APS

Question 1

Definition

Answer 1

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).

Question 2

Forms

Answer 2

Can manifest in isolation (primary 53%, HLA-DR7) or alongside other autoimmune diseases (secondary 47%) such as SLE, RA, Sjogren, Systemic Sclerosis, Vasculitis.

Question 3

Epidemiology

Answer 3

Women
< 50 years
Antiphospholipid antibodies:
~13% of individuals with stroke
~11% of individuals with myocardial infarction
~9.5% of individuals with deep vein thrombosis

Question 4

Etiology

Answer 4

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

Question 5

Pathogenesis

Answer 5

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

Question 6

Cellular involvement:

Answer 6

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.

Question 7

Monocytes

Answer 7

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

Question 8

Neutrophils

Answer 8

increased expression and activation of transcription factors
increased intracellular ROS
NETosis –> role in thrombosis

Question 9

Endothelial cells

Answer 9

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.

Question 10

Obstetrical APS

Answer 10

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.

Question 11

aPL Antibodies

Lupus anticoagulant (Anticoagulant in vitro, pro-coagulant in vivo)

Answer 11

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.

Question 12

How is it detected LA

Answer 12

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

Question 13

Anti-cardiolipin antibodies (IgG, IgM)

Answer 13

against Cardiolipin (a phospholipid), are β2GPI- dependent
Detected by ELISA: antibody titer should be either medium or high (low is insufficient)

Question 14

Antibodies against β2 Glycoprotein I (IgG, IgM)

Answer 14

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.

Question 15

Risk Stratification

Answer 15

• 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.

Question 16

Clinical manifestations

Answer 16

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.

Question 17

aPL-associated nephropathy (APLN) 

Answer 17

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.

Question 18

Subcortical white-matter changes

Answer 18

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.

Question 19

Clinical spectrum of APS

Answer 19

1. Primary form - the most frequent
2. Secondary form
3. Seronegative- patients that present the important symptoms of APS (e.g. livedo reticularis) but with persistently negative antibodies. This type was described only recently
4. Catastrophic form- where 3 or more organs are affected simultaneously by thrombosis. The risk of mortality is >50%.

Question 20

Diagnosis

Answer 20

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

Question 21

Laboratory criteria (presence on 2 or more occasions - at least 12 weeks apart):

Answer 21

-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

Question 22

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)

Answer 22

-Neurlogic Manifestations:
+Epilepsy
+Chronic headache
+Cognitive impairment
+Transverse myelitis

-Hematologic Manifestation:
+Thrombocytopenia (20%)

-Livedo Reticularis (20%)
-Ulcers
-Nephropathy
-Valvular Heart disease (Libman Sacks Endocarditis)

Question 23

Complication:

Answer 23

Catastrophic antiphospholipid syndrome → simultaneous appearance of thrombosis in > 3 organs. Mortality risk >50%

Question 24

Treatment

Answer 24

Only anticoagulation therapy

Acute thrombotic event: heparin followed by warfarin

Question 25

Long term thromboprophylaxis

Answer 25

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

Question 26

Treatment should be prolonged for life if aPL positivity persists

Question 27

For women with refractory obstetrical APS:

Answer 27

HCQ, prednisone, intravenous immunoglobulins and/or plasma exchange.

Question 28

Catastrophic APS (CAPS):

Answer 28

First line: glucocorticoids + heparine + IVIG or plasmaferesis
For refractory CAPS: B cell depletion treatment (eg. rituximab) or complement
inhibition therapy (eg. eculizumab)