Disorders of coagulation or thrombosis - thrombophilia
Description
- Inherited or acquired tendency to venous (and in APS, arterial) thrombosis
- *The central clinical point: a positive result rarely changes the acute treatment, and for most inherited defects it does not change duration either*
- Duration is decided by provoked vs unprovoked and by bleeding risk - not by a gene
- Antiphospholipid syndrome is the exception that does change management
Inherited
| Prevalence among inherited thrombophilias | Population frequency | |
|---|---|---|
| Factor V Leiden / APC resistance | 20-50% | 1-7% of Caucasians |
| Prothrombin G20210A | 3-5% | ~2% |
| Protein C deficiency | ~5% | ~0.3% |
| Protein S deficiency | ~5% | ~0.1% |
| Antithrombin deficiency | <5% | ~0.02% - rarest but strongest |
| Dysfibrinogenaemia | Rare |
- Roughly half of "inherited thrombophilias" are found after an event that was actually provoked by immobility, surgery or pregnancy - the result is then an incidental finding, not the cause
Epidemiology
- Factor V Leiden: ~10x risk in heterozygotes, ~80x in homozygotes - but ~90% of carriers never have a thrombosis
- Antiphospholipid antibodies: 1-5% of healthy people (transient, often post-infectious); persistent antibodies are far less common
- APS: ~50 per 100,000; F>M; median onset 30-40 years
- ~40% of SLE patients carry antiphospholipid antibodies; ~10-15% develop APS
Aetiopathogenesis
Mechanisms
- Factor V Leiden - point mutation at the activated protein C cleavage site of factor Va -> APC resistance -> Va not switched off
- Prothrombin G20210A - 3'UTR mutation -> inc prothrombin levels (gain of function)
- Antithrombin, protein C, protein S deficiency - loss of the natural anticoagulant brake
- Antithrombin deficiency also causes apparent heparin resistance
- Antiphospholipid antibodies - anti-beta-2-glycoprotein I is the pathogenic species
- -> endothelial and monocyte activation, inc tissue factor, complement activation, inhibition of protein C, placental trophoblast injury
Acquired thrombophilia
- Pregnancy and puerperium; oestrogen-containing contraception, HRT, tamoxifen
- Antiphospholipid syndrome - lupus anticoagulant, anticardiolipin, anti-beta-2-glycoprotein I
- Malignancy - the commonest and most important
- Myeloproliferative neoplasms / JAK2 V617F - especially splanchnic and cerebral vein thrombosis
- PNH - unusual-site thrombosis with haemolysis
- HIT / VITT - anti-PF4 antibodies
- Nephrotic syndrome (antithrombin loss), IBD, Behçet, hyperhomocysteinaemia, obesity, immobility
Diagnosis
Who to test - and who not to
Consider testing only if the result would change management or matter to relatives:
- Age <45 with unprovoked thrombosis
- Second or subsequent event
- Strong family history in first-degree relatives
- Unusual site - cerebral venous sinus, splanchnic, upper limb without catheter
- Recurrent pregnancy loss or unexplained late fetal loss
- Warfarin-induced skin necrosis, neonatal purpura fulminans
*Do not test:*
- Provoked VTE with an obvious major transient trigger
- Before starting the combined pill in an asymptomatic woman with no family history
- Arterial thrombosis - inherited thrombophilia does not cause it (except APS)
When to test
- *Not during the acute event and not on anticoagulation*
- Heparin lowers antithrombin; warfarin lowers protein C and S; acute thrombosis consumes all of them
- DOACs cause false-positive lupus anticoagulant
- Retest >=2 weeks after stopping warfarin, at least 3 months after the event
Antiphospholipid syndrome - 2023 ACR/EULAR criteria
*The old Sapporo "one clinical + one laboratory feature" model is superseded*
- Entry criterion: at least one positive aPL test within 3 years of an aPL-associated clinical feature
- Then an additive weighted score: classification needs >=3 points from clinical domains AND >=3 points from laboratory domains
Clinical domains (6)
| Weighting logic | |
|---|---|
| Macrovascular VTE | 1 if a high VTE-risk profile is present; 3 if not |
| Macrovascular arterial thrombosis | 2 if high CVD risk profile; 4 if not |
| Microvascular | 2 suspected (livedo racemosa, livedoid vasculopathy, aPL-nephropathy, pulmonary haemorrhage); 5 if biopsy-proven |
| Obstetric | >=3 consecutive losses <10 weeks, fetal death 16-34 weeks, severe pre-eclampsia or placental insufficiency <34 weeks |
| Cardiac valve | 2 thickening; 4 vegetation |
| Haematological | Thrombocytopenia 20-130 x10^9/L = 2 |
Laboratory domains (2)
- Lupus anticoagulant - functional coagulation assay: 1 point single positive, 5 points if persistent
- aCL and/or anti-beta-2-GPI by solid-phase assay - IgM low weight; IgG moderate-high positive scores heavily (up to 7 for high-titre aCL + anti-beta-2-GPI IgG)
- *Persistence required: repeat at >=12 weeks*
- "Triple positive" (LA + aCL + anti-beta-2-GPI) = highest thrombotic risk and dictates the anticoagulant choice
- Lupus anticoagulant prolongs the APTT in vitro but is prothrombotic in vivo
Catastrophic APS
- >=3 organs involved within 7 days, with histological confirmation of microthrombosis in at least one, in a patient with persistent aPL
- Presentation: AKI, ARDS, diffuse alveolar haemorrhage, encephalopathy, adrenal haemorrhage, cardiac and skin involvement
- Precipitants: infection, surgery, anticoagulation withdrawal, pregnancy, malignancy
- Mortality ~30-50% even treated
Management
A. Acute thrombosis
- Standard anticoagulation - the thrombophilia does not change the acute treatment
B. Antiphospholipid syndrome
- Warfarin, target INR 2.0-3.0 for a first venous event
- *DOACs are inferior - TRAPS (rivaroxaban vs warfarin in triple-positive APS) stopped early for excess arterial thrombotic events*
- Arterial thrombosis: warfarin INR 3.0-4.0, or INR 2.0-3.0 plus low-dose aspirin
- Indefinite anticoagulation in thrombotic APS
- Recurrent thrombosis despite therapeutic INR -> higher INR target, add aspirin, switch to LMWH, consider hydroxychloroquine and statin
- Modify all cardiovascular risk factors and avoid oestrogen-containing contraception
- Asymptomatic aPL positivity: no anticoagulation; low-dose aspirin in high-risk profiles (triple positive, SLE)
- SLE with aPL: hydroxychloroquine (antithrombotic as well as immunomodulatory)
C. Obstetric APS
- Low-dose aspirin + prophylactic LMWH from confirmation of pregnancy
- Therapeutic LMWH if prior thrombosis
- Continue LMWH 6 weeks post-partum (the highest-risk window)
- *Warfarin is teratogenic (6-12 weeks: nasal hypoplasia, stippled epiphyses) and DOACs are contraindicated*
D. Catastrophic APS
- Triple therapy: therapeutic anticoagulation + high-dose glucocorticoid + plasma exchange and/or IVIG
- Treat the precipitant (usually infection)
- Refractory: rituximab or eculizumab (complement-mediated)
E. Inherited thrombophilia
- Does not alter acute management
- Duration: unprovoked event -> the decision is driven by bleeding risk and patient preference; only antithrombin, protein C and protein S deficiency meaningfully raise recurrence risk and favour indefinite therapy
- *Factor V Leiden and prothrombin G20210A have little effect on recurrence - do not extend anticoagulation on their basis alone*
- Antithrombin deficiency: heparin resistance -> may need antithrombin concentrate, particularly peri-operatively and peripartum
- Protein C/S deficiency: overlap heparin with warfarin for >=5 days - skin necrosis risk
- Homozygous protein C deficiency -> neonatal purpura fulminans
- Pregnancy: LMWH prophylaxis decided by the specific defect plus personal and family history, not by the genotype alone
- Family testing: only where an asymptomatic relative's management would change (contraception choice, pregnancy prophylaxis) - and after counselling
Associations
- SLE - lupus anticoagulant, valve disease, nephropathy
- Infections (syphilis, hepatitis C, HIV, EBV, COVID) - transient aPL, usually non-pathogenic
- Drugs - hydralazine, procainamide, phenytoin, quinidine, interferon
- Malignancy, myeloproliferative neoplasm/JAK2, PNH, nephrotic syndrome
- APS features outside the classification criteria:
- Thrombocytopenia 50-100 x10^9/L - common, usually asymptomatic; <20 suggests thrombotic microangiopathy
- Haemolytic anaemia without schistocytes = immune; with schistocytes = thrombotic microangiopathy
- Renal: acute TMA or chronic vaso-occlusive lesions
- Cardiac: Libman-Sacks vegetations, valve thickening
- Skin: livedo reticularis/racemosa, livedoid vasculopathy with painful recurrent ulcers
- Neurological: cognitive dysfunction without another cause, chorea, transverse myelitis, migraine
- Adrenal insufficiency from adrenal vein thrombosis
Natural history & complications
- Most carriers of inherited thrombophilia never thrombose - the defect is permissive, not sufficient
- Risk is multiplicative when combined with an acquired trigger (factor V Leiden + combined pill is the classic)
- APS carries lifelong risk with recurrence rates of 10-30%/yr off anticoagulation
Adverse markers in APS
- Triple positivity, high-titre IgG, lupus anticoagulant
- Prior arterial event, SLE, additional cardiovascular risk factors
- Persistent thrombocytopenia, nephropathy, valve disease
Complications
- Recurrent VTE and arterial thrombosis, stroke in young patients
- CTEPH from recurrent PE
- Recurrent pregnancy loss, pre-eclampsia, placental insufficiency, prematurity
- Catastrophic APS - rare, mortality 30-50%
- Bleeding on long-term anticoagulation; hypoprothrombinaemia-lupus anticoagulant syndrome causes bleeding rather than clotting
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