Page 51 - Haematologica March 2020

Seronegative antiphospholipid syndrome
bosis are excluded, such as genetic thrombophilia (factor V and II mutations), active cancer, trauma, major surgery, or prolonged bed rest. This is particularly evident in young patients without established cardiovascular risk factors (i.e. obesity, diabetes, hypertension, dyslipidemia). Most importantly, other forms of coagulopathy should be excluded first, including Protein C and S and anti-thrombin deficiency. In addition, the patient's personal medical his- tory should be carefully investigated to exclude previous positivity to aPL.
To better characterize the entity of SN-APS, antibodies against different phospholipids or protein co-factors have been investigated in patients negative to conventional aPL (Table 2).
The antibodies that have been most studied so far are those directed against: 1) a zwitterionic phospholipid, namely phosphatidylethanolamine (PE); 2) negatively charged phospholipids other than cardiolipin, including phosphatidic acid (PA), phosphatidylserine (PS), phos- phatidylinositol (PI); 3) vimentin (forming a complex with
Table 2. Summary of positivity for extra-criteria antibodies in each study of seronegative antiphospholipid syndrome (SN-APS).
Authors (year)
Sanmarco39 (2001)
Sanmarco40
(2007)
Study typology Population aPL positivity in SN-APS (n)
P=prospective; studied R=retrospective
CS=cross-sectional APS SN-APS IgAaPL aPE NCP AVA/CL aPS/PT aANX
Main findings
25 of the 40 aPE-positive patients (63%) were
negative for the APS laboratory criteria
Vimentin seems to be positive in a large
number of mainly SN-APS patients.
CaS= case series
(n) (n)
CS 6718-18----
CS
- 25 - 25 - - - -
Kumar83 CaS -55----- (2009)
Ortona47
(2010)
Conti 49 (2013)
Ruiz-García35 (2014)
Cousins32 (2015)
Mekinian27
(2016)
Zohoury24 (2017)
Tortosa36 (2017)
Litvinova25 (2018)
Truglia50 (2018)
Billoir84 (2019)
CS
CS
CS
CS
CS
CS
R
CS
CS
R
40
25
22
40
83
107
-
41
-
-
29
24
35
40
96
68
38
17
61
23
12
--
--
35-
1-
- 47
-8
38 -
-
-
-
-
-
-
-
27 -
-
1
-
-
57
-
-
4
-
-
-
11
-
-
11
-
-
33
-
-
1
-
-
5
8
-
4
-
-
7
SN-APS were positive for 11/24 (45.8%) for anti-vimentin/cardiolipin antibodies, 3/24 (12.5%) for anti-prothrombin antibodies, and 1/24 (4.2%) for anti-annexin V antibodies.
Isolated IgA aβ2GPI antibodies were found in 22% of patients. Patients with arterial thrombosis were positive only for IgA aβ2GPI.
IgA aCL or IgA aβ2GPI antibodies, were present in a significant proportion of patients with APS, and in a small proportion of SN-APS.
68% of patients with obstetrical SN-APS have
non-conventional aPL
1/3 of SN-APS patients showed reactivity to 1 or more non-criteria markers
The presence of IgA aβ2GPI in people with no history of APS-events is the main independent risk factor for the development of these types of events, mainly arterial thrombosis
Ganapati61 R 58 (2019)
--5
---
-23-
---
87 patients: 41 APS, 11 aPL carriers, 17 SN-APS. <1% of patients with thrombotic/obstetrical SN-APS had non-conventional aPL Anti-PS/PT antibodies were correlated with LA. APS triple patients were also positive for anti-PS/PT antibodies
Non-conventional tests, mainly aCL/Vim and aCL seem to be the most sensitive approaches
for identifying aPL in patients with obstetric SN-APS
aPE persists in 23 patients (10%): 15 with
a thrombotic event, 6 with obstetrical morbidity and 2 with a combined event
Addition of aPS/PT to current APS criteria to SN-APS patients led to reclassification of additional 12.1% patients as APS overall and 42.8% in obstetric APS category
syndrome; aPS/PT antiphosphatidylserine/prothrombin; AVA/CL: phosphatidylserine and phosphatidylinositol); SN-APS: seronega-
aANX: Annexin A5 antibody; aPE: phosphatidylethanolamine; aPL: antiphospholipid antibodies; APS: antiphospholipid anti vimentin/cardiolipin complex; LA: lupus anticoagulant; NCP: negatively charged phospholipids (phosphatidic acid, tive APS.
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