Thrombophilia

Introduction

Thrombophilia describes an inherited or acquired tendency towards inappropriate thrombus formation, usually venous. It is best understood through Virchow's triad - the three contributors to thrombosis being stasis, endothelial injury and hypercoagulability - with thrombophilia representing a persistent tilt towards the last of these.¹

A crucial framing point: thrombophilia is usually a risk modifier rather than a cause. Most people with an inherited thrombophilia never have a thrombosis, and most thrombotic events occur when a thrombophilia coincides with an additional trigger - surgery, immobility, pregnancy, oestrogen therapy, malignancy or infection.

Inherited thrombophilias

Normal haemostasis is restrained by natural anticoagulants - protein C, protein S and antithrombin - which switch off thrombin generation. Inherited thrombophilias arise either because a clotting factor resists this restraint, or because one of the natural anticoagulants is deficient.

A further practical caveat: antithrombin deficiency causes apparent heparin resistance, since heparin works by potentiating antithrombin. A patient failing to achieve therapeutic anticoagulation despite escalating heparin doses should prompt consideration of this diagnosis.

Antiphospholipid syndrome

APS is an autoimmune disorder in which antibodies directed against phospholipid-binding plasma proteins promote thrombosis. It is the most clinically important thrombophilia because, unlike the inherited defects, it genuinely alters management.²

It may be primary (isolated) or secondary, most often to systemic lupus erythematosus.

Clinical features

• Venous thrombosis - DVT and pulmonary embolism, including at unusual sites
• Arterial thrombosis - stroke and TIA in young patients, myocardial infarction; the arterial involvement distinguishes APS from the inherited thrombophilias, which are essentially venous
• Recurrent pregnancy loss - classically three or more consecutive losses before 10 weeks, or fetal death after 10 weeks, plus pre-eclampsia and placental insufficiency
• Thrombocytopenia - mild and common, and paradoxical alongside the thrombotic tendency
• Livedo reticularis - a mottled, lace-like purplish skin discolouration
• Catastrophic antiphospholipid syndrome - rare but life-threatening, with widespread small-vessel thrombosis and multi-organ failure over days

Diagnosis

Diagnosis requires at least one clinical criterion (thrombosis or defined pregnancy morbidity) plus a persistently positive antibody test, confirmed on two occasions at least 12 weeks apart - the repeat is essential, since transient positivity occurs with infection and does not indicate APS.

• Lupus anticoagulant
• Anticardiolipin antibodies (IgG/IgM)
• Anti-beta-2 glycoprotein I antibodies (IgG/IgM)
• Patients positive for all three ("triple positive") carry the highest thrombotic risk

Acquired risk factors for thrombosis

Beyond APS, a range of acquired states increase thrombotic risk and are usually more relevant to an individual patient's event than any inherited defect:

• Malignancy - a major cause of unprovoked VTE; consider occult cancer in unexplained thrombosis, guided by age, symptoms and NICE recommendations rather than indiscriminate whole-body imaging
• Pregnancy and the puerperium - a physiological hypercoagulable state, with the postpartum period carrying the highest risk
• Oestrogen-containing contraception and hormone replacement therapy
• Surgery, trauma and immobility - including long-haul travel
• Antiphospholipid syndrome and other autoimmune disease
• Myeloproliferative neoplasms (JAK2-mutated disease) and paroxysmal nocturnal haemoglobinuria - both classically causing thrombosis at unusual sites
• Nephrotic syndrome - urinary loss of antithrombin
• Heparin-induced thrombocytopenia - a drug-induced prothrombotic state
• Obesity, smoking, increasing age and dehydration

Who to test, and why testing matters less than expected

Thrombophilia testing is frequently requested and rarely useful, and indiscriminate testing causes harm through anxiety, insurance implications, and misinterpretation of results.³ The essential question is always: would a positive result change what I do? Usually it would not.

Reasonable indications to consider testing

• Unprovoked VTE in a young patient (typically under 45)
• Thrombosis at unusual sites - cerebral venous sinus, hepatic (Budd-Chiari), portal or mesenteric veins
• Recurrent VTE, particularly while anticoagulated
• Strong family history of VTE in first-degree relatives at a young age
• Recurrent pregnancy loss or unexplained late fetal loss - specifically to test for APS, where a positive result definitively changes pregnancy management
• Arterial thrombosis in a young patient without conventional risk factors - again, principally looking for APS
• Warfarin-induced skin necrosis or apparent heparin resistance

When not to test

• After a clearly provoked VTE (e.g. following surgery) - the provoking factor explains the event
• During an acute thrombotic event or while on anticoagulation - acute thrombosis consumes protein C, protein S and antithrombin, warfarin lowers proteins C and S, and DOACs interfere with lupus anticoagulant assays, all producing misleading results. Testing should be deferred, typically until several weeks after stopping anticoagulation
• Routine screening before starting the combined oral contraceptive pill - not recommended, even with a family history, as the number needed to test to prevent one event is prohibitive
• In asymptomatic relatives as a general rule, since a positive result rarely justifies prophylactic anticoagulation and carries psychological and insurance consequences

Management

• Treat the thrombotic event as you would in any patient - anticoagulation according to standard VTE protocols
• Duration of anticoagulation determined by provoked versus unprovoked status, site, recurrence and bleeding risk. Patients with antithrombin deficiency, homozygous factor V Leiden, or triple-positive APS are among the few in whom the thrombophilia itself may tip the balance towards indefinite treatment
• Antiphospholipid syndrome: warfarin is the anticoagulant of choice, with a target INR of 2-3 for venous events (higher, or with added aspirin, for arterial events by specialist advice). DOACs are not recommended, particularly in triple-positive or arterial disease, following trials showing higher rates of recurrent thrombosis than with warfarin²
• APS in pregnancy: low-dose aspirin plus low molecular weight heparin substantially improves live birth rates; warfarin is teratogenic and contraindicated in the first trimester
• Situational prophylaxis - patients with known thrombophilia should receive careful VTE prophylaxis around surgery, immobility, pregnancy and long-haul travel, which is often the most valuable practical output of knowing the diagnosis
• Counselling - advise against oestrogen-containing contraception and HRT where the risk is significant, and discuss pregnancy planning in advance
• Asymptomatic carriers do not generally receive long-term anticoagulation - the bleeding risk outweighs the benefit

Red flags

Prognosis

The majority of people with an inherited thrombophilia never develop a thrombosis, and heterozygous factor V Leiden - by far the commonest - confers only a modest absolute risk increase. Prognosis is therefore driven far more by the clinical context (provoked versus unprovoked event, recurrence, comorbidity) than by the genetic result itself.¹

Antithrombin deficiency and homozygous or combined defects carry meaningfully higher risk and more often justify long-term anticoagulation. Antiphospholipid syndrome carries the highest morbidity of the group, with a significant rate of recurrent thrombosis if anticoagulation is stopped or if a DOAC is used inappropriately - but with well-managed warfarin, and with aspirin plus LMWH in pregnancy, most patients do well and live birth rates improve substantially.