Antiphospholipid Antibody Syndrome (APLA / APS)

Antiphospholipid antibody syndrome (APS) is a systemic autoimmune thrombophilia characterized by:

1. Arterial and/or venous thrombosis
2. Pregnancy morbidity
3. Presence of persistent antiphospholipid antibodies (aPLs)

Types of Antiphospholipid Antibodies

The antibodies are directed against phospholipid-binding proteins, not phospholipid itself.

Major pathogenic antibodies:

Pathophysiology

APS is a hypercoagulable autoimmune state.

Core Mechanism

aPL antibodies bind:β2-glycoprotein-I,prothrombin,endothelial surfaces,platelets

This leads to:

• endothelial activation
• platelet activation
• complement activation
• tissue factor expression
• impaired fibrinolysis
• Inhibition of Natural Anticoagulants
• thrombosis

Risk Factors for Clinical APS

Not everyone with antibodies develops disease.

“Second-hit hypothesis”:

• antibodies create thrombophilic tendency
• trigger precipitates thrombosis

Triggers:

• surgery
• infection
• pregnancy
• immobility
• estrogen therapy
• smoking
• malignancy

Classification

1. Primary APS

APS without another autoimmune disorder.

2. Secondary APS

Associated with:

• Systemic Lupus Erythematosus
• Sjögren syndrome
• Rheumatoid arthritis
• Mixed connective tissue disease
• autoimmune diseases
• infections
• malignancy

3. Catastrophic APS (CAPS)

Fulminant APS with:

• widespread microvascular thrombosis
• multiorgan failure
• very high mortality

Clinical Features

APS manifestations are extremely diverse.

A. THROMBOTIC MANIFESTATIONS

-Venous Thrombosis (Most common)

• Deep Vein Thrombosis (DVT)
• Pulmonary Embolism
• Unusual Venous Thrombosis
• APS strongly associated with thrombosis at unusual sites:

B. ARTERIAL THROMBOSIS

• Stroke-Common in young adults.
• TIA
• Myocardial Infarction
• Limb Ischemia

C. OBSTETRIC APS

Classic feature.

Pregnancy Manifestations

1. Recurrent Early Miscarriages

≥3 consecutive miscarriages before 10 weeks

2. Fetal Death

≥1 unexplained fetal death after 10 weeks

3. Premature Birth

Before 34 weeks due to:

• severe preeclampsia
• placental insufficiency
• eclampsia

Mechanism of Pregnancy Loss

Not only thrombosis.

Also:

• complement-mediated placental injury
• trophoblast dysfunction
• placental infarction

D. HEMATOLOGIC FEATURES

Thrombocytopenia

Usually mild.

Important:thrombosis risk still high despite low platelets

Autoimmune Hemolytic Anemia

Livedo Reticularis

Mottled violaceous skin pattern.

Highly suggestive of APS.

E. NEUROLOGIC FEATURES

F. CARDIAC MANIFESTATIONS

Libman-Sacks Endocarditis

Sterile valvular vegetations.

Most commonly:mitral valve

Other cardiac manifestations:

• valvular thickening
• coronary thrombosis
• pulmonary hypertension

G. RENAL APS

• renal artery thrombosis
• renal vein thrombosis
• APS nephropathy
• hypertension
• proteinuria
• CKD

H. PULMONARY MANIFESTATIONS

• pulmonary embolism
• pulmonary hypertension
• diffuse alveolar hemorrhage
• ARDS in catastrophic APS

I. GASTROINTESTINAL / HEPATIC

• mesenteric ischemia
• hepatic vein thrombosis
• Budd-Chiari syndrome
• splenic infarction

J. ADRENAL APS

Adrenal vein thrombosis may cause:

• bilateral adrenal hemorrhage
• adrenal insufficiency

Diagnostic Criteria (Revised Sapporo / Sydney Criteria)

Need:≥1 clinical criterion   AND ≥1 laboratory criterion

Clinical Criteria

1. Vascular Thrombosis

One or more episodes of:arterial thrombosis/venous thrombosis/small vessel thrombosis confirmed objectively.

2. Pregnancy Morbidity

Any one:

• ≥3 unexplained miscarriages <10 weeks
• ≥1 fetal death >10 weeks
• premature birth <34 weeks due to placental disease

Laboratory Criteria

Positive on TWO occasions ≥12 weeks apart:

Triple Positivity

Positive:LA+aCL+anti-β2GPI = highest thrombosis risk.

False Positive aPL

Seen in:

• infections
• HIV
• hepatitis C
• syphilis
• drugs

Hence persistence ≥12 weeks required.

Differential Diagnosis

APS and SLE

APS occurs in:

• 20–40% of lupus patients with aPL positivity

High-risk features:

• lupus anticoagulant
• triple positivity

Imaging in APS

Depends on organ involved. Examples:

• Doppler for DVT
• CTPA for PE
• MRI brain for stroke
• Echo for Libman-Sacks
• CT abdomen for visceral thrombosis

PHARMACOLOGICAL MANAGEMENT

I. MANAGEMENT OF ACUTE THROMBOSIS IN APS

A. Acute Venous Thromboembolism (DVT/PE)

1. Unfractionated Heparin (UFH)

2. Low Molecular Weight Heparin (LMWH)

Enoxaparin

Dalteparin

| Dose | 100 IU/kg BD OR 200 IU/kg OD |

Transition to Oral Anticoagulation

Warfarin

Why lifelong?

APS has:

• High recurrence risk
• Recurrent thrombosis even years later

If Recurrent Venous Thrombosis Despite INR 2–3

Options:

1. Increase INR target to 3–4
2. Add low-dose aspirin
3. Switch to LMWH

B. Acute Arterial Thrombosis

Examples:

• Stroke
• TIA
• MI
• Limb ischemia

Treatment:

1. Acute standard arterial thrombosis management
2. Long-term APS-specific anticoagulation

Acute Phase

May include:

• Heparin
• Antiplatelet therapy
• Revascularization if indicated

Long-term Therapy

Warfarin

Options

Aspirin

Dose-75–100 mg/day

Used:

• Along with warfarin in arterial APS
• Recurrent thrombosis
• High-risk APS

III. DIRECT ORAL ANTICOAGULANTS (DOACs)

Current major guidelines generally:

• DO NOT recommend DOACs in high-risk APS

Especially avoid in:

• Triple-positive APS
• Arterial thrombosis
• Recurrent thrombosis
• Catastrophic APS

Reason:Higher recurrent thrombosis rates (especially arterial) compared with warfarin.

When DOACs MAY be considered

Possible only in:

• Low-risk venous APS
• Single/double antibody positivity
• Unable to maintain INR
• Cannot take warfarin

Even here:

• Shared decision-making required

IV. PRIMARY THROMBOPROPHYLAXIS

(Positive antibodies but NO thrombosis)

Management depends on risk profile.

A. Low-risk Asymptomatic aPL-positive Patients

Usually:No anticoagulation

Risk factor modification:

• Stop smoking
• Control HTN/DM
• Avoid estrogen OCPs
• Weight reduction

B. High-risk aPL-positive Patients

High-risk profile:

• Triple positivity
• Persistent lupus anticoagulant
• SLE with aPL
• Strong antibody titers

Aspirin

Dose-75–100 mg/day

May reduce first thrombotic event risk.

C. SLE-associated APS Prevention

Hydroxychloroquine

Dose->200–400 mg/day

Benefits:

• Antithrombotic
• Reduces platelet activation
• May reduce aPL-mediated thrombosis

Widely used in:

• SLE with aPL antibodies

V. PHARMACOLOGICAL MANAGEMENT OF OBSTETRIC APS

A. Women with Recurrent Pregnancy Loss + APS

Aspirin

LMWH

Enoxaparin

Dalteparin

| Dose | 5000 IU SC OD |

Start:After confirmation of viable pregnancy

Continue:Throughout pregnancy

Postpartum:Continue anticoagulation for 6 weeks postpartum

B. Obstetric APS WITH Prior Thrombosis

Requires FULL anticoagulation.

Treatment

• Therapeutic LMWH throughout pregnancy
• Aspirin low dose

Enoxaparin

PLUS

Aspirin–75–100 mg/day

C. Drugs Contraindicated in Pregnancy

Warfarin

Risks:

• Fetal warfarin syndrome
• CNS abnormalities
• Fetal bleeding

Avoid especially:

• Weeks 6–12 gestation

DOACs-Avoid during pregnancy

MANAGEMENT OF APS-RELATED THROMBOCYTOPENIA

Usually mild.

Treatment if:

• Severe thrombocytopenia
• Bleeding
• Platelets <30–50k

First-line Prednisone Dose-0.5–1 mg/kg/day

IVIG Used for:

• Rapid platelet rise
• Severe bleeding

Rituximab–For refractory disease.