Prothrombin G20210A mutation is a hereditary point mutation in the 3' untranslated region of the prothrombin gene that leads to elevated plasma prothrombin levels and an increased risk of venous thromboembolism.

Prothrombin G20210A Mutation

2. Epidemiology

Genotype	Relative Risk of VTE	Absolute Risk
Wild-type (GG)	1× (baseline)	~0.1%/year
Heterozygous (GA)	~2–3× increased	~0.2–0.3%/year
Homozygous (AA)	~10× increased	Higher but poorly quantified (very rare)
Heterozygous + OCP use	~15–20× increased	Clinically significant
Compound heterozygous (FVL + PT G20210A)	~20× increased	Significant

The mutation confers a modest increase in VTE risk when present alone (lower risk than Factor V Leiden heterozygosity, which is ~5–7×)
However, risk is synergistic (multiplicative) when combined with other risk factors: OCP use, pregnancy, surgery, immobilisation, or co-existing thrombophilias ^[1]^[4]

3. Anatomy and Function: The Prothrombin Protein and the Coagulation Cascade

4. Etiology (Focus on Hong Kong Context)

5. Pathophysiology

6. Classification

Inherited thrombophilia can be classified by mechanism ^[1]^[5]:

Category	Examples	Mechanism
Loss of natural anticoagulant function (loss-of-function)	Antithrombin deficiency, Protein C deficiency, Protein S deficiency	Reduced inhibition of coagulation → unchecked thrombin/Xa activity
Gain of procoagulant function (gain-of-function)	Factor V Leiden, Prothrombin G20210A	FVL: Factor V resistant to APC inactivation; PT G20210A: increased prothrombin production
Metabolic	Hyperhomocysteinaemia	Endothelial injury + procoagulant effects

Genotype	Frequency (Europeans)	Prothrombin Level	VTE Risk
GG (wild-type)	~96%	Normal (~100%)	Baseline
GA (heterozygous)	~3%	↑ ~130%	~2–3× increased
AA (homozygous)	~0.01%	↑↑ ~150%+	~10× increased

Thrombophilia = a predisposition to forming blood clots inappropriately

	Inherited	Acquired
Examples	Antithrombin deficiency, Protein C deficiency, Protein S deficiency, Factor V Leiden, Prothrombin G20210A, Hyperhomocysteinaemia ^[5]	Antiphospholipid syndrome ^[5], malignancy, OCP/HRT, pregnancy, nephrotic syndrome, PNH, myeloproliferative neoplasms

7. Risk Factors for VTE in Prothrombin G20210A Carriers

Having the mutation alone confers a modest risk. Clinical VTE typically requires additional hits (a "two-hit" or multi-hit model):

8. Clinical Features

8.2 Symptoms of VTE

DVT of lower extremity subdivided into proximal (popliteal, femoral, iliac veins — clinically more significant as it more commonly associates with PE) and distal/calf vein thrombosis ^[7]:

Symptom	Pathophysiological Basis
Unilateral leg swelling	Venous outflow obstruction → increased hydrostatic pressure → fluid transudation into interstitium
Calf or thigh pain/tenderness	Distension of the vein wall → activation of nociceptors in the vessel wall and surrounding tissue. Pain along distribution of deep veins ^[7]
Warmth and erythema ^[7]	Local inflammatory response to the thrombus (thrombus triggers cytokine release, complement activation)

PE is a potentially fatal presentation of DVT ^[5]:

Symptom	Pathophysiological Basis
Dyspnoea ^[5]^[7]	Acute increase in dead space (ventilated but not perfused lung segments) → V/Q mismatch → hypoxia → compensatory tachypnoea
Pleuritic chest pain ^[5]^[7]	Pulmonary infarction → inflammation of visceral pleura → pain on breathing
Cough ^[5]^[7]	Irritation of airways by inflammatory mediators and oedema
Haemoptysis (rare) ^[5]^[7]	Tissues become anoxic or hypoxic in pulmonary infarction ^[7] → necrosis of lung parenchyma → blood in airways
Syncope ^[5]	Massive PE → acute right heart failure → ↓ cardiac output → cerebral hypoperfusion
Shock ^[7]	Obstructive shock — hypotension due to decrease in venous return in venous thrombosis and decreased cardiac output in pulmonary artery blockage ^[7]

Sign	Pathophysiological Basis
Unilateral pitting oedema ^[7]	↑ Hydrostatic pressure distal to venous obstruction → Starling forces favour fluid extravasation
Difference in calf diameters ^[7]	Asymmetric oedema — measured >3 cm difference at 10 cm below tibial tuberosity
Homan's sign (calf pain on dorsiflexion — low sensitivity/specificity, not routinely relied upon)	Passive stretching of the gastrocnemius compresses deep veins → pain if thrombosed
Dilated superficial veins	Collateral venous drainage around the obstruction
Low-grade fever	Inflammatory response to the thrombus
Tachycardia, tachypnoea (if PE present)	Sympathetic activation from hypoxia, pain, and reduced cardiac output
Raised JVP (massive PE)	Acute right ventricular failure → right atrial pressure elevation
Right ventricular heave (massive PE)	Acute pressure overload of the right ventricle
Loud P2 (massive PE)	Pulmonary hypertension → forceful closure of the pulmonary valve

9. Thrombophilia Screening — Where Prothrombin G20210A Fits

Feature	Antithrombin Deficiency	Protein C Deficiency	Protein S Deficiency	Factor V Leiden	Prothrombin G20210A	Hyperhomocysteinaemia
Mechanism	Loss of thrombin/Xa inhibitor	Loss of Va/VIIIa inactivation	Loss of cofactor for Protein C	Factor V resistant to APC	↑ Prothrombin production	Endothelial injury + procoagulant
Inheritance	AD	AD	AD	AD	AD	AR (severe) / multifactorial (mild)
Prevalence (Europeans)	0.02–0.2%	0.2–0.5%	0.1–0.7%	3–8%	2–3%	5–10% (mild)
Prevalence (Chinese)	Rare	Rare (but described)	Rare (but described)	Absent	Absent	Variable
VTE Risk (heterozygous)	10–50×	7–10×	5–10×	5–7×	2–3×	2–3×
Arterial thrombosis?	No	No	No	No	No	Controversial (yes?)
Heparin resistance?	Yes	No	No	No	No	No
Warfarin skin necrosis?	No	Yes	Yes	No	No	No

Note: Prothrombin G20210A confers the lowest VTE risk among the major inherited thrombophilias. It is considered a mild thrombophilia. Clinical significance often depends on co-existing risk factors.

High Yield Summary

Prothrombin G20210A is a point mutation (G→A) in the 3'-UTR of the prothrombin gene → ↑ mRNA stability → ↑ prothrombin protein synthesis → ↑ thrombin generation → prothrombotic state
Second most common inherited thrombophilia after Factor V Leiden (in Caucasians)
Essentially absent in Chinese/East Asian populations — irrelevant for Chinese patients in HK but important for Caucasians and for exams
Modest VTE risk (~2–3× for heterozygotes) — risk becomes clinically significant with additional hits (OCP, pregnancy, surgery, immobilisation, co-existing thrombophilia)
Only causes venous thrombosis, NOT arterial thrombosis — don't screen for it in recurrent stroke/MI
PT and APTT are normal — diagnosis requires PCR-based genetic testing
Thrombophilia screening should NOT be done during acute VTE or on anticoagulants (except DNA-based tests which are unaffected)
Inherited thrombophilia causes = AT deficiency, Protein C deficiency, Protein S deficiency, Factor V Leiden, Prothrombin G20210A, Hyperhomocysteinaemia
In HK, the most common condition associated with VTE is underlying malignancy, not inherited thrombophilia
The mutation follows autosomal dominant inheritance — important for genetic counselling

Active Recall - Prothrombin G20210A Mutation

Differential Diagnosis of Prothrombin G20210A Mutation

Part A: Differential Diagnosis of the Thrombophilia (Why Did This Patient Clot?)

When a patient presents with VTE — especially if young, unprovoked, recurrent, at unusual sites, or with a positive family history — you must systematically consider the full spectrum of inherited and acquired thrombophilias. Prothrombin G20210A is just one item on this list. ^[1]^[2]

Comprehensive List of Differentials for Hypercoagulable State

Causes of inherited thrombophilia ^[1]^[5]:

Condition	Mechanism	Relative VTE Risk (Heterozygous)	Prevalence in Chinese	Key Distinguishing Feature
Antithrombin deficiency	Loss of thrombin + Xa inhibitor → unchecked coagulation	10–50× (highest risk)	Rare but described	Heparin resistance (AT is the target of heparin — if AT is deficient, heparin doesn't work well)
Protein C deficiency	Loss of Factor Va/VIIIa inactivation → unchecked common pathway amplification	7–10×	Rare but described	Warfarin-induced skin necrosis ^[2] — because warfarin reduces Protein C (short half-life ~8h) faster than it reduces procoagulant factors → transient hypercoagulable window → microvascular thrombosis → skin necrosis
Protein S deficiency	Loss of cofactor for activated Protein C → same end result	5–10×	Rare but described	Also associated with warfarin-induced skin necrosis; Protein S is vitamin K-dependent
Factor V Leiden	Factor V becomes resistant to inactivation by Activated Protein C (APC) → Factor Va persists → continued thrombin generation	5–7×	Absent in Chinese ^[5]	Detected by Activated Protein C Resistance (APCR) assay followed by confirmatory PCR
Prothrombin G20210A	↑ Prothrombin mRNA stability → ↑ prothrombin protein → ↑ thrombin generation	2–3× (lowest risk)	Absent in Chinese ^[5]	PT/APTT normal; diagnosis only by PCR; plasma prothrombin may be mildly elevated
Hyperhomocysteinaemia	Endothelial injury + activation of tissue factor + impaired thrombomodulin function → prothrombotic	2–3×	Variable	Only inherited thrombophilia that can cause BOTH arterial and venous thrombosis ^[5] (controversial); treatable with folate/B12/B6

High Yield: How to Differentiate Inherited Thrombophilias

Heparin resistance → think Antithrombin deficiency (heparin works by potentiating AT)
Warfarin skin necrosis → think Protein C or S deficiency ^[2]
Factor V Leiden and Prothrombin G20210A basically never seen in Chinese ^[5] — irrelevant in Chinese patients
Both arterial + venous thrombosis in inherited setting → think Hyperhomocysteinaemia ^[5]
Highest VTE risk of all inherited thrombophilias → Antithrombin deficiency
Lowest VTE risk → Prothrombin G20210A

Condition	Mechanism	Key Distinguishing Feature
Antiphospholipid syndrome (APLS) ^[2]^[9]	Autoantibodies against phospholipids/β2-glycoprotein I → endothelial activation, complement activation, platelet activation → thrombosis	Can cause BOTH arterial and venous thrombosis ^[5]; associated with recurrent miscarriage; diagnosed by anti-cardiolipin, lupus anticoagulant, anti-β2-GPI on ≥2 occasions ≥12 weeks apart ^[9]; lupus anticoagulant causes prolonged APTT but paradoxically causes thrombosis, not bleeding ^[10]
Malignancy ^[6]	Cancer cells express tissue factor, secrete procoagulant mucins (especially adenocarcinoma), direct venous compression	"In our locality, the most common condition associated with VTE is underlying malignancy" ^[6]; look for constitutional symptoms; especially adenocarcinoma which secretes mucin ^[7]
Myeloproliferative neoplasms (MPN) ^[11]	Hyperviscosity from high cell counts; JAK2 mutation positive especially prone to thrombosis ^[11]; can occur at unusual locations (e.g. mesenteric vein) ^[11]	Thrombosis in peculiar locations → screen for JAK2 mutation ^[11]; can clot even before developing cytosis; causes both arterial and venous thrombosis
OCP / HRT / Pregnancy ^[5]	Oestrogen increases hepatic synthesis of procoagulant factors (fibrinogen, Factors II, VII, VIII, X) and reduces natural anticoagulants (Protein S, AT)	Estrogen is a risk factor for thrombus formation ^[5]; synergistic with inherited thrombophilias
Nephrotic syndrome	Urinary loss of Antithrombin III (molecular weight ~58 kDa, small enough to be lost through damaged glomeruli) + increased hepatic synthesis of procoagulant factors	Renal vein thrombosis is characteristic; heavy proteinuria + hypoalbuminaemia
Paroxysmal nocturnal haemoglobinuria (PNH)	PIGA gene mutation → loss of GPI-anchored complement regulatory proteins (CD55, CD59) → complement-mediated haemolysis + complement activation on platelet surfaces → thrombosis	Unusual site thrombosis (especially Budd-Chiari syndrome — hepatic vein thrombosis); haemolytic anaemia with haemoglobinuria
Heparin-induced thrombocytopenia (HIT) Type II	IgG antibodies against PF4-heparin complexes → platelet activation → "white clot" syndrome	Paradoxical: thrombocytopenia with thrombosis (not bleeding); occurs 5–14 days after heparin exposure
DIC (chronic/compensated) ^[2]	Malignancy-driven production of procoagulant factors keeps pace with ongoing thrombosis → tends to clot rather than bleed ^[2]	Unprovoked venous/arterial thromboembolism ^[2]; elevated D-dimer; may have normal or mildly deranged PT/APTT

High Yield: Malignancy-Associated VTE in Hong Kong

"In our clinic, more than 50% of our patients with a blood clot have an underlying tumour" ^[6]. Up to 10% of patients with "unprovoked" VTE were found to have an underlying malignancy ^[6]. For every patient with unprovoked VTE: take a thorough history (constitutional symptoms), physical examination, and appropriate investigations (CXR, AXR, abdominal ultrasound, tumour markers) ^[6]. Universal PET-CT screening is NOT recommended for unprovoked VTE ^[6].

The table below helps you narrow the differential based on clinical clues:

Clinical Clue	Points Toward	Points Away From PT G20210A
Chinese ethnicity	AT/Protein C/S deficiency, APLS, malignancy, MPN	FVL and PT G20210A essentially absent in Chinese ^[5]
Caucasian ethnicity	FVL, PT G20210A become relevant	—
Arterial + venous thrombosis	APLS, Hyperhomocysteinaemia ^[5]; MPN	PT G20210A (venous only)
Recurrent miscarriage	APLS (revised Sapporo criteria ^[9]), PT G20210A (mild association)	—
Warfarin skin necrosis	Protein C/S deficiency ^[2]	PT G20210A
Heparin not working	Antithrombin deficiency	PT G20210A
Unusual site thrombosis (mesenteric, hepatic, cerebral)	MPN (screen JAK2) ^[11], PNH, APLS	PT G20210A (possible but less characteristic)
Prolonged APTT	Lupus anticoagulant ^[10], Factor deficiency, heparin	PT G20210A (APTT is normal)
Normal PT and APTT	PT G20210A, FVL, Protein C/S deficiency (mild), AT deficiency	DIC, warfarin, heparin
Weight loss, night sweats	Malignancy ^[6]	PT G20210A
High platelet count	MPN (especially ET), reactive thrombocytosis	PT G20210A
Haemolysis + thrombosis	PNH, TTP/HUS, DIC	PT G20210A

Part B: Differential Diagnosis of the Clinical Presentation

When a patient with Prothrombin G20210A (or any thrombophilia) presents clinically, they present with DVT or PE. These presentations themselves have broad differentials.

Differential diagnosis of DVT ^[7]:

Condition	Key Distinguishing Feature	Why It Mimics DVT
Muscle strain / tear / twisting / injury to leg ^[7]	History of trauma or exertion; localised tenderness over muscle belly, not along deep vein distribution	Causes unilateral calf pain and swelling
Cellulitis ^[7]	Erythema, warmth, tenderness; often a portal of entry (wound, tinea pedis); systemic features (fever, raised WCC); bilateral involvement possible	Causes red, warm, swollen, tender leg
Superficial thrombophlebitis ^[7]	Palpable, tender, cord-like vein; linear erythema along superficial vein course	Localised pain and swelling, but superficial not deep
Lymphangitis ^[7]	Red streaking along lymphatic channels proximally; tender lymphadenopathy; often secondary to distal infection	Can cause limb swelling and erythema
Lymphoedema ^[7]	Usually bilateral (or unilateral post-surgery/radiation); non-pitting; chronic; Stemmer sign positive (cannot pinch dorsal skin fold at base of 2nd toe)	Causes leg swelling
Venous valvular insufficiency ^[7]	Chronic; varicose veins; skin changes (lipodermatosclerosis, haemosiderin staining); worse at end of day, improved with elevation	Chronic leg swelling and heaviness
Ruptured Baker's cyst ^[7]	History of knee joint pathology (OA, RA); sudden onset posterior calf pain and swelling; confirmed on USS knee	Mimics DVT with acute calf swelling and tenderness
Compartment syndrome	Severe pain out of proportion; pain on passive stretch; tense compartment	Acute limb swelling and pain

Differential diagnosis for PE ^[8]^[12]:

Condition	Key Distinguishing Feature
Acute myocardial infarction	Crushing central chest pain; radiation to jaw/arm; ECG changes (ST elevation/depression); raised troponin; pain not pleuritic
Acute pericarditis ^[12]	Sharp, pleuritic pain; radiates to trapezius ridge; relieved by sitting forward; widespread ST elevation with PR depression on ECG ^[12]
Aortic dissection ^[12]	Radiation to back; ripping/tearing sensation ^[12]; blood pressure discrepancy between arms; widened mediastinum on CXR
Pneumothorax	Sudden pleuritic chest pain; hyperresonance to percussion; absent breath sounds; visible on CXR
Pneumonia	Productive cough; fever; consolidation on CXR; raised inflammatory markers
Musculoskeletal chest pain	Reproducible on palpation; positional; no haemodynamic compromise
Anxiety / Panic attack	Perioral tingling; bilateral hand paraesthesia; hyperventilation; normal investigations

The trickiest exam scenario is distinguishing Prothrombin G20210A from other inherited thrombophilias, because they all present similarly (young patient with unprovoked VTE). The key is in the laboratory workup:

Test	What It Detects	Result in PT G20210A
PT	Extrinsic pathway (Factor VII → common)	Normal
APTT	Intrinsic pathway (XII, XI, IX, VIII → common)	Normal
Fibrinogen	Common pathway end-product	Normal
D-dimer	Fibrin degradation (ongoing clot breakdown)	Elevated during acute VTE (non-specific)
Protein C level ^[2]	Natural anticoagulant	Normal (↓ if Protein C deficiency)
Protein S level ^[2]	Cofactor for Protein C	Normal (↓ if Protein S deficiency)
Antithrombin level ^[2]	Natural anticoagulant	Normal (↓ if AT deficiency)
APCR assay ^[2]	Screening for Factor V Leiden	Normal (abnormal if FVL)
Factor V Leiden PCR ^[2]	Confirms FVL mutation	Negative
Prothrombin G20210A PCR ^[2]	Confirms PT G20210A mutation	Positive (GA or AA)
APLS panel (anti-cardiolipin, LA, anti-β2 GPI) ^[2]	Acquired APLS	Negative
Plasma prothrombin activity	Prothrombin protein level	May be mildly elevated (~115–130%) but non-specific
Homocysteine level	Hyperhomocysteinaemia	Normal (↑ if hyperhomocysteinaemia)

High Yield: The Diagnosis of PT G20210A Is Genetic, Not Functional

Unlike Protein C/S/AT deficiencies (diagnosed by measuring protein levels) or Factor V Leiden (screened by APCR functional assay), Prothrombin G20210A can ONLY be diagnosed by PCR-based genotyping. Standard coagulation tests are normal. Plasma prothrombin levels overlap with normal. This is a purely genetic diagnosis.

When you encounter a patient with VTE, think systematically using this framework:

Is there an obvious provoking factor? (surgery, immobilisation, OCP, pregnancy, trauma) → if yes, provoked VTE; treat accordingly; thrombophilia screen generally not indicated
Is it unprovoked, recurrent, young age, unusual site, or family history positive? → consider thrombophilia workup ^[2]
What is the ethnicity?
- Chinese → focus on AT/Protein C/S deficiency, APLS, malignancy, MPN ^[5]
- Caucasian → add FVL and PT G20210A to the workup ^[5]
Are there features of arterial thrombosis too? → think APLS or hyperhomocysteinaemia ^[5], not PT G20210A
Is there heparin resistance? → think AT deficiency
Was there warfarin skin necrosis? → think Protein C/S deficiency ^[2]
Unusual site (mesenteric, hepatic, cerebral)? → screen for JAK2 (MPN) ^[11], consider PNH
Constitutional symptoms? → exclude underlying malignancy ^[6]

High Yield Summary — Differential Diagnosis

Prothrombin G20210A is one of six inherited thrombophilias: AT deficiency, Protein C deficiency, Protein S deficiency, Factor V Leiden, PT G20210A, Hyperhomocysteinaemia
Acquired causes are more common overall: APLS, malignancy (most common VTE association in HK), MPN, OCP, pregnancy, nephrotic syndrome, PNH, HIT
In Chinese patients, FVL and PT G20210A are essentially absent — focus on AT/PC/PS deficiency and acquired causes
PT G20210A has normal PT/APTT — diagnosis only by PCR
Inherited thrombophilias cause VTE, NOT arterial thrombosis (except hyperhomocysteinaemia and APLS which cause both)
DVT differentials: muscle injury, cellulitis, superficial thrombophlebitis, lymphoedema, ruptured Baker's cyst, venous insufficiency
PE differentials: AMI, pericarditis, aortic dissection, pneumothorax, pneumonia
Always exclude malignancy in unprovoked VTE — thorough history, exam, and baseline investigations (but NOT universal PET-CT)

Active Recall - Differential Diagnosis of Prothrombin G20210A

References

^[1] Lecture slides: Block A - Leg swelling and chest pain: deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf ^[2] Senior notes: Maksim Medicine Notes.pdf (Haematology - Thrombophilia screening, p.165) ^[5] Senior notes: Block A - Leg swelling and chest pain: deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf (p.6, 7, 13) ^[6] Senior notes: Block A - Leg swelling and chest pain: deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf (p.16 - Malignancy associated VTE) ^[7] Senior notes: MBBS Final MB (Surgery) (Felix PY Lai).pdf (p.965 - Clinical manifestations, DDx of DVT) ^[8] Senior notes: Block A - Chest Pain - Department of Radiology.pdf (PE imaging differentials) ^[9] Senior notes: Ryan Ho Rheumatology.pdf (p.73 - Antiphospholipid syndrome, revised Sapporo criteria) ^[10] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf (p.22 - Lupus anticoagulant vs vWD) ^[11] Senior notes: Block A - Leg swelling and chest pain: deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf (p.18 - MPN associated thrombosis) ^[12] Senior notes: Block A - Sudden severe chest pain: acute myocardial infarction; aortic dissection.pdf (p.6 - Differentials of AMI)

Diagnostic Criteria, Algorithm & Investigations for Prothrombin G20210A Mutation

1. Diagnostic Criteria

Prothrombin G20210A is a genetic condition, not a clinical syndrome. Therefore, unlike conditions such as antiphospholipid syndrome (which has the revised Sapporo criteria ^[9]) or SLE (which has classification criteria), there are no formal diagnostic criteria per se. The diagnosis is binary: the mutation is either present or absent on genetic testing.

However, the clinical context for requesting testing — i.e., when to suspect and screen for this mutation — is well defined:

Result	Interpretation
GG (wild-type)	No mutation; normal prothrombin gene
GA (heterozygous)	One copy of the mutant allele; ~30% elevated prothrombin; ~2–3× VTE risk
AA (homozygous)	Two copies; higher prothrombin levels; ~10× VTE risk; very rare

The diagnosis of Prothrombin G20210A requires identification of the specific G→A substitution at nucleotide 20210 in the F2 gene by PCR-based genotyping. No functional assay, coagulation test, or protein-level measurement can replace this.

2. Diagnostic Algorithm

The algorithm below integrates two clinical scenarios: (A) a patient presenting with acute VTE where you also want to work up the underlying cause, and (B) a patient referred for thrombophilia screening (e.g., family member of known carrier, recurrent miscarriage workup).

3. Investigation Modalities, Key Findings and Interpretations

Test	Method	What It Detects	Key Points
Allele-specific PCR	Primers designed to specifically amplify the A allele at position 20210	G→A substitution	Fast, widely available; reports GG, GA, or AA
PCR-RFLP	PCR amplification followed by restriction enzyme digestion; the G→A change creates or abolishes a restriction site	Same mutation	Older method; being replaced by real-time PCR
Real-time PCR with melting curve analysis	Fluorescent probes detect allele-specific binding; melting temperature differs for G vs A alleles	Same mutation	High throughput; increasingly the standard method in clinical labs
Next-generation sequencing	Sequencing of targeted gene panels that include F2	Can detect G20210A along with many other variants	Used in comprehensive panels but interpretation can be difficult — have to decide what information is useful ^[13]; overkill for isolated PT G20210A testing

Interpretation:

GA (heterozygous) → confirms the diagnosis; counsel regarding VTE risk and modifiable risk factor avoidance (OCP, smoking, immobilisation)
AA (homozygous) → higher risk; very rare; more aggressive counselling and consideration of prophylactic anticoagulation in high-risk situations
GG (wild-type) → mutation absent; does not exclude other thrombophilias

Why can't we just measure plasma prothrombin levels instead of doing genetic testing? Because plasma prothrombin levels in heterozygous carriers (~115–130%) overlap substantially with the upper end of the normal range (~80–120%). There is no clean cutoff that separates carriers from non-carriers. The genetic test is binary and definitive.

These tests are NOT diagnostic of PT G20210A but are essential in the workup of any patient presenting with VTE or bleeding tendency:

Test	What It Measures	Expected Result in PT G20210A	Explanation
Prothrombin time (PT)	Extrinsic pathway: Factor VII → common pathway (X, V, II, fibrinogen)	Normal	PT measures the time for clot formation; a ~30% increase in prothrombin substrate does not meaningfully shorten the clotting time in vitro because there is already excess prothrombin in the test tube relative to the other factors
Activated partial thromboplastin time (APTT)	Intrinsic pathway: XII → XI → IX → VIII → common pathway	Normal	Same reasoning; prothrombin is in the common pathway but the rate-limiting steps are upstream
Fibrinogen	Quantitative fibrinogen level (Clauss method)	Normal	No effect on fibrinogen synthesis
D-dimer	Fibrin degradation product; indicates ongoing fibrinolysis	Elevated during acute VTE; normal at baseline	Non-specific: elevated in inflammatory states, infections, ACS, pregnancy, malignancy, surgery, liver disease, renal disease ^[14]; Sensitive → high NPV, can be used to rule out VTE if negative; cannot rule in ^[14]^[15]

High Yield: D-dimer Interpretation

D-dimer is not very specific → cannot be used to rule in/diagnose a specific condition if a positive test is obtained. It is quite sensitive → can be used to rule out if a negative test is obtained. ^[14]

Standard cutoff is 500 µg/L, but age has an effect → age-adjusted cutoff = age × 10 (e.g. 80 years old → 800 µg/L) ^[15]

A negative D-dimer in a low-probability patient effectively excludes VTE. A positive D-dimer requires confirmatory imaging.

Tests in the thrombophilia screen ^[2]:

Test	What It Measures	Expected in PT G20210A	Abnormal In
Protein C level	Functional or antigenic level of Protein C	Normal	Protein C deficiency
Protein S level (free and total)	Functional or antigenic level of Protein S	Normal	Protein S deficiency; also reduced by OCP, pregnancy, warfarin, liver disease, acute thrombosis
Antithrombin level	Functional AT activity	Normal	AT deficiency; also reduced by heparin, acute thrombosis, nephrotic syndrome, liver disease
Activated Protein C Resistance (APCR)	Screening test: measures whether adding APC prolongs APTT as expected	Normal (APTT prolongs normally with APC)	Factor V Leiden (APC fails to inactivate Factor Va → APTT does not prolong → "resistance")
Factor V Leiden PCR	Confirms R506Q mutation in Factor V gene	Negative	Factor V Leiden
Homocysteine level	Fasting plasma homocysteine	Normal	Hyperhomocysteinaemia (inherited or B12/folate deficiency)
Anti-cardiolipin antibody ^[2]	IgG/IgM antibodies against cardiolipin	Negative	Antiphospholipid syndrome
Lupus anticoagulant ^[2]	Phospholipid-dependent clot-based assay (DRVVT — Dilute Russell's Viper Venom Time ^[10])	Negative	APLS; classically causes prolonged APTT but paradoxically causes thrombosis ^[10]
Anti-β2-glycoprotein I antibody ^[2]	IgG/IgM anti-β2-GPI	Negative	Antiphospholipid syndrome

These are used to confirm the thrombotic event, not to diagnose the underlying thrombophilia:

Investigation	Indication	Key Findings	Interpretation
Compression ultrasonography	Suspected lower limb DVT	Non-compressibility of deep vein; intraluminal thrombus visualised; absence of flow on Doppler	First-line for DVT; sensitivity >95% for proximal DVT
CTPA ^[8]	Suspected PE in haemodynamically stable patient	Intraluminal filling defect in pulmonary arteries; right heart strain ^[8]	CT with contrast; eGFR cutoff > 30 mL/min ^[8]; gold standard for PE diagnosis
V/Q scan ^[8]	PE when CTPA contraindicated (eGFR too low, contrast allergy) ^[8]	Mismatch: normal ventilation with absent perfusion in affected segment	Alternative if CTPA contraindicated
DVT lower limb Doppler ultrasound (as surrogate for PE) ^[8]	If patient is pregnant and cannot tolerate radiation ^[8]	DVT present	"If you find one, then can be quite certain it is a PE" ^[8] — used as indirect evidence
Echocardiography	Haemodynamically unstable PE (massive PE)	RV dilatation, RV hypokinesis, tricuspid regurgitation, McConnell's sign (RV free wall hypokinesis with apical sparing), clot-in-transit	Bedside test for presumptive diagnosis when patient too unstable for CTPA

Investigation	Why	Expected in PT G20210A
CBC	Screen for MPN (polycythaemia, thrombocytosis, leukocytosis); thrombocytopenia in HIT/DIC/TTP	Normal
Blood film	Schistocytes (DIC, TTP); leucoerythroblastic picture (myelofibrosis)	Normal
LFT, Albumin	Liver disease causes acquired coagulopathy; nephrotic syndrome causes AT loss	Normal
RFT	Nephrotic syndrome (AT loss); renal vein thrombosis	Normal
Urinalysis	Proteinuria → nephrotic syndrome	Normal
JAK2 V617F mutation ^[11]	Screen for MPN, especially if unusual site thrombosis ^[11]; patients can clot even before developing cytosis ^[11]	Negative
Flow cytometry for PNH (CD55/CD59)	Suspect PNH if haemolysis + unusual site thrombosis	Negative
Tumour markers, CXR, abdominal USS	Exclude underlying malignancy in unprovoked VTE ^[6]	As clinically indicated

High Yield: Putting It All Together — What the Results Look Like in PT G20210A

A patient with Prothrombin G20210A presenting with VTE will have:

PT: Normal ✓
APTT: Normal ✓
Fibrinogen: Normal ✓
D-dimer: Elevated (due to the acute VTE itself, not the mutation)
Protein C, S, AT: Normal ✓
APCR: Normal ✓
FVL PCR: Negative ✓
APLS panel: Negative ✓
CBC, LFT, RFT: Normal ✓
Prothrombin G20210A PCR: GA or AA ← This is the only abnormal test that clinches the diagnosis

This is why the mutation is sometimes called a "silent" thrombophilia — all routine tests are normal, and only the genetic test reveals it.

Although mixing studies are not used to diagnose PT G20210A, they commonly appear in exams alongside thrombophilia workup, and understanding them helps differentiate conditions with abnormal APTT:

Mixing study principle ^[10]: Mix 50% patient plasma + 50% normal plasma, then repeat the prolonged test (usually APTT):

Scenario	Mixing Study Result	Interpretation	Example
Factor deficiency	Corrects (APTT normalises)	The normal plasma supplies the missing factor	Haemophilia A/B, Factor XI deficiency, vWD
Inhibitor present	Does NOT correct (APTT remains prolonged)	Antibodies in patient plasma destroy/inhibit the added normal factors	Lupus anticoagulant (immediate non-correction) ^[10], Factor VIII inhibitor (delayed non-correction after incubation)

Lupus anticoagulant ^[10] causes prolonged APTT but paradoxically causes thrombosis, not bleeding — because the antibodies interfere with phospholipid-dependent assays in vitro, but in vivo they activate endothelium, complement, and platelets → prothrombotic state. The non-correction is immediate, unlike other autoimmune inhibitors which show delayed non-correction after incubation ^[10].

For PT G20210A, the APTT is normal, so a mixing study is not relevant. But if your thrombophilia workup reveals a prolonged APTT, the mixing study helps you determine whether it is due to a factor deficiency (→ haemophilia, vWD) or an inhibitor (→ lupus anticoagulant / APLS).

Clinical Question	Investigation	Key Finding
Does the patient have VTE?	D-dimer, compression USS, CTPA, V/Q scan	Thrombus visualised / filling defect
Does the patient have PT G20210A?	Prothrombin G20210A PCR ^[2]	GA or AA genotype
Does the patient have another inherited thrombophilia?	Protein C, S, AT, APCR, FVL PCR, homocysteine ^[2]	Specific deficiency or mutation
Does the patient have acquired thrombophilia?	APLS panel (anti-cardiolipin, LA, anti-β2-GPI) ^[2], JAK2, PNH screen	Positive antibodies / mutation
Does the patient have underlying malignancy?	CXR, abdominal USS, tumour markers, CT	Mass / elevated markers
Is the coagulation system normal?	PT, APTT, fibrinogen	All normal in PT G20210A

High Yield Summary — Diagnostics

No formal diagnostic criteria exist for PT G20210A — it is a genetic diagnosis confirmed by PCR genotyping (GA or AA)
Thrombophilia screening panel ^[2]: Protein C, Protein S, APCR, Antithrombin, Factor V Leiden PCR, Prothrombin G20210A PCR, APLS panel
Timing matters ^[2]: Do NOT test Protein C/S/AT during acute VTE or on anticoagulants. DNA tests (FVL PCR, PT G20210A PCR) can be done anytime.
PT, APTT, and fibrinogen are all NORMAL in PT G20210A — the mutation produces a structurally normal protein in increased quantity
D-dimer is elevated during acute VTE but is non-specific; high NPV — useful to rule out, not rule in ^[14]
CTPA is the gold standard for PE ^[8]; V/Q scan if CTPA contraindicated; DVT USS if pregnant ^[8]
Mixing study is not needed for PT G20210A (APTT is normal), but is essential to differentiate factor deficiency from inhibitor when APTT is prolonged
In HK, always consider malignancy screening in unprovoked VTE ^[6]; JAK2 if unusual site thrombosis ^[11]

Active Recall - Diagnosis of Prothrombin G20210A

References

^[1] Lecture slides: Block A - Leg swelling and chest pain: deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf ^[2] Senior notes: Maksim Medicine Notes.pdf (Haematology - Thrombophilia screening, p.165) ^[5] Senior notes: Block A - Leg swelling and chest pain: deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf (p.6, 7, 13) ^[6] Senior notes: Block A - Leg swelling and chest pain: deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf (p.16 - Malignancy associated VTE) ^[8] Senior notes: Block A - Chest Pain - Department of Radiology.pdf (PE imaging) ^[9] Senior notes: Ryan Ho Rheumatology.pdf (p.73 - Revised Sapporo criteria) ^[10] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf (p.22-23 - Mixing study, lupus anticoagulant, DRVVT) ^[11] Senior notes: Block A - Leg swelling and chest pain: deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf (p.18 - MPN associated thrombosis) ^[13] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf (p.18 - NGS interpretation) ^[14] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf (p.23 - D-dimer interpretation) ^[15] Senior notes: Block A - Introduction to CVS investigations (including ECG).pdf (p.6 - D-dimer age-adjusted cutoff)

Management of Prothrombin G20210A Mutation

The management of Prothrombin G20210A operates on three levels, depending on the clinical scenario:

Clinical Scenario	Management Focus
Asymptomatic carrier (no VTE history)	Risk factor counselling; situational thromboprophylaxis; no routine anticoagulation
First episode of VTE (DVT or PE)	Acute anticoagulation → long-term anticoagulation; duration depends on whether provoked vs unprovoked
Recurrent VTE or high-risk features	Indefinite anticoagulation; genetic counselling for family

The mutation itself cannot be "treated" — it is a germline variant present in every cell. Management is about preventing and treating the thrombotic consequences.

3. Management of the Asymptomatic Carrier

Most heterozygous carriers of PT G20210A will never develop VTE in their lifetime. The annual absolute risk is only ~0.2–0.3%, which does not justify chronic anticoagulation (the bleeding risk would outweigh the thrombotic benefit).

Recommendation	Rationale
Avoid combined oral contraceptive pills (COCPs)	Oestrogen is a risk factor for thrombus formation ^[5]; synergistic with PT G20210A (risk ~15–20×). Use progestogen-only methods, IUDs, or barrier methods instead
Avoid hormone replacement therapy (HRT) if possible	Same oestrogen-mediated mechanism; discuss risks vs menopausal symptom severity
Avoid smoking	Smoking is an independent VTE risk factor; additive
Maintain mobility	Avoid prolonged immobilisation (long-haul flights > 6 hours, prolonged bed rest); use calf exercises, hydration, aisle seats on flights
Weight management	Obesity is an independent VTE risk factor
Inform surgical/obstetric teams	Carriers should disclose their status before any surgery or pregnancy so that appropriate thromboprophylaxis can be planned

Even in asymptomatic carriers, temporary anticoagulation is warranted in high-risk periods:

Situation	Thromboprophylaxis
Major surgery (orthopaedic, abdominal, pelvic)	Prophylactic LMWH (e.g., enoxaparin 40 mg SC daily) starting pre-operatively and continuing until fully mobile; mechanical measures (graduated compression stockings, intermittent pneumatic compression)
Prolonged immobilisation / hospitalisation	Prophylactic LMWH + mechanical measures
Long-haul air travel ( > 4–6 hours)	Calf exercises, hydration, compression stockings; consider single dose LMWH for very high-risk individuals
Pregnancy	See section 6 below

4. Management of Acute VTE (DVT and/or PE)

When a carrier develops VTE, the acute management is identical to that of any patient with VTE, regardless of whether they carry the mutation. The mutation influences duration of anticoagulation, not the choice of acute treatment.

4.2 Anticoagulation — Drugs, Mechanisms, Dosing

Drug	Mechanism	Dosing	When to Prefer	Monitoring
LMWH (e.g., enoxaparin) ^[16]	Potentiates antithrombin → preferentially inhibits Factor Xa (shorter heparin chain length means less thrombin inhibition, more Xa inhibition than UFH)	SC enoxaparin 1 mg/kg Q12h ^[16]	First-line for most stable patients; predictable pharmacokinetics; no routine monitoring needed	Anti-Xa levels if renal impairment, obesity, pregnancy
UFH (unfractionated heparin) ^[16]	Potentiates antithrombin → inhibits both thrombin (IIa) and Factor Xa equally	IV bolus 5000 U then 500–1500 U/hr infusion ^[16]	Preferred if: renal failure (CrCl < 30), pregnancy, morbid obesity (poor SC absorption), thrombolytic use considered (acute reversal by protamine is needed) ^[16]	APTT 1.5–2.5× control ^[16]
Fondaparinux	Synthetic pentasaccharide; selectively inhibits Factor Xa via antithrombin	SC 7.5 mg daily (weight-adjusted)	Alternative in HIT (no cross-reactivity with HIT antibodies); renal-adjusted	Anti-Xa levels (rarely needed)
Rivaroxaban (DOAC) ^[17]	Direct Factor Xa inhibitor ("Xa-ban" → ri-varoxa-ban)	15 mg BD for 21 days then 20 mg daily ^[17]	Can be used as initial therapy without parenteral lead-in	No routine monitoring; renal function at baseline
Apixaban (DOAC) ^[17]	Direct Factor Xa inhibitor ("api-xa-ban")	10 mg BD for 7 days then 5 mg BD ^[17]	Can be used as initial therapy without parenteral lead-in; lowest bleeding risk among DOACs	No routine monitoring

High Yield: DOACs as Monotherapy for VTE

Rivaroxaban and apixaban can be started as initial monotherapy (no need for parenteral LMWH/UFH lead-in) ^[17]. They use a higher loading dose initially to achieve rapid therapeutic levels, then step down. In contrast, dabigatran and edoxaban require at least 5 days of parenteral anticoagulant before starting ^[17].

Drug	Mechanism	Dosing	Key Points
Warfarin	Vitamin K antagonist → inhibits synthesis of Factors II, VII, IX, X and Protein C, S	5 mg daily for 2 days, 2 mg on 3rd day, then titrate to INR 2–3 ^[16]	Overlap ≥5 days with LMWH until INR 2–3 is reached ^[17] — because warfarin initially causes a transient hypercoagulable state (Protein C falls faster than procoagulant factors)
DOACs ^[17]	See above	See above	DOAC has been demonstrated to be non-inferior compared with LMWH + warfarin for prevention of symptomatic PE or lethal VTE recurrence, with significantly reduced rates of major bleeding ^[17]. Oral DOAC preferred ^[18]
LMWH long-term	See above	Therapeutic doses SC	Cancer patients: prefer LMWH (or DOAC) over warfarin, continue > 6 months if active cancer ^[19]

High Yield: Warfarin and the Paradoxical Hypercoagulable Window

When you start warfarin, Protein C (half-life ~8 hours) and Protein S (half-life ~36 hours) decline faster than the procoagulant factors (Factor II half-life ~60 hours, Factor X half-life ~40 hours). This creates a transient hypercoagulable state in the first 2–5 days. This is why:

LMWH must be overlapped with warfarin for ≥5 days ^[17]
Warfarin-induced skin necrosis can occur, especially in patients with pre-existing Protein C/S deficiency ^[2] This concern does NOT apply to DOACs, which achieve anticoagulation immediately without this paradoxical effect.

DOAC	Target	Requires Parenteral Lead-in?	Renal Excretion	Specific Reversal Agent
Dabigatran ("da-bi-ga-tran" → direct thrombin inhibitor, "gatran" = anti-thrombin)	Thrombin (IIa)	Yes (≥5 days) ^[17]	~80% (avoid if CrCl < 30)	Idarucizumab (monoclonal antibody fragment)
Rivaroxaban	Factor Xa	No ^[17]	~33%	Andexanet alfa (modified recombinant FXa decoy)
Apixaban	Factor Xa	No ^[17]	~27%	Andexanet alfa
Edoxaban	Factor Xa	Yes (≥5 days) ^[17]	~50%	Andexanet alfa

Etymology tip: The suffix "-xaban" means "Xa-ban" = Xa inhibitor. The suffix "-gatran" comes from "anti-thrombin/anti-gastrin-related target" = direct thrombin inhibitor. This helps you instantly classify any DOAC.

Absolute Contraindications	Relative Contraindications
Active major bleeding (GI, intracranial)	Recent surgery (within 2 weeks)
Severe uncontrolled hypertension	History of GI bleeding
Recent haemorrhagic stroke	Thrombocytopenia (Plt < 50)
Known bleeding diathesis (severe)	Hepatic impairment (coagulopathy)
	Pregnancy (warfarin/DOACs C/I; use LMWH)
	Renal impairment (dose-adjust or avoid DOACs)

The duration of anticoagulation is the most clinically important management decision unique to the thrombophilia context. The presence of PT G20210A (a permanent, non-modifiable risk factor) influences whether to extend anticoagulation beyond the standard period.

Duration of anticoagulation ^[16]:

Scenario	Duration	Rationale
First provoked VTE (clear transient trigger: surgery, immobilisation, OCP — now removed)	3 months	Trigger removed; low recurrence risk (~3%/year); bleeding risk outweighs benefit of extended therapy
First unprovoked VTE	3–6 months minimum ^[16]; consider indefinite	No identifiable trigger → risk of recurrence ~10%/year without anticoagulation; PT G20210A mutation is a persistent risk factor that tilts the balance toward extended therapy
Recurrent VTE (2nd episode)	Indefinite ^[16]	High recurrence risk; benefit of continued anticoagulation clearly outweighs bleeding risk
Malignancy-associated VTE	Indefinite (continue > 6 months if active cancer) ^[19]	Cancer is an ongoing prothrombotic stimulus

5.1 How PT G20210A Influences Duration

PT G20210A heterozygosity alone (without other risk factors) is considered a weak thrombophilia — it does NOT automatically mandate indefinite anticoagulation after a first VTE
However, the following features push toward extended/indefinite anticoagulation:
- Homozygous (AA) genotype
- Compound heterozygosity (PT G20210A + Factor V Leiden)
- Unprovoked first VTE
- Recurrent VTE
- Life-threatening initial presentation (massive PE)
- Additional persistent risk factors (obesity, immobility, underlying malignancy)
Current guidelines (ASH 2024, ACCP) recommend individualised decision-making using validated tools (e.g., HERDOO2, Vienna prediction model, D-dimer after stopping anticoagulation) rather than basing the decision solely on thrombophilia status

High Yield: Extended Anticoagulation Decision

The decision to extend anticoagulation beyond 3–6 months is a risk-benefit calculation:

Risk of recurrent VTE without anticoagulation (higher if unprovoked, hereditary thrombophilia, male sex, elevated D-dimer after stopping, residual DVT on USS)
Risk of bleeding on anticoagulation (higher if elderly, renal/hepatic impairment, concurrent antiplatelet therapy, history of GI bleeding, falls risk)
Patient preference and quality of life

For PT G20210A heterozygotes with a first provoked VTE (trigger removed): standard 3-month course is usually sufficient. For PT G20210A with a first unprovoked VTE: lean toward extended therapy (6–12 months or indefinite) with annual reassessment.

Pregnancy is a high-risk period for carriers of PT G20210A because:

Pregnancy itself is a hypercoagulable state (↑ Factors I, VII, VIII, X, vWF; ↓ Protein S; ↓ fibrinolysis; venous stasis from uterine compression of IVC)
The mutation provides an additional prothrombotic hit

Pregnancy management principles ^[19]:

Drug	Safety in Pregnancy	Notes
LMWH	Safe — does not cross placenta	Drug of choice throughout pregnancy
UFH	Safe — does not cross placenta	Alternative; higher HIT risk with prolonged use
Warfarin	CONTRAINDICATED (especially 1st trimester)	Crosses placenta → risk of fetal ICH and teratogenicity (warfarin embryopathy: nasal hypoplasia, stippled epiphyses) ^[19]
DOACs	CONTRAINDICATED	Cross placenta; insufficient safety data; potential teratogenicity
Fondaparinux	Limited data; use only if LMWH/UFH not tolerated	May partially cross placenta

Pregnancy anticoagulation regimen ^[19]:

Switch to LMWH when 1st trimester (to avoid teratogenicity of warfarin)
Switch at > 36 weeks (to avoid PPH risk — LMWH is easier to hold/reverse than warfarin before delivery)
Cover up to 6 weeks postpartum (highest risk as blood returns from uterus) ^[19]

6.1 Specific Scenarios in Pregnancy

Scenario	Recommendation
Asymptomatic carrier, no prior VTE	Surveillance ± prophylactic LMWH if additional risk factors; postpartum prophylaxis for 6 weeks
Prior VTE (provoked, trigger no longer present)	Antepartum prophylactic LMWH + 6 weeks postpartum prophylaxis
Prior unprovoked VTE or on long-term anticoagulation	Antepartum therapeutic LMWH + 6 weeks postpartum (then resume pre-pregnancy anticoagulation)
Recurrent miscarriage	Consider LMWH ± low-dose aspirin (evidence strongest for APLS; limited data for PT G20210A alone, but often co-managed with haematology)

General management of VTE ^[16]:

Measure	Rationale
Leg elevation ^[16]	Promotes venous return; reduces oedema
Compression stockings (graduated) ^[16]	External compression reduces venous stasis and oedema; some evidence for reducing post-thrombotic syndrome (PTS), though recent data is less supportive
O₂ supplementation ^[16]	Maximise tissue oxygenation; especially important in PE with hypoxaemia
Analgesics ^[16]	Pain control; avoid NSAIDs if on anticoagulation (↑ GI bleeding risk); paracetamol preferred
Early mobilisation	Contrary to traditional bed rest advice, current evidence supports early mobilisation in stable DVT (does not increase PE risk; reduces PTS)

Aspect	Details
Inheritance pattern	Autosomal dominant; 50% chance of transmission per offspring
Penetrance	Incomplete — most carriers never develop VTE
Who to test	First-degree relatives, especially women of childbearing age (OCP and pregnancy decisions)
What to counsel	Avoid OCP; situational thromboprophylaxis; inform healthcare providers before surgery/pregnancy; the mutation is a risk factor, not a disease
Psychological impact	Reassure that most carriers remain asymptomatic; avoid creating unnecessary anxiety while ensuring awareness

Drug Class	Mechanism of Action	Reversal Agent
UFH	Potentiates AT → inhibits IIa + Xa	Protamine sulphate (complete reversal)
LMWH	Potentiates AT → preferentially inhibits Xa	Protamine (partial reversal, ~60% for enoxaparin)
Warfarin	Inhibits VKORC1 → ↓ vitamin K-dependent factors (II, VII, IX, X, Protein C/S)	Vitamin K (slow, 6–24h); FFP or PCC (4-factor: II, VII, IX, X) ^[21] for urgent reversal
Rivaroxaban / Apixaban / Edoxaban	Direct Xa inhibitors	Andexanet alfa (recombinant modified FXa decoy); PCC as alternative
Dabigatran	Direct thrombin inhibitor	Idarucizumab (monoclonal antibody fragment that binds dabigatran)
rtPA (alteplase)	Activates plasminogen → plasmin → fibrin digestion	No specific reversal; supportive (tranexamic acid as antifibrinolytic, cryoprecipitate, FFP)

Follow up at 3–6 months: Echocardiogram for CTEPH ^[16]

Follow-Up Item	Timing	Purpose
Clinical review + INR (if on warfarin)	Every 1–4 weeks initially, then every 4–12 weeks	Ensure therapeutic anticoagulation; monitor for bleeding
D-dimer after stopping anticoagulation	1 month after cessation	Elevated D-dimer predicts higher recurrence risk → consider restarting anticoagulation
Echocardiogram	3–6 months ^[16]	Screen for chronic thromboembolic pulmonary hypertension (CTEPH) — a feared long-term complication of PE
Compression USS	3–6 months	Assess for residual DVT (residual thrombosis predicts higher recurrence risk)
Cancer screening	At diagnosis and ongoing vigilance	Malignancy workup for unprovoked VTE ^[6]
Annual reassessment	Yearly	Reassess risk-benefit of ongoing anticoagulation; check renal/hepatic function; screen for bleeding

High Yield Summary — Management

Asymptomatic carriers: no routine anticoagulation; avoid OCP/HRT/smoking; situational thromboprophylaxis for surgery/pregnancy/immobilisation
Acute VTE: anticoagulation with LMWH/UFH or DOAC (rivaroxaban/apixaban can be used as monotherapy without parenteral lead-in)
DOAC preferred over warfarin ^[18] — non-inferior efficacy with lower bleeding rates
Warfarin requires ≥5 days overlap with LMWH ^[17] due to paradoxical hypercoagulable window from early Protein C depletion
Duration: 3 months (provoked), 3–6 months to indefinite (unprovoked), indefinite (recurrent or cancer-associated) ^[16]
Thrombolysis only for haemodynamically unstable PE (rtPA 100 mg IV/2h) ^[17]; only absolute C/I is stroke ^[18]
IVC filter: very limited role; only when anticoagulation cannot be given; plan for removal within 1 month ^[20]
Pregnancy: LMWH throughout; warfarin and DOACs contraindicated; cover up to 6 weeks postpartum ^[19]
Cancer-associated VTE: LMWH or DOAC > warfarin; continue > 6 months if active cancer ^[19]
Follow-up: echo at 3–6 months for CTEPH; D-dimer after stopping anticoagulation to guide extended therapy; cancer screening

Active Recall - Management of Prothrombin G20210A

References

^[2] Senior notes: Maksim Medicine Notes.pdf (Haematology - Thrombophilia screening, p.165) ^[5] Senior notes: Block A - Leg swelling and chest pain: deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf (p.6, 7, 13) ^[6] Senior notes: Block A - Leg swelling and chest pain: deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf (p.16 - Malignancy associated VTE) ^[16] Senior notes: Maksim Medicine Notes.pdf (Respiratory medicine - VTE management, p.289) ^[17] Lecture slides: Handbook of Internal Medicine 2024.pdf (p.42 - DOAC dosing, duration, thrombolysis) ^[18] Senior notes: Block A - Chest Pain - Department of Medicine.pdf (p.3-4 - PE management, reperfusion) ^[19] Senior notes: Ryan Ho Haemtology.pdf (p.132 - VTE in pregnancy, cancer-associated VTE) ^[20] Senior notes: Block A - Leg swelling and chest pain: deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf (p.26 - Thrombolysis, IVC filter) ^[21] Senior notes: Ryan Ho Haemtology.pdf (p.144 - FFP, cryoprecipitate, PCC)

Complications of Prothrombin G20210A Mutation

The complications of Prothrombin G20210A can be divided into:

Complications of the disease itself (thrombotic consequences of the hypercoagulable state)
Complications of the treatment (anticoagulation-related adverse events)
Long-term sequelae of VTE (post-thrombotic syndrome, CTEPH)

Understanding each from first principles makes them easy to remember — they all flow logically from the pathophysiology of either too much clotting or too much anticoagulation.

1. Complications of the Disease (Thrombotic Consequences)

DVT is the most common clinical manifestation. Complications of the DVT itself include:

Complication	Pathophysiology	Clinical Significance
Clot propagation	The initial thrombus provides a nidus for further fibrin deposition and platelet trapping → clot extends proximally from calf veins into popliteal/femoral/iliac veins	Proximal extension dramatically increases PE risk; emphasises the importance of early anticoagulation to prevent propagation
Pulmonary embolism (PE) ^[5]	Thrombus fragments dislodge from the deep veins of the lower limb → travel via IVC → right heart → lodge in the pulmonary arterial tree → obstruct blood flow → V/Q mismatch + right heart strain	Potentially fatal ^[5]; the most feared acute complication of DVT; risk is much higher with proximal DVT than calf DVT
Phlegmasia alba dolens ("painful white leg")	Near-complete venous obstruction → massive oedema compresses arterial inflow → leg becomes pale, swollen, exquisitely painful	A limb-threatening emergency; represents severe iliofemoral DVT
Phlegmasia cerulea dolens ^[20] ("painful blue leg")	Complete blockage of venous drainage ^[20] → venous gangrene → blue, swollen, painful limb with compartment syndrome	Even more severe than alba dolens; indication for thrombolysis or embolectomy ^[20]; so uncommon that the lecturer hasn't seen one ^[20]

PE is the most life-threatening acute complication. Patients with PE usually die from right heart failure (cardiogenic shock) rather than hypoxaemia ^[7]:

PE Complication	Pathophysiology
Acute right ventricular failure	Large embolus obstructs main/lobar pulmonary arteries → acute ↑ pulmonary vascular resistance → RV cannot generate enough pressure to overcome the obstruction → RV dilates → interventricular septum bows into LV (D-shaped LV) → ↓ LV filling → ↓ cardiac output → obstructive shock ^[7]
Haemodynamic collapse / Death	Massive PE ( > 50% pulmonary vascular bed obstructed) → sustained RV failure → cardiogenic shock → multi-organ failure → death. PE has ~30% mortality if massive and untreated
Pulmonary infarction	Distal small emboli occlude segmental/subsegmental arteries → normally the dual blood supply (bronchial + pulmonary arteries) protects lung tissue, but in patients with compromised bronchial circulation or pre-existing heart failure, infarction occurs → haemoptysis (tissues become anoxic or hypoxic) ^[7], pleuritic pain, pleural effusion (often blood-stained exudate)
Arrhythmias	Acute RV dilatation and ischaemia → altered RV electrophysiology → AF (most common arrhythmia in PE), sinus tachycardia, RBBB

Two unusual sites of venous thrombosis ^[5]:

Site	Complication	Pathophysiology
Cerebral venous sinus thrombosis (CVST) ^[5]	Headache, seizure ^[5], focal neurological deficits, raised ICP, venous infarction with haemorrhagic transformation	Thrombosis of dural venous sinuses → impaired CSF drainage + venous congestion of brain parenchyma → raised ICP + cytotoxic oedema; venous infarcts are prone to haemorrhagic conversion because the blocked venous drainage causes capillary rupture
Mesenteric venous thrombosis ^[5]	Severe abdominal pain ^[5], bowel ischaemia, intestinal infarction, peritonitis	Thrombosis of SMV/IMV → venous congestion of intestinal wall → mucosal ischaemia → transmural necrosis if not treated → perforation → peritonitis
Renal vein thrombosis	Flank pain, haematuria, proteinuria (if bilateral: acute renal failure)	Venous outflow obstruction of kidneys → renal congestion and parenchymal ischaemia
Hepatic vein thrombosis (Budd-Chiari syndrome)	Hepatomegaly, ascites, abdominal pain, liver failure	Venous outflow obstruction of liver → sinusoidal congestion → hepatocyte necrosis; classic triad: hepatomegaly + ascites + abdominal pain
Portal vein thrombosis	Portal hypertension, variceal bleeding, ascites	Acute or chronic obstruction of portal venous flow → pre-hepatic portal hypertension

"In theory, every single vein in your body could undergo thrombosis → symptoms correspond with anatomy" ^[5]

High Yield: Unusual Site Thrombosis

Unusual sites of thrombosis (mesenteric, renal, portal vein, cerebral venous sinus) are an indication for thrombophilia screening ^[2]^[22]. While MPN (JAK2 mutation) ^[11] and PNH are more classically associated with unusual-site thrombosis, PT G20210A (especially if compound heterozygous with FVL, or homozygous) can also present this way.

These are complications of the mutation's thrombotic tendency affecting the uteroplacental circulation:

Complication	Pathophysiology
Recurrent early miscarriage ( < 10 weeks)	Thrombosis of decidual spiral arteries → placental ischaemia → embryo/fetal demise; however, evidence for PT G20210A alone causing early miscarriage is weaker than for APLS
Late fetal loss ( > 10 weeks) / Stillbirth	Same mechanism but in more established pregnancy; more robust association with PT G20210A than early miscarriage
Pre-eclampsia	Placental ischaemia from spiral artery thrombosis → release of anti-angiogenic factors (sFlt-1, sEndoglin) → systemic endothelial dysfunction → hypertension + proteinuria
Placental abruption	Thrombosis behind the placenta → retroplacental haematoma → premature placental separation → haemorrhage + fetal distress
Intrauterine growth restriction (IUGR)	Chronic placental insufficiency from partial spiral artery thrombosis → inadequate nutrient/oxygen delivery to fetus

The evidence linking PT G20210A to adverse pregnancy outcomes is less strong than for APLS. Meta-analyses show a modest association (OR ~2–3 for late fetal loss, ~1.5 for pre-eclampsia). Management decisions in pregnancy are individualised and should involve haematology input.

These are iatrogenic complications — the "price" of preventing thrombosis. Understanding these from first principles is essential because managing a patient on anticoagulation means constantly balancing thrombotic and bleeding risk.

Bleeding is the most common and most feared complication of anticoagulation therapy:

Severity	Examples	Risk Factors for Bleeding
Minor bleeding	Bruising, epistaxis, gum bleeding, haematuria	Elderly age, concurrent antiplatelet therapy, excessive anticoagulation (supratherapeutic INR)
Major bleeding	GI haemorrhage (melaena, haematemesis), intracranial haemorrhage (the most devastating), haemarthrosis, retroperitoneal haemorrhage	Age > 65, renal/hepatic impairment, history of GI bleeding, falls risk, concurrent NSAIDs/antiplatelets, labile INR on warfarin

Management of bleeding on anticoagulation:

Drug	Reversal Strategy
Warfarin	Stop warfarin; Vitamin K 5–10 mg IV (takes 6–24h to work); for life-threatening bleeding: 4-factor PCC (Factors II, VII, IX, X) ^[21] or FFP for immediate reversal
LMWH	Stop LMWH; Protamine sulphate (partial reversal ~60% for enoxaparin; binds anti-IIa activity but not anti-Xa)
UFH	Stop UFH; Protamine sulphate (complete reversal; 1 mg protamine per 100 U heparin given in preceding 2–3 hours)
Rivaroxaban / Apixaban / Edoxaban	Andexanet alfa (recombinant modified FXa that acts as a decoy to sequester the drug); PCC as alternative if andexanet unavailable
Dabigatran	Idarucizumab (monoclonal antibody fragment that binds dabigatran with extremely high affinity, neutralising it instantly)

HIT is a paradoxical complication of heparin therapy that causes thrombosis (not bleeding) despite thrombocytopenia:

Feature	Type I HIT	Type II HIT (the clinically significant one)
Mechanism	Direct platelet aggregation by heparin (non-immune)	IgG antibodies form against PF4-heparin complexes → antibody-coated complexes bind and activate platelets → massive platelet activation → "white clot syndrome"
Timing	Days 1–2 of heparin	Days 5–14 of heparin (or earlier if prior heparin exposure)
Platelet drop	Mild (rarely < 100)	Moderate to severe ( > 50% drop from baseline or < 150)
Thrombosis	No	Yes — arterial and venous thrombosis (limb ischaemia, PE, stroke, MI)
Management	Continue heparin	Immediately stop all heparin; switch to non-heparin anticoagulant (argatroban, fondaparinux, bivalirudin); bridge to warfarin only after platelet recovery (starting warfarin during HIT worsens thrombosis by depleting Protein C/S)

Why is this relevant to PT G20210A? Because these patients may be on heparin for their VTE. HIT is a complication of the treatment, not the mutation, but recognising it is essential — you are treating one hypercoagulable state (PT G20210A) and inadvertently creating another (HIT).

Complication	Pathophysiology
Warfarin-induced skin necrosis ^[2]	Warfarin reduces Protein C (half-life ~8h) faster than procoagulant factors → transient hypercoagulable state → microvascular thrombosis in subcutaneous fat → skin necrosis. Classically seen in Protein C/S deficiency ^[2], but can occur in any patient. Presents as painful, purpuric skin lesions → necrotic eschar, typically on days 3–6 of warfarin initiation
Warfarin embryopathy	Warfarin crosses the placenta → inhibits vitamin K-dependent γ-carboxylation of osteocalcin and matrix Gla protein → nasal hypoplasia, stippled epiphyses (chondrodysplasia punctata); also risk of fetal intracranial haemorrhage. Contraindicated in pregnancy ^[19]
Purple toe syndrome	Cholesterol crystal embolisation from atherosclerotic plaques dislodged by warfarin-induced haemorrhage into the plaque → small vessel occlusion in toes → painful blue/purple discolouration
Drug interactions	Warfarin is metabolised by CYP2C9 and its target (VKORC1) has genetic polymorphisms → extensive drug-drug and drug-food interactions (e.g., cranberry juice, grapefruit, antibiotics, amiodarone, phenytoin all alter INR); requires frequent monitoring

Complication	Details
Renal impairment affecting drug levels	Dabigatran is ~80% renally excreted → accumulation in CKD → bleeding risk; rivaroxaban, apixaban, edoxaban are partially renal-excreted → dose adjustment or avoidance needed when CrCl < 15–30
GI bleeding	Rivaroxaban and dabigatran have slightly higher GI bleeding rates compared to warfarin; apixaban has the lowest GI bleeding rate among DOACs
No routine monitoring (double-edged sword)	DOACs do not require INR monitoring, which improves convenience but makes it harder to detect non-compliance or supratherapeutic levels in renal decline

3. Long-Term Sequelae of VTE

Feature	Details
Definition	A chronic condition developing months to years after DVT, characterised by chronic venous insufficiency in the affected limb
Incidence	20–50% of patients after proximal DVT, even with adequate anticoagulation
Pathophysiology	DVT damages the venous valves (valvular incompetence) and causes chronic venous obstruction → persistent ambulatory venous hypertension → chronic oedema, tissue hypoxia, inflammation, skin changes
Symptoms	Chronic leg pain, heaviness, swelling (worse at end of day, improved with elevation), exercise intolerance
Signs	Oedema, varicose veins, skin hyperpigmentation (haemosiderin deposition from RBC extravasation), lipodermatosclerosis (fibrosis of subcutaneous tissue → "inverted champagne bottle" leg), venous ulceration (medial malleolus — the most severe manifestation)
Diagnosis	Villalta scale (standardised clinical scoring system combining symptoms and signs)
Management	Graduated compression stockings (20–30 mmHg); elevation; exercise; skin care; for severe ulcers: wound care, compression bandaging. No curative treatment exists — prevention of DVT recurrence is key

Why does PTS develop? During DVT, the thrombus adheres to the vein wall and organises over weeks. Even after the clot recanalises (breaks down and blood flow is restored), the venous valves are permanently damaged by the inflammatory process. Without functioning valves, blood refluxes in the deep veins during ambulation → ambulatory venous hypertension → capillary distension → fluid + RBC extravasation → chronic inflammation → fibrosis → ulceration. This is why adequate initial anticoagulation (to prevent clot extension and promote recanalisation) and recurrence prevention are critical.

Follow up at 3–6 months: Echocardiogram for CTEPH ^[16]

Feature	Details
Definition	Pulmonary hypertension (mPAP > 20 mmHg at rest) caused by organised thromboembolic material that remains in the pulmonary arteries after acute PE, causing chronic obstruction and vascular remodelling
Incidence	2–4% of patients after acute PE; likely underdiagnosed
Pathophysiology	After acute PE, incomplete thrombus resolution → organised fibrotic thrombus becomes incorporated into the pulmonary arterial wall → chronic obstruction → ↑ pulmonary vascular resistance → secondary vascular remodelling of unobstructed vessels (similar to PAH) → progressive right ventricular failure
Why doesn't everyone with PE develop CTEPH?	Most patients fully lyse their clots via endogenous fibrinolysis within weeks to months. CTEPH occurs when fibrinolysis is incomplete — risk factors include large initial PE, recurrent PE, inherited thrombophilia (including PT G20210A), antiphospholipid antibodies, elevated Factor VIII, splenectomy, inflammatory bowel disease, and blood group non-O
Symptoms	Progressive exertional dyspnoea (the hallmark), exercise intolerance, fatigue, syncope on exertion (late — indicates severely reduced cardiac output), chest pain
Signs	Loud P2 (pulmonary hypertension → forceful pulmonary valve closure), RV heave, raised JVP, peripheral oedema, hepatomegaly, tricuspid regurgitation murmur
Diagnosis	Screening: echocardiogram at 3–6 months post-PE ^[16] → if RV systolic pressure elevated → V/Q scan (perfusion defects in CTEPH) → confirmatory: right heart catheterisation (gold standard, mPAP ≥ 20 mmHg + PAWP ≤ 15 mmHg + PVR ≥ 3 WU) + CTPA (organised thrombus)
Management	Pulmonary endarterectomy (PEA) — the gold standard curative surgery; removes organised thromboembolic material from the pulmonary arteries. Balloon pulmonary angioplasty (BPA) for inoperable patients. Riociguat (soluble guanylate cyclase stimulator) for inoperable or residual CTEPH post-PEA. Lifelong anticoagulation

High Yield: CTEPH Screening After PE

CTEPH is treatable and potentially curable with pulmonary endarterectomy, but it is frequently missed because symptoms develop insidiously months after the initial PE. Echocardiography should be performed at 3–6 months post-PE ^[16] in patients with persistent dyspnoea, exercise intolerance, or signs of right heart failure. Early detection is critical because delay leads to irreversible RV failure.

Often overlooked but important in holistic care:

Complication	Details
Anxiety about recurrence	Knowing one carries a lifelong prothrombotic mutation can cause health anxiety, especially with each episode of leg discomfort or chest pain
Impact on reproductive choices	Young women may face difficult decisions about contraception (cannot use COCPs), pregnancy planning (need anticoagulation throughout), and the psychological burden of high-risk pregnancies
Anticoagulation burden	Long-term or lifelong anticoagulation affects quality of life: dietary restrictions with warfarin, activity restrictions (contact sports), need for monitoring, travel considerations
Family impact	The autosomal dominant inheritance pattern means 50% of first-degree relatives may carry the mutation → creating cascade of screening, anxiety, and lifestyle modifications across a family

Category	Complication	Mechanism	Prevention/Management
Thrombotic	DVT	↑ Prothrombin → ↑ thrombin → fibrin clot in deep veins	Anticoagulation; thromboprophylaxis
	PE	DVT embolisation → pulmonary artery obstruction	Early DVT treatment; anticoagulation
	CVST	Venous sinus thrombosis → raised ICP	Anticoagulation; sometimes decompressive surgery
	Mesenteric VT	SMV thrombosis → bowel ischaemia	Anticoagulation; surgery if peritonitis
	Recurrent VTE	Persistent prothrombotic state	Extended/indefinite anticoagulation
Obstetric	Miscarriage, pre-eclampsia, abruption, IUGR, stillbirth	Uteroplacental thrombosis → placental insufficiency	LMWH ± aspirin in pregnancy
Treatment	Bleeding	Excess anticoagulation → loss of haemostatic balance	Monitor; dose-adjust; reversal agents
	HIT Type II	Anti-PF4-heparin IgG → platelet activation → thrombosis	Stop heparin; non-heparin anticoagulant
	Warfarin skin necrosis	Early Protein C depletion → microvascular thrombosis	Overlap with LMWH ≥5 days
	Warfarin embryopathy	Crosses placenta → disrupts vitamin K-dependent bone proteins	Avoid in pregnancy; use LMWH
Long-term	Post-thrombotic syndrome	Valve destruction → chronic venous hypertension	Compression stockings; prevent recurrence
	CTEPH	Incomplete thrombolysis → chronic PA obstruction → RV failure	Echo at 3–6 months; PEA if diagnosed
Psychosocial	Anxiety, reproductive impact, family screening burden	Lifelong genetic condition with variable penetrance	Genetic counselling; psychological support

High Yield Summary — Complications

Most feared acute complication: PE → right heart failure → obstructive shock → death ^[7]; patients die from RV failure, not hypoxaemia ^[7]
Most feared limb complication: Phlegmasia cerulea dolens (venous gangrene) ^[20] — indication for thrombolysis ^[20]
Unusual site thrombosis (CVST, mesenteric, hepatic, portal, renal veins) is an indication for thrombophilia screening ^[2]^[22]
Most common long-term complication of DVT: Post-thrombotic syndrome (20–50%) — caused by venous valve destruction → chronic venous hypertension → skin changes → ulceration
Most important long-term complication of PE: CTEPH — screen with echocardiography at 3–6 months ^[16]; treatable with pulmonary endarterectomy
Most common complication of treatment: Bleeding (minor to life-threatening); reversed with specific agents (protamine for heparin, vitamin K/PCC for warfarin, idarucizumab for dabigatran, andexanet alfa for Xa-inhibitors)
Warfarin-induced skin necrosis — classically Protein C/S deficiency ^[2] — prevented by overlapping LMWH ≥5 days
Obstetric complications: miscarriage, pre-eclampsia, abruption, IUGR, stillbirth — all from uteroplacental thrombosis; managed with LMWH ± aspirin
Inherited thrombophilias cause VTE only, NOT arterial thrombosis ^[5] — so stroke and MI are NOT complications of PT G20210A

Active Recall - Complications of Prothrombin G20210A

References

^[2] Senior notes: Maksim Medicine Notes.pdf (Haematology - Thrombophilia screening, p.165) ^[5] Senior notes: Block A - Leg swelling and chest pain: deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf (p.6, 7, 13) ^[7] Senior notes: MBBS Final MB (Surgery) (Felix PY Lai).pdf (p.964–965 - Clinical manifestations, Virchow's triad) ^[11] Senior notes: Block A - Leg swelling and chest pain: deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf (p.18 - MPN associated thrombosis) ^[16] Senior notes: Maksim Medicine Notes.pdf (Respiratory medicine - VTE management, p.289) ^[19] Senior notes: Ryan Ho Haemtology.pdf (p.132 - VTE in pregnancy, cancer-associated VTE) ^[20] Senior notes: Block A - Leg swelling and chest pain: deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf (p.26 - Thrombolysis, IVC filter, phlegmasia) ^[21] Senior notes: Ryan Ho Haemtology.pdf (p.144 - FFP, PCC) ^[22] Lecture slides: Handbook of Internal Medicine 2024.pdf (p.200 - Thrombophilia screening indications)

High Yield Summary

Prothrombin G20210A is a point mutation (G→A) in the 3'-UTR of the prothrombin gene → ↑ mRNA stability → ↑ prothrombin protein synthesis → ↑ thrombin generation → prothrombotic state
Second most common inherited thrombophilia after Factor V Leiden (in Caucasians)
Essentially absent in Chinese/East Asian populations — irrelevant for Chinese patients in HK but important for Caucasians and for exams
Modest VTE risk (~2–3× for heterozygotes) — risk becomes clinically significant with additional hits (OCP, pregnancy, surgery, immobilisation, co-existing thrombophilia)
Only causes venous thrombosis, NOT arterial thrombosis — don't screen for it in recurrent stroke/MI
PT and APTT are normal — diagnosis requires PCR-based genetic testing
Thrombophilia screening should NOT be done during acute VTE or on anticoagulants (except DNA-based tests which are unaffected)
Inherited thrombophilia causes = AT deficiency, Protein C deficiency, Protein S deficiency, Factor V Leiden, Prothrombin G20210A, Hyperhomocysteinaemia
In HK, the most common condition associated with VTE is underlying malignancy, not inherited thrombophilia
The mutation follows autosomal dominant inheritance — important for genetic counselling

High Yield Summary — Differential Diagnosis

Prothrombin G20210A is one of six inherited thrombophilias: AT deficiency, Protein C deficiency, Protein S deficiency, Factor V Leiden, PT G20210A, Hyperhomocysteinaemia
Acquired causes are more common overall: APLS, malignancy (most common VTE association in HK), MPN, OCP, pregnancy, nephrotic syndrome, PNH, HIT
In Chinese patients, FVL and PT G20210A are essentially absent — focus on AT/PC/PS deficiency and acquired causes
PT G20210A has normal PT/APTT — diagnosis only by PCR
Inherited thrombophilias cause VTE, NOT arterial thrombosis (except hyperhomocysteinaemia and APLS which cause both)
DVT differentials: muscle injury, cellulitis, superficial thrombophlebitis, lymphoedema, ruptured Baker's cyst, venous insufficiency
PE differentials: AMI, pericarditis, aortic dissection, pneumothorax, pneumonia
Always exclude malignancy in unprovoked VTE — thorough history, exam, and baseline investigations (but NOT universal PET-CT)

High Yield Summary — Diagnostics

No formal diagnostic criteria exist for PT G20210A — it is a genetic diagnosis confirmed by PCR genotyping (GA or AA)
Thrombophilia screening panel ^[2]: Protein C, Protein S, APCR, Antithrombin, Factor V Leiden PCR, Prothrombin G20210A PCR, APLS panel
Timing matters ^[2]: Do NOT test Protein C/S/AT during acute VTE or on anticoagulants. DNA tests (FVL PCR, PT G20210A PCR) can be done anytime.
PT, APTT, and fibrinogen are all NORMAL in PT G20210A — the mutation produces a structurally normal protein in increased quantity
D-dimer is elevated during acute VTE but is non-specific; high NPV — useful to rule out, not rule in ^[14]
CTPA is the gold standard for PE ^[8]; V/Q scan if CTPA contraindicated; DVT USS if pregnant ^[8]
Mixing study is not needed for PT G20210A (APTT is normal), but is essential to differentiate factor deficiency from inhibitor when APTT is prolonged
In HK, always consider malignancy screening in unprovoked VTE ^[6]; JAK2 if unusual site thrombosis ^[11]

High Yield Summary — Management

Asymptomatic carriers: no routine anticoagulation; avoid OCP/HRT/smoking; situational thromboprophylaxis for surgery/pregnancy/immobilisation
Acute VTE: anticoagulation with LMWH/UFH or DOAC (rivaroxaban/apixaban can be used as monotherapy without parenteral lead-in)
DOAC preferred over warfarin ^[18] — non-inferior efficacy with lower bleeding rates
Warfarin requires ≥5 days overlap with LMWH ^[17] due to paradoxical hypercoagulable window from early Protein C depletion
Duration: 3 months (provoked), 3–6 months to indefinite (unprovoked), indefinite (recurrent or cancer-associated) ^[16]
Thrombolysis only for haemodynamically unstable PE (rtPA 100 mg IV/2h) ^[17]; only absolute C/I is stroke ^[18]
IVC filter: very limited role; only when anticoagulation cannot be given; plan for removal within 1 month ^[20]
Pregnancy: LMWH throughout; warfarin and DOACs contraindicated; cover up to 6 weeks postpartum ^[19]
Cancer-associated VTE: LMWH or DOAC > warfarin; continue > 6 months if active cancer ^[19]
Follow-up: echo at 3–6 months for CTEPH; D-dimer after stopping anticoagulation to guide extended therapy; cancer screening

High Yield Summary — Complications

Most feared acute complication: PE → right heart failure → obstructive shock → death ^[7]; patients die from RV failure, not hypoxaemia ^[7]
Most feared limb complication: Phlegmasia cerulea dolens (venous gangrene) ^[20] — indication for thrombolysis ^[20]
Unusual site thrombosis (CVST, mesenteric, hepatic, portal, renal veins) is an indication for thrombophilia screening ^[2]^[22]
Most common long-term complication of DVT: Post-thrombotic syndrome (20–50%) — caused by venous valve destruction → chronic venous hypertension → skin changes → ulceration
Most important long-term complication of PE: CTEPH — screen with echocardiography at 3–6 months ^[16]; treatable with pulmonary endarterectomy
Most common complication of treatment: Bleeding (minor to life-threatening); reversed with specific agents (protamine for heparin, vitamin K/PCC for warfarin, idarucizumab for dabigatran, andexanet alfa for Xa-inhibitors)
Warfarin-induced skin necrosis — classically Protein C/S deficiency ^[2] — prevented by overlapping LMWH ≥5 days
Obstetric complications: miscarriage, pre-eclampsia, abruption, IUGR, stillbirth — all from uteroplacental thrombosis; managed with LMWH ± aspirin
Inherited thrombophilias cause VTE only, NOT arterial thrombosis ^[5] — so stroke and MI are NOT complications of PT G20210A

Prothrombin G20210A Mutation

1. Definition

2. Epidemiology

2.1 Global Prevalence

2.2 Ethnic Distribution

2.3 VTE Risk

3. Anatomy and Function: The Prothrombin Protein and the Coagulation Cascade

3.1 Prothrombin (Factor II)

3.2 Where Prothrombin Sits in the Coagulation Cascade

3.3 Natural Anticoagulant System (Context)

4. Etiology (Focus on Hong Kong Context)

4.1 Inherited Thrombophilias — The Complete List

4.2 Relevance to Hong Kong

4.3 When Prothrombin G20210A Becomes Relevant in HK Practice

5. Pathophysiology

5.1 Molecular Mechanism

5.2 How Elevated Prothrombin Causes Thrombosis

5.3 Why Venous and Not Arterial Thrombosis?

6. Classification

6.1 Within the Framework of Inherited Thrombophilia

6.2 Prothrombin G20210A Genotypes

6.3 Within the Broader Classification of Thrombophilia

7. Risk Factors for VTE in Prothrombin G20210A Carriers

7.1 Virchow's Triad Framework

7.2 Synergistic Risk Factors

8. Clinical Features

8.1 Important Caveat

8.2 Symptoms of VTE

Deep Vein Thrombosis (DVT)

Pulmonary Embolism (PE)

Unusual Sites of Thrombosis

8.3 Signs

8.4 Obstetric Complications

8.5 Timing and Pattern

9. Thrombophilia Screening — Where Prothrombin G20210A Fits

9.1 The Thrombophilia Screen Panel

9.2 Timing of Testing

9.3 Diagnosis of Prothrombin G20210A

10. History and Examination Approach

11. Comparison of Inherited Thrombophilias

Active Recall - Prothrombin G20210A Mutation

References

Framing the Differential Diagnosis

Part A: Differential Diagnosis of the Thrombophilia (Why Did This Patient Clot?)

Diagnostic Decision Tree

Comprehensive List of Differentials for Hypercoagulable State

A. Inherited Thrombophilias

B. Acquired Thrombophilias

C. How to Narrow the Differential

Part B: Differential Diagnosis of the Clinical Presentation

Differential Diagnosis of DVT (Unilateral Leg Swelling)

Differential Diagnosis of PE (Acute Dyspnoea and Chest Pain)

Part C: Distinguishing Prothrombin G20210A from Close Differentials

Summary: Approach to the Differential

Active Recall - Differential Diagnosis of Prothrombin G20210A

1. Diagnostic Criteria

1.1 Indications for Thrombophilia Screening (Including PT G20210A)

1.2 Genetic Diagnosis — Definitive

2. Diagnostic Algorithm

2.1 Clinical Scenario A: Patient Presenting with Acute VTE

2.2 Clinical Scenario B: Thrombophilia Screening Panel

3. Investigation Modalities, Key Findings and Interpretations

3.1 Genetic Testing (Gold Standard for PT G20210A Diagnosis)

3.2 Standard Coagulation Tests (Expected to Be Normal)

3.3 Thrombophilia Panel Tests (To Differentiate from Other Causes)

3.4 Investigations for VTE Itself (Imaging)

3.5 Additional Investigations to Exclude Other Causes of VTE

4. Interpretation of the Mixing Study (Context for Exam)

5. Family Screening Considerations

6. Summary Table: Investigation Approach by Clinical Question

Active Recall - Diagnosis of Prothrombin G20210A

1. Management Framework — Overview

2. Management Algorithm

3. Management of the Asymptomatic Carrier

3.1 Risk Factor Counselling

3.2 Situational Thromboprophylaxis

4. Management of Acute VTE (DVT and/or PE)

4.1 Overall Algorithm by Haemodynamic Stability

4.2 Anticoagulation — Drugs, Mechanisms, Dosing

A. Initial Anticoagulation (First 5–21 Days)