Blood & Lymphoreticular

Antiphospholipid syndrome: diagnosis and anticoagulation

Clinical Overview and When to Suspect Antiphospholipid Syndrome

— Prevalence ~50/100,000; female-to-male ratio ~3.5:1 in secondary APS

— Primary APS (no underlying disease) or secondary (most commonly SLE, ~30–40% of SLE patients carry aPL, ~10–15% develop APS)

— Unprovoked VTE in patient <50 or recurrent VTE despite anticoagulation

— Arterial thrombosis in a young patient (stroke, MI, digital ischemia) without atherosclerotic risk factors

— Thrombosis at unusual sites: hepatic vein (Budd-Chiari), portal, renal, cerebral venous sinus

— Recurrent pregnancy loss (≥3 consecutive losses <10 wks, or ≥1 fetal death ≥10 wks, or premature delivery <34 wks for preeclampsia/placental insufficiency)

— Unexplained prolonged aPTT that does not correct on mixing study

— Thrombocytopenia (mild, 100–140k) or hemolytic anemia + thrombosis

— Livedo reticularis, cardiac valve vegetations (Libman-Sacks), nephropathy

Board pearl: Any young patient with stroke + miscarriage history + low platelets should trigger an aPL workup before chalking it up to cryptogenic stroke. Step 3 loves the patient on warfarin for "recurrent DVT" whose INR is therapeutic but who clots anyway — that's APS until proven otherwise, and the answer is rarely a DOAC.

Definition: Antiphospholipid syndrome (APS) is an autoimmune thrombophilia defined by persistent antiphospholipid antibodies (aPL) plus a clinical event — venous, arterial, or microvascular thrombosis, or characteristic pregnancy morbidity.

Epidemiology:

When to suspect on Step 3 stems:

Pathophysiology (high-yield): aPL bind β2-glycoprotein I on endothelium, platelets, monocytes → complement activation, tissue factor expression, impaired fibrinolysis, "two-hit" model where infection/surgery triggers thrombosis.

Catastrophic APS (CAPS): <1% of APS; multi-organ small-vessel thrombosis over days, mortality ~30–50%.

Presentation Patterns and Key History

— Lower extremity DVT and PE dominate

— Recurrent VTE despite anticoagulation is a red flag

— Atypical sites: cerebral sinus, splanchnic, renal vein, adrenal vein (→ adrenal hemorrhage/insufficiency)

— Stroke and TIA are the most common arterial events, often in patients <50 with no atherosclerotic risk

— MI in young women, digital gangrene, mesenteric ischemia, retinal artery occlusion (sudden monocular vision loss)

— ≥3 consecutive unexplained miscarriages <10 weeks

— ≥1 fetal death ≥10 weeks with morphologically normal fetus

— Premature birth <34 weeks due to eclampsia, severe preeclampsia, or placental insufficiency

— HELLP syndrome, intrauterine growth restriction

— Livedo reticularis and livedo racemosa (broken, irregular pattern)

— APS nephropathy (thrombotic microangiopathy, HTN, proteinuria)

— Cognitive dysfunction, chorea, transverse myelitis

— Libman-Sacks endocarditis — sterile valvular vegetations, often mitral

— Thrombocytopenia (usually 50–140k; severe is uncommon)

— Coombs-positive hemolytic anemia

— Prior unexplained prolonged aPTT (e.g., found preoperatively)

— Drug-induced lupus or SLE features (malar rash, arthritis, serositis)

— Family history is not typical — APS is acquired, not heritable

— Recent infection, surgery, OCP use, pregnancy, or immobilization as "second hit"

Key distinction: Heritable thrombophilias (Factor V Leiden, prothrombin G20210A) cause venous events almost exclusively. Arterial thrombosis + venous thrombosis in the same patient strongly suggests APS, not an inherited disorder. Recurrent first-trimester losses also point toward APS rather than chromosomal causes (which usually cause sporadic loss).

Venous thrombosis (most common, ~60%):

Arterial thrombosis (~30%):

Obstetric APS:

Microvascular/"non-criteria" manifestations:

History clues to mine:

Catastrophic APS history: rapid (<1 week) onset of ≥3 organ thromboses, often triggered by infection, surgery, anticoagulation withdrawal, or malignancy.

Physical Exam Findings and Hemodynamic Assessment

— Livedo reticularis — lacy violaceous mottling, often on thighs/trunk; livedo racemosa (broken, irregular) more specific for APS

— Digital cyanosis, splinter hemorrhages, cutaneous ulcers, gangrene

— Superficial thrombophlebitis

— New murmur from Libman-Sacks vegetations (mitral > aortic regurgitation)

— Signs of pulmonary hypertension from chronic thromboembolic disease (loud P2, RV heave)

— Hypertension (renal involvement) — check for malignant features

— Focal deficits from stroke/TIA

— Cognitive impairment, chorea, seizures

— Visual loss from retinal artery/vein occlusion — perform fundoscopy

— Pleuritic chest pain, hypoxia, tachypnea (PE)

— Diffuse alveolar hemorrhage in CAPS

— RUQ tenderness, hepatomegaly, ascites (Budd-Chiari)

— Flank pain (renal vein thrombosis, adrenal infarction)

— Peritoneal signs (mesenteric ischemia)

— Fundal height < dates (IUGR)

— Severe HTN, proteinuria, brisk reflexes (preeclampsia)

— Vitals: hypotension, tachycardia, hypoxia

— End-organ perfusion: mental status, urine output, lactate

— Look for multi-organ involvement: AKI, transaminitis, encephalopathy, ARDS, distal ischemia simultaneously

CCS pearl: On the CCS case of a young woman with sudden stroke, examine the skin (livedo), heart (murmur), and obstetric history before ordering imaging. Documenting livedo + new mitral regurgitation + miscarriage history shifts your differential and your orders (aPL panel, echo, hypercoagulable workup) much earlier than a generic cryptogenic stroke pathway, and the case scoring rewards directed, hypothesis-driven exam and orders.

Skin:

Cardiovascular:

Neurologic:

Pulmonary:

Abdominal:

Obstetric exam:

Hemodynamic assessment in suspected CAPS:

Diagnostic Workup — Initial Labs and Imaging

— Mild thrombocytopenia (100–140k) in ~30%

— Schistocytes if microangiopathic hemolysis (CAPS, APS nephropathy)

— Coombs-positive hemolytic anemia possible

— Prolonged aPTT that does NOT correct with 1:1 mixing study — classic clue suggesting a lupus anticoagulant (paradoxical name: causes thrombosis in vivo, prolongs clotting in vitro)

— PT usually normal; INR may be unreliable in patients with strong LA — use chromogenic factor X for warfarin monitoring if LA interferes

— dRVVT (dilute Russell viper venom time) is the preferred screening assay for lupus anticoagulant

— Creatinine (APS nephropathy, renal vein thrombosis)

— LFTs (Budd-Chiari)

— LDH, haptoglobin, bilirubin if hemolysis suspected

— Duplex ultrasound for suspected DVT

— CT pulmonary angiography for PE

— MRI brain for stroke/TIA; MRV for cerebral sinus thrombosis

— Doppler abdominal US for Budd-Chiari, renal vein thrombosis

— Transthoracic echocardiogram — valve vegetations, pulmonary HTN, intracardiac thrombus; TEE if TTE unrevealing and suspicion remains

Step 3 management: When you find a prolonged aPTT that fails to correct on mixing, do not give FFP or hold anticoagulation reflexively. Send lupus anticoagulant testing, anticardiolipin IgG/IgM, and anti-β2-glycoprotein I IgG/IgM — and repeat in 12 weeks to confirm persistence. A single positive titer does not diagnose APS; transient aPL appear after infections and drugs.

CBC and smear:

Coagulation panel:

Comprehensive metabolic panel:

Urinalysis: proteinuria, hematuria, casts in APS nephropathy

Pregnancy test in any reproductive-age woman before imaging/anticoagulation decisions

Imaging based on presentation:

ECG: look for RV strain (PE), ischemia (coronary thrombosis), AF (cardioembolic source competing differential)

Diagnostic Workup — Confirmatory Antibody Testing

— At least one clinical criterion (macrovascular venous/arterial thrombosis, microvascular, obstetric, cardiac valve, hematologic) AND

— Laboratory criterion: positive aPL test on two occasions ≥12 weeks apart

— Lupus anticoagulant (LA) — functional clotting assay; most specific for thrombosis

— Anticardiolipin (aCL) IgG or IgM — medium-to-high titer (>40 GPL/MPL or >99th percentile)

— Anti-β2-glycoprotein I (anti-β2GPI) IgG or IgM — >99th percentile

— Anticoagulants interfere: heparin (use heparin-neutralized assays), warfarin (false positive LA), DOACs (false positive especially with rivaroxaban)

— Ideally draw LA before starting anticoagulation or after a washout

— Acute thrombosis and acute-phase response can cause transient positives → repeat at 12 weeks

— ANA, dsDNA, complement (C3/C4), anti-Smith — SLE evaluation

— HIV, syphilis (RPR false positive classic), hepatitis serologies

— Drug history: procainamide, hydralazine, phenytoin, chlorpromazine

Board pearl: A false-positive RPR/VDRL in a young woman with miscarriages is a classic Step 3 hook — order lupus anticoagulant, aCL, and anti-β2GPI. Confirmation requires persistence at 12 weeks; one positive titer in the setting of acute thrombosis can be transient and is not diagnostic.

2023 ACR/EULAR APS classification criteria require:

The three "criteria" antibodies:

Triple positivity (LA + aCL + anti-β2GPI, same isotype) confers highest thrombosis risk and is the key driver for avoiding DOACs.

Pitfalls in lupus anticoagulant testing:

Non-criteria antibodies (supportive but not diagnostic): anti-phosphatidylserine/prothrombin (aPS/PT), IgA isotypes — useful when criteria antibodies are negative but suspicion is high ("seronegative APS").

Workup for secondary causes:

Risk stratification labs: complete aPL profile to determine triple vs single positivity guides therapy intensity and DOAC suitability.

Risk Stratification and First-Line Management Logic

— High-risk profile: triple positivity, persistently high titers, or isolated LA positivity

— Low-risk profile: isolated aCL or anti-β2GPI at low-medium titers, transient positivity

— Prior arterial event (higher rethrombosis risk than venous)

— Concomitant SLE

— Cardiovascular risk factors (HTN, smoking, hyperlipidemia, obesity)

— Pregnancy, OCP use, recent surgery (transient triggers)

— aPL positive, no thrombosis, no pregnancy morbidity ("incidental"): generally no anticoagulation; low-dose aspirin (81 mg) is reasonable if high-risk profile or SLE, though evidence is modest. Address modifiable CV risk factors aggressively. Avoid estrogen-containing OCPs.

— Definite APS with venous thrombosis: warfarin INR 2–3 indefinitely

— Definite APS with arterial thrombosis: warfarin INR 2–3 (some experts INR 2.5–3.5 or warfarin + low-dose aspirin); indefinite

— Rivaroxaban is inferior to warfarin in triple-positive APS (TRAPS, RAPS trials showed excess arterial events)

— Current guidance: avoid DOACs in triple-positive APS and in any patient with prior arterial events; warfarin remains standard

— DOACs may be considered only in selected single-positive venous-only APS who cannot tolerate warfarin

Step 3 management: A patient with triple-positive APS and prior DVT currently on rivaroxaban is a setup — the answer is switch to warfarin with heparin bridge, not "continue current therapy." Step 3 rewards recognizing DOAC failures in APS.

Risk stratification by antibody profile:

Clinical risk modifiers:

Three management buckets:

Provoked vs unprovoked: Unlike most VTE, APS thrombosis is treated as lifelong regardless of provoking factor because of high recurrence (~10%/year off anticoagulation).

DOAC caveat (critical):

Bridging: when initiating warfarin, overlap with LMWH or UFH for ≥5 days AND until INR ≥2 for 24 hours.

Pharmacotherapy — First-Line Anticoagulation Regimens

— LMWH (enoxaparin 1 mg/kg SC q12h) or UFH infusion (aPTT-guided; unreliable in LA-positive patients — use anti-Xa monitoring)

— Fondaparinux is an alternative if HIT history

— Start warfarin concurrently unless contraindicated; overlap ≥5 days AND INR ≥2 × 24 hours before stopping parenteral agent

— Warfarin INR target 2.0–3.0 for venous APS

— Warfarin INR 2.0–3.0 (preferred) or 2.5–3.5 for arterial APS, depending on recurrence risk; alternative is INR 2–3 plus low-dose aspirin

— Indefinite duration

— Strong LA can falsely elevate INR readings (point-of-care worse than lab)

— Use chromogenic factor X level (target 20–40%) or two-tube PT comparison when LA interferes

— Avoid in: triple-positive APS, any arterial thrombosis history, recurrent thrombosis on warfarin, mechanical valves

— Rivaroxaban specifically has the most negative trial data

— Low-dose aspirin for arterial APS in addition to warfarin in selected high-risk patients

— Aspirin alone is insufficient after a confirmed APS thrombotic event

— Confirm adherence and true INR (rule out LA interference)

— Options: increase INR target to 3.0–4.0, add low-dose aspirin, add hydroxychloroquine (especially if SLE), or switch to LMWH long-term

Board pearl: In APS, DOACs are not interchangeable with warfarin. The default Step 3 answer for "best long-term anticoagulant in APS" is warfarin, with LMWH as the answer in pregnancy and as a fallback when warfarin fails or is contraindicated.

Acute thrombosis (initial therapy):

Long-term oral anticoagulation:

INR monitoring caveat:

DOACs — when not to use:

Adjunctive antiplatelet therapy:

Recurrent thrombosis on therapeutic warfarin:

Hydroxychloroquine: reduces thrombosis risk in SLE-associated APS and is recommended adjunctively.

Statin therapy: reasonable in APS with dyslipidemia or arterial disease — pleiotropic anti-thrombotic effects.

Catastrophic APS and Expanded Pharmacology

— Therapeutic anticoagulation — IV heparin infusion

— High-dose corticosteroids — methylprednisolone 1 g IV × 3 days then prednisone 1 mg/kg

— Plasma exchange (TPE) and/or IVIG — TPE preferred if microangiopathic hemolysis; IVIG if infection-driven

— Rituximab (anti-CD20) — especially if hematologic features or refractory disease

— Eculizumab (anti-C5) — emerging role, particularly in TMA-predominant CAPS

— Cyclophosphamide if associated SLE flare

— Low-dose aspirin: primary prevention in high-risk aPL carriers (especially SLE), and adjunct in arterial APS

— Clopidogrel: used after coronary stenting in APS; balance bleeding risk with warfarin (triple therapy short-course, then dual)

CCS pearl: In a CAPS case, the winning order set is heparin drip + IV methylprednisolone + plasmapheresis consult + ICU admission + cultures and empiric antibiotics, all within the first hour. Delaying any one of the triple-therapy components is the most common scoring loss on CCS for this presentation.

Catastrophic APS (CAPS): rapid multi-organ thrombosis (≥3 organs in <1 week) with histopathologic evidence of small-vessel occlusion and aPL positivity. Mortality 30–50%.

CAPS triggers: infection (most common), surgery, anticoagulation withdrawal, malignancy, lupus flare, pregnancy/postpartum.

CAPS triple therapy (first-line):

Refractory CAPS:

Treat the trigger: broad-spectrum antibiotics for suspected infection, source control, hold offending drugs.

Supportive ICU care: mechanical ventilation, RRT, vasopressors as needed; manage adrenal insufficiency from bilateral adrenal hemorrhage with stress-dose hydrocortisone.

Antiplatelets in APS:

Statins: atorvastatin 20–40 mg or rosuvastatin in arterial APS, regardless of LDL, for plaque stabilization and endothelial effects.

Hydroxychloroquine 200–400 mg/day: thrombosis reduction, especially in secondary APS with SLE; baseline and annual ophthalmologic exams.

Avoid: estrogen-containing contraceptives, hormone replacement therapy, smoking, prolonged immobilization without prophylaxis.

Special Populations — Elderly and Renal/Hepatic Impairment

— Higher baseline bleeding risk on warfarin — HAS-BLED, falls assessment, polypharmacy review

— Frequent drug interactions: amiodarone, antibiotics (TMP-SMX, fluoroquinolones, metronidazole), NSAIDs all potentiate warfarin

— Goal INR 2–3 still applies; do not lower target for age alone

— Late-onset APS (>50 years) more often associated with malignancy — screen age-appropriate cancers

— Warfarin preferred — hepatically metabolized, dose unaffected by CrCl

— LMWH (enoxaparin): reduce to 1 mg/kg SC daily if CrCl <30; consider anti-Xa monitoring

— UFH preferred for AKI/dialysis (renal-independent clearance)

— Avoid DOACs in APS anyway, but note dabigatran, rivaroxaban, apixaban have CrCl thresholds

— APS nephropathy: control BP (ACEi/ARB), avoid nephrotoxins, monitor proteinuria

— Baseline elevated INR confounds warfarin monitoring — use chromogenic factor X

— Coagulopathy of liver disease does NOT protect against APS thrombosis — anticoagulate as indicated

— LMWH with anti-Xa monitoring is alternative

— Budd-Chiari is a classic APS presentation — anticoagulate aggressively, evaluate for TIPS if decompensated

— Mild (100–140k): no dose adjustment, anticoagulate as indicated

— Moderate (50–100k): individualize, often still anticoagulate with close monitoring

— Severe (<50k): hold anticoagulation, evaluate for ITP, TTP, DIC, HIT; consider IVIG/steroids if APS-related immune thrombocytopenia

— Bridge warfarin with LMWH; minimize gap (high recurrence risk)

— Restart anticoagulation promptly post-op

Step 3 management: In an elderly APS patient starting TMP-SMX for a UTI, anticipate INR rise — check INR within 3–5 days and reduce warfarin dose preemptively by ~25–50%, or choose an alternative antibiotic (nitrofurantoin, cephalexin) when feasible.

Elderly patients:

Renal impairment:

Hepatic impairment:

Thrombocytopenia in APS:

Perioperative management:

Special Populations — Pregnancy and Obstetric APS

— ≥3 consecutive unexplained miscarriages <10 weeks OR

— ≥1 fetal death ≥10 weeks with normal fetal morphology OR

— Premature birth <34 weeks for severe preeclampsia, eclampsia, or placental insufficiency

— Plus persistent aPL at 12 weeks

— Optimize BP, discontinue teratogens (warfarin is teratogenic — embryopathy weeks 6–12)

— Switch warfarin to LMWH before conception or as soon as pregnancy confirmed

— Continue hydroxychloroquine if SLE

— Obstetric APS, no prior thrombosis: prophylactic LMWH (enoxaparin 40 mg SC daily) + low-dose aspirin 81 mg starting preconception/early pregnancy, continued through 6 weeks postpartum

— Thrombotic APS, pregnant: therapeutic LMWH (1 mg/kg q12h) + low-dose aspirin throughout pregnancy and 6 weeks postpartum

— aPL positive without APS criteria: consider low-dose aspirin alone, especially with SLE

— Switch enoxaparin to UFH near term to allow neuraxial anesthesia

— Hold LMWH 24 h before planned delivery; resume 12–24 h postpartum

— Postpartum: can transition back to warfarin (safe in breastfeeding) for long-term therapy

— Serial growth ultrasounds (IUGR risk), uterine artery Dopplers

— BP, urine protein for preeclampsia

— Anti-Xa levels not routine but useful in obesity or renal disease

Board pearl: Warfarin is contraindicated in pregnancy (especially weeks 6–12) due to embryopathy — nasal hypoplasia, stippled epiphyses. LMWH + low-dose aspirin is the answer for nearly every pregnant APS patient on Step 3. DOACs are also contraindicated in pregnancy.

Diagnosis of obstetric APS requires:

Preconception counseling:

Treatment regimens by scenario:

Peripartum:

Monitoring:

Pediatric APS: rare; presents with stroke, DVT, or chorea. Management mirrors adults but with pediatric rheumatology/hematology comanagement.

Complications and Adverse Outcomes

— ~10%/year off anticoagulation; ~3–5%/year on therapeutic warfarin

— Arterial events carry higher mortality and disability

— Multi-organ failure, ARDS, AKI, encephalopathy, distal ischemia/gangrene

— 30–50% mortality even with optimal therapy

— Libman-Sacks endocarditis — sterile valve vegetations, mitral regurgitation, embolic stroke source

— Premature coronary artery disease

— Chronic thromboembolic pulmonary hypertension (CTEPH)

— Stroke and TIA (often recurrent), vascular dementia

— Chorea, transverse myelitis, optic neuropathy, sensorineural hearing loss

— APS nephropathy — thrombotic microangiopathy, glomerular ischemia, cortical atrophy

— Renal vein thrombosis, renal artery stenosis

— Progressive CKD, hypertension

— Thrombocytopenia (immune-mediated)

— Coombs-positive autoimmune hemolytic anemia (Evans syndrome if combined)

— Schistocytic hemolysis in CAPS/TMA

— Recurrent loss, IUGR, preeclampsia, HELLP, placental abruption, preterm delivery

— Postpartum thrombosis (high-risk window)

— Bilateral adrenal hemorrhage → primary adrenal insufficiency

— Present with abdominal/flank pain, hypotension, hyponatremia, hyperkalemia

— Major bleeding ~2–3%/year on warfarin

— Intracranial hemorrhage is the feared event

— Chronic livedo, leg ulcers, digital gangrene

— Warfarin-induced skin necrosis (rare; protein C/S deficiency overlap)

Key distinction: Libman-Sacks vegetations are sterile, occur in APS and SLE, and embolize. Infective endocarditis has fever, positive cultures, and vegetations on valve leaflets with destruction. Don't reflexively start antibiotics for vegetations in a known APS patient — get blood cultures first.

Recurrent thrombosis:

Catastrophic APS (CAPS):

Cardiac:

Neurologic:

Renal:

Hematologic:

Obstetric:

Adrenal:

Bleeding from anticoagulation:

Skin:

When to Escalate Care — ICU, Consult, and Inpatient Triage

— Catastrophic APS — multi-organ thrombosis, hemodynamic instability

— Massive PE with RV strain or hemodynamic compromise

— Large ischemic or hemorrhagic stroke with airway concerns

— Bilateral adrenal hemorrhage with adrenal crisis

— Diffuse alveolar hemorrhage

— Acute DVT/PE not meeting outpatient criteria (renal failure, hemodynamic borderline, social barriers)

— New stroke for neurologic monitoring and workup

— Severe thrombocytopenia requiring evaluation

— Anticoagulation failure requiring strategy change and bridging

— Stable DVT with adequate social support and reliable follow-up

— Routine warfarin initiation in low-bleeding-risk patients (with bridging)

— Asymptomatic aPL positivity

— Hematology: all new APS diagnoses, treatment failures, thrombocytopenia, CAPS

— Rheumatology: suspected SLE, secondary APS, hydroxychloroquine initiation

— Maternal-fetal medicine: all APS pregnancies — high-risk OB comanagement

— Neurology: stroke, chorea, myelopathy, cognitive complaints

— Nephrology: APS nephropathy, AKI, dialysis access planning

— Cardiology: Libman-Sacks vegetations, CTEPH evaluation, perioperative planning

— Anticoagulation gaps during procedures — minimize

— Hospital-to-home: ensure INR follow-up within 3–5 days

— Specialty handoffs: confirm aPL panel results, persistence at 12 weeks, antibody profile communicated

CCS pearl: In a CAPS case, escalate to ICU simultaneously with starting therapy — don't wait for failure of floor-level care. Order heparin drip, IV steroids, plasmapheresis consult, ICU transfer, broad-spectrum antibiotics, and rheumatology/hematology consults in the same orders block to maximize timely scoring.

ICU admission criteria:

Inpatient (non-ICU) admission:

Outpatient management appropriate for:

Consult triggers:

Transitions of care risk points:

Key Differentials — Other Thrombophilias

— Factor V Leiden: most common; activated protein C resistance; venous events almost exclusively; mild risk increase

— Prothrombin G20210A: elevated prothrombin levels; venous risk

— Protein C deficiency: warfarin-induced skin necrosis classic; venous events

— Protein S deficiency: similar to protein C

— Antithrombin deficiency: heparin resistance (low aPTT response despite high doses); severe venous thrombosis

— Inherited disorders: family history positive, venous events predominate, no pregnancy loss pattern (sporadic if any), normal aPTT

— APS: arterial AND venous events, miscarriages, prolonged aPTT not correcting, false-positive RPR, thrombocytopenia

— Thrombocytopenia 5–14 days after heparin exposure, paradoxical thrombosis

— 4T score, anti-PF4 antibodies, serotonin release assay

— Treatment: stop all heparin, start argatroban or bivalirudin; avoid warfarin until platelets >150k

— Coombs-negative hemolysis, pancytopenia, thrombosis at unusual sites (hepatic veins — overlap with APS)

— Flow cytometry for CD55/CD59 deficiency

— Treatment: eculizumab

— MAHA + thrombocytopenia + neurologic/renal involvement + fever

— ADAMTS13 <10% in TTP

— Plasma exchange is treatment

— Can mimic CAPS — distinguish by ADAMTS13 and aPL profile

— JAK2-positive polycythemia vera, essential thrombocythemia

— Splanchnic thrombosis especially

Key distinction: Recurrent first-trimester losses + arterial thrombosis + low platelets → APS. Recurrent DVT only with strong family history → inherited thrombophilia. Thrombocytopenia after heparin → HIT, not APS. Order the workup that matches the pattern.

Inherited thrombophilias:

How to distinguish from APS:

HIT (heparin-induced thrombocytopenia):

PNH (paroxysmal nocturnal hemoglobinuria):

TTP/HUS:

Myeloproliferative neoplasms:

Key Differentials — Other-Category Mimics

— ANCA-associated vasculitis (GPA, MPA, EGPA): pulmonary-renal syndrome, palpable purpura, mononeuritis multiplex; ANCA positive

— Behçet disease: recurrent oral/genital ulcers, uveitis, venous thrombosis (often refractory to anticoagulation alone — needs immunosuppression)

— Takayasu and giant cell arteritis: large-vessel involvement, elevated ESR/CRP

— Young MI/stroke: rule out FH, cocaine, dissection, paradoxical embolus (PFO)

— Atherosclerotic events have plaque on imaging; APS often has clean vessels with in situ thrombus

— Atrial fibrillation, LV thrombus post-MI, valvular vegetations

— TEE essential; consider Libman-Sacks if APS suspected

— PFO with right-to-left shunt; bubble study on echo

— Coexists with APS sometimes — both can be present

— Migratory superficial thrombophlebitis, often pancreatic/GI/lung adenocarcinoma

— Age-appropriate cancer screening in any unprovoked thrombosis, especially older patients

— Treatment: LMWH preferred over warfarin in active cancer

— Loss of antithrombin in urine, hypercoagulability, renal vein thrombosis

— Heavy proteinuria, hypoalbuminemia, edema

— Estrogen states are hypercoagulable; do not require APS to clot

— But APS magnifies risk dramatically — avoid estrogens

— HIT, COVID-19-associated coagulopathy, immune checkpoint inhibitors

Board pearl: A patient with recurrent oral and genital ulcers + venous thrombosis is Behçet, not APS. A patient with migratory thrombophlebitis + weight loss + new diabetes is Trousseau/pancreatic cancer, not APS. Match the syndrome pattern, not just the clot.

Vasculitis:

Atherosclerotic disease:

Cardioembolic stroke:

Paradoxical embolism:

Malignancy-associated thrombosis (Trousseau syndrome):

Nephrotic syndrome:

Pregnancy/OCP/HRT:

Drug-induced:

Secondary Prevention and Long-Term Plan

— Warfarin INR 2–3 for venous APS

— Warfarin INR 2–3 (± aspirin) or 2.5–3.5 for arterial APS

— No fixed stop date — APS thrombosis is treated as lifelong

— Hydroxychloroquine — especially if SLE or refractory disease; thrombosis reduction

— Low-dose aspirin — for arterial APS, asymptomatic high-risk aPL carriers

— Statin — pleiotropic effects; standard if dyslipidemia or arterial disease

— Blood pressure <130/80 (especially with APS nephropathy or diabetes)

— LDL <100 mg/dL (or <70 if ASCVD or arterial APS)

— Smoking cessation — counseling at every visit, pharmacotherapy

— Diabetes optimization — A1c <7%

— Weight management, exercise

— Estrogen-containing contraceptives — use progestin-only, copper IUD, or barrier methods

— Hormone replacement therapy

— Prolonged immobilization without VTE prophylaxis

— NSAIDs (bleeding risk on warfarin) — use acetaminophen

— Annual influenza

— Pneumococcal (PCV20 or PCV15 → PPSV23)

— Hepatitis B, HPV as age-appropriate

— COVID-19 boosters

— Avoid live vaccines if on immunosuppression for SLE

— Warfarin with bridge instructions

— LMWH teach-back if home bridging

— Aspirin if arterial event

— Statin, antihypertensive as indicated

— Hydroxychloroquine if SLE

— Acetaminophen for pain (avoid NSAIDs)

— MedicAlert bracelet

Step 3 management: At discharge from an APS-related DVT admission, the order set must include warfarin + LMWH bridge until INR ≥2 × 24h, INR check in 3–5 days, anticoagulation clinic referral, hematology follow-up in 2–4 weeks, and counseling on estrogen avoidance and NSAID avoidance. Missing the bridge or the early INR check is a common scoring loss.

Indefinite anticoagulation:

Adjunctive therapies:

Cardiovascular risk reduction:

Avoid:

Vaccinations:

Discharge medication checklist after acute APS thrombosis:

Follow-Up, Monitoring, and Counseling

— INR weekly until stable, then every 2–4 weeks; every 4–6 weeks once stable for ≥3 months

— Anticoagulation clinic referral improves time-in-therapeutic-range

— If on LMWH long-term: anti-Xa levels (peak 4 h post-dose, target 0.6–1.0 for therapeutic q12h dosing) in obesity, renal disease, pregnancy

— Repeat aPL profile periodically — some patients become persistently negative (though anticoagulation usually continues if prior thrombosis)

— Annual CBC, BMP, UA, LFTs

— BP and lipids per ASCVD guidelines

— TTE periodically for valve disease progression (every 1–2 years if Libman-Sacks)

— Repeat duplex if symptoms recur — avoid routine surveillance ultrasounds without symptoms

— Rheumatology every 3–6 months

— Hydroxychloroquine retinopathy screening — baseline then annually after 5 years

— Monitor complement, dsDNA, urine protein

— Preconception counseling; switch warfarin to LMWH before conception

— MFM consultation

— Serial growth ultrasounds, uterine artery Doppler

— Recognize bleeding (GI, hematuria, intracranial — sudden severe headache, weakness)

— Recognize recurrent thrombosis (limb swelling, dyspnea, neurologic deficits)

— Drug interactions with warfarin: antibiotics, amiodarone, NSAIDs, herbals (St. John's wort, ginkgo)

— Dietary vitamin K consistency (not avoidance) — leafy greens fine if intake stable

— Alcohol moderation (1 drink/day max)

— Avoid pregnancy on warfarin; reliable non-estrogen contraception

— MedicAlert bracelet, anticoagulation card

Board pearl: Patients on warfarin should keep dietary vitamin K consistent, not avoid it. Sudden dietary changes (starting a kale-heavy diet or stopping greens during illness) destabilize the INR more than the absolute amount of vitamin K consumed.

Anticoagulation monitoring:

Periodic reassessment:

Imaging surveillance:

SLE comanagement:

Pregnancy planning:

Counseling points:

Mental health: chronic disease, miscarriage history — screen for depression, anxiety; refer for counseling and support groups.

Ethical, Legal, and Patient Safety Considerations

— Patients must understand lifelong commitment, bleeding risk (~2–3%/year major bleeding), need for INR monitoring, drug/diet interactions, and pregnancy implications

— Document discussion of alternatives (DOACs) and rationale for warfarin in APS — patients increasingly ask about avoiding monitoring

— Counsel women of childbearing age before pregnancy about teratogenicity of warfarin and need to switch to LMWH

— Address risks of pregnancy with APS and shared decision-making about pursuing pregnancy with high-risk maternal/fetal complications

— Respect reproductive autonomy — do not discourage pregnancy without informed dialogue

— Anticoagulation gaps are the most dangerous moment in an APS patient's care

— Discharge handoff must include: indication for anticoagulation, target INR, last INR, bridge plan, next INR date, prescribing clinician, anticoagulation clinic enrollment

— Perioperative bridging plans should be documented and communicated to surgeon and anesthesia

— Warfarin is a high-alert medication — leading cause of ED visits for adverse drug events in older adults

— Reconcile medications at every visit; flag interactions (TMP-SMX, amiodarone, fluconazole, NSAIDs)

— Pharmacist-led anticoagulation clinics reduce adverse events — refer when available

— Anticoagulation-related bleeding, supratherapeutic INRs, and missed bridging are reportable safety events; root-cause analysis improves systems

— Recurrent strokes/PE may affect work capacity — refer for vocational counseling, FMLA documentation

— Warfarin requires frequent labs — ensure access for patients with transportation, insurance, or language barriers; consider point-of-care home INR if feasible

Step 3 management: When a patient with APS is discharged after a DVT admission on Friday afternoon, arrange Monday INR check and anticoagulation clinic follow-up before discharge — leaving INR follow-up to "schedule when you get home" is the wrong answer and a documented patient-safety failure pattern.

Informed consent for indefinite anticoagulation:

Pregnancy and reproductive ethics:

Transitions of care — high-risk handoffs:

Medication safety:

Patient safety event reporting:

Disability and work:

Equity considerations:

High-Yield Associations and Rapid-Fire Facts

Board pearl: If a Step 3 stem mentions prolonged aPTT preoperatively in an otherwise healthy young woman with a history of miscarriages, the next step is a mixing study and aPL panel, not transfusing FFP or canceling surgery reflexively.

Triad of suspicion: arterial + venous thrombosis + pregnancy loss = APS until proven otherwise

Lupus anticoagulant paradox: prolongs aPTT in vitro, causes thrombosis in vivo

Mixing study: APS does NOT correct (inhibitor); factor deficiency DOES correct

False-positive RPR/VDRL: classic association — cardiolipin antibody cross-reactivity

Triple positivity = LA + aCL + anti-β2GPI → highest thrombosis risk → warfarin, not DOAC

DOAC failure: rivaroxaban inferior to warfarin in TRAPS trial — avoid in triple-positive and arterial APS

Warfarin INR target: 2–3 for venous; 2–3 (± aspirin) or 2.5–3.5 for arterial

Pregnancy regimen: LMWH + low-dose aspirin; warfarin contraindicated

CAPS triple therapy: anticoagulation + steroids + plasma exchange/IVIG

Libman-Sacks: sterile mitral vegetations in APS/SLE; embolic stroke source

Sneddon syndrome: livedo racemosa + stroke (variant of APS)

Adrenal hemorrhage: bilateral, in APS → primary adrenal insufficiency

Budd-Chiari, portal vein thrombosis, cerebral sinus thrombosis: unusual-site thromboses suggest APS

Coombs-positive hemolytic anemia + thrombocytopenia + thrombosis = APS workup

SLE association: 30–40% of SLE patients have aPL; 10–15% develop APS

Hydroxychloroquine: thrombosis-protective in SLE-APS

Avoid in APS: estrogen contraceptives, HRT, smoking, NSAIDs (with warfarin), DOACs (if triple-positive)

β2-glycoprotein I: the main antigen — antibodies against it (not cardiolipin itself) drive pathology

12-week persistence: required for diagnosis — single positive titer insufficient

Pediatric APS: rare; chorea, stroke, DVT; same treatment principles

Repeat aPL when off anticoagulation if possible — DOACs and warfarin can interfere with LA assay

Chromogenic factor X: used to monitor warfarin when LA falsely elevates INR

Board Question Stem Patterns

Key distinction: When the stem emphasizes arterial event + miscarriage + thrombocytopenia + prolonged aPTT not correcting, the answer pathway is always: aPL panel → warfarin (not DOAC) → indefinite duration → hydroxychloroquine if SLE → avoid estrogen.

Stem 1 — The recurrent VTE patient: 35-year-old woman with second unprovoked DVT despite warfarin (INR 2.5 documented). What's next? → Confirm APS workup, increase INR target to 3–4, add aspirin, or switch to LMWH; consider hydroxychloroquine if SLE. Do NOT switch to DOAC.

Stem 2 — The DOAC switch: 40-year-old triple-positive APS on rivaroxaban presents with stroke. → Stop rivaroxaban, start heparin bridge to warfarin (INR 2–3 or 2.5–3.5).

Stem 3 — The young stroke: 28-year-old woman with stroke, livedo reticularis, two prior miscarriages, mild thrombocytopenia. → Order LA, aCL, anti-β2GPI; treat with anticoagulation; repeat in 12 weeks.

Stem 4 — The pregnant APS: 32-year-old with prior DVT on warfarin now 6 weeks pregnant. → Switch to therapeutic LMWH + low-dose aspirin immediately.

Stem 5 — The preop aPTT: 25-year-old woman has prolonged aPTT before elective cholecystectomy. Mixing study fails to correct. → Lupus anticoagulant suspected; order full aPL panel; do not give FFP; proceed with surgery if clinically appropriate (bleeding risk not increased).

Stem 6 — CAPS: 45-year-old with SLE develops AKI, stroke, and digital ischemia over 5 days after stopping warfarin for a procedure. → Catastrophic APS: heparin + IV methylprednisolone + plasmapheresis + ICU.

Stem 7 — The false-positive RPR: 30-year-old with positive RPR but negative treponemal test, history of miscarriages. → Workup APS.

Stem 8 — Adrenal crisis: APS patient on anticoagulation develops abdominal pain, hypotension, hyponatremia, hyperkalemia. → Bilateral adrenal hemorrhage; stress-dose hydrocortisone and adrenal imaging.

Stem 9 — Asymptomatic aPL: Routine labs show positive aPL in SLE patient without thrombosis. → Low-dose aspirin + hydroxychloroquine; avoid estrogen contraceptives.

Stem 10 — Libman-Sacks: APS patient with new mitral regurgitation and stroke. → TEE, continue anticoagulation; antibiotics only if cultures positive.

One-Line Recap

Antiphospholipid syndrome is a persistent-antibody-driven thrombophilia diagnosed by clinical thrombosis or pregnancy morbidity plus persistently positive lupus anticoagulant, anticardiolipin, or anti-β2-glycoprotein I at 12 weeks, and treated with indefinite warfarin (INR 2–3) — not DOACs — plus LMWH and low-dose aspirin in pregnancy.

Board pearl: The three Step 3 trapdoors are (1) prescribing a DOAC in triple-positive APS, (2) continuing warfarin into early pregnancy instead of switching to LMWH, and (3) calling APS "ruled out" after a single positive antibody titer without 12-week confirmation. Avoid all three and you'll answer nearly every APS question correctly.

Diagnosis: thrombosis (venous, arterial, microvascular) or obstetric morbidity + persistent aPL at 12 weeks; triple positivity is highest risk; lupus anticoagulant prolongs aPTT that does not correct on mixing; false-positive RPR is classic.

Treatment: warfarin INR 2–3 indefinitely for venous APS; INR 2–3 (± aspirin) or 2.5–3.5 for arterial APS; avoid DOACs, especially in triple-positive or arterial disease; LMWH + low-dose aspirin in pregnancy; hydroxychloroquine in SLE-associated APS.

Catastrophic APS: multi-organ thrombosis with 30–50% mortality; treat with anticoagulation + high-dose steroids + plasma exchange/IVIG; consider rituximab or eculizumab for refractory disease.

Lifestyle and prevention: avoid estrogen-containing contraceptives and HRT, NSAIDs with warfarin, and prolonged immobilization without prophylaxis; aggressive cardiovascular risk factor control; vaccinations up to date; reliable INR monitoring through anticoagulation clinic with attention to drug interactions and dietary vitamin K consistency.