Inherited Thrombophilia (Factor V Leiden & Protein C/S Deficiency)

Meet the patient

A 27-year-old woman, three weeks into the combined oral contraceptive pill, arrives with a swollen left calf and pleuritic chest pain. Her mother had a pulmonary embolism at 35. The Wells score is moderate, the CTPA confirms a segmental PE, and she is started on apixaban. Six months later, on the ward round, the registrar asks: do we test her for thrombophilia — and if we do, when?[3]

Two questions decide her care, and they are the two every examiner probes: whom to test (most patients never need the panel) and how the result changes management (for a low-risk defect, usually not at all). Hold those two and the rest of this page slots into place.[1][5]

A laboratory diagnosis masquerading as a clinical one

There is no bedside sign of an inherited thrombophilia — only the pattern of the clot. The presentation is ordinary venous thromboembolism; the defect is inferred from age, site, recurrence, and family history. Juniors order the panel on every DVT; consultants test selectively, and at the right moment.[2][5]

Every defect tips the haemostatic balance toward clotting — the hypercoagulability arm of Virchow's triad. Each works by either removing a natural anticoagulant brake (antithrombin, protein C, protein S) or strengthening a procoagulant drive (factor V Leiden resists breakdown; prothrombin G20210A raises factor II). The net cellular consequence is unopposed thrombin generation in the venous circulation.[1]

Separate inherited from acquired at the bedside, because the acquired list is commoner, often more dangerous, and frequently more treatable. All six major inherited thrombophilias are autosomal dominant with incomplete penetrance — most carriers never thrombose — and the modest genetic risk only declares itself when a second hit lands.[1][2]

The acquired mimics you must exclude before labelling a defect inherited

Acquired thrombophilia is often the real diagnosis, and it changes the treatment. Rule these out before you reach for the genetic panel.[1][2]

• Antiphospholipid syndrome — antibody-mediated (lupus anticoagulant, anticardiolipin, anti-beta-2-GPI); arterial AND venous thrombosis plus recurrent pregnancy loss; APTT prolonged and does not correct on mixing study; lifelong anticoagulation, DOACs avoided when triple-positive.
• Malignancy (Trousseau) — migratory superficial thrombophlebitis, classically pancreatic or mucinous; exclude with an age-appropriate cancer screen; may cause heparin resistance through consumption.
• Myeloproliferative neoplasm — JAK2 V617F; polycythaemia vera, essential thrombocythaemia, myelofibrosis; strong link to splanchnic vein thrombosis (Budd-Chiari, portal vein).
• Heparin-induced thrombocytopenia — falling platelet count 5 to 14 days into heparin with paradoxical thrombosis; diagnose with the 4Ts score and anti-PF4 assay; stop all heparin and switch to argatroban, bivalirudin, or danaparoid.[1][2]

Add nephrotic syndrome (urinary antithrombin loss), paroxysmal nocturnal haemoglobinuria (splanchnic and cerebral thrombosis with Coombs-negative haemolysis and pancytopenia), sickle cell disease, inflammatory bowel disease, homocystinuria (a severe distinct inborn error versus the common MTHFR polymorphisms), and the physiological hypercoagulability of pregnancy, sepsis, and severe liver disease — any of which can lower natural-anticoagulant levels and mimic an inherited deficiency on a functional assay.[1]

Two tiers — the split that governs everything downstream

The six defects divide cleanly into common-and-modest versus rare-and-dangerous. The common group amplifies a procoagulant; the rare group deletes a natural anticoagulant. That single distinction decides testing strategy, anticoagulation duration, pregnancy prophylaxis, and family counselling.[1][5]

[1] [5]

The face-off table — one line tells the defect apart

Five defects, one discriminator each. This is the table to reproduce in a viva.[1]

[1] [8]

The discriminators, spoken aloud

• Warfarin-induced skin necrosis points to protein C or S deficiency — shortest half-life, falls first.
• Heparin resistance points to antithrombin deficiency — no antithrombin for heparin to potentiate.
• APC resistance on the assay points to factor V Leiden — confirm with PCR.
• A raised prothrombin with a normal APC assay points to prothrombin G20210A.[1][8]

Who carries these defects — and why factor V Leiden is a European founder

Carrier frequency tracks ethnicity because these are founder mutations. The population genetics of factor V Leiden is a guaranteed examiner question, so know the numbers cold.[1][7]

• Factor V Leiden is the single commonest inherited thrombophilia in Europeans: roughly 3 to 8 percent of Caucasians carry it. It is uncommon in African, East Asian, Australasian, and Native American populations (under 1 percent) — a founder effect. The mutation is a G-to-A substitution at nucleotide 1691 (G1691A) in the F5 gene on chromosome 1q24, producing an Arg506Gln (R506Q) change in factor V.[7]
• Prothrombin G20210A is the second commonest in Europeans (carrier frequency about 2 percent). It is a G-to-A transition at position 20210 in the 3-prime untranslated region of the F2 gene on chromosome 11, raising plasma prothrombin by roughly 25 to 30 percent.[1]
• Antithrombin, protein C, and protein S deficiency are each rare (prevalence under 1 percent), yet over-represented in young, unprovoked, recurrent, or unusual-site VTE cohorts. Antithrombin deficiency is the rarest (about 1 in 2000 to 5000) but carries the highest VTE risk of any single inherited defect.[4]
• Hyperhomocysteinaemia (MTHFR C677T) — the homozygous TT genotype sits in roughly 10 to 15 percent of Europeans, though only a fraction (those with low folate) develop clinically significant hyperhomocysteinaemia.[1]

Penetrance is incomplete for all six, and the second hit is what actually clots. Most heterozygous factor V Leiden or prothrombin carriers never develop VTE (lifetime risk about 5 to 10 percent). The modest genetic risk is amplified by acquired triggers — the combined OCP, pregnancy, hormone replacement, surgery, trauma, immobility, malignancy, nephrotic syndrome, infection, and the puerperium.[1][3]

Meet the pattern at the bedside

The bedside exam is the exam of the clot itself, plus a structured hunt for the unusual site and the family tree. There is no pathognomonic sign of thrombophilia — you are looking for the pattern that justifies testing.[2]

• Deep vein thrombosis: calf or thigh swelling, tenderness along the deep venous system, erythema, warmth, superficial venous dilation. A calf circumference difference of more than 3 cm at a fixed point is significant. Apply the Wells score for DVT, and separate proximal (popliteal, femoral, iliac) from distal (calf) — proximal carries higher PE risk.[2]
• Pulmonary embolism: tachycardia, tachypnoea, hypoxia, pleuritic chest pain, haemoptysis, and right-heart strain (raised JVP, right ventricular heave, loud P2) in massive PE. Apply Wells or PERC for pretest probability, and PESI to decide inpatient versus outpatient.[2]
• Unusual-site patterns (the ones that earn a thrombophilia screen): progressive headache, papilloedema, and seizures — cerebral venous sinus thrombosis; abdominal pain, ascites, and diarrhoea — mesenteric or portal vein thrombosis; hepatomegaly, right upper quadrant pain, and refractory ascites — Budd-Chiari; sudden painless visual loss — retinal vein occlusion; flank pain, haematuria, and nephrotic-range proteinuria — renal vein thrombosis; effort-related arm swelling — Paget-Schroetter syndrome (subclavian or axillary).[5]
• Family history: take a three-generation pedigree of VTE events, pregnancy complications, and known thrombophilia. Two or more affected first-degree relatives is one of the strongest single discriminants for an inherited cause.[5]

The coagulation balance — every defect removes a brake or adds a drive

Haemostasis is an equilibrium, and thrombophilia tips it one way. On one side sit the procoagulant drivers (tissue factor to factor VIIa to factor Xa to thrombin to fibrin); on the other, three natural anticoagulant brakes — antithrombin, the protein C and protein S system, and tissue factor pathway inhibitor. Every inherited defect either removes a brake or strengthens a procoagulant, and the result is unopposed thrombin generation.[1]

Mechanism by defect — five short stories

Factor V Leiden (Arg506Gln, G1691A). Activated protein C normally cleaves factor Va at three sites — Arg306, Arg506, and Arg679 — to switch it off. The Leiden mutation changes Arg506 to Gln506, the primary cleavage site, so factor Va is inactivated about 10 times more slowly and keeps generating thrombin. The laboratory phenotype is activated protein C resistance: an APC sensitivity ratio under 2.0 (normal above 2.0), confirmed by PCR.[7]

Prothrombin G20210A. The mutation sits in the 3-prime untranslated region of F2. It leaves the protein sequence intact but increases messenger RNA stability and translation, raising plasma prothrombin by about 25 to 30 percent — more substrate, more thrombin, a modestly higher VTE risk. It is NOT detected by APC-resistance testing; it needs its own PCR.[1]

Antithrombin deficiency. Antithrombin (a serpin) neutralises thrombin, factor Xa, IXa, XIa, and XIIa in irreversible 1:1 complexes, and heparin potentiates this several thousand-fold — the molecular basis of heparin therapy and the reason deficiency causes heparin resistance. Type I = low antigen and low activity (quantitative); Type II = normal antigen but a dysfunctional protein, with the heparin-binding-site variants the most thrombogenic.[4]

Protein C deficiency. When thrombin binds thrombomodulin on healthy endothelium, it flips from procoagulant to anticoagulant and activates protein C. With its cofactor protein S, activated protein C then cleaves factors Va and VIIIa and shuts down further thrombin. Lose protein C and that brake is gone. Homozygous deficiency (usually severe Type I) presents as neonatal purpura fulminans.[8]

Protein S deficiency. Protein S is the essential cofactor for activated protein C and has APC-independent anticoagulant activity against the prothrombinase and tenase complexes. About 60 percent of circulating protein S is bound (and inactive) to C4b-binding protein; only the free fraction (about 40 percent) is active. Types I, II, and III are defined by total versus free versus activity; homozygous deficiency also causes neonatal purpura fulminans.[8]

Hyperhomocysteinaemia — the odd one out (venous AND arterial)

Hyperhomocysteinaemia (MTHFR C677T, Ala222Val) is the only inherited thrombophilia that raises ARTERIAL thrombosis too — MI and stroke as well as DVT and PE. The thermolabile variant impairs remethylation of homocysteine to methionine, worst when folate intake is low. Elevated homocysteine drives thrombosis through endothelial dysfunction, oxidative stress, reduced thrombomodulin, increased tissue factor, and impaired fibrinolysis. The A1298C variant is less often implicated.[1]

Warfarin-induced skin necrosis — the highest-yield fact in the topic

This mechanism is guaranteed viva material, so learn it cold. Of the vitamin K-dependent proteins, four are procoagulant (factors II, VII, IX, X) and two are anticoagulant (protein C, protein S). The critical pharmacological fact: protein C has the shortest half-life (about 8 hours), then factor VII (6 hours), then factor IX (24 hours) and prothrombin (60 to 72 hours).[8]

When warfarin starts, it blocks vitamin K epoxide reductase and halts gamma-carboxylation of all of them. Because protein C falls first — within 24 to 48 hours — a transient but profound procoagulant window opens: the anticoagulant is gone while the long-lived procoagulant factors II, IX, and X still circulate. In a patient already deficient in protein C or S, that window is catastrophic — the anticoagulant reserve hits near-zero and the skin infarcts.[8]

The result is full-thickness skin necrosis — breasts, buttocks, thighs, penis — within 3 to 10 days of starting warfarin. It is pathognomonic for protein C or S deficiency, and it is entirely preventable.[8]

The classic trap that harms patients: starting warfarin without heparin cover, or loading it hard, in a patient you have not yet screened. Heparin first, overlap warfarin slowly, and never let the INR run ahead of the protein C recovery.[8]

When to test — and when NOT to

Thrombophilia testing is selective, not universal. ASH, BSH, and ISTH all agree: routine testing of every VTE patient is not cost-effective and rarely changes management, because the common defects do not alter anticoagulation duration. Test only when the result has a real chance of changing the plan — not out of curiosity.[1][5]

[5]

Test when: unprovoked VTE under 50; unusual-site VTE (cerebral, mesenteric, portal, hepatic, renal, retinal); recurrent unprovoked VTE; VTE on the combined OCP or in pregnancy; a strong family history (two or more first-degree relatives with VTE); warfarin-induced skin necrosis; recurrent fetal loss or severe pregnancy complications; heparin resistance (pointing at antithrombin deficiency); and first-degree relatives of a confirmed proband (cascade screening).[5]

Do NOT test when: the VTE was provoked in an older patient and the result would not change duration; the patient is critically ill with multiple confounders; or you are still in the acute thrombotic event itself (acute-phase reactants distort the functional assays).[5]

The testing trap — timing makes or breaks the result

The commonest laboratory error in thrombophilia is testing at the wrong time. The functional assays (antithrombin, protein C, protein S) are distorted by the acute event, by anticoagulants, and by pregnancy. The genetic PCRs (factor V Leiden, prothrombin G20210A) are unaffected by any of it and can be run anytime.[1][5]

1. Do not test during the acute thrombotic event — factor consumption and acute-phase responses distort functional assays. Wait at least 4 to 6 weeks.
2. Do not test on anticoagulation — warfarin lowers protein C and protein S (vitamin K-dependent); heparin lowers antithrombin. Either stop for a washout (2-plus weeks for warfarin, rarely practical or safe) or use the genetic PCRs.
3. Do not test in pregnancy or on the OCP — both lower free protein S and antithrombin; defer to postpartum or after stopping the pill. The genetic tests stay valid.
4. Always exclude acquired causes first — antiphospholipid antibodies, an age-appropriate malignancy screen, full blood count and film (check JAK2 if splanchnic thrombosis), and liver and renal function.
5. Repeat any abnormal functional result before labelling inherited — transient acquired deficiency from sepsis, pregnancy, liver disease, or nephrotic syndrome is common and masquerades on a single assay.[1]

The thrombophilia panel

Know which test is distorted by what, and which is immune. The genetic PCRs (factor V Leiden, prothrombin) are the escape hatch — unaffected by anticoagulants, acute illness, or pregnancy.[1]

[1] [1] [4] [8]

The OCP and factor V Leiden — a multiplicative risk

The combined pill does not add to a factor V Leiden carrier's risk — it multiplies it. Vandenbroucke's 1994 Lancet paper is the citation examiners want: a factor V Leiden carrier on the combined OCP carries roughly a 35-fold increased VTE risk versus a non-carrier not on the pill. That is multiplicative, not additive, and it is why the combined OCP is contraindicated in high-risk defects.[3]

Counsel the carrier to switch to a progestogen-only pill (desogestrel), a levonorgestrel intrauterine system (Mirena), or non-hormonal contraception (copper IUD, barrier methods). The progestogen-only pill does not significantly raise VTE risk. The same multiplicative logic applies to pregnancy, surgery, and immobility — each is a second hit on the genetic baseline.[3]

Management — the event is treated; the defect sets the DURATION

The clot is treated with standard anticoagulation; the defect type mainly decides how LONG you treat. The commonest error in exams and in practice is over-treating a low-risk defect. A heterozygous factor V Leiden carrier with a single provoked DVT does not need lifelong anticoagulation just because of the gene.[1][5]

[5]

The key principle: for most first VTE patients, the decision to extend is driven by whether the event was provoked or unprovoked, the bleeding risk, and patient preference — not by the genotype alone. ASH, BSH, and ISTH all caution against extending therapy solely on the back of a low-risk result.[5]

Anticoagulant choice

A DOAC (apixaban, rivaroxaban, dabigatran, or edoxaban) or warfarin is first-line for most VTE. LMWH is preferred in pregnancy and active cancer (by Khorana score and guideline recommendations).[1]

• Antithrombin deficiency with heparin resistance: the APTT is unreliable — monitor with anti-Xa levels and consider antithrombin concentrate perioperatively, peripartum, or during acute thrombosis. DOACs act independently of antithrombin and may be effective, but seek specialist input.[4]
• Protein C or S deficiency: always bridge warfarin with heparin for at least 5 days and until the INR is therapeutic for two consecutive days, to prevent warfarin-induced skin necrosis.[8]

Hyperhomocysteinaemia — the one you can actually treat

Unlike the others, hyperhomocysteinaemia is directly treatable regardless of the clot: folate 0.4 to 5 mg daily, vitamin B6 (pyridoxine) 25 to 100 mg daily, and vitamin B12 (cyanocobalamin) 0.4 to 1 mg daily normalise homocysteine. But the evidence that lowering homocysteine reduces VTE recurrence is weak — randomised trials are negative — so anticoagulation duration is still set by the event itself.[1]

Acute management — heparin first, mind the two traps

The thrombophilia itself is not the emergency — the clot is, and it is managed like any VTE, with two specific traps.[2]

• Acute DVT or PE: weight-based LMWH (enoxaparin 1 mg per kg subcutaneously every 12 hours, or 1.5 mg per kg once daily) or fondaparinux (5 to 10 mg subcutaneously once daily by weight), then transition to a DOAC or warfarin. In antithrombin deficiency, heparin may fail to reach therapeutic levels — monitor with anti-Xa (not APTT) and give antithrombin concentrate.[2][4]

A massive PE with hypotension, shock, and right-heart strain is a resuscitation, not a work-up. Give systemic thrombolysis (alteplase 50 to 100 mg IV over 2 hours), or consider catheter-directed thrombolysis or surgical embolectomy. Reperfuse immediately; investigate thrombophilia later.[2]

• Warfarin-induced skin necrosis: stop warfarin, give therapeutic heparin, vitamin K 5 to 10 mg, and protein C concentrate (or FFP). Entirely preventable by heparin bridging.[8]
• Neonatal purpura fulminans (homozygous protein C or S deficiency): protein C concentrate (or FFP), therapeutic heparin, and a plan for lifelong protein C replacement or anticoagulation; liver transplantation is curative for severe protein C deficiency.[1]

Pregnancy, the puerperium, and the OCP

Pregnancy is a physiological hypercoagulable state — raised factors II, VII, VIII, X and fibrinogen, lower protein S, venous stasis, IVC compression — and a thrombophilic defect amplifies it. Management turns on the defect type, the personal VTE history, and the family history, using RCOG Green-top Guideline No. 37 (UK) or ASH guidance (US).[2][5]

• Anticoagulant in pregnancy: LMWH is the mainstay (enoxaparin 40 mg subcutaneously daily for prophylaxis, or weight-based therapeutic dosing for treatment). Warfarin is teratogenic — it crosses the placenta and causes embryopathy (nasal hypoplasia, stippled epiphyses, limb hypoplasia) between weeks 6 and 12, and fetal or placental haemorrhage later. DOACs are avoided in pregnancy and breastfeeding. Switch warfarin to LMWH before 6 weeks gestation, ideally pre-conception.[2]
• Postpartum: continue LMWH (or switch to warfarin, which is safe in breastfeeding) for at least 6 weeks postpartum, the highest-risk window. Warfarin is safe in lactation — it does not enter breast milk in clinically meaningful amounts.[2]
• Risk stratification: asymptomatic low-risk carriers (heterozygous FVL or prothrombin mutation) with no prior VTE often need postpartum prophylaxis only. High-risk defects (antithrombin deficiency, homozygous FVL) or any defect with a prior VTE warrant antenatal and postpartum prophylactic or therapeutic LMWH.[5]

Special situations — surgery, relatives, and neonates

A few scenarios change the plan, and each has a specific move.[2]

• Surgery on anticoagulation: bridge with LMWH by thrombotic risk. In antithrombin deficiency, plan antithrombin concentrate perioperatively to prevent thrombosis and heparin resistance. In protein C or S deficiency, restart warfarin carefully with heparin bridging. For DOACs, stop 24 to 48 hours preoperatively by bleeding risk and renal function; no bridging is usually needed given the short half-life.[2]
• Asymptomatic relatives (cascade screening): test first-degree relatives of a confirmed proband to guide OCP avoidance, pregnancy prophylaxis, and situational prophylaxis (surgery, immobilisation). It is not emergency testing, and it comes with genetic counselling — most carriers never thrombose, and the result should inform, not alarm.[5]
• Neonates: homozygous protein C or S deficiency presents in the first hours to days of life with neonatal purpura fulminans — widespread cutaneous microvascular thrombosis, DIC, and skin necrosis. Treat with protein C concentrate (or FFP), therapeutic heparin, and lifelong protein C replacement or anticoagulation; liver transplantation is curative for severe protein C deficiency.[1]

Prognosis — penetrance is the counselling word

Penetrance is incomplete, and that is the single most important thing to tell a carrier. Most heterozygous factor V Leiden carriers never develop VTE — lifetime risk about 5 to 10 percent; for heterozygous prothrombin G20210A, about 2 to 4 percent. Homozygous FVL and antithrombin deficiency carry much higher lifetime risks (often over 50 percent), with protein C or S heterozygotes intermediate. Untreated antithrombin-deficient relatives clot at about 1 to 3 percent per year versus a baseline of about 0.1 percent.[1]

Recurrence after a first VTE is higher in thrombophilic patients and tracks the defect: low-risk defects a modest 1.5 to 2-fold increase over non-carriers, high-risk defects (antithrombin, homozygous FVL, double defects) a 2 to 4-fold increase. That is why high-risk defects justify extended or lifelong anticoagulation.[5]

Disposition is outpatient anticoagulation once the acute event is stable, with lifelong surveillance for high-risk defects and cascade screening of first-degree relatives — counsel them on OCP avoidance, pregnancy prophylaxis, and the reassuring incompleteness of penetrance.[1][2]

The specific defects, in one-line summaries

Factor V Leiden (FVL)

G1691A in exon 10 of F5 on chromosome 1q24 (Arg506Gln) — the APC cleavage site is lost, causing APC resistance. Autosomal dominant with incomplete penetrance. Heterozygous about 3 to 8-fold VTE risk; homozygous about 80-fold; compound with prothrombin G20210A about 20-fold. DVT and PE; the commonest inherited cause of unprovoked VTE in young Caucasians. Most heterozygotes never thrombose. Heterozygous plus a single provoked event gets standard duration; homozygous or compound gets extended or lifelong. Counsel OCP avoidance (35-fold synergistic risk).[3][7]

Prothrombin G20210A

A G-to-A transition at nucleotide 20210 in the 3-prime UTR of F2 on chromosome 11p11, raising plasma prothrombin about 25 to 30 percent via increased mRNA stability. Autosomal dominant with incomplete penetrance. Heterozygous about 2 to 5-fold VTE risk; homozygous or compound with FVL is higher-risk. DVT and PE; also associated with recurrent pregnancy loss in systematic-review and meta-analysis data. Management mirrors FVL — the genotype alone does not extend anticoagulation.[1][6]

Protein C deficiency

PROC on chromosome 2q13 to q14; autosomal dominant. Type I (low antigen and activity); Type II (normal antigen, low activity). Heterozygous about 3 to 15-fold VTE risk, presenting as young unprovoked VTE and warfarin-induced skin necrosis. Homozygous gives neonatal purpura fulminans. Always bridge warfarin with heparin; extended anticoagulation after a first event is generally recommended.[1][8]

Protein S deficiency

PROS1 on chromosome 3p11.1 to 3q11.2; autosomal dominant. Type I (low total and free); Type II (low activity, normal antigen); Type III (normal total, low free). Measure free protein S antigen (the active fraction). Heterozygous about 2 to 10-fold VTE risk, presenting like protein C deficiency with young unprovoked VTE and warfarin-induced skin necrosis. Homozygous gives neonatal purpura fulminans (rare). Management mirrors protein C deficiency.[8]

Antithrombin deficiency

SERPINC1 on chromosome 1q25; autosomal dominant. Type I (low antigen and activity); Type II (normal antigen, low activity), with the heparin-binding-site variants the most thrombogenic. The strongest single inherited thrombophilia — about 10 to 25-fold VTE risk, presenting at the youngest age (often first VTE under 30) with unusual-site thrombosis (mesenteric, cerebral) and heparin resistance (APTT fails to rise despite escalating UFH). Exclude acquired deficiency (nephrotic syndrome, liver disease, asparaginase, DIC, sepsis) first. Extended or lifelong anticoagulation after a first event; monitor acute treatment with anti-Xa and give antithrombin concentrate as needed.[4]

Combined (double) defects

About 1 to 2 percent of thrombophilia patients carry two defects — classically FVL plus prothrombin G20210A. Risks are additive or synergistic (about 20 to 60-fold). Treat as high-risk with extended or lifelong anticoagulation, and offer cascade screening for both defects to relatives.[1]

Complications and the pitfalls that mismanage them

[1] [8]

Regional differences and the guidelines behind the plan

Selective testing is the global consensus — endorsed by ASH (2020 Choosing Wisely), BSH, and ISTH. Routine testing of all VTE patients is not cost-effective, rarely changes duration for low-risk defects, and can harm through unnecessary extended anticoagulation, patient anxiety, and insurance implications.[5]

The MTHFR testing controversy: most guidelines (ASH, BSH, ACMG) now recommend against routine MTHFR genotyping — the C677T and A1298C variants are extremely common, their VTE association is weak, and homocysteine-lowering vitamins do not reduce recurrence. A fasting homocysteine may occasionally help (young arterial thrombosis with a family history), but even that is contested. The topic lingers in curricula for its history and exam frequency.[1]

The mantra, the traps, the ward-round test

Ward-round test — answers in the reveal

Stem 1. A 23-year-old on the combined OCP develops a proximal DVT. Her father had a PE at 40. Which defect is commonest, and what is her clot risk on the pill?[3]

Stem 2. A patient started on warfarin for a DVT develops painful purple-black necrosis on the thigh and buttock at day 5. Name the defect, the mechanism, and the first three actions.[8]

Stem 3. A 35-year-old with mesenteric vein thrombosis is on a heparin infusion but the APTT will not rise despite escalating doses. What is the diagnosis, what monitor do you switch to, and what do you give?[4]

Stem 4. You are asked to check a thrombophilia screen on a patient on day 2 of an acute PE, currently on enoxaparin. Which tests are valid now, and which must wait?[1]

Ward-round answers

1. Factor V Leiden is the commonest inherited thrombophilia in Europeans. A heterozygous carrier on the combined OCP carries roughly a 35-fold VTE risk versus a non-carrier not on the pill — multiplicative, not additive. Counsel a contraception switch (progestogen-only pill, LNG-IUS, or copper IUD).[3]
2. Warfarin-induced skin necrosis equals protein C or S deficiency. Protein C has the shortest half-life (about 8 hours), so it falls first within 24 to 48 hours, opening a procoagulant window while factors II, IX, and X persist. Stop warfarin, give therapeutic heparin, give vitamin K 5 to 10 mg, and give protein C concentrate (or FFP). Preventable by heparin bridging.[8]
3. Heparin resistance equals antithrombin deficiency. Switch monitoring to anti-Xa levels (the APTT is unreliable) and give antithrombin concentrate. Extended or lifelong anticoagulation follows.[4]
4. Valid now: the genetic PCRs (factor V Leiden, prothrombin G20210A) — unaffected by anticoagulants or acute illness. Must wait: functional antithrombin, protein C, and protein S — wait at least 4 to 6 weeks off the acute event and off heparin or warfarin (or repeat off therapy). Exclude APS and acquired causes first.[1]

[1] [4] [8]

References

1. [1]Phillippe HM, Hornsby LB, Treadway S, et al. Inherited Thrombophilia J Pharm Pract, 2014.PMID 24739277
2. [2]Chopard R, Albertsen IE, Piazza G Diagnosis and Treatment of Lower Extremity Venous Thromboembolism: A Review JAMA, 2020.PMID 33141212
3. [3]Vandenbroucke JP, Koster T, Briët E, et al. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation Lancet, 1994.PMID 7968118
4. [4]Patnaik MM, Moll S. Inherited antithrombin deficiency: a review Haemophilia, 2008.PMID 19141163
5. [5]Stevens SM, Woller SC, Bauer KA, et al. Guidance for the evaluation and treatment of hereditary and acquired thrombophilia J Thromb Thrombolysis, 2016.PMID 26780744
6. [6]Gao H, Tao FB Prothrombin G20210A mutation is associated with recurrent pregnancy loss: a systematic review and meta-analysis update Thromb Res, 2015.PMID 25528068
7. [7]Kujovich JL. Factor V Leiden thrombophilia Genet Med, 2011.PMID 21116184
8. [8]Sallah S, Abdallah JM, Gagnon GA Recurrent warfarin-induced skin necrosis in kindreds with protein S deficiency Haemostasis, 1998.PMID 9885367