Cryoglobulinaemic Vasculitis
Rheumatology | Small-vessel Vasculitis | Vasculitides
Overview
Antiphospholipid Syndrome (APS) is an acquired autoimmune thrombophilia characterized by recurrent venous or arterial thromboses and/or pregnancy morbidity in the presence of persistent antiphospholipid antibodies (aPL). APS may occur as a primary condition or secondary to systemic lupus erythematosus (SLE). Prevalence of aPL in the general population is ~2%, but true APS is rare (~40–50 per 100,000); female predominance (F:M = 3:1). APS is a leading cause of recurrent pregnancy loss and unexplained thrombosis in young individuals.
Definition
Antiphospholipid antibodies (aPL): Autoantibodies directed against phospholipid-binding proteins such as β2-glycoprotein I or cardiolipin.
Lupus anticoagulant (LA): A misnomer; it causes in vitro prolongation of clotting tests but is prothrombotic in vivo.
Thrombophilia: A disorder that increases the risk of thrombosis.
Catastrophic APS (CAPS): A rare and life-threatening form of APS with multiorgan thrombosis over days.
Anatomy and Physiology
Steps in thrombosis
- Endothelial Injury
• Exposes subendothelial collagen and tissue factor (TF)
• Activates platelets and the coagulation cascade
• Major trigger for arterial thrombosis - Platelet Adhesion and Activation
• Von Willebrand factor (vWF) binds platelets to exposed collagen via GPIb
• Platelets become activated → change shape and release granules (ADP, thromboxane A₂)
• Activated platelets express GPIIb/IIIa receptors → aggregation - Coagulation Cascade Activation
• Tissue factor activates extrinsic pathway (Factor VII) → thrombin generation
• Thrombin converts fibrinogen to fibrin, stabilizing the clot
• Amplification loops involve intrinsic factors (VIII, IX, XI) - Clot Stabilization
• Fibrin cross-linking forms a mesh
• Platelet-fibrin plug stabilizes the thrombus
• Involves Factor XIII for cross-linking - Regulation and Resolution
• Natural anticoagulants: antithrombin III, protein C/S, tissue factor pathway inhibitor (TFPI)
• Fibrinolysis: Plasmin degrades fibrin → clot breakdown
• Balance prevents excessive clotting
Virchow’s Triad (Pathological Thrombosis)
Three major contributors to thrombosis:
- Endothelial injury
- Abnormal blood flow (stasis or turbulence)
- Hypercoagulability (inherited or acquired)
Aetiology and Risk Factors
Aetiology
- Autoimmune production of antiphospholipid antibodies targeting β2-glycoprotein I, cardiolipin, or prothrombin.
- Primary (idiopathic) or secondary (most often to SLE).
Risk Factors
- Female sex
- Co-existing autoimmune disease (esp. SLE)
- Infections (e.g. HIV, hepatitis C, syphilis – can transiently raise aPL)
- Certain medications (e.g. chlorpromazine, hydralazine)
- Smoking, estrogen therapy, pregnancy, prolonged immobility
Pathophysiology
- Trigger (genetic or environmental) → immune response → formation of aPL.
- aPL bind to β2-glycoprotein I on endothelial cells and platelets → activation of procoagulant pathways.
- Complement activation contributes to pregnancy complications.
- Results in:
- Arterial/venous thrombosis
- Placental insufficiency → miscarriage
- Cardiac and neurological sequelae
Think
Despite prolonged aPTT on labs, APS is prothrombotic due to antibody-mediated vascular injury.
Clinical Manifestations
| System | Manifestations |
| Vascular | DVT, PE, stroke, TIA, retinal thrombosis |
| Obstetric | Recurrent miscarriage (>10 weeks), fetal death, preeclampsia, IUGR |
| Cardiac | Libman-Sacks endocarditis, valvular thickening |
| Hematological | Thrombocytopenia |
| Dermatologic | Livedo reticularis, ulcers |
| Neurological | Seizures, cognitive dysfunction, chorea |
| Renal | Thrombotic microangiopathy, hypertension |
| Catastrophic APS | Rapid multiorgan thromboses, DIC-like picture |
Remember
Suspect APS in young patients with unprovoked thrombosis, especially arterial or recurrent pregnancy loss.
Diagnosis
2023 ACR/EULAR antiphospholipid syndrome classification criteria
| Domain | Feature / Event | Weighted Points |
| Entry Criterion | At least one positive aPL test (LA, moderate/high‐titer aCL or anti‑β2GPI IgG/IgM) within 3 years of clinical event | ★ Required before scoring |
| Clinical Domains (≥3 pts) | ||
| Macrovascular Venous Thrombosis | VTE with high-risk profile | 1 |
| VTE without high-risk features | 3 | |
| Macrovascular Arterial Thrombosis | Arterial event with CVD risk | 2 |
| Arterial event without CVD risk | 4 | |
| Microvascular Thrombosis | Suspected lesion (e.g. livedo, nephropathy, pulmonary hemorrhage) | 2 |
| Established pathology | 5 | |
| Obstetric Morbidity | ≥3 consecutive early losses (<10 weeks) | 1 |
| Fetal death (10–33 weeks) without pre‑eclampsia or placental insufficiency | 3 | |
| Fetal death with pre‑eclampsia or placental insufficiency <34 weeks (± fetal death) | 3 | |
| Fetal death with both pre‑eclampsia & placental insufficiency <34 weeks | 4 | |
| Cardiac Valve Disease | Valve thickening (non-infectious) | 2 |
| Valve vegetation (non-infectious) | 4 | |
| Haematologic Manifestation | Thrombocytopenia (20–130 × 10⁹/L) | 2 |
| Laboratory Domains (≥3 pts) | ||
| Lupus Anticoagulant (functional assay) | Positive (persistent) | 5 |
| aCL or anti‑β2GPI antibodies (ELISA) | Moderate‑titer IgM or IgG (40‑79 U) | 1 |
| Moderate IgG only | 4 | |
| High‑titer IgG and/or anti‑β2GPI (≥80 U) | 5 | |
| High‑titer IgG in both aCL and anti‑β2GPI | 7 | |
| Antibody | Description & Clinical Relevance |
| Anticardiolipin Antibodies (IgG or IgM) | • Target cardiolipin, a negatively charged phospholipid located on mitochondrial membranes. • May appear transiently at low levels in response to infections, malignancy, or autoimmune conditions—not always pathogenic. • IgG subtype is more strongly associated with thrombotic risk than IgM. |
| Anti-beta2-glycoprotein I Antibodies (IgG or IgM) | • Target beta2-glycoprotein I, a plasma protein that inhibits platelet aggregation and regulates the coagulation cascade. • IgG antibodies correlate more closely with thrombotic events. • IgM antibodies have lower clinical significance. |
| Lupus Anticoagulant | • Refers to a functional group of antibodies (not a single entity) that interfere with phospholipid-dependent clotting assays. • Most predictive of thrombotic and obstetric complications in APS. • A persistently positive lupus anticoagulant carries higher clinical risk than anticardiolipin or anti-beta2GPI antibodies. |
Investigations
- aPTT (may be prolonged)
- dRVVT (for Lupus anticoagulant detection)
- ELISA for anticardiolipin and anti-β2GPI
- Imaging for thrombosis (US Doppler, CT angio)
Differential Diagnoses
| Condition | Distinguishing Features |
| Inherited thrombophilia | No aPL; family history; no obstetric loss |
| DIC | Consumptive coagulopathy; ↓ fibrinogen |
| TTP | Microangiopathy, neurologic findings, ADAMTS13 deficiency |
| SLE alone | Multisystem inflammation but may coexist with APS |
Classification
- Primary APS: No associated autoimmune disease
- Secondary APS: Associated with SLE or other autoimmune disorders
- Catastrophic APS (CAPS): Life-threatening; ≥3 organs involved over <1 week, confirmed microthrombosis
Treatment
Treatment (not obstetrics)
- Primary thromboprophylaxis, aPL+, no clinical event
- Aspirin 100mg in high risk patients (without SLE)
- Aspirin 100mg and HCQ in high risk patients (with SLE)
- Secondary thromboprophylaxis in APS (VENOUS)
- Warfarin INR 2-3
- Rivaroxaban should not be used in patients with triple aPL positivity due to the high risk of recurrent events (stroke)
- Secondary thromboprophylaxis in APS (ARTERIAL)
- Warfarin often INR 3-4
Treatment (obstetrics)
- During Pregnancy
- Low-dose aspirin + prophylactic-dose low molecular weight heparin (LMWH)
- Enoxaparin 40 mg SC daily once pregnancy confirmed in women with prior obstetric APS
- Aspirin started pre-pregnancy or as soon as pregnancy is confirmed
- Switch to therapeutic-dose LMWH if APS on warfarin + low dose aspirin
- Low-dose aspirin + prophylactic-dose low molecular weight heparin (LMWH)
- Postpartum
- Continue LMWH for 6–12 weeks postpartum (highest thrombotic risk period)
- Resume warfarin postpartum if long-term anticoagulation indicated (breast-feeding ok)
Avoid Direct Oral Anticoagulants (DOACs) in triple-positive patients or arterial events (↑ recurrence risk).
Remember
Long-term warfarin is mainstay for thrombotic APS; DOACs are NOT equivalent in high-risk APS.
Complications and Prognosis
Complications
- Stroke, PE, MI, fetal loss
- Catastrophic APS (rare, high mortality)
- Valve disease (Libman-Sacks)
- Renal thrombotic microangiopathy
Prognosis
- Good with appropriate anticoagulation
- Poor in CAPS or recurrent thrombosis despite therapy
Poor Prognostic Factors:
- Triple positivity (LA + ACL + β2GPI)
- CAPS
- Delay in anticoagulation
- Coexisting SLE with nephritis
References
- Miyakis S, et al. International consensus statement on an update of the classification criteria for definite APS. J Thromb Haemost. 2006;4(2):295–306.
- Garcia D, Erkan D. Diagnosis and management of the antiphospholipid syndrome. N Engl J Med. 2018;378(21):2010–2021.
- Pengo V, et al. Rivaroxaban vs warfarin in high-risk APS: The TRAPS trial. Blood. 2018;132(13):1365–1371.
- Cervera R, et al. Catastrophic APS: clinical and immunologic manifestations and long-term outcomes. Arthritis Rheum. 2009;61(8):1144–1150.
- Tektonidou MG, et al. Risk factors for thrombosis in APS. Curr Rheumatol Rep. 2016;18(4):21.
Discussion