Venous thromboembolism is a condition encompassing deep vein thrombosis and pulmonary embolism, caused by pathological blood clot formation within the venous system that can obstruct blood flow and impair cardiopulmonary function.

Venous Thromboembolism (VTE)

Venous thromboembolism (VTE) is a single disease spectrum encompassing two clinical manifestations: deep vein thrombosis (DVT) and pulmonary embolism (PE) ^[1]^[2]. The name itself tells the story:

"Venous" = occurring within veins (as opposed to arterial thrombosis)
"Thrombo-" = blood clot (Greek: thrombos = lump/clot)
"Embolism" = a clot that has broken off and travelled (Greek: embolos = stopper/plug)

So VTE describes the formation of a pathological blood clot within the venous system, which may remain in situ (DVT) or dislodge and travel to the pulmonary vasculature (PE).

DVT and PE are two manifestations of the same disorder ^[1]. You should never think of them as separate diseases — a patient presenting with a swollen leg and a patient presenting with acute dyspnoea and pleuritic chest pain may both have VTE; the difference is simply where the clot currently sits.

Key Conceptual Point

Patients with PE usually die from right heart failure (cardiogenic shock / obstructive shock) rather than hypoxaemia ^[1]. Why? A massive PE obstructs the right ventricular outflow tract → acute rise in pulmonary vascular resistance → the thin-walled RV cannot overcome this → RV dilatation and failure → decreased LV filling → cardiovascular collapse. The hypoxaemia is the secondary problem; the haemodynamic catastrophe kills first.

Subdivisions of DVT [1]

DVT of the lower extremity is subdivided into two categories based on anatomical location, because this determines clinical significance:

Category	Veins Involved	Clinical Significance
Proximal vein thrombosis	Popliteal, femoral, iliac veins	Clinically more significant — more commonly associated with PE because these are large-calibre veins and thrombi are more likely to embolise
Distal (calf) vein thrombosis	Deep calf veins (anterior tibial, posterior tibial, peroneal, soleal, gastrocnemius veins)	Lower risk of PE, but ~20–30% can propagate proximally if untreated

Why does proximal DVT cause more PE? Simply because the popliteal and femoral veins are large-diameter conduits — thrombi forming here are bigger, less constrained, and have a direct unobstructed path via the IVC to the right heart and pulmonary arteries.

2. Epidemiology

3. Risk Factors

Understanding risk factors requires anchoring everything to Virchow's triad — the conceptual framework proposed by Rudolf Virchow in 1856 that explains why venous thrombosis occurs ^[1]:

Think of it this way: blood naturally wants to flow smoothly through intact vessels. For a clot to form pathologically, you need at least one (usually more) of these three conditions:

Component	Mechanism	Examples ^[1]
Stasis	Sluggish blood flow allows activated clotting factors to accumulate locally rather than being diluted and cleared by hepatic clearance	Prolonged bed rest, air travel > 6 hours, CHF (low cardiac output), stroke/paralysis within 3 months, immobilisation (e.g. cast), prolonged surgery
Endothelial injury	Damage to the vessel wall exposes subendothelial collagen and tissue factor, triggering the coagulation cascade	Surgery, trauma, prior DVT, central venous catheter placement, IV drug use
Hypercoagulability	The blood itself has an increased tendency to clot — either inherited or acquired	See comprehensive list below

Why does stasis cause thrombosis?

Normally, flowing blood dilutes activated clotting factors and sweeps them to the liver for clearance. Endothelial cells also release anticoagulant factors (thrombomodulin, tissue factor pathway inhibitor, heparan sulphate) only when flow is normal. When blood stagnates — e.g., in a bed-bound patient's calf veins behind venous valve pockets — local clotting factor concentrations rise, natural anticoagulant mechanisms fail, and the thrombus nucleates in the valve sinus.

Comprehensive Risk Factor Classification

Surgical / Trauma-related:

Recent surgery (especially orthopaedic — hip/knee replacement, pelvic surgery) — combines stasis (immobilisation) + endothelial injury + inflammatory hypercoagulability
Trauma to lower extremity (fracture, crush injury)
Central venous catheter placement (endothelial injury)
Spinal cord injury (paralysis → stasis)

Medical:

Malignancy (hypercoagulability) ^[1] — this deserves special emphasis:
- Especially adenocarcinomas, which secrete mucin that activates coagulation ^[1]
- Myeloproliferative neoplasms (MPN) — polycythaemia vera, essential thrombocythaemia ^[1]
- Gynaecological malignancy — can directly obstruct lower limb veins via pelvic mass effect ^[1]
- Pancreatic cancer is notorious for VTE — Trousseau syndrome (migratory superficial thrombophlebitis as a paraneoplastic phenomenon) ^[3]
- Any cancer increases VTE risk by 4–7 fold; chemotherapy increases it further
Previous VTE (strongest clinical predictor of recurrence) ^[1]
Stroke (immobility + hypercoagulability) ^[1]
Heart failure (stasis from low cardiac output)
Acute medical illness / hospitalisation
Obesity (venous stasis + chronic inflammatory state + impaired fibrinolysis) ^[1]
Nephrotic syndrome (urinary loss of antithrombin III → hypercoagulability) ^[1]

Hormonal:

Pregnancy and postpartum ^[1] — Why? Pregnancy is an evolutionary "pro-coagulant" state to protect against postpartum haemorrhage:
- ↑ Factors VII, VIII, X, fibrinogen, von Willebrand factor
- ↓ Protein S (natural anticoagulant)
- Mechanical compression of IVC and iliac veins by gravid uterus (stasis)
- Risk is highest in the postpartum period (first 6 weeks) when these changes are maximal and immobility adds to the risk
Oral contraceptive pills (OCP) / Hormone replacement therapy (HRT) ^[1]
- Oestrogen increases hepatic synthesis of procoagulant factors and reduces antithrombin
- Combined OCP increases VTE risk 3–4 fold
- Third-generation progestogens (desogestrel, gestodene) have higher risk than second-generation (levonorgestrel)

Immobilisation:

Prolonged hospitalisation or bed rest ^[1]
Occupational immobilisation ^[1]
Long-haul air travel ("economy class syndrome") — cabin pressure, dehydration, cramped seating ^[1]
Lower limb cast / splint

Condition	Mechanism	Prevalence	VTE Risk Increase
Factor V Leiden (FVL)	Point mutation (Arg506Gln) renders Factor V resistant to inactivation by activated Protein C ^[1]	5% of Caucasians; virtually absent in Chinese/HK population	5–7× (heterozygous); 50–80× (homozygous)
Prothrombin G20210A mutation	Gain-of-function mutation → increased prothrombin levels	2–3% Caucasians; very rare in Chinese	2–3×
Antithrombin III deficiency	AT-III is the main inhibitor of thrombin and Factor Xa; deficiency → unchecked thrombin generation ^[1]	Rare (1 in 2,000–5,000) but relatively more important in HK/Chinese	10–50×
Protein C deficiency	Protein C (activated by thrombin-thrombomodulin complex) inactivates Factors Va and VIIIa; deficiency → unopposed coagulation ^[1]	1 in 200–500	7–10×
Protein S deficiency	Protein S is a cofactor for activated Protein C; deficiency impairs APC function ^[1]	1 in 500	5–10×

Hong Kong Exam Pearl

Do NOT reflexively answer "Factor V Leiden" when asked about inherited thrombophilia in a Hong Kong patient. FVL is a Caucasian mutation. In the Chinese population, think of Antithrombin III, Protein C, and Protein S deficiencies as the more relevant inherited thrombophilias.

4. Anatomy and Physiology of the Venous System

Understanding VTE requires understanding the venous drainage of the lower limb, because this is where the vast majority of DVT originates.

5. Pathophysiology

Category	Definition	Mechanism
Massive PE	PE with sustained hypotension (SBP < 90 for ≥ 15 min), pulselessness, or requiring vasopressors	> 50% of pulmonary vascular bed obstructed → acute RV failure → obstructive shock
Submassive PE	PE with RV dysfunction (on echo or CT) or elevated cardiac biomarkers (troponin, BNP) BUT haemodynamically stable	Significant obstruction with compensated RV — on the verge of decompensation
Low-risk PE	Haemodynamically stable, no RV dysfunction, normal biomarkers	Small peripheral emboli; the RV can cope

Exam Pearl: RV Failure in PE

The right ventricle is a thin-walled, compliant chamber designed for a low-pressure system. It can tolerate volume overload but NOT acute pressure overload. A previously normal RV cannot generate a mean pulmonary artery pressure > 40 mmHg acutely. If mean PA pressure is higher than this in acute PE, suspect chronic thromboembolic disease with superimposed acute PE (the RV has had time to hypertrophy).

6. Etiology — Specific Causes of VTE (Focus on Hong Kong)

7. Classification Systems

Classification	Description
Proximal DVT	Popliteal vein and above (femoral, iliac veins) — higher risk of PE
Distal DVT	Calf veins (below popliteal) — lower risk but can propagate
Upper extremity DVT	Subclavian, axillary, brachial veins — increasingly common with central lines and PICC lines (Paget-Schroetter syndrome in effort-related)
Unusual site DVT	Cerebral venous sinuses, splanchnic veins (portal, mesenteric, hepatic), renal veins — think of PNH, MPN, APS, cirrhosis

Type	Description
Acute PE	New thrombus in pulmonary vasculature; the focus of clinical management
Chronic thromboembolic pulmonary hypertension (CTEPH)	Incomplete resolution of PE → organised fibrotic thrombus → progressive pulmonary hypertension; occurs in 2–4% of acute PE survivors

This classification is clinically crucial because it determines duration of anticoagulation:

Type	Definition	Examples	Implication
Provoked (transient risk factor)	VTE occurring in the context of a major identifiable transient risk factor	Surgery, trauma, immobilisation, pregnancy, OCP	Lower recurrence risk; shorter anticoagulation (3 months) may suffice
Unprovoked (idiopathic)	VTE occurring without an identifiable transient risk factor	No clear trigger	Higher recurrence risk (~10% per year after stopping anticoagulation); consider extended/indefinite anticoagulation
Cancer-associated	VTE in context of active malignancy	Any active cancer	Very high recurrence; anticoagulation continued as long as cancer is active

Important Clinical Point

An unprovoked VTE in a patient > 40 years should prompt consideration of occult malignancy screening. Malignancy screening is recommended as malignancy is a risk factor for development of DVT ^[1]. The yield of extensive screening is debated, but minimum workup includes: thorough history/examination, basic bloods (CBC, LFT, calcium), CXR, and age-appropriate cancer screening (e.g., colonoscopy, CT abdomen/pelvis).

8. Clinical Features

Symptom	Pathophysiological Basis
Leg pain (usually calf or thigh, unilateral)	Thrombus causes venous obstruction → distension of the vein wall → activation of nociceptors in the vein wall and surrounding tissue; inflammatory mediators (bradykinin, prostaglandins) from the thrombus contribute
Leg swelling (unilateral oedema — the key feature)	Venous obstruction → ↑ hydrostatic pressure proximal to thrombus → transcapillary fluid filtration into the interstitium (Starling forces)
Warmth of affected limb	Inflammatory response to the thrombus → local vasodilatation of the skin microvasculature
Skin discolouration (erythema or cyanosis)	Erythema from inflammation; cyanosis from venous congestion and deoxygenation of stagnant blood
Sensation of heaviness or tightness	Increased tissue pressure from oedema compressing sensory nerve endings
Asymptomatic (up to 60–80% are clinically silent ^[5])	Small, non-occlusive thrombi may not obstruct flow sufficiently to cause symptoms

Exam Pearl

DVT is clinically silent in the majority of cases. 60–80% of DVTs are clinically silent ^[5]. That is why prophylaxis is so important — you cannot rely on clinical detection alone.

Sign	Pathophysiological Basis
Unilateral leg oedema (> 2 cm circumference difference between legs)	Venous obstruction → hydrostatic back-pressure → oedema. Measuring calf circumference 10 cm below the tibial tuberosity is the standard technique
Calf tenderness on palpation	Inflammation of the thrombosed vein and surrounding tissue
Homan's sign (calf pain on passive dorsiflexion of foot)	Stretching of the inflamed posterior tibial veins — sensitivity only ~30%, specificity ~50%; not reliable and no longer recommended as a diagnostic test
Pitting oedema	Increased interstitial fluid from venous hypertension
Dilated superficial veins	Collateral venous drainage develops to bypass the obstructed deep vein
Low-grade fever	Systemic inflammatory response to thrombosis (release of IL-6, TNF-α)
Palpable cord (thrombosed vein felt as a firm, tender cord)	The thrombosed vein itself — less commonly palpable in deep veins compared to superficial thrombophlebitis

Severe DVT presentations:

Condition	Description	Mechanism
Phlegmasia alba dolens ("milk leg")	Massive iliofemoral DVT → painful, white, swollen leg	Severe venous obstruction → massive oedema → interstitial pressure rises → compromises arterial inflow → pale leg
Phlegmasia cerulea dolens ("blue leg")	Progression of above → cyanotic, massively swollen, exquisitely painful leg → venous gangrene	Near-total venous occlusion → arterial inflow completely compromised → tissue ischaemia → can progress to compartment syndrome and limb loss

Symptom	Pathophysiological Basis
Acute dyspnoea (most common symptom, ~80%)	V/Q mismatch → hypoxaemia → stimulates peripheral chemoreceptors → ↑ respiratory drive; also reflex hyperventilation from irritant receptors in the pulmonary vasculature
Pleuritic chest pain (~50%)	Pulmonary infarction → inflammation of visceral and parietal pleura → sharp pain worsened by inspiration
Cough	Irritation of airways from pulmonary infarction/atelectasis, or bronchospasm from serotonin/thromboxane release
Haemoptysis (~15%) ^[1]	Pulmonary infarction → necrosis of lung parenchyma → bleeding into airways
Syncope / Pre-syncope	Massive PE → acute ↓ cardiac output → cerebral hypoperfusion
Chest pressure / substernal pain	RV ischaemia from acute pressure overload → angina-like pain (RV demand ischaemia)
Anxiety / sense of impending doom	Hypoxaemia + sympathetic activation
Leg symptoms (swelling, pain)	Concurrent DVT — present in ~30–50% of PE cases

Vital Signs:

Sign	Pathophysiological Basis
Sinus tachycardia (most common sign) ^[1]	Compensatory sympathetic activation to maintain cardiac output in face of reduced stroke volume; also driven by hypoxaemia and pain
Tachypnoea (> 70% of patients) ^[1]	Hypoxaemia → chemoreceptor stimulation + V/Q mismatch → increased respiratory rate
Hypotension (in massive PE) ^[1]	Obstructive shock — RV failure → ↓ LV filling → ↓ cardiac output → systemic hypotension
Fever ^[1]	Pulmonary infarction → inflammatory response; also consider superimposed infection
Cyanosis ^[1]	Severe hypoxaemia from V/Q mismatch and reduced cardiac output

The First Sign of Post-operative PE

The first sign of PE is often unexplained tachycardia ^[5]. In a post-surgical patient, if the heart rate creeps up without an obvious cause (no fever, no bleeding, no pain), think PE. Don't wait for desaturation or chest pain.

Respiratory Examination ^[1]:

Tachypnoea
Pleural friction rub: Heard when pleural inflammation from pulmonary infarction causes roughened pleural surfaces to rub together
Crepitations (crackles): From atelectasis or pulmonary infarction
Decreased breath sounds: Over area of pleural effusion (bloody effusion from infarction)
Wheeze: From reflex bronchospasm (serotonin and thromboxane release)

Cardiovascular Examination ^[1]:

Sign	Pathophysiological Basis
Elevated JVP ^[1]	RV failure → ↑ right atrial pressure → transmitted back to jugular veins
Right-sided S3 (gallop) ^[1]	Rapid filling of a dilated, failing RV in early diastole
Loud P2 (pulmonic component of S2)	↑ Pulmonary artery pressure → forceful closure of the pulmonic valve
Graham Steell murmur ^[1]	Pulmonary regurgitation murmur — high-pitched early diastolic murmur at the left sternal edge; caused by dilatation of the pulmonary valve ring from severe pulmonary hypertension
Parasternal heave	RV hypertrophy/dilatation → palpable lift at the left sternal border
Right ventricular S4	Forceful atrial contraction against a stiff, failing RV
Tricuspid regurgitation murmur	RV dilatation → tricuspid annular dilatation → functional TR (pansystolic murmur at left lower sternal edge, louder with inspiration — Carvallo's sign)

Let's explicitly connect every key finding to its mechanism, as this is what distinguishes a good exam answer:

Clinical Finding	Why Does It Occur?
Unilateral leg swelling in DVT	Venous obstruction raises hydrostatic pressure → Starling forces push fluid into interstitium → oedema. Unilateral because DVT is almost always asymmetric
Dyspnoea in PE	V/Q mismatch (ventilated but unperfused lung segments = dead space) → hypoxaemia → chemoreceptor stimulation → hyperventilation
Pleuritic chest pain in PE	Pulmonary infarction (only ~10% of PE because of dual blood supply) → pleural inflammation → pain on inspiration
Tachycardia in PE	(a) Sympathetic compensation for ↓ CO; (b) Hypoxaemia; (c) Pain and anxiety
Elevated JVP in PE	RV failure → ↑ RA pressure → transmitted to jugular veins
Hypotension in massive PE	> 50% vascular bed obstructed → acute RV failure → ↓ LV filling → ↓ CO → shock
Graham Steell murmur	Severe pulmonary hypertension → pulmonary valve ring dilatation → pulmonary regurgitation
Post-thrombotic syndrome after DVT	Thrombus damages valves → valvular incompetence → chronic venous hypertension → oedema, skin changes, ulceration

Differential Diagnosis of VTE

The clinical challenge with VTE is that the symptoms — leg swelling, leg pain, dyspnoea, chest pain — are all non-specific. Many other conditions mimic DVT or PE, and the clinical examination alone has poor sensitivity and specificity. This is precisely why we use structured pre-test probability scores (Wells criteria) and algorithmic workup rather than relying on clinical gestalt alone.

Let's think about this from first principles: DVT presents with a unilateral swollen, painful, warm leg. PE presents with acute dyspnoea, pleuritic chest pain, tachycardia, and hypoxaemia. Now ask: what else can produce these patterns?

A. Differential Diagnosis of DVT [1]

The differentials for a swollen, painful leg can be systematically organised by the mechanism producing the swelling or pain:

Condition	Why it mimics DVT	How to distinguish
Muscle strain / tear / twisting injury ^[1]	Acute calf pain, swelling, tenderness — exactly like DVT	History of trauma or sudden exertion; localised to a specific muscle group; no risk factors for DVT; ultrasound shows muscle tear, not venous thrombus
Ruptured Baker's cyst (popliteal cyst) ^[1]	Posterior knee/calf pain with acute swelling — classic DVT mimic	Baker's cyst = herniation of synovial fluid through the posterior knee capsule. When it ruptures, fluid tracks down the calf fascial planes → acute painful swelling, ecchymosis around the medial malleolus (crescent sign). Usually in patients with pre-existing knee osteoarthritis or rheumatoid arthritis. Ultrasound of popliteal fossa shows the ruptured cyst
Calf muscle haematoma	Painful swollen calf, especially in anticoagulated patients	History of anticoagulant use or coagulopathy; ultrasound shows haematoma within muscle rather than venous thrombus

Baker's Cyst — The Classic DVT Mimic

A ruptured Baker's cyst is one of the most commonly tested DVT mimics. Both present with acute calf swelling and pain. The key differentiator: Baker's cyst patients typically have a history of knee joint disease (OA, RA), and there may be a visible ecchymosis tracking around the medial malleolus. Always ask about pre-existing knee problems. Duplex ultrasound resolves the question definitively.

Condition	Why it mimics DVT	How to distinguish
Cellulitis ^[1]	Red, warm, swollen, painful leg — overlaps directly with DVT signs	Cellulitis = bacterial infection of skin and subcutaneous tissue. Key differences: tends to be bilateral/diffuse erythema with poorly demarcated borders, may have a portal of entry (wound, tinea pedis), associated with systemic features (fever, rigors, leucocytosis) more prominently. DVT tends to cause oedema out of proportion to erythema. However, DVT and cellulitis can coexist — always have a low threshold to investigate
Superficial thrombophlebitis ^[1]	Tender, palpable cord along a superficial vein with overlying erythema and warmth	This is thrombosis of a superficial vein (e.g., GSV or SSV), not a deep vein. The thrombosed vein is palpable as a firm, tender cord just beneath the skin. The inflammation is localised along the vein's course. Important: superficial thrombophlebitis can coexist with DVT (~6–40% of cases), especially if it involves the proximal GSV near the SFJ, so a duplex ultrasound should still be done
Lymphangitis ^[1]	Red streaking up the limb with pain and swelling	Lymphangitis = infection/inflammation of lymphatic channels. Distinguished by the characteristic red linear streaks tracking proximally along the limb (following lymphatic drainage), often with a distal portal of entry (wound, insect bite). Associated with tender regional lymphadenopathy

Condition	Why it mimics DVT	How to distinguish
Lymphoedema ^[1]	Chronic unilateral (or bilateral) limb swelling	Lymphoedema = impaired lymphatic drainage → accumulation of protein-rich interstitial fluid. Key distinguishing features: non-pitting oedema (because it is protein-rich, unlike the transudative pitting oedema of venous disease), positive Stemmer's sign (inability to pinch a fold of skin on the dorsum of the second toe), skin thickening, "buffalo hump" appearance at dorsum of foot. Chronic course (months/years) rather than acute onset. Causes: primary (congenital, praecox, tarda) or secondary (lymph node dissection, filariasis, radiation, tumour obstruction)
Venous valvular insufficiency / Chronic venous insufficiency (CVI) ^[1]^[3]	Chronic leg swelling, aching, heaviness	CVI from post-thrombotic syndrome or primary valvular incompetence causes chronic symptoms that fluctuate with standing/elevation. Distinguished from acute DVT by chronicity, skin changes (hyperpigmentation, lipodermatosclerosis, atrophie blanche, venous ulcers), and characteristic distribution in the "gaiter zone" (medial lower third of leg). However, acute DVT can occur on a background of CVI
Post-thrombotic syndrome	Chronic swelling, pain, skin changes after prior DVT	History of previous DVT; chronic course; associated skin changes of CVI. The damaged valves from prior DVT cause chronic venous hypertension

Condition	Why it mimics DVT	How to distinguish
Extrinsic venous compression (pelvic mass, May-Thurner syndrome)	Unilateral leg swelling from venous outflow obstruction	Pelvic malignancy (cervical, ovarian, rectal) can compress iliac veins causing unilateral swelling ^[2]. May-Thurner syndrome: left common iliac vein compression by right common iliac artery ^[3]. Usually presents in young women with left-sided DVT. CT/MR venography shows the compression
Compartment syndrome ^[6]	Acute painful, swollen, tense limb	Compartment syndrome = raised intra-compartmental pressure (from trauma, fracture, reperfusion) → compromised tissue perfusion. Distinguished by pain out of proportion, pain with passive stretch, tense compartment on palpation. Pulses may be preserved initially. Compartment pressure measurement is diagnostic
Acute arterial ischaemia (6Ps) ^[6]^[7]	Can be confused with DVT if the presentation includes a painful leg	Distinguished by the 6Ps: Pain, Pallor, Pulselessness, Perishingly cold, Paraesthesia, Paralysis ^[6]. The limb is pale and cold (not warm and swollen as in DVT). Absent pulses. History of AF, vascular disease
Phlegmasia cerulea dolens ^[6]^[7]	This is actually a severe form of DVT but can mimic acute arterial ischaemia	Massive DVT → venous pressure so high it compromises arterial inflow → cyanotic, painful, swollen limb. Distinguished from primary arterial ischaemia by the massive oedema (arterial ischaemia causes a "thin" pale limb; phlegmasia causes a "fat" blue limb)
Dependent oedema / Heart failure	Bilateral leg swelling	Usually bilateral and symmetrical; associated with other signs of heart failure (elevated JVP, S3, lung crepitations). Pitting oedema. Worsens with dependency, improves overnight
Nephrotic syndrome / Hypoalbuminaemia	Bilateral leg swelling	Low oncotic pressure → bilateral oedema. Frothy urine, periorbital oedema, low serum albumin

B. Differential Diagnosis of Pulmonary Embolism

PE is even more challenging because its symptoms (dyspnoea, chest pain, tachycardia) overlap with many acute cardiopulmonary conditions. The differential depends on the predominant presenting feature.

Condition	Why it mimics PE	How to distinguish
Pneumothorax ^[8]	Acute pleuritic chest pain + dyspnoea, exactly like PE	Sudden onset (often in tall thin young males or COPD patients). Reduced breath sounds and hyperresonance on the affected side. CXR shows visceral pleural line with absent lung markings peripherally. Unlike PE, there is no tachycardia from RV strain, and the hypotension (if tension pneumothorax) has a different mechanism (mediastinal shift → reduced venous return)
Pneumonia / Pleuritis	Pleuritic chest pain, dyspnoea, fever, tachycardia	Productive cough, consolidation signs (bronchial breathing, dull percussion, increased vocal resonance/tactile fremitus). CXR shows lobar or segmental consolidation. Fever and leucocytosis are more prominent. However, PE can also cause fever and CXR infiltrates (from infarction), so this distinction is not always straightforward
Acute exacerbation of COPD / Asthma	Acute dyspnoea, wheeze, tachycardia	History of COPD/asthma, diffuse wheeze on auscultation, hyperinflation. But remember: PE can trigger bronchospasm (serotonin and thromboxane release), and PE is a common cause of acute COPD exacerbation that doesn't respond to standard therapy

Condition	Why it mimics PE	How to distinguish
Acute myocardial infarction (AMI) ^[8]	Chest pain, dyspnoea, tachycardia, hypotension, elevated troponin	AMI: central crushing chest pain radiating to jaw/arm, ST changes in coronary territories on ECG, regional wall motion abnormality on echo. PE: more pleuritic (sharp, worse with inspiration), ECG shows right heart strain pattern (S1Q3T3, T inversions V1-4, RBBB), troponin may be mildly elevated in PE but in a different pattern
Pericarditis ^[8]	Pleuritic/positional chest pain, dyspnoea	Pericarditis: sharp retrosternal pain relieved by sitting forward, worse lying flat. ECG shows diffuse concave ST elevation and PR depression (not localised to a coronary territory). Pericardial friction rub on auscultation. Echo may show effusion
Aortic dissection ^[8]	Acute severe chest pain, hypotension, tachycardia	Aortic dissection: "tearing" interscapular pain, blood pressure differential between arms, widened mediastinum on CXR, aortic regurgitation murmur. CT angiography shows the dissection flap. Different mechanism entirely (intimal tear → false lumen) but the acuity and chest pain overlap with massive PE
Cardiac tamponade	Hypotension, tachycardia, elevated JVP — like massive PE	Beck's triad (hypotension, muffled heart sounds, elevated JVP). Pulsus paradoxus. Echo shows pericardial effusion with RA/RV diastolic collapse. Can be distinguished from PE because tamponade has equalisation of diastolic pressures whereas PE has isolated RV pressure elevation

Condition	Why it mimics PE	How to distinguish
Acute heart failure / Pulmonary oedema	Acute dyspnoea, tachycardia, hypoxaemia	Bilateral crepitations, S3 gallop, frothy pink sputum, raised BNP/NT-proBNP. CXR shows bilateral pulmonary oedema (bat-wing pattern, Kerley B lines, upper lobe diversion). Echo shows LV dysfunction. PE echo shows RV dilatation with preserved LV function
Acute pancreatitis ^[8]	Epigastric pain radiating to back, dyspnoea (from diaphragmatic irritation and pleural effusion)	Elevated lipase/amylase, CT findings. Usually not confused with PE if the history is clear, but both can cause pleural effusion and hypoxaemia

Feature	PE (thromboembolism)	Fat Embolism Syndrome
Timing	Any time, but classically days 5–10 post-op or during immobilisation	24–72 hours after long bone fracture or orthopaedic surgery
Classic triad	Dyspnoea + pleuritic pain + DVT signs	Respiratory distress + neurological changes (confusion) + petechial rash (axillae, conjunctivae, chest)
Mechanism	Thrombus embolisation from venous system	Fat globules from bone marrow enter venous system → lodge in pulmonary capillaries → cause endothelial injury + inflammatory response
D-dimer	Elevated	May be elevated (non-specific)
CT PA	Shows filling defect	Usually normal; bilateral ground-glass opacities

Some conditions deserve special mention because they can present with both limb symptoms and cardiopulmonary compromise, overlapping with the full VTE spectrum:

Condition	Mechanism	Key distinguishing features
Disseminated intravascular coagulation (DIC) ^[9]	Widespread intravascular coagulation → microvascular thrombosis + consumption of clotting factors → paradoxical bleeding AND thrombosis	History of sepsis, malignancy (especially APL), or obstetric catastrophe. Lab: ↓ platelets, ↑ PT, ↑ aPTT, ↑ D-dimer, ↑ FDPs, schistocytes on blood film (MAHA). Both thrombosis (organ ischaemia) and bleeding occur simultaneously
Heparin-induced thrombocytopenia (HIT)	Anti-PF4/heparin antibodies → platelet activation → arterial AND venous thrombosis despite thrombocytopenia	Occurs 5–10 days after starting heparin; platelet count drops > 50%; new thrombosis (venous > arterial) while on heparin. 4T score for clinical assessment. Confirm with anti-PF4 antibody and serotonin release assay
Antiphospholipid syndrome (APS)	Autoantibodies activate endothelium, platelets, complement → thrombosis	Recurrent arterial or venous thrombosis, pregnancy morbidity (recurrent miscarriages). Lab: lupus anticoagulant, anticardiolipin, anti-β2-glycoprotein I antibodies. Paradoxically prolongs aPTT in vitro
Cancer-associated thrombosis ^[1]	Mucin secretion, tissue factor expression, endothelial activation by tumour → hypercoagulable state	Unprovoked or recurrent VTE, especially in age > 40. May be the first presentation of an occult malignancy. Trousseau syndrome: migratory superficial thrombophlebitis (classically pancreatic cancer) ^[10]

References

^[1] Senior notes: felixlai.md (DVT and PE section, pages 962–965) ^[2] Senior notes: felixlai.md (Varicose veins section, page 950) ^[3] Senior notes: maxim.md (Varicose veins section, pages 165–173) ^[6] Senior notes: felixlai.md (Acute limb ischaemia section, page 918) ^[7] Senior notes: maxim.md (Acute limb ischaemia section) ^[8] Senior notes: felixlai.md (Aortic dissection differential diagnosis section, page 904) ^[9] Senior notes: felixlai.md (DIC section) ^[10] Senior notes: maxim.md (Pancreatic carcinoma section, page 146)

1. Pre-Test Probability Scoring — The Wells Score

Clinical Feature	Score	Rationale
Active cancer (treatment within 6 months, or palliative)	+1	Cancer = hypercoagulability (Virchow's triad)
Paralysis, paresis, or recent plaster immobilisation of lower extremity	+1	Immobility = stasis
Recently bedridden > 3 days or major surgery within 12 weeks requiring general/regional anaesthesia	+1	Stasis + endothelial injury
Localised tenderness along the distribution of the deep venous system	+1	Direct sign of thrombosed vein
Entire leg swollen	+1	Proximal obstruction (iliofemoral level)
Calf swelling at least 3 cm larger than asymptomatic side (measured 10 cm below tibial tuberosity)	+1	Objective measure of unilateral oedema
Pitting oedema confined to the symptomatic leg	+1	Venous hypertension → transudative oedema
Collateral superficial veins (non-varicose)	+1	Collateral drainage developing to bypass obstructed deep vein
Previously documented DVT	+1	Prior VTE is the strongest risk factor for recurrence
Alternative diagnosis at least as likely as DVT	−2	If another diagnosis explains the symptoms better, DVT becomes less likely

Interpretation:

Score	Probability Category	DVT Prevalence
≥ 3	High	~75%
1–2	Moderate	~17%
≤ 0	Low	~3%

This is the one most commonly tested in exams:

Clinical Feature	Score	Rationale
Clinical symptoms of DVT (leg swelling, pain with palpation) ^[1]	3.0	If the source (DVT) is present, PE is much more likely
Other diagnosis less likely than PE ^[1]	3.0	Clinical gestalt — if you can't think of a better explanation, PE probability rises
Immobilisation ≥ 3 days ^[1]	1.5	Stasis
Surgery in previous 4 weeks ^[1]	1.5	Stasis + endothelial injury
Previous DVT/PE ^[1]	1.5	Strongest predictor of recurrence
Tachycardia (HR > 100) ^[1]	1.5	Compensatory sympathetic response to reduced CO / hypoxaemia
Haemoptysis ^[1]	1.0	Pulmonary infarction → bleeding into airways
Malignancy ^[1]	1.0	Hypercoagulability

Interpretation — Two scoring systems ^[1]:

Traditional (three-tier) clinical probability ^[1]:

Category	Score	PE Prevalence
High	> 6.0	~65%
Moderate	2.0 – 6.0	~25%
Low	< 2.0	~10%

Simplified (two-tier) modified Wells ^[1]:

Category	Score	Action
PE likely	> 4.0	Proceed directly to CTPA
PE unlikely	≤ 4.0	D-dimer first; if negative, PE excluded

Exam Pearl: Modified Wells Dichotomised Score

The two-tier (dichotomised) modified Wells score with a cut-off of 4.0 is the most commonly used in current clinical practice. If score ≤ 4 → D-dimer. If score > 4 → CTPA. This is simpler and equally validated. Know both the three-tier and two-tier interpretations for exams ^[1].

The revised Geneva score is a fully objective alternative (no subjective "alternative diagnosis" criterion). Less commonly tested but worth knowing:

Feature	Score
Age > 65	+1
Previous DVT or PE	+3
Surgery or fracture within 1 month	+2
Active malignancy	+2
Unilateral lower limb pain	+3
Haemoptysis	+2
HR 75–94	+3
HR ≥ 95	+5
Pain on lower limb deep vein palpation and unilateral oedema	+4

Interpretation: 0–3 = low; 4–10 = intermediate; ≥ 11 = high.

2. Investigations — Biochemical Tests

Finding	Significance
Polycythaemia ^[1]	Myeloproliferative neoplasm (polycythaemia vera) — hypercoagulable state; increased blood viscosity contributes to stasis
Thrombocytosis ^[1]	Reactive thrombocytosis (infection, inflammation, malignancy) or essential thrombocythaemia — both increase thrombotic risk
Thrombocytopenia	Consider HIT (if on heparin), DIC, TTP/HUS, or APS (mild)
Leucocytosis	May suggest infection (cellulitis mimicking DVT, or pneumonia mimicking PE)
Anaemia	Chronic disease, haemolysis (DIC), or blood loss

Test	Significance
Prothrombin time (PT) ^[1]	Baseline assessment before starting anticoagulation; elevated in DIC, liver disease, warfarin use
Activated partial thromboplastin time (aPTT) ^[1]	Baseline; presence of lupus anticoagulant antibody leads to increased aPTT ^[1] — paradoxically, these patients are PROthrombotic in vivo (APS)
INR	Baseline; will be used to monitor warfarin therapy

Why do we check clotting before treatment? Because:

We need a baseline before starting anticoagulation
Prolonged PT/aPTT might suggest DIC (consumption of clotting factors), liver disease, or APS
An unexpectedly prolonged aPTT in the context of thrombosis should raise suspicion for lupus anticoagulant (APS)

Not performed in the acute setting — should be done 2–4 weeks after completing anticoagulation (or at least 2 weeks off anticoagulant), because:

Acute thrombosis itself consumes Protein C, S, and Antithrombin → falsely low levels
Heparin lowers Antithrombin levels
Warfarin lowers Protein C and S levels
DOACs interfere with lupus anticoagulant testing

Test	What It Detects ^[1]
Antithrombin III level ^[1]	Antithrombin deficiency (most relevant in Chinese/HK population)
Protein C activity ^[1]	Protein C deficiency
Protein S activity (free and total) ^[1]	Protein S deficiency
Factor V Leiden mutation ^[1]	Activated Protein C resistance (rare in Chinese)
Prothrombin G20210A mutation	Gain-of-function prothrombin mutation (rare in Chinese)
Lupus anticoagulant, anticardiolipin Ab, anti-β2-glycoprotein I Ab ^[1]	Antiphospholipid syndrome
Homocysteine level	Hyperhomocysteinaemia

When to screen for thrombophilia:

Unprovoked VTE in young patient (< 50 years)
Recurrent VTE
VTE at unusual sites (cerebral, splanchnic, upper extremity)
Family history of VTE
Warfarin-induced skin necrosis (Protein C deficiency)

Finding	Pathophysiological Basis ^[1]
Hypoxaemia ^[1]	V/Q mismatch — areas of lung are ventilated but not perfused (dead space), plus intrapulmonary shunting
Hypocapnia ^[1]	Compensatory hyperventilation in response to hypoxaemia → blows off CO2
Respiratory alkalosis ^[1]	Consequence of hyperventilation → ↓ PaCO2 → ↑ pH
Increased A-a gradient ^[1]	The alveolar-arterial oxygen gradient is elevated because the problem is at the level of gas exchange (V/Q mismatch), not hypoventilation. A normal A-a gradient would suggest hypoventilation as the cause of hypoxaemia
Type I respiratory failure ^[1]	Hypoxaemia (PaO2 < 60 mmHg) with normal or low PaCO2 — classic pattern for PE

ABG in PE: Why Type I, Not Type II?

PE creates dead space (ventilated but not perfused areas). The body compensates by hyperventilating the perfused areas, which effectively blows off CO2 (CO2 is highly diffusible). So PaCO2 is normal or low. But this hyperventilation cannot fully compensate for the hypoxaemia because oxygen has much less ability to dissolve across the alveolar membrane at higher concentrations (the O2-Hb dissociation curve is sigmoid — you're on the flat part). Result: Type I failure (low O2, normal/low CO2).

Biomarker	Significance	Mechanism
Troponin (cTnT / cTnI)	Elevated = RV myocardial injury	Acute RV pressure overload → increased RV wall tension → RV subendocardial ischaemia (oxygen demand exceeds supply)
BNP / NT-proBNP	Elevated = RV wall stress	RV dilatation stretches cardiomyocytes → release of natriuretic peptides

Both elevated troponin AND BNP/NT-proBNP indicate submassive PE with RV dysfunction — these patients are at higher risk of decompensation and may benefit from escalated therapy.

3. Investigations — Radiological / Imaging

The ECG in PE is not diagnostic but can suggest right heart strain:

Finding	Pathophysiological Basis ^[1]
Sinus tachycardia ^[1]	Most common finding; sympathetic compensation for reduced CO and hypoxaemia
S1Q3T3 ^[1]	The classic (but not sensitive) PE pattern: S1 = deep S wave in lead I (right axis deviation); Q3 = Q wave in lead III; T3 = inverted T wave in lead III ^[1]. This reflects acute RV dilatation/strain shifting the cardiac axis rightward
Right axis deviation ^[1]	Acute RV dilatation shifts the electrical axis to the right
T wave inversions in V1–V4 ^[1]	Evidence of right heart strain ^[1] — RV ischaemia/strain produces anterior T wave inversions in the right precordial leads
Incomplete or complete RBBB ^[1]	Acute RV dilatation stretches the right bundle branch → conduction delay
P pulmonale	Right atrial enlargement (peaked P waves in II, III, aVF) from increased RA pressure
Atrial fibrillation / flutter	Acute RA dilatation can trigger supraventricular arrhythmias

S1Q3T3: Classic but NOT Sensitive

S1Q3T3 is the "textbook answer" for PE on ECG, but it is present in only ~10–25% of PE cases. Sinus tachycardia is by far the most common ECG finding ^[1]. The most useful ECG findings for suggesting significant PE are T wave inversions in V1–V4 and new RBBB, as these indicate RV strain. A completely normal ECG does NOT exclude PE.

CXR is neither sensitive nor specific for PE. Its main role is to exclude other diagnoses (pneumothorax, pneumonia, heart failure). However, several classic (though uncommon) signs exist:

Finding	Description and Mechanism ^[1]
Hampton's hump ^[1]	Wedge-shaped, pleural-based opacity — hump-shaped density in the periphery of the lung with its base abutting the pleural surface and apex pointing towards the hilum ^[1]. Represents a pulmonary infarct: the embolus occludes a peripheral pulmonary artery → ischaemic necrosis of the distal lung parenchyma → wedge-shaped consolidation
Westermark sign ^[1]	Focal oligaemia (decreased vascularity) distal to the PE ^[1] — a sharp cut-off of pulmonary vessels with distal hypoperfusion in a segmental distribution ^[1]. Represents the territory beyond the occluded pulmonary artery where blood flow has ceased
Pleural effusion ^[1]	Small ipsilateral pleural effusion (usually exudative, may be haemorrhagic from infarction). Usually does not require tapping for therapeutic and diagnostic purposes ^[1]
Atelectasis ^[1]	Decreased ventilation in alveoli deprived of blood supply ^[1] → loss of surfactant production (surfactant requires perfusion) → alveolar collapse → collapse of infarcted segment ^[1]
Elevated hemidiaphragm	Splinting from pleuritic pain or volume loss from atelectasis
Enlarged right descending pulmonary artery (Fleischner sign)	Distension of the pulmonary artery proximal to the embolus
Normal CXR	Most common finding! A normal CXR in a dyspnoeic, hypoxic patient should actually raise your suspicion for PE

The first-line diagnostic test for DVT ^[1].

Technique ^[1]:

Duplex = B-mode USG + Doppler technique ^[1]
The examiner systematically compresses the deep veins of the lower extremity with the ultrasound probe from the common femoral vein down to the popliteal vein (and calf veins in some protocols)
Loss of vein compressibility is used as the primary criterion for DVT ^[1] — a normal vein collapses completely under probe pressure; a thrombosed vein does NOT compress because the thrombus occupies the lumen

Findings:

Finding	Significance
Non-compressible vein segment	Diagnostic of DVT — the thrombus within the lumen prevents the vein walls from coapting
Echogenic material within lumen	Visible thrombus (may be acute = hypoechoic, or chronic = hyperechoic)
Absent or diminished Doppler flow	Venous obstruction by thrombus
Loss of respiratory phasicity	Normal veins show flow variation with respiration; loss suggests proximal obstruction
Increased venous diameter	Acute thrombus distends the vein

Advantages:

Non-invasive, no radiation, no contrast
Highly accurate for proximal DVT (sensitivity ~95%, specificity ~98%)
Can be performed at the bedside (including ICU)
Can also detect Baker's cyst, haematoma, superficial thrombophlebitis (helps with DDx)

Limitations:

Less sensitive for distal (calf) DVT (~70% sensitivity) — smaller veins, more technically difficult
Operator-dependent
Difficult in obese patients or those with significant oedema
Cannot assess pelvic veins (iliac veins) well due to bowel gas overlay

Role in PE workup:

Lower extremity compression USG to look for evidence of DVT and assess for source of emboli ^[1]
If a patient has a high clinical suspicion for PE and duplex USS shows proximal DVT, this confirms VTE and anticoagulation can be started without necessarily needing CTPA

The confirmatory (diagnostic) test for PE ^[1].

Technique:

IV contrast injection with CT scanning timed to the peak opacification of the pulmonary arteries
Rapid helical CT acquisition allows visualisation of the pulmonary vasculature from the main pulmonary trunk down to subsegmental branches

Key finding ^[1]:

Filling defects in the pulmonary trunk ^[1] — the thrombus appears as a dark (hypodense) area within the contrast-opacified (bright white) pulmonary artery
Can identify:
- Saddle embolus: straddling the main PA bifurcation
- Lobar, segmental, and subsegmental emboli
- RV dilatation (RV:LV ratio > 1.0 suggests RV strain — prognostic significance)

Additional findings on CTPA:

Finding	Significance
RV/LV diameter ratio > 1.0	RV strain / dysfunction — submassive PE
Interventricular septum bowing into LV	RV pressure overload
Contrast reflux into IVC and hepatic veins	RV failure → tricuspid regurgitation → contrast reflux
Pleural effusion	Pulmonary infarction
Wedge-shaped peripheral consolidation	Pulmonary infarct (Hampton's hump equivalent on CT)

Advantages:

High sensitivity (~95–100%) and specificity (~97%) for PE down to segmental level
Fast (can be done in < 5 minutes) — suitable for acutely unwell patients
Can identify alternative diagnoses (pneumonia, aortic dissection, pneumothorax)
Provides prognostic information (RV size)

Limitations:

Radiation exposure
IV contrast required → risk of contrast-induced nephropathy (check RFT) and contrast allergy
Less accurate for subsegmental PE (clinical significance of isolated subsegmental PE is debated)
Motion artefact in dyspnoeic patients
Contraindicated in severe contrast allergy and renal failure (relative)

An alternative to CTPA when CTPA is contraindicated (e.g., contrast allergy, severe renal failure, pregnancy).

Technique:

Perfusion (Q) scan: IV injection of technetium-99m-labelled macroaggregated albumin (MAA) → particles lodge in the pulmonary capillary bed proportional to blood flow → gamma camera imaging shows perfusion distribution
Ventilation (V) scan: Patient inhales aerosolised technetium-99m or xenon-133 → gamma camera shows ventilation distribution
Comparison: Areas of perfusion defect with preserved ventilation (V/Q mismatch) suggest PE

Key findings ^[1]:

V/Q mismatch with perfusion defect but preserved ventilation ^[1]
Multiple segmental and subsegmental perfusion defects ^[1]

Result categories:

Category	Interpretation
Normal	Excludes PE (~98% NPV)
Low probability	Small subsegmental mismatches; clinically unlikely PE
Intermediate (indeterminate)	Cannot confirm or exclude PE — further workup needed
High probability	Multiple segmental or larger V/Q mismatches — ~90% probability of PE

Limitations ^[1]:

High sensitivity (98%) but low specificity (10%) ^[1]
Atelectasis following pulmonary infarction or background lung disease will also lead to ventilation defect → matched defect → indeterminate scan ^[1]
Important that CXR should be normal, otherwise V/Q scan will be indeterminate ^[1]
~50% of V/Q scans are non-diagnostic (intermediate probability)

CTPA vs V/Q Scan: When to Use Which

CTPA is first-line for most patients. Use V/Q scan when: (1) contrast allergy, (2) severe renal impairment, (3) pregnancy (lower radiation dose to breast tissue, though CTPA is increasingly used with breast shields), (4) normal CXR (V/Q is only interpretable with a normal baseline CXR). In HK clinical practice, CTPA is overwhelmingly preferred.

Not a diagnostic test for PE, but crucial for risk stratification and bedside assessment in haemodynamically unstable patients.

Finding	Significance ^[1]
RV dilatation	RV pressure overload from PE
RV hypokinesis	RV failure
McConnell's sign ^[1]	Hypokinesis of the RV free wall with normal or hyperkinetic motion of the RV apex ^[1] — highly specific for acute PE (the apex is spared because it is tethered to the LV apex, which is still contracting normally)
Tricuspid regurgitation	RV dilatation → annular dilatation → functional TR
Pulmonary hypertension	Estimated from TR jet velocity; acute PE cannot usually generate PASP > 40 mmHg in a previously normal RV
D-shaped septum (interventricular septum bowing into LV)	RV pressure overload pushes septum leftward
Saddle, right or left main PE ^[1]	Identify saddle embolus in the proximal pulmonary arteries (TOE more sensitive than TTE for this) ^[1]
IVC dilatation with reduced inspiratory collapse	Elevated RA pressure (RV failure)

When to use echo:

Haemodynamically unstable patient with suspected massive PE — bedside TTE can rapidly confirm RV dysfunction and guide decision to thrombolyse
Risk stratification of haemodynamically stable patients (submassive vs low-risk)
Cannot perform CTPA (patient too unstable to transport)

4. Diagnostic Algorithm

Investigation	What It Shows	Sensitivity / Specificity	When to Use	Key Findings
D-dimer	Fibrin degradation product	High sensitivity, low specificity	Low/moderate pre-test probability to EXCLUDE VTE	Negative = excludes VTE; Positive = non-specific
Compression USS	Direct visualisation of venous thrombus	~95%/98% for proximal DVT	First-line for suspected DVT	Non-compressible vein = DVT
CTPA	Filling defects in pulmonary arteries	~95–100%/97%	Confirmatory test for PE	Intraluminal filling defect; RV/LV ratio
V/Q scan	Ventilation-perfusion mismatch	98% sensitivity, ~10% specificity	CTPA contraindicated; normal CXR	V/Q mismatch = PE
ECG	Cardiac electrical activity	Low sensitivity for PE	All suspected PE patients	Sinus tachycardia; S1Q3T3; RV strain
CXR	Lung parenchyma, pleura	Low sensitivity for PE	Exclude other diagnoses	Hampton's hump; Westermark sign
Echocardiography	Cardiac structure and function	Moderate for RV dysfunction	Haemodynamically unstable PE; risk stratification	RV dilatation; McConnell's sign
ABG	Gas exchange	N/A	Assess hypoxaemia severity	Type I respiratory failure; ↑ A-a gradient
Troponin / BNP	Myocardial injury / RV strain	N/A	PE risk stratification	Elevated = submassive PE

After confirming PE with CTPA, the next step is to determine severity, which guides treatment:

Risk Category	Haemodynamics	RV Dysfunction	Biomarkers	30-day Mortality	Treatment Approach
Massive (high-risk)	Hypotension / Shock	Yes	Usually elevated	> 15%	Thrombolysis / Embolectomy
Submassive (intermediate-high)	Stable	Yes	Elevated	3–15%	Anticoagulation ± thrombolysis (if deteriorating)
Submassive (intermediate-low)	Stable	One of RV dysfunction OR elevated biomarkers (not both)	Variable	3–15%	Anticoagulation; close monitoring
Low-risk	Stable	No	Normal	< 1%	Anticoagulation; consider early discharge / outpatient treatment

Tools for risk stratification:

PESI score (Pulmonary Embolism Severity Index) or simplified PESI (sPESI): validated scoring systems incorporating age, vital signs, comorbidities, and biomarkers to predict 30-day mortality
sPESI: Age > 80, cancer, heart failure/chronic lung disease, HR ≥ 110, SBP < 100, SpO2 < 90% — any one criterion = high risk (sPESI ≥ 1)

High Yield Summary — Diagnosis of VTE

Wells score is the starting point for both DVT and PE — it determines whether D-dimer is needed or you skip straight to imaging ^[1]
D-dimer is sensitive but NOT specific ^[1] — used only to RULE OUT VTE in low/moderate probability. Not useful post-operatively ^[5]
Age-adjusted D-dimer cut-off: 10 × age if ≥ 50 years ^[1] — increases specificity without sacrificing sensitivity
Compression USS is first-line for DVT — loss of vein compressibility = primary criterion ^[1]
CTPA is the confirmatory test for PE ^[1] — look for filling defects in pulmonary trunk ^[1]
V/Q scan is an alternative to CTPA — requires normal CXR for interpretation ^[1]; high sensitivity but low specificity ^[1]
ECG in PE: Sinus tachycardia (most common), S1Q3T3, T inversions V1–V4, RBBB ^[1]
CXR in PE: Hampton's hump (wedge-shaped infarct), Westermark sign (focal oligaemia), atelectasis ^[1]
Echo: McConnell's sign (RV free wall hypokinesis with apical sparing) ^[1] — used for risk stratification and bedside assessment in unstable patients
ABG shows Type I respiratory failure: hypoxaemia, hypocapnia, respiratory alkalosis, increased A-a gradient ^[1]
Massive PE: Skip algorithms → bedside echo → thrombolysis if RV dysfunction present
Thrombophilia screen: Do NOT test acutely — wait until anticoagulation is completed

Active Recall - VTE Diagnosis

The treatment approach is determined by a 2×2 matrix of haemodynamic stability and bleeding risk ^[1]:

Haemodynamic Stability	Bleeding Risk	Treatment Modality ^[1]
Stable	Low	Anticoagulation
Stable	High	IVC filter
Unstable	Low	Thrombolysis
Unstable	High	Embolectomy

This table is the single most important framework for VTE management. Let's reason through it:

Stable + Low bleeding risk: The standard situation — anticoagulation alone is sufficient because the patient is not in immediate danger. The body's own fibrinolytic system will gradually dissolve the clot; anticoagulation prevents propagation.
Stable + High bleeding risk: Cannot anticoagulate safely → place an IVC filter as a mechanical barrier to prevent PE while the bleeding risk resolves.
Unstable + Low bleeding risk: The patient is in shock from massive PE → need to actively destroy the clot NOW → systemic thrombolysis.
Unstable + High bleeding risk: Cannot give thrombolytics (too much bleeding risk) → surgical or catheter-based embolectomy is the only option.

4. Medical Treatment — Anticoagulation

Anticoagulation is the backbone of VTE treatment. It does NOT dissolve the existing clot — rather, it prevents the clot from growing while the body's intrinsic fibrinolytic system (plasmin) gradually breaks it down. Think of it as "holding the line" while the body does the cleanup.

4A. Initial Parenteral Anticoagulation

Treatment approach: Parenteral therapy (UFH/LMWH/Fondaparinux) bridged to warfarin OR parenteral therapy bridged to NOAC ^[1].

Mechanism: LMWH binds to antithrombin III and accelerates its inhibition of Factor Xa (and to a lesser extent, thrombin/Factor IIa). The "low molecular weight" means it preferentially inhibits Factor Xa over thrombin compared to UFH.

Feature	Details ^[1]
Duration	Continued for ≥ 5 days ^[1]
Preference	Preferred over UFH, especially in cancer patients since it can decrease recurrence and mortality compared with UFH and warfarin ^[1]
Examples and dosing ^[1]	SC Enoxaparin 1 mg/kg BID or SC Dalteparin 200 IU/kg QD ^[1]
Monitoring	Generally does NOT require lab monitoring (predictable dose-response); check anti-Xa levels in renal impairment, obesity, or pregnancy
Renal clearance	Renally cleared → dose adjustment needed if CrCl < 30 mL/min

Advantages of LMWH over UFH ^[1]:

Greater bioavailability ^[1]
Longer duration of anticoagulant effect → fewer daily injections ^[1]
Better dose-response correlation → fixed-dose administration without lab monitoring ^[1]
Extensive clinical experience with subcutaneous administration ^[1]
Lower risk of HIT ^[1] — Why? LMWH has less affinity for platelet factor 4 (PF4) → less formation of the HIT antibody complex
Lower risk of osteoporosis ^[1] — long-term heparin use can cause osteoporosis; LMWH has less osteoclast activation than UFH

Mechanism: UFH binds to antithrombin III and accelerates its inhibition of both thrombin (IIa) and Factor Xa equally (1:1 ratio). It is a heterogeneous mixture of polysaccharide chains of varying molecular weights.

Feature	Details ^[1]
Duration	Continued for ≥ 5 days ^[1]
Dosing ^[1]	IV UFH 80 U/kg bolus → 18 U/kg/hr and titrate to aPTT 1.5–2.5× normal ^[1]
Monitoring	Dose should be sufficient to prolong aPTT to 1.5–2.5× the mean of control value or upper limit of normal aPTT range ^[1]

Advantages of UFH over LMWH ^[1]:

Faster onset of action with intravenous administration ^[1] — important in acute, unstable situations
Easier to stop therapy due to shorter half-life (60–90 min) ^[1] — critical if the patient develops bleeding or needs emergency surgery
Easier to inactivate with protamine sulphate ^[1] — protamine is a specific antidote that neutralises UFH; it only partially reverses LMWH (~60% of anti-Xa activity)

When to prefer UFH over LMWH ^[1]:

When contemplating thrombolysis or catheter-based treatment ^[1] — need to be able to stop anticoagulation quickly
Renal failure (CrCl < 25) ^[1] — UFH is cleared by the reticuloendothelial system, NOT the kidneys
Extreme obesity ^[1] — unpredictable LMWH pharmacokinetics
Haemodynamic instability ^[1] — may need to switch to thrombolysis; UFH's short half-life allows rapid transition
High bleeding risk ^[1] — can be reversed quickly with protamine

Mechanism: A synthetic pentasaccharide that selectively inhibits Factor Xa via antithrombin III. It has no direct thrombin inhibition.

Feature	Details ^[1]
Duration	Continued for ≥ 5 days ^[1]
Dosing ^[1]	SC Fondaparinux 5–10 mg QD ^[1] (weight-based: 5 mg if < 50 kg, 7.5 mg if 50–100 kg, 10 mg if > 100 kg)
Note ^[1]	Oral anticoagulants with vitamin K antagonist should be overlapped for ≥ 4–5 days ^[1]

Advantages:

Zero risk of HIT — fondaparinux does not bind PF4 at all. This makes it the agent of choice in patients with confirmed or suspected HIT
Once-daily subcutaneous dosing, no monitoring required

Limitations:

No specific antidote (protamine does NOT reverse fondaparinux)
Renally cleared — contraindicated if CrCl < 30 mL/min
Long half-life (~17 hours) — harder to reverse if bleeding occurs

HIT and Fondaparinux

If a patient on heparin develops thrombocytopenia (platelet drop > 50%) and/or new thrombosis at day 5–10, suspect heparin-induced thrombocytopenia (HIT). Immediately stop ALL heparin products (including LMWH — there is ~5% cross-reactivity). Switch to a non-heparin anticoagulant: fondaparinux (most commonly used in HK), argatroban (direct thrombin inhibitor, useful in renal failure), or bivalirudin.

4B. Transition to Oral Anticoagulation

Mechanism: Warfarin inhibits vitamin K epoxide reductase → prevents the regeneration of reduced vitamin K → impairs the gamma-carboxylation of vitamin K-dependent clotting factors (II, VII, IX, X) AND the natural anticoagulant proteins (Protein C and Protein S).

The critical teaching point about warfarin:

Warfarin is NOT initiated as monotherapy during acute thrombotic illness due to a paradoxical exacerbation of hypercoagulability which increases likelihood of thrombosis ^[1].

Why does this paradox occur? ^[1]:

Warfarin inhibits vitamin K-dependent gamma carboxylation of the anticoagulant factors Protein S and Protein C, which inhibit activated factors VIII and V ^[1]
Warfarin has a transient procoagulant effect during the first 1–2 days of use ^[1]
Protein C has a very short half-life (~6–8 hours) — it falls FIRST
The procoagulant factors (especially Factor II, half-life ~60 hours) take much longer to fall
So in the first 1–2 days: Protein C is depleted but Factor II is still active → net procoagulant state → risk of paradoxical thrombosis, including the dreaded warfarin-induced skin necrosis (especially in Protein C deficient patients)

Initiation protocol ^[1]:

Initiated simultaneously with heparin with initial dose = 5 mg/day ^[1]
Overlap with parenteral anticoagulants for ≥ 5 days until INR ≥ 2.0 for ≥ 24 hours ^[1]
Warfarin requires at least 5 days to reach therapeutic level ^[1] — because Factor II (half-life ~60h) takes 5+ days to fall sufficiently
Target INR: 2.5 (range 2.0–3.0) ^[1]
Heparin product can be discontinued on day 5/6 when INR has been therapeutic for two consecutive days ^[1]

Antidote ^[1]:

Vitamin K with FFP in case of overshoot INR ^[1]
Vitamin K (phytomenadione): 1–10 mg IV/oral depending on severity; takes 6–24 hours to work (needs hepatic synthesis of new clotting factors)
FFP / Prothrombin complex concentrate (PCC): provides immediate replacement of clotting factors for life-threatening bleeding (works within minutes)
PCC (e.g., Octaplex, Beriplex) is preferred over FFP: smaller volume, faster to administer, more concentrated clotting factors, no need for crossmatching

Monitoring: INR checked regularly; initially every 1–2 days, then weekly, then monthly once stable.

Drug interactions: Warfarin has notoriously numerous interactions (CYP2C9 and CYP3A4):

Potentiate warfarin (↑ INR, ↑ bleeding risk): amiodarone, azole antifungals, macrolides, metronidazole, SSRIs, NSAIDs, cranberry juice
Antagonise warfarin (↓ INR): rifampicin, carbamazepine, phenytoin, St John's wort, green leafy vegetables (vitamin K content)

DOACs are attractive candidates as initial oral anticoagulants in patients with acute VTE due to quicker onset of action ^[1].

There are two classes ^[1]:

Class	Drug ^[1]	Mechanism	Initiation Strategy
Direct thrombin (Factor IIa) inhibitor ^[1]	Dabigatran ^[1]	Directly binds and inhibits thrombin (both free and clot-bound)	Initiate after ≥ 5 days of parenteral anticoagulation ^[1]
Direct Factor Xa inhibitor ^[1]	Rivaroxaban ^[1]	Directly inhibits Factor Xa (both free and within the prothrombinase complex)	Can be given as sole anticoagulant with initial loading dose ^[1] — no parenteral lead-in needed
Direct Factor Xa inhibitor ^[1]	Apixaban ^[1]	Same as rivaroxaban	Can be given as sole anticoagulant with initial loading dose ^[1]
Direct Factor Xa inhibitor ^[1]	Edoxaban ^[1]	Same as above	Initiate after ≥ 5 days of parenteral anticoagulation ^[1]

Loading dose regimens (no parenteral lead-in needed):

Rivaroxaban: 15 mg BID for 21 days → then 20 mg QD
Apixaban: 10 mg BID for 7 days → then 5 mg BID

Post-parenteral regimens:

Dabigatran: After ≥ 5 days LMWH → 150 mg BID
Edoxaban: After ≥ 5 days LMWH → 60 mg QD (30 mg if CrCl 15–50, weight ≤ 60 kg, or on certain P-gp inhibitors)

Advantages of DOACs over warfarin:

Fixed dosing, no routine INR monitoring
Fewer drug and food interactions
Rapid onset (hours vs days)
At least non-inferior to warfarin for VTE treatment; lower risk of intracranial haemorrhage
Lower rates of major bleeding overall

Limitations:

Renal clearance: dose adjustment needed for renal impairment; dabigatran contraindicated if CrCl < 30
More expensive than warfarin
Limited experience in certain populations (mechanical heart valves — contraindicated; severe liver disease; antiphospholipid syndrome — warfarin remains standard)
Antidotes:
- Dabigatran: Idarucizumab (Praxbind) — specific monoclonal antibody fragment that binds dabigatran ^[11]
- Factor Xa inhibitors (rivaroxaban, apixaban, edoxaban): Andexanet alfa — recombinant modified Factor Xa that acts as a decoy; alternatively, PCC can be used

DOACs in Cancer-Associated Thrombosis

Current guidelines (ISTH 2023, ASH 2024) recommend DOACs (particularly edoxaban or rivaroxaban) over LMWH for most cancer-associated VTE, EXCEPT in patients with GI or genitourinary tract cancers (where DOACs increase mucosal bleeding risk). In these patients, LMWH remains preferred. Historically, LMWH was preferred in cancer patients ^[1] — this has evolved with recent RCT evidence (HOKUSAI VTE-Cancer, SELECT-D, CARAVAGGIO trials).

This is one of the most important clinical decisions and depends on whether the VTE was provoked or unprovoked:

Scenario	Duration	Rationale
First episode, provoked by major transient risk factor (surgery, trauma, immobilisation)	3 months	Risk factor is gone; recurrence risk is low (~3% per year)
First episode, provoked by minor transient risk factor (OCP, long-haul flight)	3 months (consider extended if multiple risk factors)	Similar logic but reassess
First unprovoked VTE	≥ 3 months, then reassess for indefinite/extended therapy	Recurrence risk ~10% per year after stopping; weigh against bleeding risk
Second unprovoked VTE	Indefinite / lifelong	Very high recurrence risk (~15% per year)
Cancer-associated VTE	Indefinite (as long as cancer is active or being treated)	Ongoing hypercoagulable state from cancer; reassess if cancer is cured
Cerebral venous thrombosis ^[4]	3 months (LMWH acute → warfarin or dabigatran) ^[4]

5. Thrombolytic (Fibrinolytic) Therapy [1]

6. Surgical / Interventional Treatment [1]

Used for prevention of PE by filtering blood clots ^[1].

Mechanism: A metallic cone-shaped device deployed into the IVC that acts as a physical sieve — it allows blood to flow through but traps large emboli travelling from the lower extremity veins towards the lungs.

Access sites ^[1]:

Internal jugular vein ^[1]
Common femoral vein ^[1]
Brachial / basilic vein (upper extremity approach — less commonly used) ^[1]

Filter positioning ^[1]:

Position: Tip of filter just at the inflow of renal veins ^[1]
Minimises the accumulation of thrombus above the filter in the event of filter thrombosis ^[1]
If the filter is substantially below the renal vein inflow, then the dead space between the thrombosed filter and renal veins may allow a clot to form, potentially leading to pulmonary embolism ^[1]
If the filter is placed across the renal veins, it may not be stable in a pararenal location due to inability of the fixation mechanism to fully engage the IVC wall, but it has no significant effect on renal function ^[1]

Indications ^[1]:

Contraindicated or failure of anticoagulant therapy ^[1]
Chronic recurrent embolism with pulmonary PE ^[1]
High risk for proximal vein thrombosis or PE ^[1]
Recurrent thromboembolism despite adequate anticoagulation ^[1]
Pre-operative: Established DVT pre-op: IVC filter to prevent PE → remove 2 weeks later ^[11]

Important considerations:

Modern filters are retrievable — they should be removed once the indication has resolved (e.g., when anticoagulation can be safely restarted). Permanent filters increase risk of IVC thrombosis and post-thrombotic syndrome
IVC filters do NOT treat the DVT — they only prevent PE. The patient still needs anticoagulation when safe to do so
Complications ^[11]:
- Migration ^[11]
- Fractured filter ^[11]
- Infection ^[11]
- IVC thrombosis
- Filter tilting or perforation of IVC wall
- Recurrent DVT (the filter itself is a thrombogenic foreign body)

IVC Filter: A Bridge, Not Definitive Treatment

A common mistake is placing an IVC filter and forgetting about it. An IVC filter is a temporary measure — it should be removed once the patient can safely receive anticoagulation. Leaving a filter in permanently increases the long-term risk of IVC thrombosis, filter fracture, and recurrent DVT. Always document a plan for filter retrieval.

7. Prophylaxis of VTE [1][11]

Prevention is better than cure. VTE prophylaxis in hospitalised and surgical patients is one of the most impactful interventions in medicine.

8. Special Management Scenarios

Feature	UFH	LMWH	Fondaparinux	Warfarin	DOACs
Route	IV	SC	SC	PO	PO
Onset	Minutes	2–4 hours	2 hours	3–5 days	2–4 hours
Monitoring	aPTT	Anti-Xa (only in special cases)	None	INR	None (routine)
Antidote	Protamine	Protamine (partial)	None specific	Vitamin K + FFP/PCC	Idarucizumab (dabigatran); Andexanet alfa (Xa inhibitors)
HIT risk	Highest	Lower	None	None	None
Renal impairment	Safe	Dose adjust if CrCl < 30	CI if CrCl < 30	Safe	Dose adjust; CI if severe
Pregnancy	Safe	Safe	Limited data	Teratogenic	Contraindicated
Cancer	Second-line	Preferred (historical)	Alternative	Inferior	Preferred (current guidelines, except GI/GU cancers)

High Yield Summary — Management of VTE

Treatment is determined by haemodynamic stability × bleeding risk ^[1]: Stable+low=anticoagulation; Stable+high=IVC filter; Unstable+low=thrombolysis; Unstable+high=embolectomy
LMWH is preferred over UFH for most patients (lower HIT risk, no monitoring, better in cancer) ^[1]; UFH is preferred when contemplating thrombolysis, in renal failure, extreme obesity, or haemodynamic instability ^[1]
Warfarin must NEVER be started alone — paradoxical procoagulant effect from early Protein C/S depletion ^[1]. Overlap with heparin ≥ 5 days, INR ≥ 2.0 for ≥ 24h before stopping heparin ^[1]
DOACs: Rivaroxaban and Apixaban can be used as sole agents from day 1 (with loading dose); Dabigatran and Edoxaban require ≥ 5 days parenteral lead-in ^[1]
Thrombolysis indications: haemodynamically unstable PE, massive ilio-femoral thrombosis, RV dilatation ^[1]
IVC filter: for patients who cannot be anticoagulated; position at inflow of renal veins ^[1]; always plan for retrieval
VTE prophylaxis in HK: mechanical prophylaxis for all surgical patients; pharmacological only for high-risk groups ^[11]
Duration: 3 months for provoked VTE; extended/indefinite for unprovoked or cancer-associated VTE
Warfarin antidote: Vitamin K + FFP ^[1]; Dabigatran antidote: idarucizumab; Xa inhibitor antidote: andexanet alfa
Fondaparinux is the drug of choice in HIT — zero PF4 binding

Active Recall - VTE Management

A. Acute Complications of DVT

These represent the severe end of the DVT spectrum where massive venous obstruction threatens the limb:

Condition	Mechanism	Clinical Features	Outcome if Untreated
Phlegmasia alba dolens ("painful white leg")	Massive ilio-femoral DVT → extreme venous hypertension → severe oedema → interstitial pressure rises enough to compress arterial inflow → limb pallor	Massively swollen, white/pale, painful leg; pulses may be diminished	Can progress to phlegmasia cerulea dolens
Phlegmasia cerulea dolens ("painful blue leg")	Progression: near-total venous occlusion → venous pressure exceeds arterial inflow pressure → tissue ischaemia → cyanosis → venous gangrene	Massively swollen, cyanotic, exquisitely painful leg; absent pulses; petechiae/blisters may develop	Venous gangrene → limb loss; systemic: hypovolaemic shock (massive fluid sequestration in the leg), DIC, multi-organ failure; mortality ~25–40%

Management: This is a limb- and life-threatening emergency:

Immediate anticoagulation (IV UFH)
Limb elevation
Consider catheter-directed thrombolysis or surgical thrombectomy
If venous gangrene has developed → fasciotomy or amputation may be required

B. Chronic Complications of DVT

PTS is the most common long-term complication of DVT, occurring in 20–50% of patients with proximal DVT even with adequate anticoagulation. One of the key treatment objectives is limiting development of late complications including post-thrombotic syndrome ^[1].

Pathophysiology: The thrombus in the deep vein causes two types of long-term damage:

Valvular destruction: As the thrombus organises and recanalises, it damages the delicate bicuspid venous valves → valvular incompetence → reflux → ambulatory venous hypertension
Residual venous obstruction: Incomplete thrombus resolution → persistent luminal narrowing → outflow obstruction → further venous hypertension

The combined effect is chronic venous hypertension in the affected limb → increased capillary pressure → fluid transudation (oedema), fibrin cuff deposition around capillaries (blocking oxygen diffusion), white cell trapping and activation (chronic inflammation), and eventually tissue damage.

Clinical Features (progressive) ^[3]:

Leg pain and heaviness — worsens with standing, improves with elevation (same mechanism as CVI)
Chronic oedema — persistent swelling of the affected limb
Skin changes:
- Hyperpigmentation ^[3] — haemosiderin deposition from extravasated red blood cells. Venous hypertension → capillary distension → RBC leak → macrophages phagocytose RBCs → deposit haemosiderin (brown pigment) in the dermis
- Venous eczema (stasis dermatitis) ^[3] — itchy, erythematous, scaly skin. Chronic inflammation from trapped leucocytes releasing inflammatory mediators
- Lipodermatosclerosis ^[3] — fibrosis and hardening of the subcutaneous tissue, particularly in the "gaiter zone" (medial lower third of the leg). The skin becomes woody, indurated, and tight. The leg develops an "inverted champagne bottle" appearance (narrowed at the ankle from fibrosis, swollen above from oedema)
- Atrophie blanche ^[3] — white, avascular, scar-like plaques surrounded by dilated capillaries and hyperpigmentation. Represents focal skin infarction from severe microvascular disease
- Corona phlebectatica (malleolar flare) ^[3] — fan-shaped pattern of intradermal venules at the ankle, representing cutaneous venous hypertension
Venous ulceration ^[3] — the end-stage of PTS/CVI. Typically occurs in the gaiter zone (medial malleolar area). Shallow, irregular, with sloping edges, overlying areas of lipodermatosclerosis. May be painful but characteristically less painful than arterial ulcers

Villalta Scale: Standardised scoring system for PTS severity, incorporating 5 patient-reported symptoms (pain, cramps, heaviness, paraesthesia, pruritus) and 6 clinician-assessed signs (pretibial oedema, skin induration, hyperpigmentation, redness, venous ectasia, pain on calf compression).

Prevention of PTS:

Adequate anticoagulation for DVT (prevents thrombus propagation and allows maximal natural thrombolysis)
Elastic compression stockings were previously recommended for 2 years post-DVT, but the SOX trial (2014) showed no benefit over placebo. Current guidelines do NOT routinely recommend compression stockings solely for PTS prevention, though they may still be used symptomatically
Catheter-directed thrombolysis for extensive ilio-femoral DVT — catheter-directed intervention considered if extensive DVT to decrease post-thrombotic syndrome ^[1]
Early mobilisation with anticoagulation (bed rest does NOT reduce PE risk and worsens venous stasis)

C. Chronic Complications of PE

Chronic thromboembolic pulmonary hypertension ^[1] is the most important chronic complication of PE, occurring in approximately 2–4% of patients who survive an acute PE episode.

Pathophysiology: After acute PE, the body's fibrinolytic system normally dissolves the thrombus over weeks to months. In a subset of patients, this resolution is incomplete:

The thrombus organises — fibrin is replaced by fibrous tissue that incorporates into the pulmonary artery wall
The organised thrombus causes fixed obstruction of pulmonary arteries (not amenable to anticoagulation or thrombolysis)
Chronic obstruction → persistently elevated pulmonary vascular resistance → remodelling of distal (unobstructed) pulmonary arteries (secondary pulmonary arteriopathy, similar to idiopathic PAH) → progressive pulmonary hypertension
RV faces chronically elevated afterload → RV hypertrophy → eventually RV failure (cor pulmonale)

Clinical features:

Progressive exertional dyspnoea (months to years after acute PE)
Exercise intolerance
Signs of pulmonary hypertension: loud P2, RV heave, TR murmur
Signs of right heart failure: elevated JVP, hepatomegaly, peripheral oedema, ascites
Syncope on exertion (fixed cardiac output from RV failure → cannot augment output with exercise)

Diagnosis:

V/Q scan: mismatched perfusion defects (screening test of choice — more sensitive than CTPA for chronic disease)
Right heart catheterisation: mean PA pressure ≥ 25 mmHg (at rest) with pulmonary artery wedge pressure ≤ 15 mmHg (pre-capillary PH) after ≥ 3 months of anticoagulation
CT PA: may show organised thrombus, webs, bands, mural thickening, mosaic perfusion pattern
Pulmonary angiography: gold standard for defining surgical accessibility

Management:

Lifelong anticoagulation (prevents further thrombosis)
Pulmonary thromboendarterectomy (PTE): The definitive, potentially curative treatment. Involves median sternotomy, cardiopulmonary bypass with deep hypothermic circulatory arrest, and surgical removal of the organised fibrotic thrombus from the pulmonary artery intima. Can dramatically reduce PA pressure and improve symptoms. Performed at specialised centres only
Balloon pulmonary angioplasty (BPA): For patients with inoperable disease — percutaneous catheter-based dilatation of obstructed pulmonary arteries
Medical therapy: Riociguat (soluble guanylate cyclase stimulator) — the only drug specifically approved for inoperable or residual CTEPH. Increases NO-mediated pulmonary vasodilation

VTE is a recurrent disease. The recurrence rate depends on whether the initial event was provoked or unprovoked:

Scenario	Annual Recurrence Rate After Stopping Anticoagulation
First provoked VTE (major transient risk factor)	~3% per year
First unprovoked VTE	~10% per year
Second unprovoked VTE	~15% per year
Cancer-associated VTE (ongoing cancer)	~20% per year

This is why the duration of anticoagulation is so carefully calibrated — the goal is to balance recurrence risk against bleeding risk.

D. Complications of Treatment

The most common complication of VTE treatment is bleeding from anticoagulation. This is an inherent trade-off: by preventing pathological clotting, we also impair physiological haemostasis.

Severity	Examples	Management
Minor bleeding	Epistaxis, gum bleeding, minor bruising, haematuria	Dose adjustment; local measures; ensure INR/anti-Xa in range
Major bleeding	GI haemorrhage, intramuscular haematoma, haemarthrosis, retroperitoneal haemorrhage	Stop anticoagulant; give specific antidote; supportive care (IV fluids, transfusion); surgical intervention if needed
Life-threatening / intracranial bleeding	Intracranial haemorrhage (ICH) ^[4]	Immediate cessation of anticoagulant; rapid reversal (PCC for warfarin; idarucizumab for dabigatran; andexanet alfa for Xa inhibitors); neurosurgical consultation; ICU care

Annual risk of major bleeding on anticoagulation: ~1–3% per year (higher with warfarin than DOACs; higher in elderly, renal impairment, concomitant antiplatelet use).

Antidotes:

Warfarin → Vitamin K (slow) + FFP or PCC (immediate) ^[1]
Dabigatran → Idarucizumab (specific antibody fragment)
Rivaroxaban/Apixaban/Edoxaban → Andexanet alfa (recombinant modified Factor Xa decoy); PCC as an alternative
UFH → Protamine sulphate (full reversal)
LMWH → Protamine sulphate (partial reversal, ~60%)
Fondaparinux → No specific antidote; recombinant Factor VIIa may be considered in extremis

HIT is a potentially catastrophic immune-mediated complication of heparin therapy.

Two types:

Type	HIT Type I	HIT Type II
Mechanism	Non-immune; direct heparin effect on platelet aggregation	Immune-mediated: IgG antibodies against PF4-heparin complex activate platelets
Timing	Days 1–2 of heparin	Days 5–10 of heparin (or sooner if prior heparin exposure)
Platelet drop	Mild (rarely < 100)	> 50% drop from baseline (or nadir < 150)
Thrombosis	No	YES — paradoxical thrombosis (arterial AND venous) in ~50% of cases
Management	Self-resolves; continue heparin	Stop ALL heparin immediately; switch to non-heparin anticoagulant (fondaparinux, argatroban)

Pathophysiology of HIT Type II:

Heparin binds to platelet factor 4 (PF4) on platelet surfaces → forms a neoantigen complex
IgG antibodies recognise the PF4-heparin complex → bind to it
The Fc portion of the antibody activates platelets via FcγRIIa receptors → massive platelet activation → release of procoagulant microparticles → thrombin generation
Paradox: platelets are consumed (thrombocytopenia) while simultaneously causing thrombosis
Activated platelets and endothelium create a prothrombotic storm → venous and arterial thrombosis (DVT, PE, limb ischaemia, stroke, MI)

Diagnosis:

4T score (clinical pre-test probability): Thrombocytopenia, Timing, Thrombosis, oTher causes
Anti-PF4 antibody ELISA (sensitive, moderate specificity)
Serotonin release assay (SRA) (gold standard, highly specific)

Complication	Mechanism	Incidence
Major haemorrhage	Systemic fibrinolysis dissolves not only the pathological thrombus but also physiological fibrin plugs at other sites	~10–15% for systemic thrombolysis
Intracranial haemorrhage	The most feared complication; fibrinolysis at sites of pre-existing cerebral small vessel disease	~1–3%
Reperfusion injury	Sudden restoration of blood flow to ischaemic tissue → generation of reactive oxygen species → endothelial damage → capillary leak	Manifests as reperfusion pulmonary oedema or systemic inflammatory response

Complication	Mechanism
Filter migration ^[11]	Inadequate fixation → filter dislodges and moves proximally (into right heart) or distally
Fractured filter ^[11]	Metal fatigue over time → strut fracture → fragments can embolise to heart or lungs
Infection ^[11]	Foreign body in the bloodstream → biofilm formation → bacteraemia
IVC thrombosis	The filter is itself a thrombogenic foreign body → clot forms on the filter → IVC occlusion → bilateral leg swelling, renal vein thrombosis
Recurrent DVT	Paradoxically, IVC filters increase the long-term risk of DVT (foreign body thrombogenicity + loss of venous flow dynamics)
Filter penetration / perforation	Filter tines erode through the IVC wall into adjacent structures (aorta, duodenum, vertebral body)

E. Complications of Massive DVT Requiring Intervention

High Yield Summary — Complications of VTE

PE is the most feared acute complication of DVT — kills through RV failure, not hypoxaemia ^[1]. Proximal DVT carries the highest embolisation risk ^[1].
Phlegmasia cerulea dolens = massive DVT → venous gangrene; treat with catheter-directed thrombolysis or thrombectomy; may require fasciotomy or amputation.
Post-thrombotic syndrome occurs in 20–50% of proximal DVT — caused by valve destruction → chronic venous hypertension → oedema, hyperpigmentation, lipodermatosclerosis, venous ulcers ^[1]^[3]. Catheter-directed thrombolysis for ilio-femoral DVT may reduce PTS ^[1].
CTEPH occurs in 2–4% of PE survivors — organised thrombus in pulmonary arteries → fixed obstruction → progressive pulmonary hypertension → RV failure ^[1]. Definitive treatment: pulmonary thromboendarterectomy.
HIT = immune-mediated platelet activation by anti-PF4/heparin antibodies → paradoxical thrombosis + thrombocytopenia. Stop all heparin; switch to fondaparinux or argatroban.
Warfarin-induced skin necrosis = early Protein C depletion → microvascular thrombosis → skin infarction (days 3–5). Always bridge with heparin.
Reperfusion injury after thrombolysis/thrombectomy → compartment syndrome and rhabdomyolysis ^[12]. Watch for pain out of proportion, tense compartment, hyperkalaemia, AKI.
IVC filter complications ^[11]: migration, fracture, infection, IVC thrombosis, recurrent DVT. Always plan for retrieval.
Anticoagulant-related bleeding is the most common treatment complication — 1–3% major bleeding per year. Know all the antidotes.
Recurrent VTE rates: ~3%/yr provoked; ~10%/yr unprovoked; ~15%/yr after second event — drives decisions about duration of anticoagulation.

Active Recall - Complications of VTE

High Yield Summary

VTE = DVT + PE — same disease, different manifestations ^[1]
Virchow's Triad (Stasis, Endothelial injury, Hypercoagulability) is the foundational framework for all VTE risk factors ^[1]
PE kills through RV failure / obstructive shock, not hypoxaemia ^[1]
Proximal DVT (popliteal and above) is much more likely to cause PE than distal DVT ^[1]
60–80% of DVTs are clinically silent — prophylaxis is key ^[5]
Unexplained tachycardia may be the first sign of PE post-operatively ^[5]
In Hong Kong/Chinese patients, Factor V Leiden is virtually absent — think AT-III, Protein C, Protein S deficiency for inherited thrombophilia
Adenocarcinomas (especially pancreatic — Trousseau syndrome) are highly thrombogenic due to mucin secretion ^[1]^[3]
Unprovoked VTE warrants occult malignancy screening ^[1]
Warfarin must NOT be started alone — it has a transient procoagulant effect (depletes Protein C and S before factors II, IX, X); always overlap with heparin for ≥ 5 days ^[1]
Cerebral venous thrombosis is more common in women (pregnancy, OCP) and accounts for ~1% of strokes ^[4]
Post-thrombotic syndrome occurs in 20–50% after proximal DVT due to valve destruction

High Yield Exam Points — DDx of VTE

DVT differentials to always mention ^[1]: Ruptured Baker's cyst, cellulitis, superficial thrombophlebitis, muscle strain/tear, lymphangitis, lymphoedema, chronic venous insufficiency
PE differentials to always mention ^[8]: Pneumothorax, AMI, pericarditis, pneumonia, aortic dissection, acute heart failure, fat embolism syndrome
Baker's cyst rupture is the most classic DVT mimic — look for history of knee OA/RA and crescent sign at medial malleolus
Cellulitis vs DVT: Both cause a red, warm, swollen leg. Cellulitis has a portal of entry, more prominent erythema, and systemic sepsis features. But they can coexist — always consider duplex USS
Phlegmasia cerulea dolens mimics acute arterial ischaemia — "fat blue leg" vs "thin pale leg" is the key distinction ^[6]^[7]
Fat embolism syndrome occurs 24–72h post-long-bone fracture with the classic triad: respiratory distress, neurological changes, petechial rash — do NOT confuse with thrombotic PE
An unexplained or recurrent VTE should always prompt consideration of underlying malignancy, APS, or inherited thrombophilia

High Yield Summary — Diagnosis of VTE

Wells score is the starting point for both DVT and PE — it determines whether D-dimer is needed or you skip straight to imaging ^[1]
D-dimer is sensitive but NOT specific ^[1] — used only to RULE OUT VTE in low/moderate probability. Not useful post-operatively ^[5]
Age-adjusted D-dimer cut-off: 10 × age if ≥ 50 years ^[1] — increases specificity without sacrificing sensitivity
Compression USS is first-line for DVT — loss of vein compressibility = primary criterion ^[1]
CTPA is the confirmatory test for PE ^[1] — look for filling defects in pulmonary trunk ^[1]
V/Q scan is an alternative to CTPA — requires normal CXR for interpretation ^[1]; high sensitivity but low specificity ^[1]
ECG in PE: Sinus tachycardia (most common), S1Q3T3, T inversions V1–V4, RBBB ^[1]
CXR in PE: Hampton's hump (wedge-shaped infarct), Westermark sign (focal oligaemia), atelectasis ^[1]
Echo: McConnell's sign (RV free wall hypokinesis with apical sparing) ^[1] — used for risk stratification and bedside assessment in unstable patients
ABG shows Type I respiratory failure: hypoxaemia, hypocapnia, respiratory alkalosis, increased A-a gradient ^[1]
Massive PE: Skip algorithms → bedside echo → thrombolysis if RV dysfunction present
Thrombophilia screen: Do NOT test acutely — wait until anticoagulation is completed

High Yield Summary — Management of VTE

Treatment is determined by haemodynamic stability × bleeding risk ^[1]: Stable+low=anticoagulation; Stable+high=IVC filter; Unstable+low=thrombolysis; Unstable+high=embolectomy
LMWH is preferred over UFH for most patients (lower HIT risk, no monitoring, better in cancer) ^[1]; UFH is preferred when contemplating thrombolysis, in renal failure, extreme obesity, or haemodynamic instability ^[1]
Warfarin must NEVER be started alone — paradoxical procoagulant effect from early Protein C/S depletion ^[1]. Overlap with heparin ≥ 5 days, INR ≥ 2.0 for ≥ 24h before stopping heparin ^[1]
DOACs: Rivaroxaban and Apixaban can be used as sole agents from day 1 (with loading dose); Dabigatran and Edoxaban require ≥ 5 days parenteral lead-in ^[1]
Thrombolysis indications: haemodynamically unstable PE, massive ilio-femoral thrombosis, RV dilatation ^[1]
IVC filter: for patients who cannot be anticoagulated; position at inflow of renal veins ^[1]; always plan for retrieval
VTE prophylaxis in HK: mechanical prophylaxis for all surgical patients; pharmacological only for high-risk groups ^[11]
Duration: 3 months for provoked VTE; extended/indefinite for unprovoked or cancer-associated VTE
Warfarin antidote: Vitamin K + FFP ^[1]; Dabigatran antidote: idarucizumab; Xa inhibitor antidote: andexanet alfa
Fondaparinux is the drug of choice in HIT — zero PF4 binding

High Yield Summary — Complications of VTE

PE is the most feared acute complication of DVT — kills through RV failure, not hypoxaemia ^[1]. Proximal DVT carries the highest embolisation risk ^[1].
Phlegmasia cerulea dolens = massive DVT → venous gangrene; treat with catheter-directed thrombolysis or thrombectomy; may require fasciotomy or amputation.
Post-thrombotic syndrome occurs in 20–50% of proximal DVT — caused by valve destruction → chronic venous hypertension → oedema, hyperpigmentation, lipodermatosclerosis, venous ulcers ^[1]^[3]. Catheter-directed thrombolysis for ilio-femoral DVT may reduce PTS ^[1].
CTEPH occurs in 2–4% of PE survivors — organised thrombus in pulmonary arteries → fixed obstruction → progressive pulmonary hypertension → RV failure ^[1]. Definitive treatment: pulmonary thromboendarterectomy.
HIT = immune-mediated platelet activation by anti-PF4/heparin antibodies → paradoxical thrombosis + thrombocytopenia. Stop all heparin; switch to fondaparinux or argatroban.
Warfarin-induced skin necrosis = early Protein C depletion → microvascular thrombosis → skin infarction (days 3–5). Always bridge with heparin.
Reperfusion injury after thrombolysis/thrombectomy → compartment syndrome and rhabdomyolysis ^[12]. Watch for pain out of proportion, tense compartment, hyperkalaemia, AKI.
IVC filter complications ^[11]: migration, fracture, infection, IVC thrombosis, recurrent DVT. Always plan for retrieval.
Anticoagulant-related bleeding is the most common treatment complication — 1–3% major bleeding per year. Know all the antidotes.
Recurrent VTE rates: ~3%/yr provoked; ~10%/yr unprovoked; ~15%/yr after second event — drives decisions about duration of anticoagulation.

Venous Thromboembolism

Venous Thromboembolism (VTE)

Subdivisions of DVT [1]

2. Epidemiology

3. Risk Factors

Comprehensive Risk Factor Classification

4. Anatomy and Physiology of the Venous System

5. Pathophysiology

6. Etiology — Specific Causes of VTE (Focus on Hong Kong)

7. Classification Systems

8. Clinical Features

Active Recall - VTE Definition, Epidemiology, Risk Factors, Anatomy, Pathophysiology & Clinical Features

Differential Diagnosis of VTE

A. Differential Diagnosis of DVT [1]

B. Differential Diagnosis of Pulmonary Embolism

Active Recall - Differential Diagnosis of VTE

References

1. Pre-Test Probability Scoring — The Wells Score

2. Investigations — Biochemical Tests

3. Investigations — Radiological / Imaging

4. Diagnostic Algorithm

Active Recall - VTE Diagnosis

4. Medical Treatment — Anticoagulation

4A. Initial Parenteral Anticoagulation

4B. Transition to Oral Anticoagulation

5. Thrombolytic (Fibrinolytic) Therapy [1]

6. Surgical / Interventional Treatment [1]

7. Prophylaxis of VTE [1][11]

8. Special Management Scenarios

Active Recall - VTE Management

A. Acute Complications of DVT

B. Chronic Complications of DVT

C. Chronic Complications of PE

D. Complications of Treatment

E. Complications of Massive DVT Requiring Intervention

Active Recall - Complications of VTE

On this page

Venous Thromboembolism

Venous Thromboembolism (VTE)

1. Definition

Subdivisions of DVT [1]

2. Epidemiology

Global Epidemiology

Hong Kong Context

Demographics

3. Risk Factors

Virchow's Triad: Stasis + Endothelial Injury + Hypercoagulability [1]

Comprehensive Risk Factor Classification

A. Acquired / Transient Risk Factors

B. Inherited (Heritable) Thrombophilias [1]

C. Other Acquired Hypercoagulable States

4. Anatomy and Physiology of the Venous System

Lower Limb Venous Anatomy

Physiology of Venous Return [2]

Relevant Anatomy for PE

May-Thurner Syndrome (Iliac Vein Compression Syndrome)

5. Pathophysiology

5.1 Thrombus Formation

5.2 Pathophysiology of DVT

5.3 Pathophysiology of Pulmonary Embolism

5.4 Classification of PE by Haemodynamic Severity

6. Etiology — Specific Causes of VTE (Focus on Hong Kong)

Hospital-Acquired VTE (HA-VTE)

Cancer-Associated Thrombosis (CAT) [1][3]

Pregnancy-Related VTE

Travel-Related VTE

Cerebral Venous Thrombosis [4]

7. Classification Systems

7.1 Anatomical Classification of DVT

7.2 Classification of PE by Timing

7.3 Provoked vs. Unprovoked VTE

7.4 CEAP Classification (for Chronic Venous Disease)

8. Clinical Features

8.1 Deep Vein Thrombosis — Symptoms

8.2 Deep Vein Thrombosis — Signs

8.3 Pulmonary Embolism — Symptoms

8.4 Pulmonary Embolism — Signs [1]

8.5 Special Presentations

9. Pathophysiology of Key Clinical Findings — Connecting the Dots

10. Summary of Key Pathophysiological Mechanisms

Active Recall - VTE Definition, Epidemiology, Risk Factors, Anatomy, Pathophysiology & Clinical Features

References

Differential Diagnosis of VTE

A. Differential Diagnosis of DVT [1]

1. Musculoskeletal Causes

2. Infectious / Inflammatory Causes

3. Lymphatic / Venous Causes

4. Other Causes of Unilateral Leg Swelling

Distinguishing Features Summary — DVT vs Key Mimics

B. Differential Diagnosis of Pulmonary Embolism

1. Acute Dyspnoea + Pleuritic Chest Pain

2. Acute Chest Pain — Cardiac Differentials

3. Acute Dyspnoea — Other Differentials

4. Haemoptysis Differential

5. Special Differential: Fat Embolism Syndrome

C. Differential Diagnosis — Conditions That Cause BOTH DVT and PE-like Presentations

D. Summary Mermaid: Systematic Approach to VTE Differential Diagnosis

Active Recall - Differential Diagnosis of VTE

References

Diagnostic Criteria, Algorithm & Investigation Modalities for VTE

1. Pre-Test Probability Scoring — The Wells Score

The Logic Behind Clinical Prediction Rules

1A. Wells Score for DVT

1B. Wells Score for PE [1]

1C. Alternative Scoring: Geneva Score (Revised)

1D. PERC Rule (Pulmonary Embolism Rule-out Criteria)

2. Investigations — Biochemical Tests

2A. D-dimer [1]

2B. Complete Blood Count (CBC) with Differentials [1]

2C. Clotting Profile [1]

2D. Thrombophilia Screen [1]

2E. Arterial Blood Gas (ABG) [1]

2F. Other Bloods

2G. Cardiac Biomarkers for PE Risk Stratification

3. Investigations — Radiological / Imaging

3A. ECG [1]

3B. Chest X-ray (CXR) [1]