APS Flashcards
Definition
Antiphospholipid syndrome (APS) is an autoimmune disease associated with increased risk of thrombosis due to the presence of procoagulatory antiphospholipid antibodies.
Typical clinical manifestations include recurring venous, arterial, and/or microcirculation thrombotic events (DVT, PE, stroke) and obstetrical complications (recurrent miscarriages, premature births).
Forms
Can manifest in isolation (primary 53%, HLA-DR7) or alongside other autoimmune diseases (secondary 47%) such as SLE, RA, Sjogren, Systemic Sclerosis, Vasculitis.
Epidemiology
Women
< 50 years
Antiphospholipid antibodies:
~13% of individuals with stroke
~11% of individuals with myocardial infarction
~9.5% of individuals with deep vein thrombosis
Etiology
Two-hit hypothesis
Antiphospholipid antibodies
Clotting cascade activated by second hit:
Infection: HIV, Hep A/B/C
Genetic: polymorphism of genes encoding for signalling pathways of proinflammatory mediators (ie, the tlr4 gene), platelet glycoproteins
Thrombotic risk factors: hypertension, smoking, hypercholesterolemia, OC/HRT use
Thrombophilic conditions: protein C resistance due to factor V defect, protein C/protein S deficiency, factor II deficiency)
Sex hormones
Pathogenesis
1.Formation of procoagulatory antiphospholipid antibodies
→ form complexes with anticoagulant proteins, thereby inactivating them (e.g., protein C, protein S, antithrombin III)
→ activate platelets and vascular endothelium
2.Induction of a hypercoagulable state → ↑ risk of thrombosis and embolism
Cellular involvement:
Platelets
β2GPI interacts with apolipoprotein E receptor 2, platelet glycoprotein Ib alpha chain and platelet factor 4 (PF4, also known as CXCL4) tetramers on the surface of platelets
aPL-induced aggregation and release of PF4 and thromboxane B2.
Monocytes
Annexin A2 and Toll-like receptor 4 (TLR4) colocalize with β2-glycoprotein 1 (β2GPI) on monocyte cell membranes
Increased transcription factor NF-kβ and Rel expression
Release of TNF
Activation of the p38 MAPK and MAP2K1-ERK pathways
Neutrophils
increased expression and activation of transcription factors
increased intracellular ROS
NETosis –> role in thrombosis
Endothelial cells
Dimers of β2GPI anchored to negatively charged phospholipids and TLR4 are recognized by anti-β2GPI antibodies
p38 MAPK-mediated endothelial cell activation induces expression of intercellular adhesion molecule 1, vascular cell adhesion molecule 1, E-selectin, IL-1, IL-6 and IL-8.
Obstetrical APS
β2GPI-dependend antibodies bind to human trophoblasts and affect several cell functions. High levels of β2GPI on decidual endothelial cells, extravillous trophoblasts and syncytiotrophoblasts. The high expression of β2GPI in the placenta might explain why persistent low titres of aPL are associated with miscarriages, whereas high aPL titres are needed to trigger vascular events.
aPL Antibodies
Lupus anticoagulant (Anticoagulant in vitro, pro-coagulant in vivo)
A is an autoantibody directed against phospholipid-binding proteins, primarily beta-2 glycoprotein I (β2GPI) and prothrombin, rather than phospholipids themselves. Despite the name, it is associated with a paradoxical increase in clotting rather than anticoagulation.
How is it detected LA
Antibodies against phospholipids in cellular membranes
Detection: 3-step procedure
Screening for phospholipid-dependent coagulation
Prolonged aPTT
Prolonged dilute Russell viper venom time (dRVVT)
Mixing study: The patient’s plasma is mixed with normal plasma (which c clotting factors)
aPTT or dRVVT normalize: Presence of LA ruled out
remain prolonged: LA may be present
Confirmation of phospholipid dependence: Phospholipid is added
normalize: LA confirmed
remain prolonged: Consider a factor deficiency
Anti-cardiolipin antibodies (IgG, IgM)
against Cardiolipin (a phospholipid), are β2GPI- dependent
Detected by ELISA: antibody titer should be either medium or high (low is insufficient)
Antibodies against β2 Glycoprotein I (IgG, IgM)
The more recently detected antibody
ONLY bind to β2GPI (a plasma protein that is involved in controlling complement and coagulation)
more frequently associated with the risk of thrombosis.
Risk Stratification
- High risk profile- a positive LA test with or without a moderate to- high-titer of aCL or anti-β2GPI IgG or IgM.
- Moderate risk profile- a negative LA test with a moderate-to high titer of aCL or anti-β2GPI IgG or IgM.
- Low risk profile- a negative LA test with a low titer of aCL or anti-β2GPI IgG or IgM.
Clinical manifestations
Recurring thrombotic events that may affect any organ
- Any organ can be affected but the most frequent manifestation is deep-vein-thrombosis (38.9%), pulmonary embolism (14.1%), stroke (19.8%) - while TIA is 11.1%. Keep in mind that in APS the more severe manifestations are detected more frequently than the less severe ones. In the general population it is the other way around - e.g. TIA is more frequent than a stroke.
o Thrombocytopenia (22%)
o Livedo reticularis (20%)
The risk of recurrence is about 20% EVEN IN PATIENTS THAT ARE BEING TREATED with an anticoagulation therapy. A very typical manifestation can be a young lady showing up with a stroke due to a deep vein thrombosis and taking estrogen pills.
aPL-associated nephropathy (APLN)
The most commonly reported and characteristic intrarenal vascular lesion is thrombotic microangiopathy without either histological evidence of inflammation or immune complex deposition (hypertension, proteinuria, and renal impairment). Intra-renal vascular lesion due to thrombosis of the small vessels resulting in hypertension.
Subcortical white-matter changes
When appear in SLE patients they are usually due to APS. This means that if we encounter these changes in the white matter in an SLE patient we must search for the presence of anti-phospholipid antibodies.
It can be confused with Multiple Scelrosis. The clinical similarities between APS and MS are striking, and brain magnetic resonance imaging appearance was often indistinguishable. APS and MS are autoimmune conditions which affect similar age groups (age 20 to 50) and may have similar neurological manifestations.
In general, in SLE patients, the presence of AP antibodies should be checked as a part of the follow-up every 1-2 years. The family of AP antibodies is a huge family, with the main one being anti-β2GPI.
Clinical spectrum of APS
- Primary form - the most frequent
- Secondary form
- Seronegative- patients that present the important symptoms of APS (e.g. livedo reticularis) but with persistently negative antibodies. This type was described only recently
- Catastrophic form- where 3 or more organs are affected simultaneously by thrombosis. The risk of mortality is >50%.
Diagnosis
At least 1 clinical + 1 laboratory criteria
Clinical Criteria
1)Vascular thrombosis: ≥ 1 episodes of arterial, venous, or small vessel thrombosis, in any tissue or organ
Venous
DVT (40%)
PE (15%)
Arterial
Stroke (20%)
TIA (10%)
Small vessel
Splinter Hemorrages
2)Pregnancy morbidity
≥ 1 unexplained deaths of a morphologically normal fetus ≥ 10th week gestation
≥ 1 premature births of a morphologically normal neonate < 34th week of gestation because of:
eclampsia or severe preeclampsia
recognized features of placental insufficiency
≥ 3 unexplained consecutive spontaneous abortions < 10th week of gestation
Laboratory criteria (presence on 2 or more occasions - at least 12 weeks apart):
-Lupus anticoagulant (LA) present in plasma.
-Anticardiolipin (aCL) antibody of IgG and/or IgM isotype in serum or plasma, present in medium or high titer (i.e. >40 GPL or MPL, or >the 99th percentile), measured by a standardized ELISA.
-Anti-b2 glycoprotein-I antibody of IgG and/or IgM isotype in serum or plasma (in titer >the 99th percentile), measured by a standardized ELISA, according to recommended procedures
EXTRA CRITERIA
(The clinical spectrum of APS encompasses additional manifestations that can affect many organs and cannot be explained exclusively by patients being in a prothrombotic state)
-Neurlogic Manifestations:
+Epilepsy
+Chronic headache
+Cognitive impairment
+Transverse myelitis
-Hematologic Manifestation:
+Thrombocytopenia (20%)
-Livedo Reticularis (20%)
-Ulcers
-Nephropathy
-Valvular Heart disease (Libman Sacks Endocarditis)
Complication:
Catastrophic antiphospholipid syndrome → simultaneous appearance of thrombosis in > 3 organs. Mortality risk >50%
Treatment
Only anticoagulation therapy
Acute thrombotic event: heparin followed by warfarin
Long term thromboprophylaxis
Primary thromboprophylaxis: low-dose aspirin therapy
Secondary thromboprophylaxis
First-line: warfarin
Second-line: LMWH or UFH
In pregnant individuals*: low-dose aspirin therapy PLUS heparin (LMWH or UFH)
warfarin is teratogenic
**Without treatment: 8:10 pregnancies will end in abortion
Treatment with aspirin AND Heparin: inverses the ratio to 2:10
Treatment should be prolonged for life if aPL positivity persists
For women with refractory obstetrical APS:
HCQ, prednisone, intravenous immunoglobulins and/or plasma exchange.
Catastrophic APS (CAPS):
First line: glucocorticoids + heparine + IVIG or plasmaferesis
For refractory CAPS: B cell depletion treatment (eg. rituximab) or complement
inhibition therapy (eg. eculizumab)
