Antiphospholipid syndrome (APS) is an autoimmune disorder causing recurrent thrombosis and pregnancy complications, predominantly in women. It can exist as primary APS or secondary to other autoimmune diseases like systemic lupus erythematosus, with catastrophic APS being a severe form affecting multiple organs. Diagnosis and management involve identifying specific autoantibodies and utilizing treatments such as vitamin K antagonists, low-dose aspirin, and heparin to mitigate thrombotic risks.

1. ANTIPHOSPHOLIPID
SYNDROME ( APS )

2. What is antiphospholipid syndrome ?
An autoantibody-mediated acquired thrombophilia characterized by
recurrent arterial or venous thrombosis and/or pregnancy morbidity.
It affects primarily females.
APS may occur alone (primary) or in association with other autoimmune
diseases, mainly systemic lupus erythematosus (SLE) (secondary).

3. What is catastrophic APS ?
Catastrophic APS (CAPS) is a life-threatening rapidly progressive
thromboembolic disease involving simultaneously three or more
organs.

4. The major autoantibodies detected in patients’ sera are directed against
negatively charged phospholipids and/or phospholipid (PL)-binding
plasma proteins such as prothrombin and β2 glycoprotein I (β2GPI) .

5. Phospholipids are components of the cytoplasmic membrane of
all living cells.

7. The antibodies are directed against PLs, such as cardiolipin,
phosphocholine, and phosphatidylserine.
The plasma protein β2 GPI is a 43-kDa plasma apolipoprotein, which
consists of 326 amino acids arranged in five domains (I through V).
Domain V forms a positively charged patch, suitable to interact with
negatively charged PLs. In plasma, β2 GPI has a circular conformation
with domain V binding to and concealing the B-cell epitopes lying on
domain I.
The presenceof anti–domain I IgG antibodies has been recently
associated with increased thrombotic risk.

10. EPIDEMIOLOGY
The incidence of APS is estimated to be around 5 cases per 100,000
persons per year. The prevalence of APS in the general population is
estimated to be 40–50 per 100,000
Anti-PL antibodies occur in 1–5% of the general population. Their
prevalence increases with age; however, it is questionable whether they
are able to induce thrombotic events in elderly individuals. Moreover,
one-third of patients with SLE and other autoimmune diseases possess
these antibodies, with only 5–10% of them developing APS.

11. PATHOGENESIS
The initiating event for the induction of antibodies to PL-binding
proteins seems to be infections, oxidative stress, and major physical
stresses such as surgery or trauma.
All these factors appear to increase the apoptosis of the vessel
endothelial cells and subsequent exposure of PLs.

12. The latter, bound with serum proteins such as β2GPI or prothrombin,
lead to neoantigen formation , which in turn triggers the induction of
anti-PLs. The binding of anti-PLs to the disrupted endothelial cells
leads to initiation of intravascular coagulation and thrombus
formation.
Complement activation has been also proposed as a mechanism of
APS-related fetal injury.

13. CLINICAL FEATURES

16. The diagnosis of APS should be seriously considered in cases of
thrombosis, cerebral vascular accidents in individuals <55 years of age,
or pregnancy morbidity in the presence of livedo reticularis or
thrombocytopenia.
In these cases, aPL antibodies should be measured.

17. Livedo reticularis consists of a
mottled reticular vascular
pattern that appears as a
lace-like, purplish
discoloration of the skin.
It is probably caused by
swelling of the venules due to
obstruction of capillaries by
thrombi. This clinical
manifestation usually occurs
together with vascular lesions
in the central nervous system
and with aseptic bone
necrosis.

18. Pregnancy morbidity manifests with increased risk of recurrent
miscarriages, intrauterine growth retardation, preeclampsia,
eclampsia, and preterm birth. The major causes of these
complications are due to infarctions of the placenta.

19. Clinical criteria
(1) Vascular thrombosis defined as one or more clinical episodes of arterial, venous,
or small vessel thrombosis in any tissue or organ; and
(2) Pregnancy morbidity, defined as
(a) one or more unexplained deaths of a morphologically normal fetus at or beyond
the tenth week of gestation;
(b) one or more premature births of a morphologically normal neonate before the
thirty-fourth week of gestation because of eclampsia, severe preeclampsia, or placental
insufficiency; or
(c) three or more unexplained consecutive spontaneous abortions before the tenth
week of gestation.

20. Laboratory criteria
Laboratory criteria include
(1) Lupus Anticoagulant ,
(2) anticardiolipin (aCL), and/or
(3) anti-β2GPI antibodies,
at intermediate or high titers on two occasions, 12 weeks apart.

21. Patients with APS often possess antibodies recognizing Treponema
pallidum PL/cholesterol complexes, detected by Venereal Disease
Research Laboratory (VDRL) tests and characterized as biologic
false-positive serologic tests for syphilis (BFP-STS).

22. The risk of thrombotic and obstetric events is closely related
to the underlying anti-PL profile. The latter depends on the
type of autoantibodies (IgG high risk vs IgM low risk), the
number of anti-PL antibodies (simultaneous presence of two or
three classical autoantibodies denotes a higher risk profile vs a
single antibody), their titer (moderate-high titer vs low), and the
persistence of anti-PL positivity in repeated measurements.
TREATMENT

23. Following the first thrombotic event, APS patients should be placed on
vitamin K antagonists (VKAs) for life , aiming to achieve an
international normalized ratio (INR) ranging from 2.0 to 3.0 in case of
an unprovoked venous thrombosis.
For patients with arterial thrombosis, the corresponding INR target
should be 3.0–4.0 or 2.0–3.0 along with low-dose aspirin (LDA, 75–100
mg daily), depending on the thrombotic/hemorrhagic patient profile.

24. Administration of direct oral thrombin inhibitors recently has
been shown to increase the risk of arterial events, especially in
patients with triple positivity or previous arterial thrombosis.
However, they could be considered with extreme caution in cases
in which contraindications to VKAs or inability to achieve a
target INR despite adherence to the treatment are present.

25. In pregnant women with a history of obstetric APS, combination
treatment with LDA and prophylactic dose of low molecular-weight
heparin (LMWH) is recommended, whereas in cases of thrombotic APS,
LDA plus therapeutic LMWH dose should be administered.
When recurrent obstetric complications occur despite standard treatment,
increasing the LMWH dose (from prophylactic to therapeutic) or
administering oral hydroxychloroquine 400 mg/d or IV immunoglobulin
(IVIg) 400 mg/kg every day for 5 days are alternative options.

26. For asymptomatic individuals or SLE patients with a high-risk
anti-PL profile and no evidence of a previous thrombotic event or
pregnancy morbidity, prophylactic treatment with LDA is
recommended.
In nonpregnant women with a history of APS-related obstetric
complications, independently of the presence of underlying SLE
diagnosis, treatment with LDA seems to reduce the risk of a
subsequent thrombotic event.

27. Patients with CAPS should be treated with combination therapy
with glucocorticoids, heparin, and plasma exchange or IVIG
together with appropriate management of triggering events such
as infections.
For refractory CAPS, B-cell depletion (e.g., with rituximab) or
complement inhibition (e.g., with eculizumab) therapies are
alternative options

28. REFERENCE