Antiphospholipid syndrome

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Antiphospholipid syndrome is an acquired autoimmune thrombophilia. Clinical manifestations include objectively confirmed venous, arterial or small-vessel thrombosis and defined pregnancy morbidity. Laboratory evidence comprises lupus anticoagulant, medium or high clinically relevant anticardiolipin, or anti-beta2-glycoprotein I antibodies that remain positive at least 12 weeks apart. Classification criteria support consistent research cohorts and diagnostic reasoning, but a clinician must still exclude transient positivity and competing explanations.

Antibody profile modifies risk. Lupus anticoagulant and persistent triple positivity confer greater recurrence risk than an isolated low-titre antibody. Acute infection can cause transient anticardiolipin; anticoagulants interfere particularly with lupus-anticoagulant assays. Whenever possible, the coagulation laboratory plans sampling before anticoagulation or uses drug-aware methods. Treatment of an acute thrombosis must never be delayed for ideal antibody timing; store appropriate samples and repeat later.

After thrombotic APS, anticoagulation is usually long term because the persistent autoimmune driver remains. For a first venous event, heparin followed by warfarin with INR 2.0–3.0 is standard. Triple-positive APS should not receive a DOAC under NICE guidance. Arterial thrombosis, recurrence despite objectively therapeutic INR, thrombocytopenia and bleeding require expert review of adherence, INR time in range, higher target, aspirin addition or LMWH rather than automatic escalation.

Obstetric APS is managed through a preconception and maternal-fetal plan. Aspirin and LMWH improve outcomes for appropriate pregnancy histories, but dose depends on prior thrombosis, weight, renal function and bleeding. Warfarin is generally avoided during pregnancy and resumed postpartum when suitable. Catastrophic APS is distinct: rapidly progressive multiorgan thrombosis requires anticoagulation, corticosteroid and plasma exchange or IVIG plus trigger control, often in critical care.

Key points

APS requires a compatible clinical event plus persistent antiphospholipid antibodies; a positive test alone is not the syndrome and should not automatically trigger anticoagulation.
First-line laboratory panel is lupus anticoagulant, anticardiolipin IgG and IgM and anti-beta2-glycoprotein I IgG and IgM, chosen because risk and classification differ across isolated and triple-positive profiles.
Confirm persistence by repeating the positive test at least 12 weeks later; acute thrombosis, inflammation and anticoagulants can distort results, especially lupus anticoagulant testing.
For confirmed APS after venous thrombosis, a vitamin K antagonist with usual INR target 2.0–3.0 is the standard long-term pathway after initial heparin treatment, individualised for recurrence and bleeding.
Do not offer a DOAC to a person with triple-positive APS under NICE VTE guidance; discuss VKA treatment with a specialist because arterial and recurrent thrombosis need tailored intensity or added antiplatelet therapy.
For obstetric APS without prior thrombosis, low-dose aspirin and prophylactic LMWH are commonly used from early pregnancy under maternal-fetal and haematology plans; prior thrombosis usually requires therapeutic LMWH.
Catastrophic APS is rapid multiorgan small-vessel thrombosis: treat the trigger and use therapeutic heparin, high-dose corticosteroid and plasma exchange or IV immunoglobulin through an expert multidisciplinary pathway.
Reduce modifiable thrombosis risk, avoid oestrogen-containing contraception when inappropriate, plan pregnancy before VKA exposure, and provide explicit perioperative anticoagulation and bridging instructions.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Primary autoimmunity

Persistent pathogenic antibodies can occur without another defined autoimmune disease and interact with phospholipid-binding proteins, endothelium, platelets and complement.

Systemic lupus association

APS commonly accompanies SLE and other autoimmune disease, requiring parallel control of inflammation, cardiovascular risk and organ-specific damage.

Second-hit triggers

Infection, surgery, pregnancy, oestrogen, immobility and interruption of anticoagulation can provide the inflammatory or vascular trigger that converts antibody risk into thrombosis.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Procoagulant cell activation
Anti-beta2-glycoprotein I and related antibodies activate endothelium, monocytes and platelets and increase tissue factor, thrombin generation and adhesion.
2
Complement and placental injury
Complement activation, trophoblast dysfunction and placental thrombosis impair implantation and perfusion, producing loss, growth restriction, pre-eclampsia and prematurity.
3
Laboratory phospholipid interference
Lupus anticoagulant prolongs phospholipid-dependent clotting assays in vitro despite increasing thrombosis risk in vivo, explaining the misleading APTT.
4
Catastrophic amplification
Complement, cytokines, tissue factor and microvascular thrombosis reinforce one another during CAPS, causing multiorgan failure that resembles sepsis, TTP and DIC.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Venous thrombosis

DVT, pulmonary embolism and cerebral, portal, hepatic or retinal venous thrombosis may be initial events, often at a young age or unusual site.

Arterial thrombosis

Ischaemic stroke, transient ischaemic attack, myocardial infarction or limb ischaemia without proportionate atherosclerosis should prompt selective APS assessment.

Pregnancy phenotype

Recurrent early miscarriage, fetal death, severe pre-eclampsia, placental insufficiency or premature delivery can satisfy clinical criteria when alternatives are assessed.

Non-criteria clues

Livedo reticularis, thrombocytopenia, valve thickening, migraine, seizures and nephropathy support suspicion but do not establish APS alone.

Catastrophic tempoRed flag

Kidney, lung, brain, skin or adrenal dysfunction developing together over days demands immediate CAPS, sepsis, TTP and DIC evaluation.

Red flags requiring action

New hypoxaemia, kidney injury, encephalopathy, livedoid necrosis, adrenal failure or myocardial injury developing across several systems over less than a week suggests catastrophic APS rather than isolated VTE.
Pregnancy hypertension, placental insufficiency, fetal growth restriction or recurrent loss in an antibody-positive patient requires coordinated maternal-fetal and haematology assessment rather than aspirin prescribed without a plan.
A prolonged APTT caused by lupus anticoagulant does not protect against clotting and can make APTT-based unfractionated-heparin monitoring unreliable.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
First-line: complete antiphospholipid antibody panelFirst stepFirst line
Why
Identify lupus anticoagulant, anticardiolipin and anti-beta2-glycoprotein I positivity and define risk profile.
Interpretation and limitations
Order all three laboratory domains after a qualifying phenotype. Isolated low-titre results are less specific; anticoagulants may invalidate lupus-anticoagulant interpretation.
02
Confirmatory repeat after at least 12 weeksConfirmatory
Why
Distinguish persistent autoimmune positivity from transient infection- or illness-related antibodies.
Interpretation and limitations
Repeat the same positive domain no sooner than 12 weeks, ideally with the laboratory managing anticoagulant interference. A single positive test does not confirm APS.
03
Objective event confirmation
Why
Document that the clinical criterion is a true thrombosis or defined pregnancy complication.
Interpretation and limitations
Use compression ultrasound, CTPA, arterial or organ imaging, histology without major vessel-wall inflammation, and obstetric records appropriate to the event.
04
Baseline treatment and mimic screen
Why
Assess bleeding, organ function and alternative systemic disease before long-term anticoagulation.
Interpretation and limitations
Check FBC, film, renal and liver tests, PT, APTT, urinalysis and SLE-directed testing. Fragmentation, low fibrinogen or sepsis may indicate TTP, HELLP or DIC.
05
CAPS organ mapping
Why
Identify simultaneous thrombosis and dysfunction that needs critical-care and specialty support.
Interpretation and limitations
Use serial FBC, haemolysis, coagulation, troponin, renal and liver markers, cultures and targeted brain, chest, abdominal, cardiac and vascular imaging without delaying treatment.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Transient antibody positivity

Infection and medicines may produce short-lived or low-titre antibodies; persistence on a separate sample at least 12 weeks later is essential.

Inherited thrombophilia

Factor V Leiden, prothrombin variants and natural-anticoagulant deficiencies mainly predispose to venous thrombosis and do not explain lupus-anticoagulant assay patterns or pregnancy criteria.

Thrombotic microangiopathy

TTP, complement-mediated HUS, severe hypertension and HELLP cause thrombocytopenia and organ injury; film, ADAMTS13, pregnancy and renal phenotype guide urgent separation.

Disseminated intravascular coagulation

Sepsis or malignancy with consumption, low fibrinogen and markedly abnormal PT suggests DIC, which may coexist with catastrophic APS and requires cause control.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Suspected thrombotic APSTreat clot and prove persistenceFirst stepObjective venous, arterial or small-vessel thrombosis occurs with autoimmune clues, young age, unusual site or recurrence.

1Treat the acute event immediately and obtain a full antiphospholipid panel before anticoagulation when feasible without delay.
2Review infection, cancer, SLE, cardiovascular risks, medicines and hereditary factors, and arrange repeat positive antibodies after at least 12 weeks.
3If clinical and persistent laboratory criteria coexist, choose long-term VKA intensity and follow-up through haematology or rheumatology.

02Venous APSUse durable VKA anticoagulationAPS is confirmed after DVT, pulmonary embolism or other venous thrombosis.

1Begin therapeutic LMWH or UFH for the acute event and transition to warfarin with overlap until the INR is therapeutic.
2Use a usual INR target of 2.0–3.0 and do not substitute a DOAC in triple-positive disease; record duration as generally long term with periodic benefit review.
3For recurrence, confirm a new event and assess adherence and time in range before specialist-directed higher intensity, aspirin addition or LMWH.

03Obstetric APSPlan aspirin and heparin before pregnancyPersistent antibodies coexist with qualifying pregnancy morbidity, with or without previous thrombosis.

1Provide preconception counselling on VKA transition, folate, cardiovascular risks and a written maternal-fetal and haematology plan.
2Use low-dose aspirin plus prophylactic LMWH for appropriate obstetric APS, or therapeutic LMWH when prior thrombosis requires full anticoagulation.
3Plan neuraxial timing, delivery, postpartum haemorrhage response and at least the indicated postpartum thromboprophylaxis or resumption of lifelong VKA.

04Possible CAPSStart combined treatment earlyThree or more organs develop thrombotic dysfunction within approximately one week, often after infection, surgery or anticoagulation interruption.

1Admit to critical care, treat infection or other trigger and obtain biopsy or imaging evidence where safe without postponing therapy.
2Start therapeutic heparin when bleeding permits and high-dose corticosteroid, then arrange plasma exchange or IVIG with the expert team.
3Add disease-specific treatment for SLE or refractory CAPS and monitor every organ for progression, haemorrhage and treatment complications.

Key medicines and prescribing safety4 treatments · regimens, roles and cautions

Provides durable secondary prevention for confirmed thrombotic APS, including high-risk triple-positive disease where DOAC treatment is inappropriate.

Warfarin after venous thrombotic APS

Start with therapeutic heparin overlap and individualise oral warfarin to an INR target of 2.0–3.0 for a first venous APS event; continue long term unless specialist reassessment identifies a compelling reason to stop or change strategy.

Check interactions, diet, alcohol, adherence and time in range. Warfarin is teratogenic and pregnancy requires advance LMWH transition; major bleeding needs PCC plus intravenous vitamin K and a restart plan.

Reduces placental and maternal thrombotic risk in obstetric APS without a previous indication for full-dose anticoagulation.

Low-dose aspirin with prophylactic enoxaparin for obstetric APS

Use aspirin 75–150 mg orally once daily and, when the obstetric APS plan indicates, enoxaparin 40 mg subcutaneously once daily from the specialist-defined early-pregnancy point, adjusted for weight, renal function and thrombosis history.

This is not a universal regimen for antibody positivity alone. Coordinate bleeding, placenta, renal function, extremes of weight, neuraxial anaesthesia and delivery timing; prior thrombosis commonly requires therapeutic LMWH instead.

Treats acute thrombosis, provides pregnancy-safe anticoagulation and can replace VKA after recurrence or when oral therapy is unsuitable.

Therapeutic enoxaparin

Give 1 mg/kg subcutaneously every 12 hours for acute VTE or pregnancy requiring full anticoagulation, using actual body weight and a renal, anti-Xa and peripartum plan from the specialist service.

Adjust or use UFH in severe renal impairment, monitor platelets for HIT context, and plan interruption before neuraxial procedures and delivery. Avoid casual anti-Xa targets outside validated groups.

Interrupts the thrombo-inflammatory and antibody-mediated amplification of catastrophic APS.

CAPS combined immunomodulation

Give intravenous methylprednisolone 500–1,000 mg once daily for 3 days followed by an individualised corticosteroid course, plus daily plasma exchange or IV immunoglobulin 0.4 g/kg daily for 5 days, alongside therapeutic heparin and trigger treatment under expert direction.

Regimens depend on infection, bleeding, kidney and cardiac function. Plasma exchange alters drug and antibody levels; IVIG can cause thrombosis or kidney injury, and high-dose steroid markedly increases infection and glucose risk.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Recurrent thrombosis

Venous, arterial and small-vessel events can recur, particularly with triple-positive antibodies, poor VKA control, smoking or interrupted anticoagulation.

Pregnancy morbidity

Recurrent early loss, fetal death, placental insufficiency, pre-eclampsia, growth restriction and premature birth can occur despite no previous maternal thrombosis.

Chronic organ damage

Cognitive dysfunction, epilepsy, valvular disease, livedo, kidney microangiopathy, pulmonary hypertension and adrenal injury may follow repeated vascular events.

Anticoagulant harm

Major bleeding, pregnancy exposure, interactions and unstable INR complicate lifelong therapy, while inappropriate DOAC use may increase recurrent events in high-risk APS.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

For warfarin, monitor INR and time in therapeutic range, bleeding, recurrent vascular symptoms, interactions, adherence and plans for procedures or pregnancy.
Do not repeat antiphospholipid antibodies as a routine measure of treatment response once persistent APS is established; clinical events and anticoagulant quality guide care.
In pregnancy, monitor maternal blood pressure, urine protein, platelets, renal function, fetal growth and placental function with documented LMWH and delivery timing.
After any recurrence, obtain objective imaging and review whether INR was therapeutic, doses were missed or provoking factors occurred before intensifying anticoagulation.
During CAPS, use daily or more frequent multiorgan, coagulation, haemolysis and infection assessment and coordinate thrombosis and bleeding decisions across the multidisciplinary team.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Antibody is not syndrome

Persistent laboratory positivity needs a qualifying clinical event; many transient or incidental positives never justify lifelong anticoagulation.

Twelve weeks prevents overdiagnosis

The minimum interval separates durable autoimmune positivity from antibodies generated transiently during infection, inflammation or pregnancy.

APTT can point backwards

Lupus anticoagulant may prolong a clotting assay while conferring thrombosis rather than bleeding risk in the patient.

Confirm recurrence before escalation

Post-thrombotic symptoms and imaging residue can mimic a new clot; higher-intensity anticoagulation adds substantial bleeding risk.

CAPS needs combination treatment

Anticoagulation alone does not suppress the inflammatory and antibody components of rapid multiorgan microvascular thrombosis.

11Common pitfallsFrequent interpretation and management errors.

01
Diagnosing APS from one positive antibody result.
02
Ordering lupus anticoagulant without recording anticoagulant exposure.
03
Withholding anticoagulation because APTT is prolonged.
04
Using a DOAC routinely in triple-positive APS.
05
Escalating warfarin intensity without confirming recurrent thrombosis.
06
Treating antibody positivity alone during pregnancy without specialist criteria.