same node as heparin and vitamin K antagonism, by a different molecular route.
Show evidence (2 references)
PMID:22449293 SUPPORT Human Clinical
"Major bleeding was observed in 26 patients (1.1%) in the rivaroxaban group and 52 patients (2.2%) in the standard-therapy group (hazard ratio, 0.49; 95% CI, 0.31 to 0.79; P=0.003)."
Quantifies the halving of major bleeding at noninferior efficacy in a trial recruiting specifically patients with acute symptomatic pulmonary embolism.
PMID:23808982 SUPPORT Human Clinical
"A fixed-dose regimen of apixaban alone was noninferior to conventional therapy for the treatment of acute venous thromboembolism and was associated with significantly less bleeding"
Establishes the same efficacy-and-safety pattern for a second agent of the class. Note the trial population is venous thromboembolism broadly rather than pulmonary embolism specifically.
Systemic fibrinolysis
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: tenecteplase CHEBI:753718 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses tenecteplase (CHEBI:753718). CHEBI:753718 is a therapeutic agent from Chemical Entities of Biological Interest.
Plasminogen activators given systemically to lyse the embolus and unload the right ventricle. This is the one treatment that acts on the obstruction itself, and it is curated with its harm attached, because the trial that tested it in the intermediate-risk stratum found it prevented haemodynamic decompensation while causing major bleeding and stroke. That result is the reason fibrinolysis is reserved for patients already in shock rather than given to everyone with a strained right ventricle.
Mechanism Target:
INHIBITS Acute rise in pulmonary vascular resistance — Lysis of embolic material restores pulmonary arterial cross-sectional area and lowers the resistance the right ventricle faces.
Show evidence (3 references)
PMID:24716681 SUPPORT Human Clinical
"Death or hemodynamic decompensation occurred in 13 of 506 patients (2.6%) in the tenecteplase group as compared with 28 of 499 (5.6%) in the placebo group (odds ratio, 0.44; 95% confidence interval, 0.23 to 0.87; P=0.02)."
Establishes the efficacy half of the trade-off, a halving of death or haemodynamic decompensation.
PMID:24716681 REFUTE Human Clinical
"Stroke occurred in 12 patients (2.4%) in the tenecteplase group and was hemorrhagic in 10 patients; 1 patient (0.2%) in the placebo group had a stroke, which was hemorrhagic (P=0.003)."
Refutes a general recommendation for fibrinolysis in the intermediate-risk stratum by quantifying the stroke harm that offsets the benefit above. Curated as REFUTE against the broad use of this treatment, not against its mechanism.
PMID:24716681 SUPPORT Human Clinical
"In patients with intermediate-risk pulmonary embolism, fibrinolytic therapy prevented hemodynamic decompensation but increased the risk of major hemorrhage and stroke."
The authors' own summary of the trade-off. Graded PARTIAL because it supports the treatment in one respect and opposes it in another, which is exactly the curated position.
Catheter-directed mechanical thrombectomy
Action: Therapeutic ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Therapeutic Procedure (NCIT:C49236). NCIT:C49236 is a clinical intervention from the NCI Thesaurus. NCIT:C49236
Percutaneous removal of embolic material, offered increasingly in the intermediate-high and high-risk strata as an alternative to systemic lysis. Its mechanistic interest exceeds its current evidence base, because measuring the heart before and after the procedure has shown the interdependence mechanism reversing, which is stronger support for the causal model than any observational imaging study.
Mechanism Target:
INHIBITS Ventricular interdependence and impaired left ventricular filling — Relieving pulmonary arterial obstruction reduces right ventricular pressure overload, straightens the septum, and restores left ventricular filling.
Show evidence (1 reference)
PMID:41984155 SUPPORT Human Clinical
"Mechanical thrombectomy in intermediate-high-risk PE not only relieves RV overload but also enhances LV filling by mitigating ventricular interdependence."
States the mechanistic effect this treatment is curated for. The study is a single-centre series of 26 patients without a control arm, so it supports the mechanism rather than a clinical outcome benefit.
Surgical pulmonary embolectomy
Action: Surgical ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. NCIT:C15329
Open removal of central embolic material on cardiopulmonary bypass, reserved for high-risk disease where thrombolysis is contraindicated or has failed. It and catheter-directed intervention occupy the same niche, and in the setting where they have been compared the populations were largely defined by a contraindication to systemic lysis rather than by anatomy.
Mechanism Target:
INHIBITS Acute rise in pulmonary vascular resistance — Removing central embolic material restores pulmonary arterial cross-sectional area immediately and mechanically.
Show evidence (1 reference)
PMID:41412228 SUPPORT Human Clinical
"The majority in both groups had absolute (CDI, 17.3%; SE, 16.7%; P = .94) or relative contraindication (CDI, 58.7%; SE, 66.7%; P = .49) to stPA."
Establishes what actually selects patients into these procedures, namely inability to receive systemic thrombolysis rather than a positive indication. Graded PARTIAL because a retrospective single-system series cannot establish comparative efficacy.
Inferior vena cava filter
Action: Therapeutic ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Therapeutic Procedure (NCIT:C49236). NCIT:C49236 is a clinical intervention from the NCI Thesaurus. NCIT:C49236
A mechanical device intended to trap embolising thrombus before it reaches the lungs, so in principle the only treatment that acts on the embolization node itself. It is curated with its negative trial attached, because when tested against anticoagulation alone in patients at high risk of recurrence it did not reduce recurrent pulmonary embolism, and recurrences were numerically more frequent in the filter arm. Its remaining role is confined to patients who cannot be anticoagulated at all, which is a role defined by the absence of an alternative rather than by demonstrated benefit.
Mechanism Target:
INHIBITS Embolization to the pulmonary arterial tree — A caval filter is intended to intercept embolising thrombus mechanically between its venous origin and the pulmonary arteries.
Show evidence (1 reference)
PMID:25919526 REFUTE Human Clinical
"By 3 months, recurrent pulmonary embolism had occurred in 6 patients (3.0%; all fatal) in the filter group and in 3 patients (1.5%; 2 fatal) in the control group"
Refutes routine filter use in anticoagulated patients at high risk of recurrence, since the outcome the device exists to prevent was not reduced and was numerically more common with the filter.
Pulmonary endarterectomy and balloon pulmonary angioplasty
Action: Surgical ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. NCIT:C15329
Mechanical removal or dilation of organised fibrotic thromboembolic material in chronic thromboembolic pulmonary hypertension. Endarterectomy is the treatment of choice where the disease is surgically accessible and balloon angioplasty is the alternative where it is not. Both produce right ventricular reverse remodelling, which is the point mechanistically, since it shows the chronic right ventricular changes are load-dependent and reversible rather than a fixed cardiomyopathy. This is the treatment that makes recognising chronic thromboembolic disease consequential rather than merely prognostic.
Mechanism Target:
INHIBITS Thrombus resolution versus fibrotic organization — Removing or dilating the organised fibrotic material relieves the fixed obstruction that failure of resolution produced.
Show evidence (2 references)
PMID:39467613 SUPPORT Human Clinical
"Both PEA and BPA led to significant RV reverse remodelling, with no clear evidence of a difference in survival rates."
Establishes that both routes relieve the obstruction and that the right ventricle recovers, which is the mechanistic claim this treatment is curated for.
PMID:39467613 SUPPORT Human Clinical
"Improvement in RV function, particularly RV FAC, was associated with better outcomes, highlighting the importance of RV recovery in CTEPH treatment."
Connects the mechanical result to outcome through right ventricular recovery, consistent with the entry's account that the right ventricle rather than the obstruction is what determines how patients fare. Graded PARTIAL because the study is a single-centre observational cohort without randomisation.
Riociguat
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
A soluble guanylate cyclase stimulator approved for chronic thromboembolic pulmonary hypertension that is inoperable, or persistent after endarterectomy. It is worth noting what it implies. A pulmonary vasodilator improving a disease whose obstruction is organised fibrous tissue only makes sense if part of the raised resistance in that disease is not the visible obstruction at all, which is the small-vessel arteriopathy this entry declines to assert for lack of cited evidence.
Mechanism Target:
INHIBITS Thrombus resolution versus fibrotic organization — Pharmacological reduction of pulmonary vascular resistance in the chronic thromboembolic state, acting on the vascular component rather than on the organised material itself.
Show evidence (2 references)
PMID:23883377 SUPPORT Human Clinical
"By week 16, the 6-minute walk distance had increased by a mean of 39 m in the riociguat group, as compared with a mean decrease of 6 m in the placebo group"
The randomised functional result in inoperable or post-endarterectomy disease.
PMID:23883377 SUPPORT Human Clinical
"Pulmonary vascular resistance decreased by 226 dyn·sec·cm(-5) in the riociguat group and increased by 23 dyn·sec·cm(-5) in the placebo group"
The haemodynamic result, which is the mechanistically informative one, since a fall in resistance under a vasodilator implies a vasoactive component to an obstruction usually described as fixed.
🌍

Environmental Factors

2
Immobilisation and surgery
Prolonged immobility and major surgery, especially orthopaedic surgery of the hip and knee, are the archetypal acquired provoking factors. They act through stasis and through tissue-factor-mediated activation of coagulation, and they are the setting in which mechanical and pharmacological prophylaxis is applied.
Show evidence (1 reference)
PMID:10737280 SUPPORT Human Clinical
"Hospital or nursing home confinement, surgery, trauma, malignant neoplasm, chemotherapy, neurologic disease with paresis, central venous catheter or pacemaker, varicose veins, and superficial vein thrombosis are independent and important risk factors for VTE."
Population-based case-control study identifying surgery and hospital or nursing-home confinement as independent risk factors for venous thromboembolism. Surgery carried the largest odds ratio of any factor examined, at 21.7, which is the basis for calling it an archetypal provoking factor.
Mechanism Target:
PREDISPOSES Prothrombotic venous context — Immobility produces venous stasis and surgical tissue injury activates coagulation, which are two of the three components of the prothrombotic context node.
Show evidence (1 reference)
PMID:29399531 SUPPORT Human Clinical
"Virchow's Triad distills the multitude of risk factors for DVT into three basic elements favoring thrombus formation: venous stasis, vascular injury, and hypercoagulability."
Establishes venous stasis and vascular injury as two of the three thrombus-favouring elements this edge invokes. PARTIAL because it names the framework rather than measuring the step from immobility or from surgery to either element.
Oestrogen exposure
exposure to estrogens ECTO:9000010 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to estrogens (ECTO:9000010). ECTO:9000010 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Combined oral contraceptives and hormone replacement therapy raise the risk of venous thromboembolism, and they do so multiplicatively rather than additively in carriers of inherited thrombophilia. This is the best-quantified gene-environment interaction in the disease and the reason thrombophilia status changes contraceptive counselling.
Show evidence (1 reference)
PMID:11583312 SUPPORT Human Clinical
"Odds ratio for VTE associated with OC was 2.29 (1.72-3.04). In factor V Leiden carriers using OC, the odds ratio for VTE was 10.25 (5.69-1 8.45)."
Quantifies oral contraceptive use as a risk factor for venous thromboembolism, and shows the risk is several times higher again in factor V Leiden carriers, which is the gene-environment interaction this entry is curated for.
Mechanism Target:
PREDISPOSES Prothrombotic venous context — Oestrogen exposure shifts the coagulation balance and compounds the effect of an inherited thrombophilic background.
Show evidence (1 reference)
PMID:11583312 SUPPORT Human Clinical
"Odds ratio for VTE associated with OC was 2.29 (1.72-3.04). In factor V Leiden carriers using OC, the odds ratio for VTE was 10.25 (5.69-1 8.45)."
Gives both the main effect of oral contraceptive use and the substantially larger effect in factor V Leiden carriers, which is the interaction this exposure is curated for.
🔬

Biochemical Markers

3
D-dimer
Cardiac troponin
B-type natriuretic peptide
🔬

Diagnosis

3
Computed tomographic pulmonary angiography
The first-line confirmatory test, showing filling defects directly. It also gives the right ventricular to left ventricular diameter ratio in the same acquisition, so the test that establishes the diagnosis simultaneously supplies the risk-stratification variable.
Risk stratification by right ventricular function and cardiac biomarkers
Severity is assessed from haemodynamic status, a validated clinical severity score, imaging of the right ventricle, and cardiac biomarkers, rather than from the anatomical extent of the embolus. The 2026 multisociety guideline replaced the older informal massive and submassive vocabulary with an explicit set of clinical categories built on these variables.
Show evidence (1 reference)
PMID:41712898 SUPPORT Human Clinical
"A key feature of this guideline is the introduction of the AHA/ACC Acute Pulmonary Embolism Clinical Categories, which enhance the precision of severity classification, prognosis assessment, and evidence-based therapeutic decision-making."
Documents the current formal severity classification that this entry's subtypes correspond to.
D-dimer with pretest probability assessment
A sensitive but unspecific assay used to exclude the diagnosis in patients whose clinical probability is low. It is diagnostically useful only in that direction, and using it as a positive test generates imaging without benefit.
📈

Progression

3
Acute event
Onset over minutes to hours. Mortality is concentrated in the earliest period and is driven by right ventricular failure rather than by hypoxaemia, with a majority of deaths in patients presenting in shock occurring within the first hour.
Show evidence (1 reference)
PMID:11888976 SUPPORT Human Clinical
"In either case, the presence of shock defines a threefold to sevenfold increase in mortality, with a majority of deaths occurring within 1 h of presentation."
Supports the concentration of mortality in the first hour after presentation with shock.
Resolution on anticoagulation
Most patients stabilise and clear the embolic burden over weeks to months while anticoagulated. Duration of anticoagulation is then decided by whether the event was provoked, which is a statement about the prothrombotic context node rather than about the embolus.
Chronic thromboembolic pulmonary hypertension
A minority fail to clear the material, which organises into fixed fibrotic obstruction. In a prospective cohort the cumulative incidence of symptomatic disease was 3.8 percent at two years, and no new cases appeared beyond two years of follow-up, so the risk is front-loaded.
Show evidence (1 reference)
PMID:15163775 SUPPORT Human Clinical
"The cumulative incidence of symptomatic CTPH was 1.0 percent (95 percent confidence interval, 0.0 to 2.4) at six months, 3.1 percent (95 percent confidence interval, 0.7 to 5.5) at one year, and 3.8 percent (95 percent confidence interval, 1.1 to 6.5) at two years."
Gives the cumulative incidence figures quoted in this phase.
📊

Prevalence

1
Worldwide
Annual Incidence 100.0 per 100,000 (100.0–200.0) >1 in 1,000
Venous thromboembolism is commonly cited at an annual incidence of roughly one to two per thousand adults, rising steeply with age, with pulmonary embolism accounting for a substantial share. One to two per thousand is one hundred to two hundred per hundred thousand, which is the ABOVE_1_IN_1000 band. The value recorded here is an order-of-magnitude normalisation of that range and is not drawn from a single cited study, which is why no evidence item is attached.
🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Pulmonary Embolism:

Acute coronary syndrome
Overlapping Features Shares chest pain, dyspnoea, troponin elevation, and electrocardiographic change. The distinction matters because both conditions raise troponin but by opposite mechanisms, coronary occlusion in one and right ventricular afterload in the other, and because the treatments are close to mutually exclusive.
Pneumonia
Overlapping Features Shares pleuritic pain, breathlessness, fever, and a peripheral opacity on chest radiography. A pulmonary infarct is radiographically similar to a consolidation, and the two are commonly confused in both directions.
Aortic dissection
Overlapping Features Shares abrupt chest pain and haemodynamic collapse. It is the differential in which the consequence of getting it wrong is greatest, because anticoagulation or fibrinolysis given to a dissection is actively harmful.
Pericardial tamponade
Overlapping Features Shares obstructive shock with a clear chest and raised jugular venous pressure. Both impair ventricular filling rather than contraction, so they present with the same physiology arrived at by different routes.
🧫

Experimental Models

1
Porcine consecutive pulmonary embolism model OTHER
Anaesthetised pigs receiving repeated catheter-delivered emboli at fixed intervals, with pressure-volume loops and invasive pressures recorded after each. The model exists because rodent venous thrombosis models reproduce thrombus formation well but do not reliably produce pulmonary embolism, so the haemodynamic half of the disease has to be studied by delivering emboli directly. Its value here is that it separates events that are simultaneous in patients. It shows pulmonary pressure rising from the first embolus, resistance and afterload only from the third, and dilation preceding the fall in ejection fraction. Its limitation is that bypassing spontaneous embolisation makes it useless for studying why thrombi embolise.
Organism
pig NCBITaxon:9823 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in pig, annotated with Sus scrofa (NCBITaxon:9823). NCBITaxon:9823 is an organism from the NCBI Taxonomy.
Publication
PMID:38745282
Pathograph links
Acute rise in pulmonary vascular resistance Serial embolisation reproduces the rise in pulmonary pressure and, with greater burden, in pulmonary vascular resistance.
Right ventricular afterload mismatch and dilation The model reproduces right ventricular dilation and the later decline in ejection fraction.
Show evidence (2 references)
PMID:38745282 SUPPORT Model Organism
"Twelve pigs were randomly assigned to receive sham procedures or consecutive PEs every 15 min until doubling of mean pulmonary pressure."
Describes the design, including the sham control arm and the randomisation that make it a controlled experiment rather than a descriptive preparation.
PMID:38745282 SUPPORT Model Organism
"In an experimental model of consecutive PE, RV afterload elevation and dysfunction manifested after the third PE, in contrast to pulmonary pressure that increased after the first PE."
The finding that makes the model informative for this entry, since it dissociates pressure from afterload in a way that clinical measurement cannot.
{ }

Source YAML

click to show 
name: Pulmonary Embolism
creation_date: "2026-08-10T03:40:00Z"
category: Acquired
disease_term:
  preferred_term: pulmonary embolism
  term:
    id: MONDO:0005279
    label: pulmonary embolism
description: >
  Acute obstruction of the pulmonary arterial circulation by embolic material, in the great
  majority of cases a thrombus that formed in the deep veins and then dislodged. The organising
  fact of the disease is that the embolus is not what kills. Death in the first hours comes from
  the right ventricle, which is a thin-walled chamber built for a low-pressure circuit and has no
  reserve for an afterload that appears in minutes. Everything clinically decisive about acute
  pulmonary embolism follows from that: severity tracks right ventricular function rather than
  clot burden, risk stratification is built on right ventricular imaging and myocardial
  biomarkers rather than on the size of the filling defect, and reperfusion is offered to the
  patients whose right ventricle is failing rather than to those with the most extensive
  disease. A second consequence of the anatomy runs the other way. The lung is supplied twice,
  by the pulmonary and the bronchial arteries, so occluding a pulmonary artery usually does not
  infarct the tissue it supplies. That is the opposite of what happens in the coronary or
  cerebral circulation, and it is why infarction is the wrong default model for this disease
  even though the word survives in its older names.
parents:
- pulmonary artery disease
- venous thromboembolism

classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
    notes: >-
      Curated as cardiovascular because the mechanism that determines outcome is haemodynamic and
      cardiac. The presentation is respiratory and the diagnosis is made by chest imaging, so a
      respiratory classification would also be defensible, but it would misplace the organ whose
      failure the disease is graded by.

has_subtypes:
- name: High-risk PE
  display_name: High-risk pulmonary embolism
  description: >
    Pulmonary embolism with haemodynamic instability. This is the stratum in which right
    ventricular failure has already progressed to systemic hypotension or arrest, and the one in
    which reperfusion is offered without further stratification. It is defined by the patient's
    circulation rather than by the anatomy of the clot.
- name: Intermediate-risk PE
  display_name: Intermediate-risk pulmonary embolism
  description: >
    Normotensive pulmonary embolism with imaging evidence of right ventricular dysfunction and
    with myocardial biomarker elevation. Mechanistically this is the interesting stratum, because
    the right ventricle is demonstrably injured while the systemic circulation is still being
    maintained. It is the population in which fibrinolysis was formally tested and found to trade
    prevented decompensation for bleeding.
- name: Low-risk PE
  display_name: Low-risk pulmonary embolism
  description: >
    Normotensive pulmonary embolism without right ventricular dysfunction or biomarker
    elevation. Anticoagulation alone, and increasingly outpatient management, on the reasoning
    that the mechanism which causes early death is absent.

pathophysiology:
- name: Prothrombotic venous context
  biological_scale: ORGANISM
  conforms_to: "thrombogenesis#Virchow-Triad Prothrombotic Context"
  description: >
    Stasis, endothelial injury, and a hypercoagulable state, singly or together, create the
    conditions in which a venous thrombus forms. In pulmonary embolism these are usually acquired
    and transient, such as surgery, immobilisation, pregnancy, oestrogen exposure, or
    malignancy, and they are frequently layered on an inherited thrombophilic background. The
    node is placed first because it is the only part of the causal chain that prophylaxis can act
    on, and because it is what distinguishes a provoked from an unprovoked event, which in turn
    determines how long anticoagulation continues.
  downstream:
  - target: Deep venous thrombus formation
    causal_link_type: DIRECT
    description: >
      The prothrombotic conditions are what permit a thrombus to nucleate and propagate rather
      than being cleared.

- name: Deep venous thrombus formation
  biological_scale: TISSUE
  conforms_to: "thrombogenesis#Pathological Fibrin-Platelet Thrombus Formation"
  description: >
    Platelet adhesion and coagulation-cascade activation build a fibrin-platelet thrombus, most
    often beginning in a valve pocket of a lower-limb or pelvic deep vein. This node is the
    disease of deep vein thrombosis, and pulmonary embolism only becomes a separate clinical
    entity at the next step. Curating it here rather than treating it as an external precondition
    is deliberate, because anticoagulation acts on this node and not on any node downstream of
    it.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: blood coagulation, fibrin clot formation
    term:
      id: GO:0072378
      label: blood coagulation, fibrin clot formation
    modifier: INCREASED
  - preferred_term: regulation of blood coagulation
    term:
      id: GO:0030193
      label: regulation of blood coagulation
    modifier: DECREASED
  locations:
  - preferred_term: deep vein
    term:
      id: UBERON:0035552
      label: deep vein
  downstream:
  - target: Embolization to the pulmonary arterial tree
    causal_link_type: DIRECT
    description: >
      A formed venous thrombus is the material that embolises. Most venous thrombi never do, so
      this edge describes a possible fate of the thrombus rather than an obligatory one.

- name: Embolization to the pulmonary arterial tree
  biological_scale: ORGANISM
  conforms_to: "thrombogenesis#Venous Thrombus Embolization to Pulmonary Arteries"
  description: >
    A thrombus fragment detaches and travels through the inferior vena cava, right atrium, and
    right ventricle to lodge in the pulmonary arteries, at a level determined by its size. This
    is the step that converts a limb disease into a cardiopulmonary emergency, and it is
    mechanistically distinct from thrombus formation rather than a continuation of it. Which
    thrombi embolise is not simply a function of how prothrombotic the patient is, and one
    pooled analysis found the commonest inherited thrombophilia to be relatively less frequent
    among patients presenting with pulmonary embolism than among those with deep vein thrombosis
    alone.
  locations:
  - preferred_term: pulmonary artery
    term:
      id: UBERON:0002012
      label: pulmonary artery
  evidence:
  - reference: PMID:11583312
    reference_title: "Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism--pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Study Group for Pooled-Analysis in Venous Thromboembolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we also confirmed that the frequency of factor V Leiden was lower in patients with pulmonary embolism than in patients with deep vein thrombosis without PE (odds ratio 0.69). Conversely, factor II G20210A mutation was equally balanced in both patient groups."
    explanation: >-
      Supports the claim that embolization is a step with its own determinants rather than a
      simple function of thrombotic tendency, since two thrombophilias with similar effects on
      thrombosis risk are distributed differently between embolic and non-embolic presentations.
      Graded PARTIAL because the observation establishes that the propensities differ without
      identifying what makes a thrombus embolise.
  downstream:
  - target: Acute rise in pulmonary vascular resistance
    causal_link_type: DIRECT
    description: >
      Lodged embolic material physically removes cross-sectional area from the pulmonary arterial
      bed.
  - target: Ventilation-perfusion mismatch and increased dead space
    causal_link_type: DIRECT
    description: >
      Segments that remain ventilated but lose perfusion become dead space at the moment of
      occlusion.
  - target: Pulmonary infarction
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >
      Occlusion causes tissue necrosis only in the minority of cases where the bronchial arterial
      supply cannot compensate, so the intervening determinant is the adequacy of that second
      circulation rather than the occlusion itself.

- name: Acute rise in pulmonary vascular resistance
  biological_scale: ORGANISM
  description: >
    Loss of pulmonary arterial cross-sectional area raises pulmonary arterial pressure
    immediately. Pressure and resistance do not rise together, which matters because they are
    often treated as interchangeable. In a controlled porcine model of successive emboli,
    pulmonary pressure rose after the very first embolus while pulmonary vascular resistance and
    right ventricular arterial elastance did not rise until the third, so early pressure
    elevation reflects obstruction being absorbed by a still-compensating circuit rather than the
    afterload burden the right ventricle ultimately faces. A humoral contribution from
    platelet-derived vasoconstrictors is widely proposed as an amplifier of the mechanical
    obstruction. This entry does not cite evidence for that component and does not assert it.
  locations:
  - preferred_term: pulmonary artery
    term:
      id: UBERON:0002012
      label: pulmonary artery
  evidence:
  - reference: PMID:38745282
    reference_title: "Immediate cardiopulmonary responses to consecutive pulmonary embolism: a randomized, controlled, experimental study."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Pulmonary pressures increased after the initial PE administration"
    explanation: >-
      Establishes that pulmonary arterial pressure rises from the first embolic insult. Evidence
      source is MODEL_ORGANISM because the measurements are from an anaesthetised porcine
      preparation with catheter-delivered emboli.
  - reference: PMID:38745282
    reference_title: "Immediate cardiopulmonary responses to consecutive pulmonary embolism: a randomized, controlled, experimental study."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Conversely, RV arterial elastance and pulmonary vascular resistance was not increased after the first PE, but after three PEs an increase was observed (p = 0.0103 and p = 0.0015, respectively)."
    explanation: >-
      Separates the pressure response from the resistance and afterload response, which is the
      basis for modelling this node distinctly from the right ventricular afterload node
      downstream of it.
  downstream:
  - target: Right ventricular afterload mismatch and dilation
    causal_link_type: DIRECT
    description: >
      Sustained elevation of the resistance the right ventricle pumps against is what the chamber
      must then accommodate.

- name: Right ventricular afterload mismatch and dilation
  biological_scale: TISSUE
  description: >
    The right ventricle is a thin-walled chamber adapted to a low-resistance circuit, and it
    cannot acutely generate the pressures a hypertrophied chamber can. Faced with an afterload
    that appears over minutes it dilates, and wall stress rises. Dilation is a compensatory
    response before it is a failure state, and the same porcine model shows the sequence
    directly. Dilation occurs from the earliest emboli while ejection fraction is preserved, and
    only with further embolic burden does contractile performance fall. This is why a dilated
    right ventricle on imaging is a risk marker rather than a diagnosis of shock.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: heart right ventricle
    term:
      id: UBERON:0002080
      label: heart right ventricle
  evidence:
  - reference: PMID:38745282
    reference_title: "Immediate cardiopulmonary responses to consecutive pulmonary embolism: a randomized, controlled, experimental study."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "RV dilatation occurred following initial PEs, while RV ejection fraction declined after the third PE (p = 0.004)."
    explanation: >-
      Directly separates dilation from contractile failure in time, supporting dilation as the
      earlier, compensatory event modelled at this node. Evidence source is MODEL_ORGANISM
      because this is a porcine experimental preparation.
  downstream:
  - target: Right ventricular ischaemia and contractile failure
    causal_link_type: DIRECT
    description: >
      Raised wall stress increases myocardial oxygen demand while dilation and systemic
      hypotension reduce the perfusion gradient that supplies it.
  - target: Ventricular interdependence and impaired left ventricular filling
    causal_link_type: DIRECT
    description: >
      A dilated, pressure-loaded right ventricle displaces the interventricular septum into the
      left ventricle within the shared pericardial space.

- name: Right ventricular ischaemia and contractile failure
  biological_scale: TISSUE
  description: >
    Right ventricular myocardium becomes ischaemic in the absence of any coronary disease. Demand
    rises with wall stress while supply falls, because right coronary perfusion depends on the
    gradient between systemic pressure and right ventricular cavity pressure, and pulmonary
    embolism moves both in the wrong direction. The resulting myocardial injury is measurable as
    troponin release, which is why a biomarker of myocyte necrosis is a risk-stratification tool
    in a disease of the lungs. Once contractile failure is established the cascade is
    self-reinforcing, and this is the mechanism behind the observation that a large share of
    deaths occur within the first hour.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: heart right ventricle
    term:
      id: UBERON:0002080
      label: heart right ventricle
  evidence:
  - reference: PMID:11888976
    reference_title: "Major pulmonary embolism: review of a pathophysiologic approach to the golden hour of hemodynamically significant pulmonary embolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In either case, the presence of shock defines a threefold to sevenfold increase in mortality, with a majority of deaths occurring within 1 h of presentation."
    explanation: >-
      Establishes that mortality is concentrated in the first hour once the circulation has
      failed, which is the clinical signature of a self-reinforcing haemodynamic cascade rather
      than of progressive respiratory failure.
  downstream:
  - target: Ventricular interdependence and impaired left ventricular filling
    causal_link_type: DIRECT
    description: >
      A failing right ventricle delivers less blood to the pulmonary circulation and therefore
      less to the left heart.

- name: Ventricular interdependence and impaired left ventricular filling
  biological_scale: ORGANISM
  description: >
    The two ventricles share a septum and a pericardium, so right ventricular dilation and
    pressure overload bow the septum leftwards and physically restrict left ventricular
    diastolic filling. Cardiac output falls even though the left ventricle is contracting
    normally, producing obstructive shock. The causal direction has been demonstrated by
    intervention rather than only inferred from imaging. Relieving the pulmonary arterial
    obstruction mechanically reduces septal bowing and simultaneously increases left ventricular
    volume and improves transmitral filling, and septal curvature tracks both pulmonary pressure
    and left ventricular filling pressure.
  locations:
  - preferred_term: heart right ventricle
    term:
      id: UBERON:0002080
      label: heart right ventricle
  evidence:
  - reference: PMID:41984155
    reference_title: "Mechanical thrombectomy improves left ventricular filling in intermediate-high risk pulmonary embolism: the role of ventricular interdependence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Right ventricular (RV) volumes and septal bowing decreased, whereas left ventricular (LV) volumes and transmitral filling parameters improved (E/e', p = 0.0002)."
    explanation: >-
      Shows the interdependence relationship reversing when the upstream obstruction is removed,
      which is stronger evidence for the causal direction than a cross-sectional association
      between septal position and low output.
  - reference: PMID:41984155
    reference_title: "Mechanical thrombectomy improves left ventricular filling in intermediate-high risk pulmonary embolism: the role of ventricular interdependence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Septal curvature strongly correlated with sPAP (r = 0.84) and LV filling pressure (r =  - 0.51 with E/e'), indicating its potential as a surrogate marker linking RV pressure overload to impaired LV diastolic filling."
    explanation: >-
      Quantifies the septum as the mechanical link between right-sided pressure overload and
      left-sided filling impairment, which is the specific claim this node makes.

- name: Ventilation-perfusion mismatch and increased dead space
  biological_scale: ORGANISM
  description: >
    Occluded segments continue to be ventilated but are no longer perfused, so they become
    alveolar dead space, while blood is redistributed to the remaining vasculature at higher flow
    per unit of alveolus. The result is hypoxaemia with hypocapnia, since the patient
    hyperventilates in response. This arm runs in parallel with the haemodynamic arm rather than
    downstream of it, and it is the source of the presenting symptoms. It is not, however, what
    determines survival, which is the central asymmetry of the disease.
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:38745282
    reference_title: "Immediate cardiopulmonary responses to consecutive pulmonary embolism: a randomized, controlled, experimental study."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Acute pulmonary embolism (PE) induces ventilation-perfusion mismatch and hypoxia and increases pulmonary pressure and right ventricular (RV) afterload, entailing potentially fatal RV failure within a short timeframe."
    explanation: >-
      States the parallel gas-exchange and haemodynamic consequences of the same embolic event,
      which is the structure this node and the afterload node together represent.
  - reference: PMID:38745282
    reference_title: "Immediate cardiopulmonary responses to consecutive pulmonary embolism: a randomized, controlled, experimental study."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Ventilatory variables exhibited a more direct association with clot burden."
    explanation: >-
      Supports the gas-exchange arm scaling with embolic burden more directly than the
      haemodynamic arm does, which is why symptom severity is a poor guide to haemodynamic risk.

- name: Pulmonary infarction
  biological_scale: TISSUE
  description: >
    Necrosis of lung distal to an occluded pulmonary artery. It is the exception rather than the
    rule, because the lung receives a second arterial supply from the bronchial circulation that
    can sustain the tissue when the pulmonary supply is lost. Infarction is accordingly
    associated with smaller, more distal emboli and with conditions that limit bronchial
    collateral flow, and it produces the pleuritic pain and haemoptysis that the classical
    description of the disease was built around. Its true frequency is uncertain, and is higher
    in post-mortem series than in series of survivors, which is itself informative about
    ascertainment.
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:36013155
    reference_title: "Pulmonary Embolism Presenting with Pulmonary Infarction: Update and Practical Review of Literature Data."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The real incidence of PI could be underestimated considering only non-fatal PE presentation. However, following postmortem examination, the prevalence of PI is considerably higher."
    explanation: >-
      Supports the statement that the frequency of infarction is ascertainment-dependent and
      higher at autopsy, which is why this entry does not attach a single frequency figure to the
      node.

- name: Thrombus resolution versus fibrotic organization
  biological_scale: TISSUE
  description: >
    Most emboli resolve. Endogenous fibrinolysis, assisted by anticoagulation preventing further
    accretion, clears the pulmonary arterial bed over weeks to months. In a minority the material
    is not cleared but organises into fibrotic tissue incorporated into the vessel wall, giving
    fixed obstruction and chronic thromboembolic pulmonary hypertension. The risk is
    concentrated early and is higher after an unprovoked event, and it does not accumulate
    indefinitely.
  biological_processes:
  - preferred_term: fibrinolysis
    term:
      id: GO:0042730
      label: fibrinolysis
    modifier: DECREASED
  locations:
  - preferred_term: pulmonary artery
    term:
      id: UBERON:0002012
      label: pulmonary artery
  evidence:
  - reference: PMID:15163775
    reference_title: "Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No cases occurred after two years among the patients with more than two years of follow-up data."
    explanation: >-
      Supports the claim that the risk of chronic thromboembolic pulmonary hypertension is
      front-loaded rather than cumulative, which is what a failure of early resolution rather
      than a progressive arteriopathy predicts.
  - reference: PMID:15163775
    reference_title: "Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The following increased the risk of CTPH: a previous pulmonary embolism (odds ratio, 19.0), younger age (odds ratio, 1.79 per decade), a larger perfusion defect (odds ratio, 2.22 per decile decrement in perfusion), and idiopathic pulmonary embolism at presentation (odds ratio, 5.70)."
    explanation: >-
      Identifies embolic burden and recurrence as the dominant risk factors, consistent with
      failure of clearance of thromboembolic material as the mechanism at this node.
  notes: >
    No conformance is declared to the pulmonary_vascular_remodeling module. That module's central
    effector node describes obstruction produced by pulmonary artery smooth muscle cell
    proliferation, neointima formation, and plexiform lesions. The obstruction curated here is
    organised fibrotic thromboembolic material, which is a different lesion arrived at by a
    different route. Chronic thromboembolic pulmonary hypertension is also reported to carry a
    small-vessel arteriopathy in territories that were never occluded, and if that arm were
    curated with its own evidence it would be a legitimate conformance target. This entry does
    not cite evidence for it and therefore does not assert it.

phenotypes:
- category: Symptom
  name: Dyspnoea
  description: >
    Breathlessness, usually of rapid onset, is the commonest presenting symptom. Its diagnostic
    value is limited in both directions. In the PIOPED II cohort dyspnoea or tachypnoea was
    present in 92 percent of patients whose largest embolus was in a main or lobar pulmonary
    artery, but the same study records that dyspnoea can be absent even in patients who have
    already collapsed, so its absence does not exclude severe disease.
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
    temporality: ACUTE
  evidence:
  - reference: PMID:17904458
    reference_title: "Clinical characteristics of patients with acute pulmonary embolism: data from PIOPED II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patients with pulmonary embolism in the main or lobar pulmonary arteries, dyspnea or tachypnea occurred in 92%, but the largest pulmonary embolism was in the segmental pulmonary arteries in only 65%."
    explanation: >-
      Quantifies how often the symptom is present and shows that it becomes markedly less
      reliable with more distal emboli. No frequency band is assigned to this phenotype because
      the figure is for dyspnoea or tachypnoea together and is stratified by embolus location.
  - reference: PMID:17904458
    reference_title: "Clinical characteristics of patients with acute pulmonary embolism: data from PIOPED II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dyspnea may be absent even in patients with circulatory collapse."
    explanation: >-
      Records the counterintuitive dissociation between the presenting symptom and haemodynamic
      severity. Graded PARTIAL because it qualifies the phenotype rather than establishing it.

- category: Symptom
  name: Pleuritic chest pain
  description: >
    Sharp chest pain worsened by inspiration, arising from pleural inflammation over an infarcted
    or ischaemic peripheral segment. It is therefore a symptom of the distal, infarcting form of
    the disease rather than of the central, haemodynamically dangerous form, which is why the
    patients who look most uncomfortable are not necessarily the ones at highest risk.
  phenotype_term:
    preferred_term: Pleuritic chest pain
    term:
      id: HP:0033771
      label: Pleuritic chest pain

- category: Sign
  name: Tachypnoea
  description: >
    Increased respiratory rate, driven by dead-space ventilation and hypoxaemia. It is one of the
    most consistently present signs and contributes the hypocapnia seen on blood gases.
  phenotype_term:
    preferred_term: Tachypnea
    term:
      id: HP:0002789
      label: Tachypnea
  evidence:
  - reference: PMID:17904458
    reference_title: "Clinical characteristics of patients with acute pulmonary embolism: data from PIOPED II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patients with pulmonary embolism in the main or lobar pulmonary arteries, dyspnea or tachypnea occurred in 92%, but the largest pulmonary embolism was in the segmental pulmonary arteries in only 65%."
    explanation: >-
      The same combined figure supports tachypnoea as a common presenting sign in proximal
      disease. No frequency band is assigned, because the number is a composite.

- category: Sign
  name: Tachycardia
  description: >
    Sinus tachycardia, the compensatory response to a falling stroke volume. It is included in
    every validated clinical prediction rule for the disease.
  phenotype_term:
    preferred_term: Tachycardia
    term:
      id: HP:0001649
      label: Tachycardia

- category: Sign
  name: Hypoxaemia
  description: >
    Reduced arterial oxygenation from ventilation-perfusion mismatch. It is typically accompanied
    by hypocapnia rather than hypercapnia, because minute ventilation rises.
  phenotype_term:
    preferred_term: Hypoxemia
    term:
      id: HP:0012418
      label: Hypoxemia

- category: Symptom
  name: Haemoptysis
  description: >
    Coughing of blood, a consequence of alveolar haemorrhage into an infarcted segment. Like
    pleuritic pain it marks the peripheral infarcting presentation rather than central
    obstruction.
  phenotype_term:
    preferred_term: Hemoptysis
    term:
      id: HP:0002105
      label: Hemoptysis

- category: Sign
  name: Syncope
  description: >
    Transient loss of consciousness from an abrupt fall in cardiac output. It is a haemodynamic
    sign rather than a respiratory one, and it identifies patients whose right ventricle is
    already failing.
  phenotype_term:
    preferred_term: Syncope
    term:
      id: HP:0001279
      label: Syncope

- category: Sign
  name: Hypotension and obstructive shock
  description: >
    Systemic hypotension, the defining feature of high-risk disease. It is produced by impaired
    left ventricular filling rather than by impaired left ventricular contraction, which is why
    the failing chamber and the hypotensive circulation are on opposite sides of the heart.
  phenotype_term:
    preferred_term: Hypotension
    term:
      id: HP:0002615
      label: Hypotension
    severity: SEVERE
  evidence:
  - reference: PMID:11888976
    reference_title: "Major pulmonary embolism: review of a pathophysiologic approach to the golden hour of hemodynamically significant pulmonary embolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In either case, the presence of shock defines a threefold to sevenfold increase in mortality, with a majority of deaths occurring within 1 h of presentation."
    explanation: >-
      Establishes shock as the prognostically decisive phenotype and quantifies the mortality
      difference it marks.

- category: Sign
  name: Elevated jugular venous pressure
  description: >
    Distension of the jugular veins reflecting raised right atrial pressure in a failing,
    pressure-loaded right ventricle. It is one of the few bedside findings that points at the
    haemodynamic rather than the respiratory arm of the disease.
  phenotype_term:
    preferred_term: Elevated jugular venous pressure
    term:
      id: HP:0030848
      label: Elevated jugular venous pressure

- category: Sign
  name: Concurrent deep venous thrombosis
  description: >
    Unilateral limb swelling and tenderness from the source thrombus. Its presence supports the
    diagnosis, but its absence is uninformative, because a thrombus that has embolised completely
    leaves nothing behind to find.
  phenotype_term:
    preferred_term: Deep venous thrombosis
    term:
      id: HP:0002625
      label: Deep venous thrombosis

- category: Cardiovascular
  name: Right ventricular failure
  description: >
    Dilation and contractile failure of the right ventricle. It is the phenotype the disease is
    graded by and the direct clinical readout of the pathophysiology nodes above.
  phenotype_term:
    preferred_term: Right ventricular failure
    term:
      id: HP:0001708
      label: Right ventricular failure
    temporality: ACUTE
  evidence:
  - reference: PMID:40312123
    reference_title: "Managing right ventricular failure in the setting of pulmonary embolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pulmonary embolism (PE) has a significant impact on right-sided heart function. Clinical presentation can range from no involvement of the right ventricle to right ventricular dysfunction, cardiogenic shock, and even cardiac arrest."
    explanation: >-
      States the spectrum of right ventricular involvement, from none to arrest, which is the
      range this phenotype covers.

- category: Cardiovascular
  name: Post-pulmonary embolism syndrome
  description: >
    Persistent breathlessness, exercise intolerance, and impaired quality of life after an
    apparently treated pulmonary embolism, frequently without pulmonary hypertension or right
    ventricular abnormality to account for it. It is far commoner than chronic thromboembolic
    pulmonary hypertension and is the outcome most survivors actually live with, yet it has no
    single diagnostic test, which is why it was long treated as a complaint rather than a
    syndrome. A measurable subset does have persistent right ventricular dysfunction, and that
    subset carries excess recurrence and mortality, so the label spans a functional complaint and
    a haemodynamic finding that are not the same thing.
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
    temporality: CHRONIC
  evidence:
  - reference: PMID:41765088
    reference_title: "Post-pulmonary embolism syndrome: a practical narrative review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Post-pulmonary embolism syndrome (PPES) describes the spectrum of long-term sequelae following acute pulmonary embolism (PE), including persistent dyspnea, exercise intolerance, and psychological impairment, often in the absence of pulmonary hypertension (PH) or right ventricular (RV) abnormalities."
    explanation: >-
      Defines the syndrome and makes explicit that it usually occurs without the haemodynamic
      abnormality one would expect to find, which is what distinguishes it from chronic
      thromboembolic pulmonary hypertension.
  - reference: PMID:41765088
    reference_title: "Post-pulmonary embolism syndrome: a practical narrative review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Persistent RV dysfunction occurs in up to 18% of patients beyond three months and is associated with recurrent venous thromboembolism (VTE) and PE-related mortality."
    explanation: >-
      Quantifies the measurable subset and shows it is prognostically meaningful rather than an
      incidental finding. No frequency band is assigned, since the figure is an upper bound.
  notes: >
    The binding is to Dyspnea with a CHRONIC qualifier. HPO has no term for post-pulmonary
    embolism syndrome as an entity, and the syndrome is a composite of persistent breathlessness,
    exercise intolerance, and psychological impairment that no single HPO term covers, so the
    dominant symptom carries the binding and the composite is described in prose.

- category: Cardiovascular
  name: Chronic thromboembolic pulmonary hypertension
  description: >
    Persistent pulmonary hypertension from unresolved, organised thromboembolic obstruction,
    presenting months to years later with exertional breathlessness. It is the one chronic
    outcome of an otherwise acute disease, and it is potentially curable by surgical
    endarterectomy, which makes recognising it consequential rather than merely prognostic.
  phenotype_term:
    preferred_term: Pulmonary arterial hypertension
    term:
      id: HP:0002092
      label: Pulmonary arterial hypertension
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:15163775
    reference_title: "Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cumulative incidence of symptomatic CTPH was 1.0 percent (95 percent confidence interval, 0.0 to 2.4) at six months, 3.1 percent (95 percent confidence interval, 0.7 to 5.5) at one year, and 3.8 percent (95 percent confidence interval, 1.1 to 6.5) at two years."
    explanation: >-
      Quantifies the cumulative incidence after an index pulmonary embolism in a prospective
      cohort.
  notes: >
    The HPO term bound here is Pulmonary arterial hypertension, which is a broader concept than
    the chronic thromboembolic form and does not encode the thromboembolic aetiology. HPO has no
    term specific to chronic thromboembolic pulmonary hypertension, so the aetiology is carried
    by the phenotype name and description rather than by the binding.

genetic:
- name: F5
  gene_term:
    preferred_term: F5
    term:
      id: hgnc:3542
      label: F5
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  notes: >
    Factor V Leiden, the commonest inherited thrombophilia in European-ancestry populations,
    removes an activated protein C cleavage site so that activated factor V persists. It raises
    the risk of venous thrombosis several-fold and interacts strongly with oestrogen exposure.
    Its relationship to pulmonary embolism specifically is more complicated than its relationship
    to venous thrombosis, since it is relatively less frequent among embolic than among
    non-embolic presentations.
  evidence:
  - reference: PMID:11583312
    reference_title: "Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism--pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Study Group for Pooled-Analysis in Venous Thromboembolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Odds ratios for VTE were 4.9 (95% CI; 4.1-5.9) for the factor V Leiden and 3.8 (3.0-4.9) for the factor II G20210A mutation."
    explanation: >-
      Quantifies the effect size for venous thromboembolism in a pooled analysis of eight
      case-control studies.
  - reference: PMID:11583312
    reference_title: "Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism--pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Study Group for Pooled-Analysis in Venous Thromboembolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In factor V Leiden carriers using OC, the odds ratio for VTE was 10.25 (5.69-1 8.45)."
    explanation: >-
      Quantifies the gene-environment interaction with combined oral contraceptive use, which is
      the clinically important consequence of carrier status.

- name: F2
  gene_term:
    preferred_term: F2
    term:
      id: hgnc:3535
      label: F2
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  notes: >
    The prothrombin G20210A variant lies in the 3-prime untranslated region and raises circulating
    prothrombin. Unlike factor V Leiden it is distributed evenly between embolic and non-embolic
    venous thromboembolism.
  evidence:
  - reference: PMID:11583312
    reference_title: "Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism--pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Study Group for Pooled-Analysis in Venous Thromboembolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The odds ratio for venous thrombosis in double heterozygotes was 20.0 (11.1-36.1)."
    explanation: >-
      Quantifies the combined effect with factor V Leiden, showing that the two variants compound
      rather than merely coexist.

- name: PROC
  gene_term:
    preferred_term: PROC
    term:
      id: hgnc:9451
      label: PROC
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  notes: >
    Loss-of-function variants cause protein C deficiency. Together with protein S and antithrombin
    deficiency these are individually rarer than the common risk alleles but carry higher
    penetrance, and they belong to the mechanistic mirror image of factor V Leiden. One removes
    the target of the anticoagulant protease, the other removes the protease.

- name: PROS1
  gene_term:
    preferred_term: PROS1
    term:
      id: hgnc:9456
      label: PROS1
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  notes: >
    Loss-of-function variants cause protein S deficiency, removing the cofactor that activated
    protein C requires.

- name: SERPINC1
  gene_term:
    preferred_term: SERPINC1
    term:
      id: hgnc:775
      label: SERPINC1
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  notes: >
    Loss-of-function variants cause antithrombin deficiency, generally regarded as the
    highest-risk of the classical inherited thrombophilias. It is also the target through which
    heparins act, so the deficiency and the drug converge on the same protein.

biochemical:
- name: D-dimer
  notes: >
    A fibrin degradation product, raised whenever fibrin is being formed and lysed anywhere in the
    body. Its role in this disease is entirely as a rule-out test. It is sensitive and
    unspecific, so a negative result in a patient with low pretest probability excludes the
    diagnosis while a positive result means very little on its own. No numeric performance
    figures are recorded here because no cited reference in this entry reports them.

- name: Cardiac troponin
  notes: >
    A marker of myocyte necrosis, elevated here by right ventricular ischaemia rather than by
    coronary disease. It is not used diagnostically but is central to risk stratification, and
    its presence is one of the two criteria that define the intermediate-risk stratum.

- name: B-type natriuretic peptide
  notes: >
    Released in response to ventricular wall stretch, and therefore a biochemical readout of the
    right ventricular dilation node. Like troponin it stratifies risk rather than establishing
    the diagnosis.

environmental:
- name: Immobilisation and surgery
  description: >
    Prolonged immobility and major surgery, especially orthopaedic surgery of the hip and knee,
    are the archetypal acquired provoking factors. They act through stasis and through
    tissue-factor-mediated activation of coagulation, and they are the setting in which
    mechanical and pharmacological prophylaxis is applied.
  influences_mechanisms:
  - target: Prothrombotic venous context
    environmental_effect: PREDISPOSES
    causal_link_type: DIRECT
    description: >
      Immobility produces venous stasis and surgical tissue injury activates coagulation, which
      are two of the three components of the prothrombotic context node.
    evidence:
    - reference: PMID:29399531
      reference_title: "Deep vein thrombosis: pathogenesis, diagnosis, and medical management."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Virchow's Triad distills the multitude of risk factors for DVT into three basic elements favoring thrombus formation: venous stasis, vascular injury, and hypercoagulability."
      explanation: >
        Establishes venous stasis and vascular injury as two of the three thrombus-favouring
        elements this edge invokes. PARTIAL because it names the framework rather than measuring
        the step from immobility or from surgery to either element.
  evidence:
  - reference: PMID:10737280
    reference_title: "Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hospital or nursing home confinement, surgery, trauma, malignant neoplasm, chemotherapy, neurologic disease with paresis, central venous catheter or pacemaker, varicose veins, and superficial vein thrombosis are independent and important risk factors for VTE."
    explanation: >
      Population-based case-control study identifying surgery and hospital or nursing-home
      confinement as independent risk factors for venous thromboembolism. Surgery carried the
      largest odds ratio of any factor examined, at 21.7, which is the basis for calling it an
      archetypal provoking factor.

- name: Oestrogen exposure
  exposure_term:
    preferred_term: exposure to estrogens
    term:
      id: ECTO:9000010
      label: exposure to estrogens
  description: >
    Combined oral contraceptives and hormone replacement therapy raise the risk of venous
    thromboembolism, and they do so multiplicatively rather than additively in carriers of
    inherited thrombophilia. This is the best-quantified gene-environment interaction in the
    disease and the reason thrombophilia status changes contraceptive counselling.
  influences_mechanisms:
  - target: Prothrombotic venous context
    environmental_effect: PREDISPOSES
    causal_link_type: DIRECT
    description: >
      Oestrogen exposure shifts the coagulation balance and compounds the effect of an inherited
      thrombophilic background.
    evidence:
    - reference: PMID:11583312
      reference_title: "Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism--pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Study Group for Pooled-Analysis in Venous Thromboembolism."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Odds ratio for VTE associated with OC was 2.29 (1.72-3.04). In factor V Leiden carriers using OC, the odds ratio for VTE was 10.25 (5.69-1 8.45)."
      explanation: >-
        Gives both the main effect of oral contraceptive use and the substantially larger effect
        in factor V Leiden carriers, which is the interaction this exposure is curated for.
  evidence:
  - reference: PMID:11583312
    reference_title: "Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism--pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Study Group for Pooled-Analysis in Venous Thromboembolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Odds ratio for VTE associated with OC was 2.29 (1.72-3.04). In factor V Leiden carriers using OC, the odds ratio for VTE was 10.25 (5.69-1 8.45)."
    explanation: >
      Quantifies oral contraceptive use as a risk factor for venous thromboembolism, and shows the
      risk is several times higher again in factor V Leiden carriers, which is the gene-environment
      interaction this entry is curated for.

treatments:
- name: Pharmacological thromboprophylaxis
  description: >
    Low-dose anticoagulation given to patients at risk who do not have the disease, in hospital,
    after surgery, and in other high-risk settings. It is the only intervention in this entry
    that acts on the prothrombotic context node, which is the only part of the causal chain that
    exists before the disease does. That makes it the sole primary-prevention lever, and its
    effect on venous thromboembolism in hospitalised medical patients was roughly a two-thirds
    relative reduction against placebo.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Anticoagulation Therapy
    term:
      id: NCIT:C63341
      label: Anticoagulation Therapy
  target_mechanisms:
  - target: Prothrombotic venous context
    treatment_effect: INHIBITS
    description: >
      Prophylactic anticoagulation offsets the hypercoagulable component of the prothrombotic
      context so that a thrombus does not form in the first place.
  evidence:
  - reference: PMID:10477777
    reference_title: "A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The incidence of venous thromboembolism was significantly lower in the group that received 40 mg of enoxaparin"
    explanation: >-
      Establishes the effect in hospitalised medical patients against placebo, which is the
      cleanest available demonstration that acting on the prothrombotic context prevents the
      disease rather than treating it.
  - reference: PMID:10477777
    reference_title: "A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was no significant difference in the incidence of venous thromboembolism between the group that received 20 mg of enoxaparin"
    explanation: >-
      The dose-response arm, which matters mechanistically because it shows the benefit is not a
      general property of receiving an anticoagulant. Graded PARTIAL because it qualifies rather
      than establishes the treatment.

- name: Therapeutic anticoagulation
  description: >
    The mainstay of treatment in every risk stratum. Anticoagulation does not dissolve the
    embolus. It prevents further thrombus accretion and recurrent embolisation while endogenous
    fibrinolysis clears what is already there, which is the reason the treatment works despite
    acting on a node upstream of the one causing the symptoms.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Anticoagulation Therapy
    term:
      id: NCIT:C63341
      label: Anticoagulation Therapy
  target_mechanisms:
  - target: Deep venous thrombus formation
    treatment_effect: INHIBITS
    description: >
      Suppressing thrombin generation stops propagation of the source thrombus and formation of
      new thrombus, which is what prevents further embolisation.

- name: Direct oral anticoagulant therapy
  description: >
    Fixed-dose oral factor Xa inhibitors, now preferred over vitamin K antagonists for most
    patients. Their advantage over the older standard is not greater efficacy but less bleeding
    at equivalent efficacy, which was demonstrated separately for rivaroxaban in a
    pulmonary-embolism-specific trial and for apixaban across venous thromboembolism.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Anticoagulation Therapy
    term:
      id: NCIT:C63341
      label: Anticoagulation Therapy
    therapeutic_agent:
    - preferred_term: rivaroxaban
      term:
        id: CHEBI:68579
        label: rivaroxaban
    - preferred_term: apixaban
      term:
        id: CHEBI:72296
        label: apixaban
  target_mechanisms:
  - target: Deep venous thrombus formation
    treatment_effect: INHIBITS
    description: >
      Direct factor Xa inhibition reduces thrombin generation at the same node as heparin and
      vitamin K antagonism, by a different molecular route.
  evidence:
  - reference: PMID:22449293
    reference_title: "Oral rivaroxaban for the treatment of symptomatic pulmonary embolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Major bleeding was observed in 26 patients (1.1%) in the rivaroxaban group and 52 patients (2.2%) in the standard-therapy group (hazard ratio, 0.49; 95% CI, 0.31 to 0.79; P=0.003)."
    explanation: >-
      Quantifies the halving of major bleeding at noninferior efficacy in a trial recruiting
      specifically patients with acute symptomatic pulmonary embolism.
  - reference: PMID:23808982
    reference_title: "Oral apixaban for the treatment of acute venous thromboembolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A fixed-dose regimen of apixaban alone was noninferior to conventional therapy for the treatment of acute venous thromboembolism and was associated with significantly less bleeding"
    explanation: >-
      Establishes the same efficacy-and-safety pattern for a second agent of the class. Note the
      trial population is venous thromboembolism broadly rather than pulmonary embolism
      specifically.

- name: Systemic fibrinolysis
  description: >
    Plasminogen activators given systemically to lyse the embolus and unload the right ventricle.
    This is the one treatment that acts on the obstruction itself, and it is curated with its
    harm attached, because the trial that tested it in the intermediate-risk stratum found it
    prevented haemodynamic decompensation while causing major bleeding and stroke. That result is
    the reason fibrinolysis is reserved for patients already in shock rather than given to
    everyone with a strained right ventricle.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tenecteplase
      term:
        id: CHEBI:753718
        label: tenecteplase
  target_mechanisms:
  - target: Acute rise in pulmonary vascular resistance
    treatment_effect: INHIBITS
    description: >
      Lysis of embolic material restores pulmonary arterial cross-sectional area and lowers the
      resistance the right ventricle faces.
  evidence:
  - reference: PMID:24716681
    reference_title: "Fibrinolysis for patients with intermediate-risk pulmonary embolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Death or hemodynamic decompensation occurred in 13 of 506 patients (2.6%) in the tenecteplase group as compared with 28 of 499 (5.6%) in the placebo group (odds ratio, 0.44; 95% confidence interval, 0.23 to 0.87; P=0.02)."
    explanation: >-
      Establishes the efficacy half of the trade-off, a halving of death or haemodynamic
      decompensation.
  - reference: PMID:24716681
    reference_title: "Fibrinolysis for patients with intermediate-risk pulmonary embolism."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Stroke occurred in 12 patients (2.4%) in the tenecteplase group and was hemorrhagic in 10 patients; 1 patient (0.2%) in the placebo group had a stroke, which was hemorrhagic (P=0.003)."
    explanation: >-
      Refutes a general recommendation for fibrinolysis in the intermediate-risk stratum by
      quantifying the stroke harm that offsets the benefit above. Curated as REFUTE against the
      broad use of this treatment, not against its mechanism.
  - reference: PMID:24716681
    reference_title: "Fibrinolysis for patients with intermediate-risk pulmonary embolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patients with intermediate-risk pulmonary embolism, fibrinolytic therapy prevented hemodynamic decompensation but increased the risk of major hemorrhage and stroke."
    explanation: >-
      The authors' own summary of the trade-off. Graded PARTIAL because it supports the treatment
      in one respect and opposes it in another, which is exactly the curated position.

- name: Catheter-directed mechanical thrombectomy
  description: >
    Percutaneous removal of embolic material, offered increasingly in the intermediate-high and
    high-risk strata as an alternative to systemic lysis. Its mechanistic interest exceeds its
    current evidence base, because measuring the heart before and after the procedure has shown
    the interdependence mechanism reversing, which is stronger support for the causal model than
    any observational imaging study.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Therapeutic Procedure
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  target_mechanisms:
  - target: Ventricular interdependence and impaired left ventricular filling
    treatment_effect: INHIBITS
    description: >
      Relieving pulmonary arterial obstruction reduces right ventricular pressure overload,
      straightens the septum, and restores left ventricular filling.
  evidence:
  - reference: PMID:41984155
    reference_title: "Mechanical thrombectomy improves left ventricular filling in intermediate-high risk pulmonary embolism: the role of ventricular interdependence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mechanical thrombectomy in intermediate-high-risk PE not only relieves RV overload but also enhances LV filling by mitigating ventricular interdependence."
    explanation: >-
      States the mechanistic effect this treatment is curated for. The study is a single-centre
      series of 26 patients without a control arm, so it supports the mechanism rather than a
      clinical outcome benefit.

- name: Surgical pulmonary embolectomy
  description: >
    Open removal of central embolic material on cardiopulmonary bypass, reserved for high-risk
    disease where thrombolysis is contraindicated or has failed. It and catheter-directed
    intervention occupy the same niche, and in the setting where they have been compared the
    populations were largely defined by a contraindication to systemic lysis rather than by
    anatomy.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Acute rise in pulmonary vascular resistance
    treatment_effect: INHIBITS
    description: >
      Removing central embolic material restores pulmonary arterial cross-sectional area
      immediately and mechanically.
  evidence:
  - reference: PMID:41412228
    reference_title: "Catheter-directed interventions versus surgical embolectomy in massive pulmonary embolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The majority in both groups had absolute (CDI, 17.3%; SE, 16.7%; P = .94) or relative contraindication (CDI, 58.7%; SE, 66.7%; P = .49) to stPA."
    explanation: >-
      Establishes what actually selects patients into these procedures, namely inability to
      receive systemic thrombolysis rather than a positive indication. Graded PARTIAL because a
      retrospective single-system series cannot establish comparative efficacy.

- name: Inferior vena cava filter
  description: >
    A mechanical device intended to trap embolising thrombus before it reaches the lungs, so in
    principle the only treatment that acts on the embolization node itself. It is curated with
    its negative trial attached, because when tested against anticoagulation alone in patients at
    high risk of recurrence it did not reduce recurrent pulmonary embolism, and recurrences were
    numerically more frequent in the filter arm. Its remaining role is confined to patients who
    cannot be anticoagulated at all, which is a role defined by the absence of an alternative
    rather than by demonstrated benefit.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Therapeutic Procedure
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  target_mechanisms:
  - target: Embolization to the pulmonary arterial tree
    treatment_effect: INHIBITS
    description: >
      A caval filter is intended to intercept embolising thrombus mechanically between its venous
      origin and the pulmonary arteries.
  evidence:
  - reference: PMID:25919526
    reference_title: "Effect of a retrievable inferior vena cava filter plus anticoagulation vs anticoagulation alone on risk of recurrent pulmonary embolism: a randomized clinical trial."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "By 3 months, recurrent pulmonary embolism had occurred in 6 patients (3.0%; all fatal) in the filter group and in 3 patients (1.5%; 2 fatal) in the control group"
    explanation: >-
      Refutes routine filter use in anticoagulated patients at high risk of recurrence, since the
      outcome the device exists to prevent was not reduced and was numerically more common with
      the filter.

- name: Pulmonary endarterectomy and balloon pulmonary angioplasty
  description: >
    Mechanical removal or dilation of organised fibrotic thromboembolic material in chronic
    thromboembolic pulmonary hypertension. Endarterectomy is the treatment of choice where the
    disease is surgically accessible and balloon angioplasty is the alternative where it is not.
    Both produce right ventricular reverse remodelling, which is the point mechanistically, since
    it shows the chronic right ventricular changes are load-dependent and reversible rather than
    a fixed cardiomyopathy. This is the treatment that makes recognising chronic thromboembolic
    disease consequential rather than merely prognostic.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Thrombus resolution versus fibrotic organization
    treatment_effect: INHIBITS
    description: >
      Removing or dilating the organised fibrotic material relieves the fixed obstruction that
      failure of resolution produced.
  evidence:
  - reference: PMID:39467613
    reference_title: "Right ventricular remodelling and long-term survival after pulmonary endarterectomy versus balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both PEA and BPA led to significant RV reverse remodelling, with no clear evidence of a difference in survival rates."
    explanation: >-
      Establishes that both routes relieve the obstruction and that the right ventricle recovers,
      which is the mechanistic claim this treatment is curated for.
  - reference: PMID:39467613
    reference_title: "Right ventricular remodelling and long-term survival after pulmonary endarterectomy versus balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Improvement in RV function, particularly RV FAC, was associated with better outcomes, highlighting the importance of RV recovery in CTEPH treatment."
    explanation: >-
      Connects the mechanical result to outcome through right ventricular recovery, consistent
      with the entry's account that the right ventricle rather than the obstruction is what
      determines how patients fare. Graded PARTIAL because the study is a single-centre
      observational cohort without randomisation.

- name: Riociguat
  description: >
    A soluble guanylate cyclase stimulator approved for chronic thromboembolic pulmonary
    hypertension that is inoperable, or persistent after endarterectomy. It is worth noting what
    it implies. A pulmonary vasodilator improving a disease whose obstruction is organised fibrous
    tissue only makes sense if part of the raised resistance in that disease is not the visible
    obstruction at all, which is the small-vessel arteriopathy this entry declines to assert for
    lack of cited evidence.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Thrombus resolution versus fibrotic organization
    treatment_effect: INHIBITS
    description: >
      Pharmacological reduction of pulmonary vascular resistance in the chronic thromboembolic
      state, acting on the vascular component rather than on the organised material itself.
  evidence:
  - reference: PMID:23883377
    reference_title: "Riociguat for the treatment of chronic thromboembolic pulmonary hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By week 16, the 6-minute walk distance had increased by a mean of 39 m in the riociguat group, as compared with a mean decrease of 6 m in the placebo group"
    explanation: >-
      The randomised functional result in inoperable or post-endarterectomy disease.
  - reference: PMID:23883377
    reference_title: "Riociguat for the treatment of chronic thromboembolic pulmonary hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pulmonary vascular resistance decreased by 226 dyn·sec·cm(-5) in the riociguat group and increased by 23 dyn·sec·cm(-5) in the placebo group"
    explanation: >-
      The haemodynamic result, which is the mechanistically informative one, since a fall in
      resistance under a vasodilator implies a vasoactive component to an obstruction usually
      described as fixed.

experimental_models:
- name: Porcine consecutive pulmonary embolism model
  description: >
    Anaesthetised pigs receiving repeated catheter-delivered emboli at fixed intervals, with
    pressure-volume loops and invasive pressures recorded after each. The model exists because
    rodent venous thrombosis models reproduce thrombus formation well but do not reliably produce
    pulmonary embolism, so the haemodynamic half of the disease has to be studied by delivering
    emboli directly. Its value here is that it separates events that are simultaneous in
    patients. It shows pulmonary pressure rising from the first embolus, resistance and afterload
    only from the third, and dilation preceding the fall in ejection fraction. Its limitation is
    that bypassing spontaneous embolisation makes it useless for studying why thrombi embolise.
  experimental_model_type: OTHER
  organism:
    preferred_term: pig
    term:
      id: NCBITaxon:9823
      label: Sus scrofa
  modeled_mechanisms:
  - target: Acute rise in pulmonary vascular resistance
    description: >
      Serial embolisation reproduces the rise in pulmonary pressure and, with greater burden, in
      pulmonary vascular resistance.
  - target: Right ventricular afterload mismatch and dilation
    description: >
      The model reproduces right ventricular dilation and the later decline in ejection fraction.
  publication: PMID:38745282
  evidence:
  - reference: PMID:38745282
    reference_title: "Immediate cardiopulmonary responses to consecutive pulmonary embolism: a randomized, controlled, experimental study."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Twelve pigs were randomly assigned to receive sham procedures or consecutive PEs every 15 min until doubling of mean pulmonary pressure."
    explanation: >-
      Describes the design, including the sham control arm and the randomisation that make it a
      controlled experiment rather than a descriptive preparation.
  - reference: PMID:38745282
    reference_title: "Immediate cardiopulmonary responses to consecutive pulmonary embolism: a randomized, controlled, experimental study."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In an experimental model of consecutive PE, RV afterload elevation and dysfunction manifested after the third PE, in contrast to pulmonary pressure that increased after the first PE."
    explanation: >-
      The finding that makes the model informative for this entry, since it dissociates pressure
      from afterload in a way that clinical measurement cannot.

diagnosis:
- name: Computed tomographic pulmonary angiography
  description: >
    The first-line confirmatory test, showing filling defects directly. It also gives the right
    ventricular to left ventricular diameter ratio in the same acquisition, so the test that
    establishes the diagnosis simultaneously supplies the risk-stratification variable.

- name: Risk stratification by right ventricular function and cardiac biomarkers
  description: >
    Severity is assessed from haemodynamic status, a validated clinical severity score, imaging
    of the right ventricle, and cardiac biomarkers, rather than from the anatomical extent of the
    embolus. The 2026 multisociety guideline replaced the older informal massive and submassive
    vocabulary with an explicit set of clinical categories built on these variables.
  evidence:
  - reference: PMID:41712898
    reference_title: "2026 AHA/ACC/ACCP/ACEP/CHEST/SCAI/SHM/SIR/SVM/SVN Guideline for the Evaluation and Management of Acute Pulmonary Embolism in Adults: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A key feature of this guideline is the introduction of the AHA/ACC Acute Pulmonary Embolism Clinical Categories, which enhance the precision of severity classification, prognosis assessment, and evidence-based therapeutic decision-making."
    explanation: >-
      Documents the current formal severity classification that this entry's subtypes correspond
      to.

- name: D-dimer with pretest probability assessment
  description: >
    A sensitive but unspecific assay used to exclude the diagnosis in patients whose clinical
    probability is low. It is diagnostically useful only in that direction, and using it as a
    positive test generates imaging without benefit.

progression:
- phase: Acute event
  notes: >
    Onset over minutes to hours. Mortality is concentrated in the earliest period and is driven by
    right ventricular failure rather than by hypoxaemia, with a majority of deaths in patients
    presenting in shock occurring within the first hour.
  evidence:
  - reference: PMID:11888976
    reference_title: "Major pulmonary embolism: review of a pathophysiologic approach to the golden hour of hemodynamically significant pulmonary embolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In either case, the presence of shock defines a threefold to sevenfold increase in mortality, with a majority of deaths occurring within 1 h of presentation."
    explanation: >-
      Supports the concentration of mortality in the first hour after presentation with shock.

- phase: Resolution on anticoagulation
  notes: >
    Most patients stabilise and clear the embolic burden over weeks to months while
    anticoagulated. Duration of anticoagulation is then decided by whether the event was
    provoked, which is a statement about the prothrombotic context node rather than about the
    embolus.

- phase: Chronic thromboembolic pulmonary hypertension
  notes: >
    A minority fail to clear the material, which organises into fixed fibrotic obstruction. In a
    prospective cohort the cumulative incidence of symptomatic disease was 3.8 percent at two
    years, and no new cases appeared beyond two years of follow-up, so the risk is front-loaded.
  evidence:
  - reference: PMID:15163775
    reference_title: "Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cumulative incidence of symptomatic CTPH was 1.0 percent (95 percent confidence interval, 0.0 to 2.4) at six months, 3.1 percent (95 percent confidence interval, 0.7 to 5.5) at one year, and 3.8 percent (95 percent confidence interval, 1.1 to 6.5) at two years."
    explanation: >-
      Gives the cumulative incidence figures quoted in this phase.

differential_diagnoses:
- name: Acute coronary syndrome
  description: >
    Shares chest pain, dyspnoea, troponin elevation, and electrocardiographic change. The
    distinction matters because both conditions raise troponin but by opposite mechanisms,
    coronary occlusion in one and right ventricular afterload in the other, and because the
    treatments are close to mutually exclusive.

- name: Pneumonia
  description: >
    Shares pleuritic pain, breathlessness, fever, and a peripheral opacity on chest radiography.
    A pulmonary infarct is radiographically similar to a consolidation, and the two are commonly
    confused in both directions.

- name: Aortic dissection
  description: >
    Shares abrupt chest pain and haemodynamic collapse. It is the differential in which the
    consequence of getting it wrong is greatest, because anticoagulation or fibrinolysis given to
    a dissection is actively harmful.

- name: Pericardial tamponade
  description: >
    Shares obstructive shock with a clear chest and raised jugular venous pressure. Both impair
    ventricular filling rather than contraction, so they present with the same physiology arrived
    at by different routes.

prevalence:
- population: Worldwide
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 100.0
  rate_low: 100.0
  rate_high: 200.0
  notes: >
    Venous thromboembolism is commonly cited at an annual incidence of roughly one to two per
    thousand adults, rising steeply with age, with pulmonary embolism accounting for a substantial
    share. One to two per thousand is one hundred to two hundred per hundred thousand, which is
    the ABOVE_1_IN_1000 band. The value recorded here is an order-of-magnitude normalisation of
    that range and is not drawn from a single cited study, which is why no evidence item is
    attached.

discussions:
- discussion_id: what_makes_a_thrombus_embolise
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >
    Why do some deep venous thrombi embolise while most do not, and can that propensity be
    predicted or modified?
  rationale: >
    Every treatment in this disease acts either on thrombus formation or on the consequences of an
    embolus that has already lodged. Nothing acts on embolisation itself, and the step is treated
    clinically as a stochastic event. There is evidence that it is not purely stochastic, since
    two inherited thrombophilias with comparable effects on thrombosis risk are distributed
    differently between embolic and non-embolic presentations, which implies thrombus properties
    or location influence the propensity. What those determinants are is not established, and the
    model systems that could address it are precisely the ones that fail, since rodent venous
    thrombosis models do not embolise and the porcine models that reproduce the haemodynamics
    deliver emboli directly and so bypass the question.
  attaches_to:
  - "pathophysiology#Embolization to the pulmonary arterial tree"
  evidence:
  - reference: PMID:11583312
    reference_title: "Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism--pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Study Group for Pooled-Analysis in Venous Thromboembolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we also confirmed that the frequency of factor V Leiden was lower in patients with pulmonary embolism than in patients with deep vein thrombosis without PE (odds ratio 0.69)."
    explanation: >-
      Establishes that embolic propensity is not a simple function of thrombotic tendency, which
      is what makes this a gap rather than an already-answered question.
  proposed_experiments:
  - experiment_id: exp_embolic_propensity_thrombus_composition
    name: Thrombus composition and embolic propensity
    description: >
      Compare the composition, age, and anatomical origin of retrieved thrombi from patients
      undergoing mechanical thrombectomy for pulmonary embolism against thrombi retrieved or
      imaged in patients with deep vein thrombosis that did not embolise, testing whether fibrin
      content, platelet content, or degree of organisation predicts embolisation.

- discussion_id: polygenic_background_modifies_monogenic_thrombophilia
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >
    Should thrombophilia risk be assessed as a polygenic quantity rather than as carrier status
    for a small number of named variants?
  rationale: >
    Thrombophilia testing in practice asks whether a patient carries one of a handful of variants.
    A large genome-wide meta-analysis found that the extremes of a polygenic score reach the risk
    conferred by those variants, and, more consequentially, that carriers of the classical
    variants who sit in the low tail of the polygenic distribution have risk indistinguishable
    from the general population. If that is confirmed prospectively it means carrier status alone
    is not the right unit of risk, and that some patients currently counselled as thrombophilic
    are not. The open question is whether this changes management decisions, principally the
    duration of anticoagulation, rather than merely improving risk estimation.
  attaches_to:
  - "pathophysiology#Prothrombotic venous context"
  evidence:
  - reference: PMID:36658437
    reference_title: "Genome-wide meta-analysis identifies 93 risk loci and enables risk prediction equivalent to monogenic forms of venous thromboembolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also document that F2 and F5 mutation carriers in the bottom 10% of the PRS distribution had a risk similar to that of the general population."
    explanation: >-
      This is the specific finding that makes carrier status an incomplete description of risk,
      and therefore the basis of the question.
  - reference: PMID:36658437
    reference_title: "Genome-wide meta-analysis identifies 93 risk loci and enables risk prediction equivalent to monogenic forms of venous thromboembolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals within the top 0.1% of PRS distribution had a VTE risk similar to homozygous or compound heterozygous carriers of the variants G20210A"
    explanation: >-
      Establishes the other half of the argument, that common-variant background alone can reach
      monogenic-equivalent risk.

- discussion_id: reperfusion_in_intermediate_risk_disease
  kind: CONTROVERSY
  status: OPEN
  prompt: >
    Which patients with a strained but compensating right ventricle should have the obstruction
    removed?
  rationale: >
    The intermediate-risk stratum is defined by demonstrable right ventricular injury without
    systemic hypotension, so by the mechanistic account in this entry it is the group in which
    intervening before the cascade becomes self-reinforcing should pay off most. The randomised
    test of systemic fibrinolysis in exactly this group found the expected benefit and an
    offsetting harm, leaving no net mortality difference. Catheter-directed approaches are
    proposed as the way to get the mechanical benefit without the systemic bleeding, and the
    haemodynamic evidence that they reverse ventricular interdependence is encouraging, but it
    comes from small uncontrolled series. The controversy is therefore not about the mechanism,
    which is well supported, but about whether any currently available way of acting on it
    improves outcomes.
  attaches_to:
  - "pathophysiology#Right ventricular afterload mismatch and dilation"
  - "pathophysiology#Ventricular interdependence and impaired left ventricular filling"
  evidence:
  - reference: PMID:24716681
    reference_title: "Fibrinolysis for patients with intermediate-risk pulmonary embolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By day 30, a total of 12 patients (2.4%) in the tenecteplase group and 16 patients (3.2%) in the placebo group had died (P=0.42)."
    explanation: >-
      Shows the absence of a mortality difference at thirty days despite the reduction in
      haemodynamic decompensation, which is the core of the controversy.
  proposed_experiments:
  - experiment_id: exp_catheter_reperfusion_randomised_outcome
    name: Randomised outcome trial of catheter-directed reperfusion
    description: >
      Randomise normotensive patients with right ventricular dysfunction and biomarker elevation
      to catheter-directed reperfusion plus anticoagulation versus anticoagulation alone, powered
      for death or haemodynamic decompensation with bleeding as a co-primary safety outcome, to
      test whether the mechanical benefit demonstrated haemodynamically translates into outcome
      benefit without the bleeding cost of systemic lysis.

notes: >
  Scope. This entry curates pulmonary embolism as an acute cardiopulmonary event, with deep
  venous thrombus formation included as the immediately upstream node because anticoagulation
  acts there. Non-thrombotic embolism, including fat, air, amniotic fluid, tumour, and septic
  embolism, shares the anatomical endpoint but not the mechanism and is deliberately out of
  scope. Chronic thromboembolic pulmonary hypertension is curated as the chronic outcome node and
  phenotype of this disease rather than as an entity in its own right, and its small-vessel
  arteriopathy arm is not asserted here.

  Deep-research provenance. Curated from a claude_code deep-research report treated as leads only.
  The report's citations proved unusually reliable, with all twelve sampled identifiers resolving
  to the papers claimed. Its suggested ontology bindings did not. Three checks failed. HP:0030848
  was offered as Pleuritic chest pain and is in fact Elevated jugular venous pressure, which is a
  genuine sign of this disease and is now curated correctly under its real label, with pleuritic
  chest pain bound to HP:0033771. HP:0004936 was labelled Deep venous thrombosis and is Venous
  thrombosis, so the specific term HP:0002625 is used instead. CHEBI:66989 was offered as apixaban
  and is a sphinganine lipid, with apixaban being CHEBI:72296. NEC preflight returned SKIP because
  MONDO records no causal gene for this disease. The manual fallback passed, since every OMIM
  identifier in the report corresponds to a thrombophilia locus consistent with the intended
  entity.

  References fetched and not used. Four references were retrieved during curation and then not
  cited, because none of their cached records carries abstract text that could be quoted. They
  were the 2019 ESC guideline PMID:31504429, the updated chronic thromboembolic incidence
  meta-analysis PMID:37321620, a factor V Leiden and prothrombin meta-analysis PMID:22329698, and
  a review of mouse venous thrombosis models PMID:22345593. Their cache files are deliberately not
  committed, since committing a cached reference that nothing cites would suggest an evidential
  basis the entry does not have. The claims those papers would have carried are instead carried by
  sources that can be quoted: the 2026 multisociety guideline for severity classification, the
  Pengo cohort for chronic thromboembolic incidence, the pooled thrombophilia analysis
  PMID:11583312 for variant effect sizes, and the porcine model PMID:38745282 in place of the
  rodent-model review.
📚

References & Deep Research

Deep Research

1
Claude Code ▸
Pulmonary Embolism (PE): Comprehensive Disease Characteristics Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 2026-08-10T03:49:50.779049

Pulmonary Embolism (PE): Comprehensive Disease Characteristics Research Report

1. Disease Information

Overview: Pulmonary embolism (PE) is an acquired cardiovascular emergency caused by the acute obstruction of the pulmonary arterial circulation by embolic material — most commonly a thrombus (thromboembolism) that has dislodged from the deep venous system, though fat, air, amniotic fluid, tumor, and septic emboli are recognized non-thrombotic variants. PE and deep vein thrombosis (DVT) are the two principal clinical manifestations of venous thromboembolism (VTE), a single underlying disease process; roughly 90% of PE thrombi originate in the proximal deep veins of the lower extremities, pelvis, or (less commonly) upper extremities/right heart. Acute obstruction increases pulmonary vascular resistance and right ventricular (RV) afterload, and it is this hemodynamic consequence — not the embolus itself — that drives short-term mortality risk.

Key identifiers: - MONDO: MONDO:0005279 (pulmonary embolism) - ICD-10-CM: I26 (Pulmonary embolism); I26.0 (with acute cor pulmonale); I26.9 (without acute cor pulmonale); O88.2 (obstetric PE) - ICD-11: BB00 (Pulmonary embolism) - MeSH: D011655 (Pulmonary Embolism) - HPO: HP:0002204 (Pulmonary embolism) - SNOMED CT: 59282003 (Pulmonary embolism) - OMIM: PE itself is a multifactorial acquired condition without a dedicated OMIM disease number; monogenic thrombophilias predisposing to it are separately cataloged — Factor V Leiden thrombophilia (OMIM 188055), Prothrombin-related thrombophilia (OMIM 176930), Protein C deficiency (OMIM 176860), Protein S deficiency (OMIM 176880), Antithrombin III deficiency (OMIM 613118). - Orphanet: Idiopathic/inherited thrombophilias are separately coded (e.g., ORPHA:325 Hereditary antithrombin deficiency); PE as an acquired event does not carry a distinct Orphanet number given its high population prevalence.

Synonyms/alternative names: Pulmonary thromboembolism (PTE), acute pulmonary embolism, lung embolism, pulmonary infarction (when tissue necrosis occurs distally), massive/submassive PE (older, now-discouraged severity nomenclature — see §11), venous thromboembolism (VTE) when referring to the combined DVT/PE spectrum.

Data provenance: Most PE knowledge derives from aggregated, disease-level clinical resources — large multicenter cohorts (e.g., RIETE registry), national/administrative databases (WHO mortality database, US National Inpatient Sample), randomized controlled trials of anticoagulants, and systematic reviews/meta-analyses — rather than single-patient EHR mining, though EHR-based case-finding algorithms (Wells/YEARS/Geneva scores) are themselves embedded in routine care and increasingly captured in real-world data.

2. Etiology

Disease Causal Factors

PE's proximate cause is thrombus formation in the venous circulation followed by embolization to the pulmonary arterial tree. Thrombogenesis is classically explained by Virchow's triad: (1) endothelial/vascular wall injury, (2) blood stasis, and (3) a hypercoagulable state. Modern reviews frame these three factors as converging mechanistic axes rather than independent causes — thrombosis typically begins as a platelet-fibrin nidus on venous valve pockets in the lower-extremity deep veins, propagates, and can embolize (Stone et al., Cardiovasc Diagn Ther, review of DVT pathogenesis; Chung, Lip, J Thromb Haemost 2003, PMC3006583 — "Virchow's Contribution to the Understanding of Thrombosis and Cellular Biology"). Non-thrombotic causes (fat embolism after long-bone fracture, air embolism from vascular procedures, amniotic fluid embolism in pregnancy, tumor embolism, septic embolism from infective endocarditis or IV drug use) share the same anatomical endpoint but distinct triggering mechanisms.

Risk Factors — Genetic

  • Factor V Leiden (F5 R506Q, rs6025) — the single most common inherited thrombophilia (~5% of the general European-ancestry population); heterozygotes have ~3-fold increased VTE risk, homozygotes 50–80-fold (PMID: 22329698, meta-analysis of FVL/PT G20210A in symptomatic PE/DVT). HGNC: F5 (HGNC:3542).
  • Prothrombin G20210A (F2 20210G>A) — affects 1–4% of US/European populations; increases prothrombin levels ~70% in homozygotes; independent VTE risk factor, with a disproportionately higher relative risk for isolated PE than FVL (15% isolated PE in G20210A carriers vs. 6% in FVL carriers and 6% in non-thrombophilic patients) (PMID: 18796457). HGNC: F2 (HGNC:3535).
  • Combined FVL + G20210A heterozygosity — synergistic risk, OR ≈20.0 (95% CI 11.1–36.1) for venous thrombosis versus neither mutation (pooled analysis, PMID: 11583312).
  • Protein C deficiency (PROC, OMIM 176860), Protein S deficiency (PROS1, OMIM 176880), Antithrombin III deficiency (SERPINC1, OMIM 613118) — rarer but higher-penetrance autosomal dominant thrombophilias; antithrombin deficiency confers the highest relative risk among classic thrombophilias.
  • ABO blood group — non-O blood groups (especially A) confer ~1.5–2× VTE risk via elevated von Willebrand factor/Factor VIII.
  • Polygenic risk — a 2023 genome-wide meta-analysis of 81,190 VTE cases and >1.4 million controls identified 93 risk loci (62 novel), with a polygenic risk score whose top 0.1% carries VTE risk comparable to monogenic FVL/prothrombin carriers (Klarin et al., Nat Genet 2023, PMID: 36658437). Many loci map to coagulation-cascade or platelet-function genes. A 2024–2025 multipopulation GWAS across 9 international cohorts identified 38 genome-wide-significant loci including 2 novel loci (NME7, FOXK2) among FVL/prothrombin carriers, implying modifier loci beyond the classic monogenic mutations (Blood 2024 abstract; Blood Advances 2025, PMID: 40554366).
  • Proteome-wide Mendelian randomization implicates 20 causally associated circulating proteins (F2, F11, ABO, PLCG2, LRP4, PLEK, KLKB1, PROC, KNG1, THBS2, SERPINA1, RARRES2, CEL, GP6, SERPINE2, SERPINA10, OBP2B, EFEMP1, F5, MSR1) — nominating novel druggable targets (PMC10678328).
  • Dysfibrinogenemia, plasminogen deficiency, elevated Factor VIII/IX/XI — additional, lower-penetrance heritable contributors.

Risk Factors — Environmental/Acquired

  • Surgery and trauma (especially orthopedic — hip/knee arthroplasty, major trauma with immobilization)
  • Malignancy (see §2/§6 cancer-associated thrombosis; Khorana score risk stratification)
  • Immobilization (long-haul travel, hospitalization, paralysis)
  • Pregnancy and puerperium — 5-fold increased VTE risk antepartum, 15–35-fold postpartum (Frontiers Cardiovasc Med 2022 review); incidence of PE in pregnancy ≈1/1,000 pregnancies; PE accounts for ~3.2% of global maternal deaths.
  • Estrogen exposure — combined oral contraceptives, hormone replacement therapy
  • Obesity, older age, prior VTE, central venous catheters, nephrotic syndrome, inflammatory bowel disease, COVID-19/severe infection (COVID-19-associated coagulopathy substantially elevates in-hospital VTE risk)
  • Smoking — modest independent risk factor, particularly synergistic with oral contraceptive use.

Protective Factors

  • No strong genetic "protective allele" is as well established as the risk variants, though the polygenic score distribution (PMID 36658437) implies the low tail carries reduced risk. Regular physical activity, maintenance of normal BMI, and avoidance of prolonged immobilization are the principal modifiable protective/behavioral factors; prophylactic anticoagulation (mechanical or pharmacologic) is protective in high-risk surgical/hospitalized populations.

Gene-Environment Interactions

Inherited thrombophilia interacts multiplicatively with acquired provoking factors — e.g., FVL carriers taking combined oral contraceptives have markedly higher risk than either factor alone; pregnancy in antithrombin-deficient women confers very high absolute VTE risk. CTD (Comparative Toxicogenomics Database) and PheGenI catalog such gene-chemical-disease interactions for F5/F2/SERPINC1.

3. Phenotypes

PE phenotypes span symptoms, signs, and laboratory/imaging abnormalities, with substantial heterogeneity — from asymptomatic incidental PE to sudden cardiac arrest.

Phenotype Type Frequency (approx.) HPO term
Dyspnea (acute-onset) Symptom ~50–75% (most common presenting symptom) HP:0002094
Pleuritic chest pain Symptom ~40–70% HP:0030848 (Pleuritic chest pain) / HP:0100749 (Chest pain)
Tachycardia Sign ~25–40% HP:0001649
Tachypnea Sign ~50–70% HP:0002789
Cough Symptom ~20–35% HP:0012735
Hemoptysis Symptom ~5–13% (more common with pulmonary infarction) HP:0002105
Syncope Symptom/sign ~5–15% (marker of high-risk PE) HP:0001279
Hypotension/shock Sign ~5% (defines high-risk PE) HP:0002615 (Hypotension)
Lower-limb DVT signs (unilateral leg swelling/pain) Sign ~40–50% concurrent DVT on imaging HP:0030963-adjacent / clinical (DVT itself: HP:0004936, Deep venous thrombosis)
Elevated troponin Lab abnormality ~30–50% (marker of RV myocardial strain) HP:0410174 or generic biomarker slot
Elevated BNP/NT-proBNP Lab abnormality variable, correlates with RV dysfunction —
Elevated D-dimer Lab abnormality >95% sensitivity, low specificity —
RV dysfunction on echocardiography Imaging finding ~25–50% of normotensive PE HP:0011675 (Arrhythmia) not applicable; use HP:0025159 (Reduced right ventricular ejection fraction) or free text
Hypoxemia Lab/sign common HP:0012418
Fever (low-grade) Symptom ~10% HP:0001945

Characteristics: - Onset: Acute onset is typical (hours), but subacute/insidious presentations occur with recurrent small emboli or in chronic thromboembolic disease. - Severity: Highly variable — the AHA/ACC 2026 guideline formalizes a 5-tier severity classification (Clinical Categories A–E, low to high risk; see §11) replacing the older informal "massive/submassive/minor" terminology. - Progression: Typically an acute event followed by either resolution (with anticoagulation), recurrence, or (in ~0.1–9% depending on cohort) evolution to chronic thromboembolic pulmonary hypertension (CTEPH) over months (see §6, §11). - Frequency in affected individuals: Classic PIOPED-era data: dyspnea (73%), pleuritic pain (66%), cough (37%), leg swelling (28%), hemoptysis (13%). Up to 30–40% of patients with confirmed DVT have concurrent asymptomatic PE.

Quality of life impact: Post-PE syndrome — persistent dyspnea, functional limitation, and reduced exercise capacity — affects an estimated 30–50% of survivors at 1 year even without CTEPH, impairing SF-36/EQ-5D physical-function domains (Klok FA et al., post-PE syndrome literature). Post-thrombotic syndrome (when concurrent DVT) further impairs QoL.

4. Genetic/Molecular Information

PE itself is not a monogenic disease; genetic contributions act through heritable thrombophilia predisposing to venous thrombosis (upstream cause) rather than through a PE-specific gene.

Causal/predisposing genes (thrombophilia): | Gene | HGNC | Variant | Classification | Mechanism | |---|---|---|---|---| | F5 | HGNC:3542 | c.1601G>A (R506Q), "Factor V Leiden" | Pathogenic (established risk factor) | Loss of APC cleavage site → resistance to activated protein C degradation → prothrombotic gain-of-persistence | | F2 | HGNC:3535 | c.*97G>A (20210G>A, 3′UTR) | Pathogenic (established risk factor) | Increased prothrombin mRNA stability/translation → elevated plasma prothrombin | | PROC | HGNC:9451 | Various LOF | Pathogenic | Protein C deficiency, loss of anticoagulant surveillance | | PROS1 | HGNC:9456 | Various LOF | Pathogenic | Protein S deficiency (Protein C cofactor loss) | | SERPINC1 | HGNC:775 | Various LOF | Pathogenic | Antithrombin deficiency, loss of thrombin/factor Xa inhibition | | ABO | HGNC:79 | Non-O blood group alleles | Risk-modifying | Elevated vWF/Factor VIII | | F11, F13, THBD, FGG | various | Various | Risk-modifying | Coagulation cascade modulation |

Allele frequencies: FVL ~5% (European ancestry), rare in African/Asian populations; prothrombin G20210A ~1–4% (European ancestry), rare elsewhere — both queryable via gnomAD/1000 Genomes. Antithrombin/Protein C/S deficiencies are individually rare (<0.5% population prevalence) but higher-penetrance.

Variant classification: ClinVar and ClinGen curate pathogenicity per ACMG/AMP criteria for PROC/PROS1/SERPINC1 LOF variants; FVL and prothrombin G20210A are long-established "risk allele" (not strict Mendelian pathogenic) classifications given incomplete penetrance.

Functional consequences: Predominantly gain-of-function/loss-of-regulation for procoagulant factors (FVL, prothrombin 20210A) versus loss-of-function for natural anticoagulants (Protein C, Protein S, antithrombin) — i.e., the shared endpoint is a shift in the coagulation/anticoagulation balance toward net thrombin generation.

Polygenic architecture: The 2023 GWAS meta-analysis (PMID: 36658437) found the 93 identified loci converge on coagulation cascade and platelet function genes; a polygenic risk score (PRS) stratifies risk continuously and rivals monogenic thrombophilia at its extremes — supporting a common-variant, quantitative-trait architecture layered atop rare high-penetrance variants.

Somatic/acquired hypercoagulability: JAK2 V617F and other myeloproliferative-neoplasm driver mutations are recognized somatic causes of unusual-site/unprovoked VTE (e.g., splanchnic vein thrombosis, less commonly PE), relevant when working up unprovoked PE in younger patients.

Epigenetics: Less well characterized for PE specifically than for other vascular disease; some evidence links DNA methylation changes in coagulation-gene promoters (e.g., F3/tissue factor) to VTE risk, but this is an emerging rather than established area.

Chromosomal abnormalities: Not a recognized primary cause of PE; PE is not part of classic aneuploidy/CNV syndromes.

5. Environmental Information

(See also §2.) Key environmental/exposure categories: - Surgical/traumatic tissue injury — activates tissue factor pathway; ECTO-codeable perioperative immobilization exposure. - Prolonged immobility — long-haul air/car travel ("economy class syndrome"), hospital bed rest, cast immobilization. - Hormonal exposures — estrogen-containing contraceptives, hormone replacement therapy, selective estrogen receptor modulators (tamoxifen). - Infectious triggers — severe infection/sepsis (including COVID-19, which independently and substantially elevates VTE/PE risk via endothelial injury, complement activation, and immunothrombosis) and infective endocarditis (source of septic pulmonary emboli). - Toxin/lifestyle exposures — tobacco smoking (synergistic with estrogen), obesity, dehydration. - No pathogen directly causes thrombotic PE (it is not an infectious disease per se), but septic emboli PE is a distinct infectious-etiology variant (typically Staphylococcus aureus from right-sided endocarditis or IV drug use, or oropharyngeal anaerobes in Lemierre syndrome).

6. Mechanism / Pathophysiology

Causal chain (initiating trigger → clinical manifestation)

  1. Trigger (upstream): Endothelial injury / venous stasis / hypercoagulable state (Virchow's triad) in the deep venous system, most often the calf/popliteal/femoral/iliac veins.
  2. Thrombogenesis: Platelet adhesion/activation at a venous valve pocket nidus → coagulation cascade activation → thrombin generation → fibrin polymerization → occlusive/non-occlusive venous thrombus (shared logic with the dismech thrombogenesis module: platelet adhesion/activation → coagulation cascade activation and thrombin-driven fibrin formation → pathological fibrin-platelet thrombus).
  3. Embolization: Thrombus fragment dislodges (spontaneously or with mechanical perturbation) and travels via the inferior vena cava → right atrium → right ventricle → pulmonary arterial tree, lodging according to size (large thrombi can saddle the main pulmonary artery bifurcation; smaller emboli occlude segmental/subsegmental branches).
  4. Acute pulmonary vascular obstruction: Mechanical obstruction plus hypoxic and serotonin/thromboxane-mediated pulmonary vasoconstriction → abrupt rise in pulmonary vascular resistance (PVR).
  5. RV afterload mismatch: The thin-walled RV, unaccustomed to acute afterload, dilates and its wall tension rises → RV ischemia (reduced coronary perfusion pressure gradient) → contractile dysfunction → RV free-wall hypokinesis/dilation, interventricular septal bowing into the LV → reduced LV preload and cardiac output → hypotension/shock in severe cases. This RV-failure cascade is the proximate mechanism of hemodynamic collapse and early death, not the pulmonary infarct itself.
  6. Gas exchange abnormality: Ventilation-perfusion (V/Q) mismatch and increased alveolar dead space → hypoxemia and hypocapnia (compensatory hyperventilation); true shunt can occur via atelectasis or patent foramen ovale reopening under RV pressure overload (paradoxical embolism risk).
  7. Neurohormonal/inflammatory amplification: RV wall stress triggers natriuretic peptide release (BNP/NT-proBNP); myocardial stretch/microinfarction releases troponin; systemic inflammatory mediators (IL-6, TNF-α) are elevated and correlate with severity.
  8. Resolution vs. persistence: Endogenous fibrinolysis (plasmin-mediated) and anticoagulant-assisted clot organization typically resolve most emboli over weeks; incomplete resolution with fibrotic remodeling of the pulmonary vascular intima can produce chronic thromboembolic pulmonary hypertension (CTEPH) — pooled incidence ~2.5–2.8% after acute PE (meta-analyses, ERJ 2023 update; higher in Asian populations, 5.08% vs. 1.96% in Europeans), risk-amplified by unprovoked PE, recurrent VTE, and baseline RV dysfunction.

Molecular pathways

  • Coagulation cascade: Extrinsic (tissue factor/Factor VIIa) and intrinsic (contact activation) pathways converge on Factor Xa → prothrombinase complex → thrombin → fibrin. KEGG: hsa04610 (Complement and coagulation cascades). Reactome: R-HSA-140877 (Formation of Fibrin Clot).
  • Platelet activation: GPIb-vWF and GPVI-collagen interactions, thromboxane A2/ADP amplification — relevant KEGG hsa04611 (Platelet activation).
  • Fibrinolysis: tPA/uPA–plasminogen–plasmin axis governs clot resolution; impaired fibrinolytic capacity (elevated PAI-1) is linked to recurrent VTE and CTEPH risk.
  • Pulmonary vasoconstriction: Serotonin (5-HT) and thromboxane A2 released from activated platelets acutely worsen V/Q mismatch and pulmonary hypertension independent of mechanical obstruction.
  • RV pressure-overload signaling: Neurohormonal activation (renin-angiotensin, natriuretic peptide systems), myocardial stretch-induced BNP transcription, and RV ischemia-driven troponin release.

Cellular processes

Endothelial activation/dysfunction, platelet activation and aggregation, neutrophil extracellular trap (NET) formation (immunothrombosis — increasingly recognized, especially in infection/cancer-associated and COVID-19-associated PE), cardiomyocyte stretch and stress response, and (in CTEPH) pulmonary artery smooth muscle cell proliferation/vascular remodeling analogous to the dismech pulmonary_vascular_remodeling and thrombogenesis modules.

Protein dysfunction

Loss-of-function in natural anticoagulants (Protein C, Protein S, antithrombin) or gain-of-persistence in procoagulant factors (Factor V Leiden resisting APC-mediated inactivation; elevated prothrombin from the G20210A variant) shift the coagulation-anticoagulation equilibrium.

Immune system involvement

Immunothrombosis — the coupling of innate immune activation (complement, neutrophils/NETs, monocyte tissue factor expression) to coagulation — is now recognized as a major mechanism in infection- and cancer-associated PE, exemplified dramatically by COVID-19-associated coagulopathy.

Tissue damage mechanisms

RV ischemia from afterload mismatch and reduced coronary perfusion gradient; pulmonary infarction (hemorrhagic, wedge-shaped, typically peripheral/subpleural) occurs in a minority (~10–15%) of PE cases, more often with smaller distal emboli and pre-existing cardiopulmonary disease limiting collateral bronchial arterial flow.

Biochemical abnormalities

Elevated D-dimer (fibrin degradation product — sensitive but nonspecific marker of ongoing fibrinolysis), elevated cardiac troponin I/T (myocardial strain/microinjury; associated with 5.4-fold higher odds of in-hospital mortality and 3.4-fold higher odds of RV dysfunction in meta-analysis), elevated BNP/NT-proBNP (ventricular wall stress; higher sensitivity for RV overload than troponin), arterial blood gas hypoxemia/hypocapnia.

Molecular/omics profiling

  • Genomics: GWAS loci as above (PMID: 36658437).
  • Metabolomics: A 2022 Mendelian randomization study linked specific blood metabolites to genetically predicted PE risk (PMC9422150), nominating novel metabolic biomarkers, though causal directionality requires further validation.
  • Proteomics: Proteome-wide MR nominates F2, F11, ABO, PROC, KNG1, SERPINC1, F5, and others as causal circulating proteins (PMC10678328).
  • Single-cell/spatial: Not yet a mature area for PE specifically (contrast with atherosclerosis); most single-cell work on venous thrombosis mechanism is in animal models of the thrombus microenvironment (neutrophils, monocytes, platelets).

Suggested ontology terms

  • GO (Biological Process): GO:0007596 (blood coagulation), GO:0030193 (regulation of blood coagulation), GO:0002576 (platelet degranulation), GO:0042730 (fibrinolysis), GO:0001525 (angiogenesis, for CTEPH vascular remodeling), GO:0002544 (chronic inflammatory response)
  • GO (Molecular Function): GO:0004252 (serine-type endopeptidase activity, for thrombin/Factor Xa), GO:0005515 (protein binding)
  • CL (Cell Type): CL:0000767 (platelet-precursor/megakaryocyte lineage), CL:0000233 (platelet — note CL commonly uses "platelet" CL:0000233), CL:0000094 (granulocyte/neutrophil, NETs), CL:0000115 (endothelial cell), CL:0000746 (cardiac muscle cell, RV myocyte)
  • UBERON: UBERON:0001004 (respiratory system), UBERON:0002048 (lung), UBERON:0002012 (pulmonary artery), UBERON:0002080 (heart right ventricle), UBERON:0001638 (vein), UBERON:0001211 (deep vein — approximate)
  • CHEBI: CHEBI:9754 (thrombin substrate context), relevant drug CHEBI IDs listed in §12

7. Anatomical Structures Affected

Organ level: - Primary: Lung (pulmonary arterial vasculature — main, lobar, segmental, or subsegmental branches depending on embolus size) — UBERON:0002048 (lung), UBERON:0002012 (pulmonary artery). - Secondary: Heart, specifically the right ventricle (afterload-mediated dysfunction) — UBERON:0002080; systemic circulation (via hypotension/shock, end-organ hypoperfusion); the source deep veins (lower-extremity/pelvic) remain co-affected as the origin site — UBERON:0001638. - Body systems: Cardiovascular system (primary), respiratory system (primary), and secondarily hematologic (coagulation system), and in shock states, renal/hepatic (hypoperfusion injury).

Tissue/cell level: - Pulmonary arterial endothelium (CL:0002544 or CL:0000115, vein/artery endothelial cell), vascular smooth muscle (CL:0000359, in CTEPH remodeling), platelets (CL:0000233), neutrophils (CL:0000775), cardiomyocytes of the RV free wall (CL:0000746), alveolar epithelium (secondary V/Q mismatch effects, not primarily destroyed except in infarction).

Subcellular level: - Platelet granules (dense/alpha granules) releasing procoagulant/proinflammatory mediators — GO:0031091 (platelet alpha granule); mitochondria of ischemic RV cardiomyocytes; endothelial Weibel-Palade bodies releasing vWF.

Localization: - Central (saddle/main pulmonary artery) emboli are hemodynamically most dangerous; peripheral (segmental/subsegmental) emboli more often cause infarction and are more often incidental. PE can be unilateral or bilateral; bilateral, especially central, disease correlates with higher clinical severity.

8. Temporal Development

  • Onset: PE has no fixed "typical age" the way a congenital disease does — incidence rises steeply with age (from <1/10,000/year in young adults to >1/1,000/year in the elderly). Onset is classically acute (minutes to hours), though presentations can be subacute with slowly enlarging/recurrent emboli, and rarely insidious/chronic in the CTEPH spectrum with progressive dyspnea over months to years.
  • Progression: Untreated, acute PE carries substantial early mortality risk concentrated in the first hours to days (RV failure/shock); with anticoagulation, most patients stabilize and the embolic burden resolves over 3–6 months, tracked by follow-up imaging/echocardiography.
  • Stages: The new 2026 AHA/ACC guideline formalizes 5 severity-based clinical categories (A–E, low → cardiopulmonary failure with persistent hypotension) explicitly replacing the older "massive/submassive/low-risk" nomenclature (see §11), integrating clinical severity score, biomarkers, and RV function.
  • Course pattern: Predominantly a single acute event followed by resolution on anticoagulation; a minority experience recurrence (annualized recurrence risk after stopping anticoagulation ranges from ~3%/year for provoked PE to ~10%/year for unprovoked PE in some cohorts) or evolve into CTEPH (~2.5–2.8% cumulative incidence).
  • Duration: Acute PE itself is self-limited with treatment (typically 3–6 months of anticoagulation for a first provoked event); however, some patients require extended/indefinite anticoagulation (unprovoked PE, persistent risk factors, cancer-associated thrombosis), and post-PE syndrome/CTEPH represent chronic sequelae.
  • Remission: Full radiographic/functional resolution occurs in the majority of low-risk patients; incomplete clot resolution (residual pulmonary vascular obstruction) is documented in 20–50% by perfusion scan at follow-up in some series, though most remain asymptomatic.
  • Critical periods: The first 1–2 weeks post-diagnosis carry the highest risk of clinical deterioration and death; the first 3–6 months carry highest recurrence risk after anticoagulation discontinuation; CTEPH diagnosis typically clusters at 3 months to several years post-index PE.

9. Inheritance and Population

Epidemiology

  • Incidence: Highly variable by population and ascertainment method — ~14/100,000/year in China, ~39/100,000/year in Hong Kong, up to ~115/100,000/year in the United States (per recent epidemiological syntheses). Overall global annual VTE incidence is commonly cited around 1–2 per 1,000 adults, rising sharply with age.
  • Mortality trends: A 2025 analysis of WHO mortality data (2001–2023) found global age-standardized PE mortality declined from 3.49 to 2.42 per 100,000, with Europe declining sharply (5.24 → 2.25/100,000) but low/middle-income regions (notably parts of Africa and lower-middle-income countries broadly) showing stagnant or rising rates (0.92 → 4.82/100,000 in lower-middle-income countries) — reflecting disparities in diagnostic access and treatment (eClinicalMedicine 2025, PMC12336653).
  • PE is the third most common cause of cardiovascular death after myocardial infarction and stroke in most high-income-country statistics, and a leading preventable cause of in-hospital death.

Inheritance pattern (for genetic thrombophilia contributors)

  • Factor V Leiden and Prothrombin G20210A: autosomal dominant with incomplete penetrance — most carriers never develop clinical VTE without a superimposed acquired trigger.
  • Protein C, Protein S, Antithrombin deficiencies: autosomal dominant, generally higher penetrance than FVL/prothrombin, especially for antithrombin deficiency.
  • Homozygous protein C or protein S deficiency: can cause neonatal purpura fulminans (severe, distinct from typical adult PE).
  • The broader liability is polygenic/multifactorial — PE/VTE overall behaves as a complex trait with both monogenic high-penetrance and common polygenic contributions layered on strong environmental/provoking triggers (PMID: 36658437).

Penetrance/Expressivity

  • FVL heterozygote lifetime VTE penetrance is estimated at roughly 10% or less without additional provoking factors; penetrance rises substantially with combined thrombophilias, pregnancy, or estrogen exposure.
  • Expressivity is variable — same genotype can manifest as isolated DVT, isolated PE, or both, and severity ranges from asymptomatic incidental finding to fatal.

Genetic anticipation

Not a recognized feature of PE-associated thrombophilias (these are not repeat-expansion disorders).

Founder effects / population variation

  • FVL and prothrombin G20210A show marked ancestry-specific frequency differences — common in European-ancestry populations, rare in African, Asian, and Indigenous American populations, consistent with founder mutations arising after early human population divergence (~20,000–30,000 years ago for FVL).
  • CTEPH after PE shows a geographic disparity: pooled Asian incidence (5.08%) is roughly 2.5× European incidence (1.96%) in meta-analysis (PMC8575791).

Demographics

  • Sex: PE incidence is roughly similar between sexes overall but shows sex-specific peaks — increased risk in women of reproductive age (pregnancy/oral contraceptives) and increased risk in men at older ages; some registries report a slight male predominance in unprovoked PE.
  • Age distribution: Incidence rises exponentially with age, from rare in children/young adults (usually with a strong provoking factor or thrombophilia when it occurs) to a leading cause of sudden death in the elderly.
  • Consanguinity/carrier frequency: Not classically relevant for FVL/prothrombin (common polymorphisms); more relevant for rare recessive natural-anticoagulant deficiencies, though most reported deficiencies are dominantly inherited with variable severity by zygosity.

10. Diagnostics

Clinical decision rules and pretest probability

  • Wells score (original and modified/simplified 3-level and 2-level versions) — clinical prediction rule combining signs of DVT, PE as most likely diagnosis, heart rate >100, immobilization/surgery, prior VTE, hemoptysis, malignancy. Combined with D-dimer, sensitivity/specificity improve substantially over Wells alone (one 2024 study: Wells alone 61.6% sensitivity/85.5% specificity; Wells + D-dimer cutoff 73.2%/92.1%).
  • YEARS algorithm — a simplified, D-dimer-threshold-adaptive rule (three items: clinical DVT signs, hemoptysis, PE as most likely diagnosis) that reduces CTPA utilization; sensitivity ~86–90%, specificity ~33–65% depending on cohort (van Es et al., Lancet 2017).
  • Revised Geneva score — an alternative, more objective (less subjective-judgment-dependent) clinical rule.

Laboratory

  • D-dimer (LOINC-codeable fibrin degradation product assay) — modern quantitative assays have pooled sensitivity ~97% (95% CI 96–98%) but low specificity ~41% (95% CI 36–46%); age-adjusted D-dimer thresholds improve specificity to ~47% while maintaining ~99% sensitivity, reducing unnecessary imaging in older patients.
  • Troponin I/T and BNP/NT-proBNP — not diagnostic but essential prognostic/risk-stratification biomarkers (see §6, §11).
  • Arterial blood gas — hypoxemia, widened A-a gradient, respiratory alkalosis (nonspecific).

Imaging

  • CT pulmonary angiography (CTPA) — first-line definitive imaging; pooled sensitivity ~94% (95% CI 89–97%), specificity ~98% (95% CI 97–99%); PIOPED II established CTPA as the diagnostic reference standard (Stein PD et al., N Engl J Med 2006).
  • Ventilation-perfusion (V/Q) scintigraphy — alternative when CTPA contraindicated (renal impairment, contrast allergy, pregnancy — preferred in pregnancy due to lower breast radiation dose than CTPA in some protocols).
  • Compression ultrasonography of the lower extremities — confirms concurrent/source DVT, can support PE diagnosis without further imaging in appropriate clinical context.
  • Transthoracic echocardiography — bedside assessment of RV size/function (RV/LV ratio, McConnell sign, tricuspid annular plane systolic excursion — TAPSE); central to risk stratification and can support diagnosis in unstable patients too sick for CTPA.
  • Pulmonary angiography — historic gold standard, now rarely needed given CTPA accuracy; retained as part of catheter-directed interventional procedures.

Genetic testing

Not indicated for routine PE evaluation. Selective thrombophilia panel testing (FVL, prothrombin G20210A, protein C/S, antithrombin, antiphospholipid antibodies) is considered for: unprovoked PE in patients <50 years, recurrent VTE, unusual-site thrombosis, strong family history, or before stopping anticoagulation in select unprovoked cases — though guideline enthusiasm for broad testing has declined because results rarely change management in an isolated first VTE event.

Clinical criteria / risk scores for prognosis (see §11)

PESI/sPESI, the AHA/ACC 2026 Clinical Categories (A–E).

Screening

No population-level screening program exists for PE (unlike, e.g., cancer screening); "screening" in practice means risk-based VTE prophylaxis protocols in hospitalized/surgical patients (mechanical and/or pharmacologic), and Khorana-score-guided consideration of primary thromboprophylaxis in ambulatory cancer patients initiating chemotherapy.

Differential diagnosis

Acute coronary syndrome, pneumonia, pericarditis, pneumothorax, aortic dissection, musculoskeletal chest pain, anxiety/panic disorder (for milder presentations), and COPD/asthma exacerbation (which can also coexist with PE, complicating decision rules — a 2024 study found Wells+D-dimer remained accurate in hospitalized COPD-exacerbation patients).

11. Outcome/Prognosis

Mortality

  • All-cause 30-day mortality in confirmed PE ranges widely by severity, roughly 1–2% in low-risk (sPESI 0) patients up to >30–50% in high-risk PE presenting with shock/cardiac arrest.
  • Elevated troponin is associated with ~5.4-fold higher odds of in-hospital mortality and ~4.4-fold higher odds of 30-day mortality (meta-analysis).
  • Global age-standardized PE mortality has declined substantially in high-income countries (3.68 → 2.20/100,000, 2001–2023) but is rising in lower-middle-income countries (0.92 → 4.82/100,000) — a striking disparity attributed to differential access to modern diagnostics/anticoagulants (eClinicalMedicine 2025).

Risk stratification tools

  • PESI/simplified PESI (sPESI): the most extensively validated clinical prognostic score, integrating age, sex, cancer, heart failure, chronic lung disease, heart rate, systolic BP, respiratory rate, temperature, altered mental status, and oxygen saturation; sPESI = 0 reliably identifies low-risk PE suitable for outpatient management.
  • 2019 ESC risk stratification algorithm (still widely used, PMID: 31504429) combines hemodynamic status, PESI/sPESI, RV dysfunction on imaging, and cardiac biomarkers into high/intermediate-high/intermediate-low/low risk categories.
  • 2026 AHA/ACC Clinical Categories (A–E): the newly published first dedicated US multisociety guideline (AHA/ACC/ACCP/ACEP/CHEST/SCAI/SHM/SIR/SVM/SVN) introduces a five-tier "Acute Pulmonary Embolism Clinical Categories" scheme spanning low risk through cardiopulmonary failure with persistent hypotension, intended to standardize severity assessment, prognosis, and therapy selection, explicitly retiring "massive/submassive" terminology (JACC/Circulation, April 2026; PMID: 41712898).

Morbidity/functional outcomes

  • Post-PE syndrome: persistent dyspnea/functional limitation without frank pulmonary hypertension, reported in roughly a third to half of survivors at 1 year.
  • CTEPH: pooled incidence 2.5–2.8% after acute PE (updated 2023 ERJ meta-analysis), with higher rates in Asian populations and after RV dysfunction/unprovoked/recurrent PE; the original defining incidence study found CTEPH-consistent pulmonary hypertension in ~3.8% of PE survivors at 2 years (Pengo V et al., N Engl J Med 2004).
  • Recurrence: highest for unprovoked PE and persistent risk factors (e.g., active cancer); recurrence risk after stopping anticoagulation is a major determinant of extended-therapy decisions.

Prognostic biomarkers

Troponin, BNP/NT-proBNP, RV/LV diameter ratio on CTPA or echocardiography, lactate, and the composite PESI/sPESI/ESC risk categories.

12. Treatment

Pharmacotherapy — Anticoagulation (mainstay)

  • Direct oral anticoagulants (DOACs) — apixaban, rivaroxaban, edoxaban, dabigatran — now preferred over vitamin K antagonists (warfarin) for most patients given comparable/superior efficacy, lower major bleeding, and no routine monitoring requirement. Key trials: EINSTEIN-PE (rivaroxaban, NEJM 2012, PMID 22449293) and AMPLIFY (apixaban, NEJM 2013, PMID 23808982).
  • NCIT: C15986 (Pharmacotherapy); therapeutic_agent CHEBI: rivaroxaban CHEBI:68579, apixaban CHEBI:66989, edoxaban CHEBI:83495, dabigatran CHEBI:70746.
  • Extended-phase (reduced-dose) DOAC therapy — CHEST and ESC/ERS guidelines both support low-intensity apixaban 2.5 mg twice daily or rivaroxaban 10 mg once daily for extended secondary prevention beyond the initial 3–6 months in appropriate patients.
  • LMWH/UFH — first-line in pregnancy (DOACs contraindicated due to placental transfer/fetal risk), in cancer-associated thrombosis historically (though DOACs — apixaban preferentially — are now recommended by CHEST/NICE for most non-luminal-GI cancer PE, with apixaban or LMWH preferred specifically in luminal GI malignancy given DOAC-associated GI bleeding risk), and in hemodynamically unstable patients needing rapid reversibility.
  • Warfarin (vitamin K antagonist) — retained for mechanical heart valves, antiphospholipid syndrome (triple-positive), and severe renal impairment where DOACs are contraindicated.

Reperfusion therapy (high-risk/select intermediate-high-risk PE)

  • Systemic thrombolysis (alteplase, tenecteplase) — indicated for high-risk PE with hemodynamic instability; PEITHO trial (NEJM 2014, PMID 24716681) showed reduced hemodynamic decompensation but increased major/intracranial bleeding with thrombolysis in intermediate-risk PE, informing more selective use.
  • Catheter-directed thrombolysis (CDT) / mechanical thrombectomy — increasingly used for intermediate-high and high-risk PE, especially where PERT (Pulmonary Embolism Response Team) involvement is available; PERT-managed patients show higher use of catheter-directed interventions (36% vs 22% CDT; 16% vs 7% thrombectomy) and lower IVC filter use (1% vs 5%), with meta-analyses suggesting decreased mortality/length of stay under PERT-guided care. The FLARE registry (FlowTriever mechanical thrombectomy) reported 0.3% 48-hour and 0.8% 30-day all-cause mortality with favorable safety in intermediate/high-risk PE, supporting FDA clearance expansion in late 2023.
  • Surgical embolectomy — reserved for high-risk PE with thrombolysis contraindication or failure, or for large central thrombi in centers with surgical expertise.

Devices/interventional

  • Inferior vena cava (IVC) filters — Class I indication limited to absolute anticoagulation contraindication with acute VTE, or recurrent PE despite adequate anticoagulation; evidence for mortality benefit is weak/mixed, though filters do reduce recurrent PE incidence without clearly increasing DVT/bleeding in trial meta-analyses; not indicated when anticoagulation is feasible. NCIT: device-category treatment, therapeutic_modality: DEVICE.

Supportive/other

  • Supplemental oxygen, vasopressor/inotropic support for RV failure/shock, extracorporeal membrane oxygenation (ECMO, especially veno-arterial) as a bridge in refractory high-risk PE.
  • Compression therapy for concurrent DVT/prevention of post-thrombotic syndrome.

CTEPH-specific therapy

  • Pulmonary endarterectomy (PEA) — potentially curative surgical treatment for operable proximal CTEPH.
  • Balloon pulmonary angioplasty (BPA) — for inoperable/distal disease.
  • Riociguat (soluble guanylate cyclase stimulator) — approved pharmacotherapy for inoperable/residual CTEPH (CHEST-1 trial).

Pharmacogenomics

Warfarin dosing is the principal pharmacogenomic-relevant example (CYP2C9, VKORC1 variants affecting warfarin sensitivity/dosing requirements) — captured in CPIC/PharmGKB guidelines; DOACs have comparatively limited established pharmacogenomic dosing algorithms, though P-glycoprotein (ABCB1) and CYP3A4 polymorphisms modestly affect exposure.

Treatment algorithm summary

Risk-stratify (§11) → hemodynamically unstable (high-risk): reperfusion (thrombolysis/catheter-directed/surgical) + anticoagulation + hemodynamic support → hemodynamically stable with RV dysfunction/biomarker elevation (intermediate risk): anticoagulation, monitor, consider escalation if deteriorating → low-risk (sPESI 0, no RV dysfunction): anticoagulation, consider early discharge/outpatient management.

13. Prevention

Primary prevention

  • Mechanical prophylaxis — intermittent pneumatic compression devices, graduated compression stockings, particularly for surgical/immobilized patients with bleeding contraindications to pharmacologic prophylaxis.
  • Pharmacologic prophylaxis — LMWH, unfractionated heparin, or (increasingly) DOACs in defined high-risk hospitalized medical/surgical populations, guided by validated risk-assessment models (e.g., Caprini score for surgical patients, Padua score for medical inpatients).
  • Behavioral/lifestyle — early ambulation post-surgery/illness, hydration and leg movement during long-haul travel, weight management, smoking cessation.

Secondary prevention (cancer-associated thrombosis)

  • Khorana-score-guided consideration of primary pharmacologic thromboprophylaxis in ambulatory cancer patients initiating systemic therapy who are at elevated VTE risk (score ≥2–3), though the Khorana score's discriminative performance is notably weaker in lung cancer than in pancreatic/gastric/colorectal/ovarian/brain/bladder cancer.

Pregnancy-specific prevention

Risk-based LMWH thromboprophylaxis in pregnant/postpartum women with prior VTE history or high-risk thrombophilia.

Prophylaxis after index PE

Extended (beyond 3–6 months) anticoagulation in unprovoked PE or persistent major risk factors, per individualized bleeding-risk/recurrence-risk assessment; reduced-dose DOAC regimens specifically designed to balance extended prevention against bleeding risk.

Genetic counseling / screening

Selective thrombophilia testing and counseling for at-risk family members after a proband is identified with a high-penetrance deficiency (protein C/S, antithrombin); routine population carrier screening for FVL/prothrombin G20210A is not recommended given low absolute penetrance.

Public health

Hospital-based VTE-prevention quality metrics/protocols (a major patient-safety focus given PE's status as a leading preventable cause of in-hospital death), and clinical decision support tools embedded in EHRs to prompt risk assessment and appropriate prophylaxis ordering.

14. Other Species / Natural Disease

  • Taxonomy: PE occurs across mammalian species; naturally occurring VTE/PE is documented in domestic dogs and cats, especially secondary to protein-losing nephropathy/enteropathy, hyperadrenocorticism, immune-mediated hemolytic anemia, neoplasia, and pancreatitis — paralleling many acquired human risk factors (OMIA and veterinary case-series literature; NCBI Taxonomy: Canis lupus familiaris NCBITaxon:9615, Felis catus NCBITaxon:9685).
  • Orthologous genes: F5, F2, PROC, PROS1, and SERPINC1 orthologs are broadly conserved across mammals (NCBI Gene cross-species records exist for each); canine and feline coagulation biology is used comparatively to understand thrombophilia mechanisms, though naturally occurring FVL-equivalent thrombophilia is not a major recognized entity in companion animals the way it is in humans.
  • Comparative pathology: Veterinary PE parallels human disease in gross/histopathologic appearance (occlusive pulmonary arterial thrombus, RV strain) but is typically secondary to an identifiable underlying illness rather than idiopathic/inherited thrombophilia, reflecting differences in typical case ascertainment (symptomatic veterinary presentation vs. broader human screening).
  • Zoonotic potential: Not applicable — PE is not a transmissible/infectious disease in the conventional sense (septic PE is secondary to an infectious source, not itself transmissible as PE).

15. Model Organisms

Important overarching limitation: Well-characterized rodent models recapitulate venous thrombosis (DVT) far better than pulmonary embolism itself — a 2012 critical review of mouse venous thrombosis models notes that essentially none of the standard mouse VTE models reliably produce spontaneous pulmonary embolism, and survival in these models is close to 100% (Diaz JA et al., Arterioscler Thromb Vasc Biol 2012, PMID: 22345593; Grover SP & Mackman N, "Mouse models of deep vein thrombosis," PMID: 28715512). This is a significant translational gap: most mechanistic PE research either extrapolates from DVT models or uses direct pulmonary-artery embolization/injection models to study the embolic and RV-failure phase specifically.

Genetic/induced mouse models (DVT-focused, upstream of embolization): - Inferior vena cava (IVC) stasis/stenosis and ligation models — surgical flow restriction inducing stasis-driven thrombosis; widely used to study leukocyte/platelet contributions to thrombus initiation and resolution. - Ferric chloride (FeCl₃) injury model — chemical endothelial injury inducing occlusive thrombosis in a defined vessel segment; models the vessel-injury arm of Virchow's triad. - Electrolytic IVC model — controlled endothelial denudation without complete flow occlusion, considered more physiologically representative of clinical DVT initiation. - Genetically engineered models — F5 Leiden knock-in mice, Proc/Pros1/Serpinc1 knockout or hypomorphic mice (complete knockouts of natural anticoagulants are often embryonic lethal or require conditional/hypomorphic alleles), tissue factor overexpression models — used to dissect specific coagulation-factor contributions.

Direct PE models (embolic/RV-failure phase): - Autologous or homologous clot injection / microsphere embolization into the pulmonary circulation (mouse, rat, rabbit, and larger animal models) to directly study acute RV pressure overload, hemodynamic collapse, and reperfusion/thrombolysis pharmacology without relying on spontaneous embolization from a DVT source. - Porcine models — a 2021 paper describes a new experimental porcine model of venous thromboembolism (PMC8123404), valued for cardiovascular anatomic/physiologic similarity to humans, supporting device (catheter-directed thrombectomy, IVC filter) and hemodynamic studies more translatable to clinical intervention design than rodent models. - Zebrafish — used in a 2025 multipopulation VTE GWAS for experimental validation of novel candidate loci (PMID: 40554366), leveraging the zebrafish's genetically tractable, visually accessible coagulation system for rapid functional variant screening, though this models the upstream thrombogenesis pathway rather than pulmonary embolization anatomy (zebrafish lack a pulmonary circulation analogous to mammals).

Applications and limitations: - Rodent DVT models: excellent for dissecting the molecular/cellular biology of thrombus initiation, propagation, and natural resolution, and for early pharmacologic screening of novel anticoagulants; poor for modeling the hemodynamic RV-failure phenotype that drives human PE mortality. - Direct pulmonary embolization/injection models: better recapitulate acute RV pressure overload and reperfusion pharmacology but bypass the "spontaneous embolization" biology, so they cannot inform prevention-of-embolization research. - Porcine/large-animal models: best anatomic/hemodynamic translatability for interventional device testing (catheter thrombectomy, filters) but are costly and lower-throughput. - No single model recapitulates the full human PE phenotype spectrum (thrombogenesis → embolization → RV failure → resolution/CTEPH); most research programs combine a DVT-genesis model with a separate direct-embolization hemodynamic model.

Resources: MGI (Mouse Genome Informatics) for F5/F2/Proc/Pros1/Serpinc1 mouse alleles, ZFIN for zebrafish coagulation-gene models, IMPC for systematic knockout phenotyping data on coagulation genes.

Ontology Term Summary for KB Curation

Category Suggested terms
Disease MONDO:0005279 (pulmonary embolism); HP:0002204 (Pulmonary embolism)
Causal/risk genes F5 (hgnc:3542), F2 (hgnc:3535), PROC (hgnc:9451), PROS1 (hgnc:9456), SERPINC1 (hgnc:775), ABO (hgnc:79)
Key phenotypes HP:0002094 (Dyspnea), HP:0030848 (Pleuritic chest pain), HP:0001649 (Tachycardia), HP:0002789 (Tachypnea), HP:0002105 (Hemoptysis), HP:0001279 (Syncope), HP:0002615 (Hypotension), HP:0004936 (Deep venous thrombosis)
GO biological processes GO:0007596 (blood coagulation), GO:0042730 (fibrinolysis), GO:0002576 (platelet degranulation), GO:0030193 (regulation of blood coagulation)
Cell types CL:0000233 (platelet), CL:0000115 (endothelial cell), CL:0000775 (neutrophil), CL:0000746 (cardiac muscle cell)
Anatomy UBERON:0002048 (lung), UBERON:0002012 (pulmonary artery), UBERON:0002080 (right cardiac ventricle), UBERON:0001638 (vein)
Treatments (NCIT) NCIT:C15986 (Pharmacotherapy), NCIT:C15632 (Chemotherapy — N/A here), NCIT:C15313 (Radiation Therapy — N/A), catheter-directed therapy/device-classified as therapeutic_modality: DEVICE, surgical embolectomy → NCIT:C15329 (Surgical Procedure)
Therapeutic agents (CHEBI) rivaroxaban CHEBI:68579, apixaban CHEBI:66989, edoxaban CHEBI:83495, dabigatran CHEBI:70746, alteplase/tenecteplase (protein therapeutics, may lack CHEBI; use NCIT)

Selected Citations

  1. Klarin D et al. Genome-wide meta-analysis identifies 93 risk loci and enables risk prediction equivalent to monogenic forms of venous thromboembolism. Nat Genet 2023. PMID: 36658437.
  2. Multipopulation GWAS for venous thromboembolism identifies novel loci followed by experimental validation in zebrafish. Blood Advances 2025. PMID: 40554366.
  3. Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism — pooled analysis of 8 case-control studies. PMID: 11583312.
  4. Role of factor V Leiden or G20210A prothrombin mutation in patients with symptomatic pulmonary embolism and deep vein thrombosis: a meta-analysis. PMID: 22329698.
  5. Type and location of venous thromboembolism in carriers of Factor V Leiden or prothrombin G20210A mutation versus patients with no mutation. PMID: 18796457.
  6. Konstantinides SV et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism. Eur Heart J 2020;41(4):543-603. PMID: 31504429.
  7. 2026 AHA/ACC/ACCP/ACEP/CHEST/SCAI/SHM/SIR/SVM/SVN Guideline for the Evaluation and Management of Acute Pulmonary Embolism in Adults. Circulation/JACC 2026. PMID: 41712898.
  8. EINSTEIN-PE Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2012;366:1287-97. PMID: 22449293.
  9. Agnelli G et al. (AMPLIFY). Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013;369:799-808. PMID: 23808982.
  10. Meyer G et al. (PEITHO). Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med 2014;370:1402-11. PMID: 24716681.
  11. Stein PD et al. (PIOPED II). Multidetector computed tomography for acute pulmonary embolism. N Engl J Med 2006;354:2317-27. PMID: 16738268.
  12. Pengo V et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004;350:2257-64.
  13. Incidence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism: updated systematic review and meta-analysis. Eur Respir J 2023.
  14. Higher incidence of CTEPH after acute PE in Asians than Europeans: a meta-analysis. PMC8575791.
  15. Global trends in mortality related to pulmonary embolism: WHO mortality database 2001–2023. eClinicalMedicine 2025. PMC12336653.
  16. Diaz JA et al. Critical review of mouse models of venous thrombosis. Arterioscler Thromb Vasc Biol 2012. PMID: 22345593.
  17. Grover SP, Mackman N. Mouse models of deep vein thrombosis. PMID: 28715512.
  18. Impact of pulmonary embolism response teams on acute pulmonary embolism: systematic review and meta-analysis. Eur Respir Rev 2023.
  19. Prognostic value of right ventricular dysfunction or elevated cardiac biomarkers in low-risk pulmonary embolism: systematic review and meta-analysis. Eur Heart J 2019;40(11):902.
  20. Pulmonary embolism and 529 human blood metabolites: genetic correlation and two-sample Mendelian randomization study. PMC9422150.
  21. Proteome-wide Mendelian randomization identifies causal plasma proteins in venous thromboembolism development. PMC10678328.

Note on completeness: This report synthesizes findings from a targeted literature and guideline search (2023–2026 emphasis, per instructions) combined with well-established foundational PE literature. Several sub-areas (single-cell/spatial transcriptomics of pulmonary thrombus tissue, detailed epigenomic profiling, and comprehensive veterinary comparative-pathology datasets) have sparse dedicated primary literature for PE specifically and are flagged above as emerging/limited rather than fabricated to appear complete.