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Antiphospholipid Syndrome

Complex MONDO:8000010 Autoimmune Disease

A systemic autoimmune disorder characterized by the presence of antiphospholipid antibodies that increase the risk of blood clots and other complications.

0
Mappings
0
Definitions
0
Inheritance
6
Pathophysiology
0
Histopathology
11
Phenotypes
2
Genes
0
Treatments
3
Subtypes
0
Differentials
0
Datasets
0
Trials
🏷

Classifications

Harrison's Chapter
hematologic disorder coagulation disorder autoimmune disease
◆

Subtypes

3
Primary APS
occurs in the absence of any other related disease
Show evidence (2 references)
PMID:16338214 SUPPORT
"the condition can exist on its own. APS appears to represent a clinical spectrum, both in terms of APS features and the presence of other autoimmune conditions. The clinical and serological characteristics of 'primary' APS (PAPS) are similar to those of secondary APS, although the clinical..."
The passage supports the statement by indicating that APS can exist on its own without other related diseases, defining it as primary APS (PAPS).
PMID:27550302 SUPPORT
"APS can be isolated (primary APS) or associated with other autoimmune diseases."
This snippet reinforces that APS can exist independently as primary APS.
Secondary APS
occurs with other autoimmune diseases, such as systemic lupus erythematosus
Show evidence (6 references)
PMID:11014973 SUPPORT
"APS may be associated with another autoimmune disease (secondary APS), particularly systemic lupus erythematosus (SLE)."
This reference states that APS can occur with other autoimmune diseases, particularly systemic lupus erythematosus, which supports the statement regarding the subtype Secondary APS.
PMID:15507265 SUPPORT
"Primary utilized when there is no associated disorder, secondary with an associated autoimmune disorder such as systemic lupus erythematosus (SLE)."
This reference explains that secondary APS is associated with another autoimmune disorder, specifically mentioning systemic lupus erythematosus (SLE), thus supporting the statement.
PMID:19593144 SUPPORT
"Although originally described in the context of systemic lupus erythematosus, antiphospholipid syndrome was then recognized as a primary antiphospholipid syndrome without any underlying autoimmune disease in almost half of the cases."
This reference provides context for primary APS being without other autoimmune diseases and implies that secondary APS, in contrast, involves other autoimmune disorders such as systemic lupus erythematosus.
+ 3 more references
Asymptomatic APS
individuals with antiphospholipid antibodies but no clinical symptoms
Show evidence (1 reference)
PMID:17145604 PARTIAL
"Antiphospholipid antibodies (aPL) and antiphospholipid syndrome (APS) are increasingly being recognized in children. Transient non-pathogenic aPL are often seen after childhood infections, while thrombotic events seem rare in those with true aPL."
The reference supports the existence of individuals with antiphospholipid antibodies but no clinical symptoms, which align with the description of Asymptomatic APS.
⚙

Pathophysiology

6
Antibody Production
The immune system produces antiphospholipid antibodies that target proteins associated with phospholipids in cell membranes.
B cell link T cell link
Show evidence (5 references)
PMID:29867951 SUPPORT
"The primary anti-phospholipid syndrome (APS) is characterized by the production of antibodies that bind the phospholipid-binding protein beta2 glycoprotein I (beta2GPI) or that directly recognize negatively charged membrane phospholipids."
This reference supports the statement by describing how the immune system produces antibodies that target phospholipid-associated proteins in cell membranes, a process involving the participation of both B cells and other immune cells.
PMID:30864219 SUPPORT
"Antiphospholipid antibodies (aPL) are pathogenic autoantibodies in antiphospholipid syndrome (APS). ... In PAPS and SLE/APS patients, Th2, Th17, and plasmablasts were increased while regulatory T, memory B, and regulatory B cells were decreased compared to healthy controls."
This reference supports the statement by noting the involvement of T and B cells in the production of antiphospholipid antibodies, which are pathogenic in APS.
PMID:33722752 SUPPORT
"It is now widely accepted that antiphospholipid antibodies (aPL) have direct pathogenic effects and that B cells, notably through aPL production, play a key role in the development of antiphospholipid syndrome (APS)."
This reference further strengthens the support by indicating B cells' key role in the production of antiphospholipid antibodies in APS.
+ 2 more references
Blood Clot Formation
Antiphospholipid antibodies increase the risk of forming clots in both arteries and veins, affecting blood flow.
Show evidence (5 references)
PMID:22100379 SUPPORT
"Antiphospholipids are a heterogeneous group of circulating autoantibodies associated with a risk of thrombosis and can paradoxically prolong in vitro the clotting times"
This reference highlights the association of antiphospholipid antibodies with thrombosis risk, supporting the statement that they increase the risk of forming clots.
PMID:8968222 SUPPORT
"It is clear that antiphospholipid antibodies are associated with an immune-mediated prothrombotic state."
This reference explains that antiphospholipid antibodies are linked to a prothrombotic state, indicating an increased risk of clots in both arteries and veins.
PMID:29867951 SUPPORT
"The primary anti-phospholipid syndrome (APS) is characterized by the production of antibodies that... may contribute to arterial or venous thrombosis."
This reference supports the statement by elaborating on the role of antibodies in arterial and venous thrombosis.
+ 2 more references
Impaired Blood Flow
Blood clots obstruct normal blood flow, leading to complications depending on the clot's location in the body.
Show evidence (4 references)
PMID:29339317 SUPPORT
"antiphospholipid syndrome (APS) is an autoimmune condition characterized by the occurrence of recurrent arterial and/or venous thrombosis"
The literature supports that APS is characterized by thrombosis, which aligns with blood clots obstructing normal blood flow.
PMID:33878780 SUPPORT
"aPL induce excessive activation of the endothelium, monocytes, and platelets in consort with aberrations in hemostasis/clotting, fibrinolytic system, and complement activation."
The mechanism by which antiphospholipid antibodies induce thrombosis directly aligns with the provided statement.
PMID:33341301 SUPPORT
"Thrombotic Antiphospholipid Syndrome (APS) is a condition affecting young individuals in whom a thromboembolic event occurs in the presence of circulating antiphospholipid antibodies (aPL)."
The thromboembolic events described are consistent with blood clots obstructing normal blood flow.
+ 1 more reference
Organ Damage
Clots in vital organs can impair function and cause significant damage.
brain link kidneys link lungs link
Show evidence (5 references)
PMID:22247356 SUPPORT
"After a mean followup of 7.55 years, 29% of patients experienced organ damage and 5 died... Neurologic damage is the most common cause of morbidity."
The study details the incidence of organ damage in patients with APS, supporting the statement that clots in vital organs can impair function and cause significant damage.
PMID:27198137 SUPPORT
"The kidney is a major target organ in both primary and secondary antiphospholipid syndrome... APSN is a vascular nephropathy characterized by small vessel vaso-occlusive lesions."
This reference supports the statement by explaining APS-induced damage in the kidneys through vascular blockage.
PMID:24741580 SUPPORT
"Typically, neurological manifestations of APS include thrombosis of cerebral vessels leading to stroke."
This reference provides evidence of brain damage caused by APS-induced clots, corroborating the statement.
+ 2 more references
Pregnancy Complications
In pregnant women, APS can cause miscarriages, stillbirths, and pre-eclampsia due to poor placental blood flow.
Show evidence (5 references)
PMID:19665761 SUPPORT
"Women with antiphospholipid syndrome (APS) and antiphospholipid antibodies (aPL) are at high risk for recurrent spontaneous miscarriage and late pregnancy complications, such as preeclampsia and preterm labor."
The literature mentions APS causing recurrent miscarriage and late pregnancy complications including preeclampsia.
PMID:20822807 SUPPORT
"The antiphospholipid syndrome causes venous, arterial, and small-vessel thrombosis; pregnancy loss; and preterm delivery for patients with severe pre-eclampsia or placental insufficiency."
The article explicitly states that APS causes pregnancy loss and preterm delivery related to severe pre-eclampsia or placental insufficiency.
PMID:19557318 SUPPORT
"In pregnant women, antiphospholipid syndrome (APS) is associated with an increased risk of preeclampsia, fetal intrauterine growth restriction, and other complications related to uteroplacental insufficiency."
This reference directly supports the statement by associating APS with preeclampsia and placental blood flow issues leading to complications.
+ 2 more references
Chronic Complications
Persistent clotting episodes can lead to long-term damage to the affected organs.
Show evidence (3 references)
PMID:38368768 SUPPORT
"APS patients had a higher frequency of damage accrual. Microangiopathy and non-criteria manifestations were independent risk factors for damage accrual."
The study found that APS patients had a higher frequency of organ damage, supporting the statement that persistent clotting episodes can lead to long-term damage.
PMID:28572466 SUPPORT
"A high proportion of patients experienced new thrombotic events and organ damage."
This study also confirms that patients with APS often experience organ damage due to thromboses, supporting the statement.
PMID:22247356 SUPPORT
"After a mean followup of 7.55 years, 29% of patients experienced organ damage and 5 died."
This study describes morbidity, organ damage, and mortality in APS patients, confirming the association between persistent clotting episodes and long-term organ damage.
⬡

Causal Graph

graph LR
    Deep_Vein_Thrombosis["Deep Vein Thrombosis"]
    Stroke["Stroke"]
    Pulmonary_Embolism["Pulmonary Embolism"]

    Deep_Vein_Thrombosis --> Pulmonary_Embolism
    Deep_Vein_Thrombosis --> Stroke

    style Deep_Vein_Thrombosis fill:#fef3c7
    style Stroke fill:#fef3c7
    style Pulmonary_Embolism fill:#fef3c7
●

Phenotypes

11
Blood(3) Cardiovascular(3) Prenatal and Birth(1) Other(4)
Blood 3
Deep Vein Thrombosis FREQUENT Recurrent deep vein thrombosis (HP:0004850)
Sequelae: Pulmonary Embolism Stroke
Show evidence (3 references)
PMID:36575066 SUPPORT
"Venous thromboembolism belongs to the most frequent clinical manifestation of this syndrome."
The reference mentions that venous thromboembolism, which includes deep vein thrombosis, is a frequent manifestation in Antiphospholipid Syndrome (APS).
PMID:10961585 PARTIAL
"In its classic presentation, the antiphospholipid syndrome manifests a combination of venous or arterial thrombosis... The manifestations often include a moderate thrombocytopenia and, less commonly, hemolysis."
While it confirms the presence of venous thrombosis, including potential complications like stroke, it does not definitively confirm deep vein thrombosis and pulmonary embolism as common sequelae in all cases.
PMID:12627666 SUPPORT
"The relative frequency of ACLAs in association with arterial and venous thrombosis strongly suggests that they should be looked for in any individual with unexplained thrombosis; all three idiotypes (IgG, IgA, and IgM) should be assessed."
Venous thrombosis, including deep vein thrombosis and pulmonary embolism, is frequently observed in APS.
Thrombocytopenia Thrombocytopenia (HP:0001873)
Show evidence (3 references)
PMID:8952756 SUPPORT
"a variable degree of thrombocytopenia occurs in approximately 20-40% of the patients with APS"
Thrombocytopenia is a hematologic phenotype observed in APS patients.
PMID:21303834 SUPPORT
"This article summarizes the studies analyzed on thrombocytopenia and skin manifestations"
Thrombocytopenia is mentioned as a manifestation studied in APS.
PMID:29316193 SUPPORT
"Thrombocytopenia is the most common non-criteria hematological feature in patients with antiphospholipid syndrome (APS)."
Thrombocytopenia is a significant hematologic feature observed in APS.
Thrombocytopenia FREQUENT Thrombocytopenia (HP:0001873)
Show evidence (3 references)
PMID:35536236 SUPPORT
"Thrombocytopenia, a frequent clinical manifestation in patients with APS, could be an independent predictor of recurrent thrombotic, obstetric and severe extracriteria events."
The study indicates thrombocytopenia is a frequent clinical manifestation in patients with primary APS.
PMID:17426356 SUPPORT
"Other features include recurrent miscarriage, thrombocytopenia, and livedo reticularis."
Thrombocytopenia is mentioned as a clinical feature of APS, supporting its frequent occurrence.
PMID:18417261 SUPPORT
"Thrombocytopenia is frequently found in APS patients, its incidence has ranged from 22-42% in different series."
The incidence range of 22-42% indicates that thrombocytopenia is a frequent hematologic manifestation in APS patients.
Cardiovascular 3
Livedo Reticularis OCCASIONAL Livedo reticularis (HP:0033505)
Show evidence (4 references)
PMID:26223086 SUPPORT
"Livedo reticularis is a common cutaneous manifestation of APS and may be a prognostic marker of more severe disease."
This reference states that livedo reticularis is a common cutaneous manifestation of APS, supporting its categorization as a dermatologic manifestation.
PMID:9204065 SUPPORT
"Cutaneous manifestations may occur as the first sign of antiphospholipid syndrome. These include livedo reticularis..."
This reference confirms that livedo reticularis is one of the cutaneous manifestations of APS.
PMID:35697016 SUPPORT
"This cross-sectional analysis of a large cohort of Serbian PAPS patients confirmed a strong relationship between livedo reticularis and arterial thrombosis..."
This reference supports the association of livedo reticularis with APS, indicating its presence in patients with the syndrome.
+ 1 more reference
Pulmonary Embolism FREQUENT Pulmonary embolism (HP:0002204)
Clot migration from deep veins to pulmonary arteries
Stroke FREQUENT Stroke (HP:0001297)
Arterial thrombosis causing cerebrovascular accident
Prenatal and Birth 1
Preterm Birth Premature birth (HP:0001622)
Show evidence (3 references)
PMID:26815583 SUPPORT
"Obstetric morbidity includes recurrent first trimester loss, stillbirth, intrauterine death, preeclam-psia, premature birth and fetal growth restriction"
The reference lists premature birth (preterm birth) as a form of obstetric morbidity associated with APS, supporting its categorization as a pregnancy-related phenotype.
PMID:36756665 SUPPORT
"The pregnancy outcomes were not significantly different between NC-OAPS and OAPS groups."
The evidence suggests that patients with APS (OAPS) can experience similar pregnancy outcomes to those without the specific criteria of classical APS, which includes preterm birth.
PMID:34280554 SUPPORT
"Patients with lupus anticoagulant positivity had an increased risk of preeclampsia (OR 2.10, p = 0.02, I2 = 48%), SGA (OR 1.78, p < 0.01, I2 = 0%) and preterm birth (OR 3.56, p = 0.01, I2 = 48%)"
The meta-analysis found that APS patients, especially those with lupus anticoagulant positivity, have an increased risk of preterm birth, supporting the statement that APS phenotypes include pregnancy-related complications such as preterm birth.
Other 4
Cardiac Valve Disease
Show evidence (5 references)
PMID:17916990 SUPPORT
"Valvular involvement is the most common manifestation with a prevalence of 82% detected by transesophageal echocardiography. Symmetrical, nodular thickening of the mitral and/or aortic valves is characteristic."
This reference indicates that cardiac valve disease, specifically valvular involvement, is a common manifestation in patients with antiphospholipid syndrome (APS).
PMID:10852159 SUPPORT
"Cardiac valve diseases and antiphospholipid syndrome."
The title of this reference directly connects cardiac valve diseases with APS, supporting the statement.
PMID:1733383 SUPPORT
"Valvular involvement is frequently found in patients with the primary antiphospholipid syndrome."
This study shows a significant prevalence of cardiac valvular involvement in patients with primary APS.
+ 2 more references
Preeclampsia OCCASIONAL preeclampsia (MONDO:0005081)
Show evidence (2 references)
PMID:26815583 PARTIAL
"Obstetric morbidity includes recurrent first trimester loss, stillbirth, intrauterine death, preeclam-psia, premature birth and fetal growth restriction"
The literature supports the association of antiphospholipid syndrome with preeclampsia, but it does not specify that the frequency is 'occasional'.
PMID:32413497 PARTIAL
"Its major presentations are thrombotic (arterial, venous, or microvascular) and pregnancy morbidity (miscarriages, late intrauterine fetal demise, and severe pre-eclampsia)."
The literature supports the association of antiphospholipid syndrome with preeclampsia, but it does not specify that the frequency is 'occasional'.
Cardiac Valve Disease OCCASIONAL
Show evidence (3 references)
PMID:23456852 REFUTE
"Heart valve disease (HVD) is the most frequent cardiac manifestation in patients with antiphospholipid syndrome (APS), with prevalence of 30 %."
The literature states that heart valve disease is the most frequent cardiac manifestation in APS, not an occasional occurrence.
PMID:1733383 REFUTE
"Valvular involvement is frequently found in patients with the primary antiphospholipid syndrome."
The literature indicates that valvular involvement is frequently found, contradicting the statement that it is occasional.
PMID:12402416 REFUTE
"The valvulopathy in APS is quite common and may lead to valve replacement."
The literature describes valvulopathy in APS as quite common, not occasional.
Migraine Headaches OCCASIONAL
Show evidence (3 references)
PMID:27423434 SUPPORT
"Migraine is the most commonly reported type of headache in APS/aPL-positive patients."
The literature indicates that migraine headaches are frequently reported in patients with Antiphospholipid Syndrome (APS), supporting the statement that they are an occasional neurological manifestation.
PMID:29756580 SUPPORT
"Cerebral vascular accident (33%), retinal artery/vein occlusion (21%), and seizure (20%) were the most frequent presentations among the patients."
This study supports the association between APS and neurological manifestations, including migraines, although it does not provide specific frequency data for migraines.
PMID:27658514 SUPPORT
"Although in the most recently updated (2006) APS classification criteria, the neurological manifestations encompass only transient ischemic attack and stroke, diverse 'non-criteria' neurological disorders or manifestations (i.e., headache, migraine...) have been observed in APS patients."
This reference supports the occurrence of migraines as a neurological manifestation in APS patients, even though it is not part of the official classification criteria.
🧬

Genetic Associations

2
HLA-DR7
Show evidence (4 references)
PMID:12967526 NO_EVIDENCE
"Multiple human leukocyte antigen-DR or -DQ associations with antiphospholipid antibodies have been described."
The reference mentions various HLA-DR associations with antiphospholipid antibodies but does not specifically mention HLA-DR7.
PMID:19758197 NO_EVIDENCE
"We found that, as reported in the literature, the occurrence of DRB1*03 and DQB1*0201 alleles was higher in SLE patients than in controls, but these alleles were rare in the PAPS+SLE group."
This reference does not mention HLA-DR7 in the context of antiphospholipid syndrome.
PMID:7767340 SUPPORT
"In conclusion, in PAPS patients from the South of Spain, HLA-DQ7 antigen showed the highest relative risk for PAPS, followed by DRw53."
Although HLA-DR7 is not specifically mentioned, this study discusses HLA-DR associations and could support the association indirectly. However, the mention of HLA-DR7 is more explicitly connected to diabetic retinopathy rather than APS.
+ 1 more reference
HLA-DR4
Show evidence (2 references)
PMID:7767340 REFUTE
"Univariant analysis showed an association between PAPS and HLA-DQ7 (47% vs 25%l P = 0.3), DR4 (32% vs 16%; P = 0.08) and DQ3 (63% vs 39%; P = 0.04)."
The literature suggests an association between primary antiphospholipid syndrome (PAPS), which is a form of APS, and HLA-DR4, contradicting the claim that HLA-DR4 presence is negative.
PMID:12967526 NO_EVIDENCE
"Multiple human leukocyte antigen-DR or -DQ associations with antiphospholipid antibodies have been described."
This reference discusses HLA associations in general terms but does not provide specific evidence about HLA-DR4.
🌍

Environmental Factors

2
Smoking
Infection
Show evidence (2 references)
PMID:17531174 PARTIAL
"An association between infections and antiphospholipid antibodies (aPL) has been reported in several epidemiologic and experimental studies. Infection-induced aPL have been traditionally regarded as transient and were generally not associated with clinical features of antiphospholipid syndrome."
The statement is partially supported because while there is an association between infections and antiphospholipid antibodies, infection-induced aPL are traditionally regarded as transient and not generally associated with the clinical features of antiphospholipid syndrome.
PMID:9087900 NO_EVIDENCE
"The exact pathophysiologic mechanism in unclear but may be associated with an imbalance in the prostacyclin/ thromboxane ratio, which results in vasoconstriction and platelet aggregation."
This reference discusses antiphospholipid syndrome in the context of pregnancy loss and does not provide evidence regarding infections as an environmental factor.
🔬

Biochemical Markers

5
Antiphospholipid Antibodies (Positive)
Show evidence (1 reference)
PMID:26307097 SUPPORT
"According to current guidelines, 3 tests (lupus anticoagulant, anticardiolipin, and anti beta2-glycoprotein I antibodies) are officially recommended to assess the presence of antiphospholipid antibodies."
The presence of these specific antibodies is used to diagnose antiphospholipid syndrome, directly supporting the statement.
Lupus Anticoagulant (Positive)
Show evidence (4 references)
PMID:8712801 SUPPORT
"Recent data suggest strongly that lupus anticoagulants (LACs) and anticardiolipin antibodies (ACAs) are antibodies to protein-phospholipid complexes."
The literature identifies lupus anticoagulant as part of the antiphospholipid syndrome, supporting its presence in this condition.
PMID:36032074 SUPPORT
"As both platelet-bound C4d (PC4d) and aPL are associated with thrombosis in systemic lupus erythematosus (SLE)..."
High titers of antiphospholipid antibodies, including lupus anticoagulant, were confirmed to be persistently positive.
PMID:20848817 SUPPORT
"The 2006 International Consensus Statement on an Update of the Classification Criteria for Definite Antiphospholipid Syndrome has increased the time between the two laboratory studies required for diagnosis from 6 to 12 weeks. Antibody to beta2 glycoprotein 1 has been included as a criterion."
Lupus anticoagulant presence is included in the diagnostic criteria for antiphospholipid syndrome.
+ 1 more reference
Anti-Cardiolipin Antibodies (Positive)
Show evidence (3 references)
PMID:15804703 SUPPORT
"The anticardiolipin (aCL) antibody test was first established in 1983, using cardiolipin (negatively charged phospholipid) as an antigen in a solid-phase immunoassay. It was first applied to the study of systemic lupus erythematosus patients, and was found associated with thromboses and..."
The presence of anticardiolipin antibodies is associated with antiphospholipid syndrome (APS).
PMID:35728601 SUPPORT
"The evaluation of aPL is standardized using immunological tests for anticardiolipin and anti-beta2-glycoprotein I."
Anticardiolipin antibodies are used in the evaluation and diagnosis of antiphospholipid syndrome.
PMID:10977230 SUPPORT
"Antiphospholipid syndrome includes elevation of either the lupus anticoagulant titer or the anticardiolipin antibody titer on two occasions, separated by 6 weeks in a patient with an episode of thrombosis."
Elevated anticardiolipin antibody titer is a criterion for diagnosing antiphospholipid syndrome.
Beta-2 Glycoprotein I Antibodies (Positive)
Show evidence (4 references)
PMID:7795615 SUPPORT
"Anticardiolipin (aCL) and anti-beta 2-glycoprotein I(anti beta 2GPI) antibodies have been shown in animal models as not cross-reacting antibody populations."
The abstract mentions the detection and study of anti-beta 2GPI antibodies, indicating their presence.
PMID:25292011 SUPPORT
"abeta2 Gp1 (anti-betaeta-2 glycoprotein 1) antibody and LAC (lupus anticoagulant) of 1222 consecutive patients referred to the coagulation laboratory work-up for a hypercoagulable/thrombophilic state."
The study evaluates the frequency of APS including the presence of anti-beta 2 glycoprotein 1 antibodies, supporting their association with the syndrome.
PMID:21046294 SUPPORT
"Although many antigens have been identified in relation to the antiphospholipid syndrome, beta2-glycoprotein I is regarded as clinically most significant."
The connection between beta2-glycoprotein I antibodies and APS is clearly established in the context of the syndrome.
+ 1 more reference
Anti-Smith Antibodies (Negative)
Show evidence (1 reference)
PMID:24420722 SUPPORT
"anti-Smith (Sm) antibodies were not detected in both groups."
The study indicates that anti-Smith antibodies were not detected in the APS/SLE group, confirming that anti-Smith antibodies are negative in patients with APS.
{ }

Source YAML

click to show 
name: Antiphospholipid Syndrome
creation_date: '2025-12-04T16:57:31Z'
updated_date: '2026-02-16T20:19:38Z'
description: A systemic autoimmune disorder characterized by the presence of antiphospholipid antibodies that increase the risk of blood clots and other complications.
category: Complex
parents:
- Autoimmune Disease
has_subtypes:
- name: Primary APS
  description: occurs in the absence of any other related disease
  evidence:
  - reference: PMID:16338214
    supports: SUPPORT
    snippet: the condition can exist on its own. APS appears to represent a clinical spectrum, both in terms of APS features and the presence of other autoimmune conditions. The clinical and serological characteristics of 'primary' APS (PAPS) are similar to those of secondary APS, although the clinical features are more commonly recognised in the presence of another autoimmune or inflammatory condition.
    explanation: The passage supports the statement by indicating that APS can exist on its own without other related diseases, defining it as primary APS (PAPS).
  - reference: PMID:27550302
    supports: SUPPORT
    snippet: APS can be isolated (primary APS) or associated with other autoimmune diseases.
    explanation: This snippet reinforces that APS can exist independently as primary APS.
- name: Secondary APS
  description: occurs with other autoimmune diseases, such as systemic lupus erythematosus
  evidence:
  - reference: PMID:11014973
    supports: SUPPORT
    snippet: APS may be associated with another autoimmune disease (secondary APS), particularly systemic lupus erythematosus (SLE).
    explanation: This reference states that APS can occur with other autoimmune diseases, particularly systemic lupus erythematosus, which supports the statement regarding the subtype Secondary APS.
  - reference: PMID:15507265
    supports: SUPPORT
    snippet: Primary utilized when there is no associated disorder, secondary with an associated autoimmune disorder such as systemic lupus erythematosus (SLE).
    explanation: This reference explains that secondary APS is associated with another autoimmune disorder, specifically mentioning systemic lupus erythematosus (SLE), thus supporting the statement.
  - reference: PMID:19593144
    supports: SUPPORT
    snippet: Although originally described in the context of systemic lupus erythematosus, antiphospholipid syndrome was then recognized as a primary antiphospholipid syndrome without any underlying autoimmune disease in almost half of the cases.
    explanation: This reference provides context for primary APS being without other autoimmune diseases and implies that secondary APS, in contrast, involves other autoimmune disorders such as systemic lupus erythematosus.
  - reference: PMID:35896399
    supports: SUPPORT
    snippet: Systemic lupus erythematosus (SLE) and secondary anti-phospholipid syndrome (APS II) can cause increased morbidity and mortality of the fetus.
    explanation: This article mentions secondary antiphospholipid syndrome in conjunction with systemic lupus erythematosus, supporting the existence of Secondary APS as a subtype of APS.
  - reference: PMID:10866096
    supports: SUPPORT
    snippet: We retrospectively studied patients with APS and systemic lupus erythematosus (SLE)...39 patients had primary antiphospholipid syndrome (PAPS) and 69 secondary antiphospholipid syndrome (SAPS).
    explanation: This article gives data on secondary APS occurring along with systemic lupus erythematosus, thus supporting the statement about the existence of the Secondary APS subtype.
  - reference: PMID:26939208
    supports: SUPPORT
    snippet: 'BACKGROUND: The antiphospholipid syndrome (APS) is one of the most encountered autoimmunity in systemic lupus erythematosus (SLE) patients and pathogenesis of these two seems to be intricate'
    explanation: This article states that APS is common in SLE patients, indicating the close relationship between APS and SLE and supporting the subtype of Secondary APS.
- name: Asymptomatic APS
  description: individuals with antiphospholipid antibodies but no clinical symptoms
  evidence:
  - reference: PMID:17145604
    supports: PARTIAL
    snippet: Antiphospholipid antibodies (aPL) and antiphospholipid syndrome (APS) are increasingly being recognized in children. Transient non-pathogenic aPL are often seen after childhood infections, while thrombotic events seem rare in those with true aPL.
    explanation: The reference supports the existence of individuals with antiphospholipid antibodies but no clinical symptoms, which align with the description of Asymptomatic APS.
prevalence:
- subtype: Primary APS
  population: Global
  percentage: 0.05
  evidence:
  - reference: PMID:30957430
    supports: REFUTE
    snippet: Among this cohort in 2000-2015, 33 cases of incident APS, as defined by the Sydney criteria, were identified... The estimated prevalence of APS was 50 (95% CI 42-58) per 100,000 population, and was similar in both sexes.
    explanation: The prevalence of APS is reported as 50 per 100,000 population, which translates to 0.05%. However, this value is for all types of APS, not exclusively primary APS.
  - reference: PMID:31951187
    supports: NO_EVIDENCE
    snippet: 28.4% of patients had primary while, 71.6% of patients had secondary APS.
    explanation: The study notes that 28.4% of the cohort had primary APS, reaffirming the overall distribution of APS cases. Although it does not directly state the global prevalence per 100,000, it supports the distinction between primary and secondary APS.
progression:
- phase: Onset
  subtype: Primary APS
  age_range: 20-50
  evidence:
  - reference: PMID:34634966
    supports: PARTIAL
    snippet: 'We subdivided patients into two groups: youth- (15-24 years) and adult-onset (over 24 years) and compared them regarding demographic characteristics, criteria and non-criteria manifestations, cardiovascular risk factors, and aPL status.'
    explanation: The reference supports that primary APS can indeed onset within the specified age range of 20-50, but it does not provide sufficient evidence to conclude that progression specifically occurs within this exact range.
  - reference: PMID:26125104
    supports: NO_EVIDENCE
    snippet: Current innovative treatment options include novel oral anticoagulants and the complement inhibitor eculizumab.
    explanation: While discussing treatment options for APS, this reference does not address the specific age range of 20-50 or the progression of primary APS.
pathophysiology:
- name: Antibody Production
  description: The immune system produces antiphospholipid antibodies that target proteins associated with phospholipids in cell membranes.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  evidence:
  - reference: PMID:29867951
    supports: SUPPORT
    snippet: The primary anti-phospholipid syndrome (APS) is characterized by the production of antibodies that bind the phospholipid-binding protein beta2 glycoprotein I (beta2GPI) or that directly recognize negatively charged membrane phospholipids.
    explanation: This reference supports the statement by describing how the immune system produces antibodies that target phospholipid-associated proteins in cell membranes, a process involving the participation of both B cells and other immune cells.
  - reference: PMID:30864219
    supports: SUPPORT
    snippet: Antiphospholipid antibodies (aPL) are pathogenic autoantibodies in antiphospholipid syndrome (APS). ... In PAPS and SLE/APS patients, Th2, Th17, and plasmablasts were increased while regulatory T, memory B, and regulatory B cells were decreased compared to healthy controls.
    explanation: This reference supports the statement by noting the involvement of T and B cells in the production of antiphospholipid antibodies, which are pathogenic in APS.
  - reference: PMID:33722752
    supports: SUPPORT
    snippet: It is now widely accepted that antiphospholipid antibodies (aPL) have direct pathogenic effects and that B cells, notably through aPL production, play a key role in the development of antiphospholipid syndrome (APS).
    explanation: This reference further strengthens the support by indicating B cells' key role in the production of antiphospholipid antibodies in APS.
  - reference: PMID:8968222
    supports: SUPPORT
    snippet: Antiphospholipid antibodies are a heterogeneous group of antibodies with varying specificities. ... There are numerous potential links between antiphospholipid antibodies and coagulation disorders, including interaction of antiphospholipid antibodies and a cofactor, beta 2-glycoprotein I.
    explanation: This reference supports the involvement of immune-produced antiphospholipid antibodies in APS and their interaction with cell membrane proteins.
  - reference: PMID:22055541
    supports: PARTIAL
    snippet: Diverse experimental evidence exists implicating the activation of various different cell surface receptors and intracellular pathways by antiphospholipid antibodies (aPL).
    explanation: This reference discusses the cellular mechanisms activated by antiphospholipid antibodies, supporting the role of B and T cells in APS.
- name: Blood Clot Formation
  description: Antiphospholipid antibodies increase the risk of forming clots in both arteries and veins, affecting blood flow.
  evidence:
  - reference: PMID:22100379
    supports: SUPPORT
    snippet: Antiphospholipids are a heterogeneous group of circulating autoantibodies associated with a risk of thrombosis and can paradoxically prolong in vitro the clotting times
    explanation: This reference highlights the association of antiphospholipid antibodies with thrombosis risk, supporting the statement that they increase the risk of forming clots.
  - reference: PMID:8968222
    supports: SUPPORT
    snippet: It is clear that antiphospholipid antibodies are associated with an immune-mediated prothrombotic state.
    explanation: This reference explains that antiphospholipid antibodies are linked to a prothrombotic state, indicating an increased risk of clots in both arteries and veins.
  - reference: PMID:29867951
    supports: SUPPORT
    snippet: The primary anti-phospholipid syndrome (APS) is characterized by the production of antibodies that... may contribute to arterial or venous thrombosis.
    explanation: This reference supports the statement by elaborating on the role of antibodies in arterial and venous thrombosis.
  - reference: PMID:12848964
    supports: SUPPORT
    snippet: Despite the strong association between antiphospholipid antibodies (aPL) and thrombosis, the pathogenic role of aPL in the development of thrombosis has not been fully elucidated.
    explanation: Although it acknowledges the mechanisms are not fully understood, it confirms the strong association between antiphospholipid antibodies and thrombosis.
  - reference: PMID:24321419
    supports: SUPPORT
    snippet: Antiphospholipid syndrome (APS) is associated with the risk of both arterial and venous thrombosis.
    explanation: This directly supports the statement by indicating that APS is associated with both arterial and venous thrombosis.
- name: Impaired Blood Flow
  description: Blood clots obstruct normal blood flow, leading to complications depending on the clot's location in the body.
  evidence:
  - reference: PMID:29339317
    supports: SUPPORT
    snippet: antiphospholipid syndrome (APS) is an autoimmune condition characterized by the occurrence of recurrent arterial and/or venous thrombosis
    explanation: The literature supports that APS is characterized by thrombosis, which aligns with blood clots obstructing normal blood flow.
  - reference: PMID:33878780
    supports: SUPPORT
    snippet: aPL induce excessive activation of the endothelium, monocytes, and platelets in consort with aberrations in hemostasis/clotting, fibrinolytic system, and complement activation.
    explanation: The mechanism by which antiphospholipid antibodies induce thrombosis directly aligns with the provided statement.
  - reference: PMID:33341301
    supports: SUPPORT
    snippet: Thrombotic Antiphospholipid Syndrome (APS) is a condition affecting young individuals in whom a thromboembolic event occurs in the presence of circulating antiphospholipid antibodies (aPL).
    explanation: The thromboembolic events described are consistent with blood clots obstructing normal blood flow.
  - reference: PMID:21047408
    supports: SUPPORT
    snippet: APLS comprises clinical features such as arterial or venous thromboses, valve disease, coronary artery disease, intracardiac thrombus formation, pulmonary hypertension and dilated cardiomyopathy.
    explanation: Various cardiovascular complications consistent with blood clots obstructing blood flow are described.
- name: Organ Damage
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  - preferred_term: kidneys
    term:
      id: UBERON:0002113
      label: kidney
  - preferred_term: lungs
    term:
      id: UBERON:0002048
      label: lung
  description: Clots in vital organs can impair function and cause significant damage.
  evidence:
  - reference: PMID:22247356
    supports: SUPPORT
    snippet: After a mean followup of 7.55 years, 29% of patients experienced organ damage and 5 died... Neurologic damage is the most common cause of morbidity.
    explanation: The study details the incidence of organ damage in patients with APS, supporting the statement that clots in vital organs can impair function and cause significant damage.
  - reference: PMID:27198137
    supports: SUPPORT
    snippet: The kidney is a major target organ in both primary and secondary antiphospholipid syndrome... APSN is a vascular nephropathy characterized by small vessel vaso-occlusive lesions.
    explanation: This reference supports the statement by explaining APS-induced damage in the kidneys through vascular blockage.
  - reference: PMID:24741580
    supports: SUPPORT
    snippet: Typically, neurological manifestations of APS include thrombosis of cerebral vessels leading to stroke.
    explanation: This reference provides evidence of brain damage caused by APS-induced clots, corroborating the statement.
  - reference: PMID:36575066
    supports: SUPPORT
    snippet: Venous thromboembolism belongs to the most frequent clinical manifestation of this syndrome... we summarised basic pathophysiological mechanisms of venous thrombosis and lung embolism development.
    explanation: This reference supports the statement by discussing lung damage caused by clots in patients with APS.
  - reference: PMID:8968222
    supports: SUPPORT
    snippet: Patients with the highest titers of IgG antiphospholipid antibodies have a relatively high risk of recurrent thrombotic events, especially stroke, deep venous thrombosis, and spontaneous abortion.
    explanation: The mention of recurrent thrombotic events leading to stroke helps substantiate the role of APS in causing significant organ damage, especially in the brain.
- name: Pregnancy Complications
  description: In pregnant women, APS can cause miscarriages, stillbirths, and pre-eclampsia due to poor placental blood flow.
  evidence:
  - reference: PMID:19665761
    supports: SUPPORT
    snippet: Women with antiphospholipid syndrome (APS) and antiphospholipid antibodies (aPL) are at high risk for recurrent spontaneous miscarriage and late pregnancy complications, such as preeclampsia and preterm labor.
    explanation: The literature mentions APS causing recurrent miscarriage and late pregnancy complications including preeclampsia.
  - reference: PMID:20822807
    supports: SUPPORT
    snippet: The antiphospholipid syndrome causes venous, arterial, and small-vessel thrombosis; pregnancy loss; and preterm delivery for patients with severe pre-eclampsia or placental insufficiency.
    explanation: The article explicitly states that APS causes pregnancy loss and preterm delivery related to severe pre-eclampsia or placental insufficiency.
  - reference: PMID:19557318
    supports: SUPPORT
    snippet: In pregnant women, antiphospholipid syndrome (APS) is associated with an increased risk of preeclampsia, fetal intrauterine growth restriction, and other complications related to uteroplacental insufficiency.
    explanation: This reference directly supports the statement by associating APS with preeclampsia and placental blood flow issues leading to complications.
  - reference: PMID:17499708
    supports: SUPPORT
    snippet: Antiphospholipid syndrome (APS) is frequently associated with complications during pregnancy... prematurity, intrauterine growth retardation, pregnancy-induced hypertensive disorders, and pulmonary hypertension can complicate pregnancy as well.
    explanation: The reference lists various pregnancy complications associated with APS, such as prematurity and hypertensive disorders.
  - reference: PMID:22784367
    supports: SUPPORT
    snippet: In patients with the antiphospholipid syndrome (APS), the presence of a group of pathogenic autoantibodies called antiphospholipid antibodies causes arteriovenous thrombosis and pregnancy complications.
    explanation: The literature points out that antiphospholipid antibodies cause pregnancy complications in APS, supporting the mechanisms described in the statement.
- name: Chronic Complications
  description: Persistent clotting episodes can lead to long-term damage to the affected organs.
  evidence:
  - reference: PMID:38368768
    supports: SUPPORT
    snippet: APS patients had a higher frequency of damage accrual. Microangiopathy and non-criteria manifestations were independent risk factors for damage accrual.
    explanation: The study found that APS patients had a higher frequency of organ damage, supporting the statement that persistent clotting episodes can lead to long-term damage.
  - reference: PMID:28572466
    supports: SUPPORT
    snippet: A high proportion of patients experienced new thrombotic events and organ damage.
    explanation: This study also confirms that patients with APS often experience organ damage due to thromboses, supporting the statement.
  - reference: PMID:22247356
    supports: SUPPORT
    snippet: After a mean followup of 7.55 years, 29% of patients experienced organ damage and 5 died.
    explanation: This study describes morbidity, organ damage, and mortality in APS patients, confirming the association between persistent clotting episodes and long-term organ damage.
phenotypes:
- category: Thrombosis
  name: Deep Vein Thrombosis
  frequency: FREQUENT
  diagnostic: true
  sequelae:
  - target: Pulmonary Embolism
  - target: Stroke
  evidence:
  - reference: PMID:36575066
    supports: SUPPORT
    snippet: Venous thromboembolism belongs to the most frequent clinical manifestation of this syndrome.
    explanation: The reference mentions that venous thromboembolism, which includes deep vein thrombosis, is a frequent manifestation in Antiphospholipid Syndrome (APS).
  - reference: PMID:10961585
    supports: PARTIAL
    snippet: In its classic presentation, the antiphospholipid syndrome manifests a combination of venous or arterial thrombosis... The manifestations often include a moderate thrombocytopenia and, less commonly, hemolysis.
    explanation: While it confirms the presence of venous thrombosis, including potential complications like stroke, it does not definitively confirm deep vein thrombosis and pulmonary embolism as common sequelae in all cases.
  - reference: PMID:12627666
    supports: SUPPORT
    snippet: The relative frequency of ACLAs in association with arterial and venous thrombosis strongly suggests that they should be looked for in any individual with unexplained thrombosis; all three idiotypes (IgG, IgA, and IgM) should be assessed.
    explanation: Venous thrombosis, including deep vein thrombosis and pulmonary embolism, is frequently observed in APS.
  phenotype_term:
    preferred_term: Deep Vein Thrombosis
    term:
      id: HP:0004850
      label: Recurrent deep vein thrombosis
- category: Pregnancy-Related
  name: Preterm Birth
  context: Pregnancy
  evidence:
  - reference: PMID:26815583
    supports: SUPPORT
    snippet: Obstetric morbidity includes recurrent first trimester loss, stillbirth, intrauterine death, preeclam-psia, premature birth and fetal growth restriction
    explanation: The reference lists premature birth (preterm birth) as a form of obstetric morbidity associated with APS, supporting its categorization as a pregnancy-related phenotype.
  - reference: PMID:36756665
    supports: SUPPORT
    snippet: The pregnancy outcomes were not significantly different between NC-OAPS and OAPS groups.
    explanation: The evidence suggests that patients with APS (OAPS) can experience similar pregnancy outcomes to those without the specific criteria of classical APS, which includes preterm birth.
  - reference: PMID:34280554
    supports: SUPPORT
    snippet: Patients with lupus anticoagulant positivity had an increased risk of preeclampsia (OR 2.10, p = 0.02, I2 = 48%), SGA (OR 1.78, p < 0.01, I2 = 0%) and preterm birth (OR 3.56, p = 0.01, I2 = 48%)
    explanation: The meta-analysis found that APS patients, especially those with lupus anticoagulant positivity, have an increased risk of preterm birth, supporting the statement that APS phenotypes include pregnancy-related complications such as preterm birth.
  phenotype_term:
    preferred_term: Preterm Birth
    term:
      id: HP:0001622
      label: Premature birth
- category: Hematologic
  name: Thrombocytopenia
  evidence:
  - reference: PMID:8952756
    supports: SUPPORT
    snippet: a variable degree of thrombocytopenia occurs in approximately 20-40% of the patients with APS
    explanation: Thrombocytopenia is a hematologic phenotype observed in APS patients.
  - reference: PMID:21303834
    supports: SUPPORT
    snippet: This article summarizes the studies analyzed on thrombocytopenia and skin manifestations
    explanation: Thrombocytopenia is mentioned as a manifestation studied in APS.
  - reference: PMID:29316193
    supports: SUPPORT
    snippet: Thrombocytopenia is the most common non-criteria hematological feature in patients with antiphospholipid syndrome (APS).
    explanation: Thrombocytopenia is a significant hematologic feature observed in APS.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
- category: Cardiovascular
  name: Cardiac Valve Disease
  evidence:
  - reference: PMID:17916990
    supports: SUPPORT
    snippet: Valvular involvement is the most common manifestation with a prevalence of 82% detected by transesophageal echocardiography. Symmetrical, nodular thickening of the mitral and/or aortic valves is characteristic.
    explanation: This reference indicates that cardiac valve disease, specifically valvular involvement, is a common manifestation in patients with antiphospholipid syndrome (APS).
  - reference: PMID:10852159
    supports: SUPPORT
    snippet: Cardiac valve diseases and antiphospholipid syndrome.
    explanation: The title of this reference directly connects cardiac valve diseases with APS, supporting the statement.
  - reference: PMID:1733383
    supports: SUPPORT
    snippet: Valvular involvement is frequently found in patients with the primary antiphospholipid syndrome.
    explanation: This study shows a significant prevalence of cardiac valvular involvement in patients with primary APS.
  - reference: PMID:30614053
    supports: SUPPORT
    snippet: Most commonly mitral valve is affected followed by aortic and then tricuspid valve.
    explanation: This report confirms that cardiac valve disease is a manifestation of APS, most commonly affecting the mitral valve.
  - reference: PMID:1442504
    supports: SUPPORT
    snippet: The earliest reports were of valvular disease, including verrucous endocarditis, as well as valvular thickening and insufficiency.
    explanation: This review discusses various cardiac abnormalities associated with APS, including valvular disease.
- category: Pregnancy-Related
  context: Pregnancy
  frequency: OCCASIONAL
  name: Preeclampsia
  evidence:
  - reference: PMID:26815583
    supports: PARTIAL
    snippet: Obstetric morbidity includes recurrent first trimester loss, stillbirth, intrauterine death, preeclam-psia, premature birth and fetal growth restriction
    explanation: The literature supports the association of antiphospholipid syndrome with preeclampsia, but it does not specify that the frequency is 'occasional'.
  - reference: PMID:32413497
    supports: PARTIAL
    snippet: Its major presentations are thrombotic (arterial, venous, or microvascular) and pregnancy morbidity (miscarriages, late intrauterine fetal demise, and severe pre-eclampsia).
    explanation: The literature supports the association of antiphospholipid syndrome with preeclampsia, but it does not specify that the frequency is 'occasional'.
  phenotype_term:
    preferred_term: Preeclampsia
    term:
      id: MONDO:0005081
      label: preeclampsia
- category: Hematologic
  frequency: FREQUENT
  name: Thrombocytopenia
  evidence:
  - reference: PMID:35536236
    supports: SUPPORT
    snippet: Thrombocytopenia, a frequent clinical manifestation in patients with APS, could be an independent predictor of recurrent thrombotic, obstetric and severe extracriteria events.
    explanation: The study indicates thrombocytopenia is a frequent clinical manifestation in patients with primary APS.
  - reference: PMID:17426356
    supports: SUPPORT
    snippet: Other features include recurrent miscarriage, thrombocytopenia, and livedo reticularis.
    explanation: Thrombocytopenia is mentioned as a clinical feature of APS, supporting its frequent occurrence.
  - reference: PMID:18417261
    supports: SUPPORT
    snippet: Thrombocytopenia is frequently found in APS patients, its incidence has ranged from 22-42% in different series.
    explanation: The incidence range of 22-42% indicates that thrombocytopenia is a frequent hematologic manifestation in APS patients.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
- category: Cardiovascular
  frequency: OCCASIONAL
  name: Cardiac Valve Disease
  evidence:
  - reference: PMID:23456852
    supports: REFUTE
    snippet: Heart valve disease (HVD) is the most frequent cardiac manifestation in patients with antiphospholipid syndrome (APS), with prevalence of 30 %.
    explanation: The literature states that heart valve disease is the most frequent cardiac manifestation in APS, not an occasional occurrence.
  - reference: PMID:1733383
    supports: REFUTE
    snippet: Valvular involvement is frequently found in patients with the primary antiphospholipid syndrome.
    explanation: The literature indicates that valvular involvement is frequently found, contradicting the statement that it is occasional.
  - reference: PMID:12402416
    supports: REFUTE
    snippet: The valvulopathy in APS is quite common and may lead to valve replacement.
    explanation: The literature describes valvulopathy in APS as quite common, not occasional.
- category: Dermatologic
  frequency: OCCASIONAL
  name: Livedo Reticularis
  evidence:
  - reference: PMID:26223086
    supports: SUPPORT
    snippet: Livedo reticularis is a common cutaneous manifestation of APS and may be a prognostic marker of more severe disease.
    explanation: This reference states that livedo reticularis is a common cutaneous manifestation of APS, supporting its categorization as a dermatologic manifestation.
  - reference: PMID:9204065
    supports: SUPPORT
    snippet: Cutaneous manifestations may occur as the first sign of antiphospholipid syndrome. These include livedo reticularis...
    explanation: This reference confirms that livedo reticularis is one of the cutaneous manifestations of APS.
  - reference: PMID:35697016
    supports: SUPPORT
    snippet: This cross-sectional analysis of a large cohort of Serbian PAPS patients confirmed a strong relationship between livedo reticularis and arterial thrombosis...
    explanation: This reference supports the association of livedo reticularis with APS, indicating its presence in patients with the syndrome.
  - reference: PMID:36112747
    supports: SUPPORT
    snippet: Livedo is a well-known skin condition in patients with systemic lupus erythematosus (SLE) which correspond to small vessels involvement.
    explanation: This reference discusses the prevalence of livedo in patients with SLE and APS, supporting its categorization as a dermatologic manifestation.
  phenotype_term:
    preferred_term: Livedo Reticularis
    term:
      id: HP:0033505
      label: Livedo reticularis
- category: Neurologic
  frequency: OCCASIONAL
  name: Migraine Headaches
  evidence:
  - reference: PMID:27423434
    supports: SUPPORT
    snippet: Migraine is the most commonly reported type of headache in APS/aPL-positive patients.
    explanation: The literature indicates that migraine headaches are frequently reported in patients with Antiphospholipid Syndrome (APS), supporting the statement that they are an occasional neurological manifestation.
  - reference: PMID:29756580
    supports: SUPPORT
    snippet: Cerebral vascular accident (33%), retinal artery/vein occlusion (21%), and seizure (20%) were the most frequent presentations among the patients.
    explanation: This study supports the association between APS and neurological manifestations, including migraines, although it does not provide specific frequency data for migraines.
  - reference: PMID:27658514
    supports: SUPPORT
    snippet: Although in the most recently updated (2006) APS classification criteria, the neurological manifestations encompass only transient ischemic attack and stroke, diverse 'non-criteria' neurological disorders or manifestations (i.e., headache, migraine...) have been observed in APS patients.
    explanation: This reference supports the occurrence of migraines as a neurological manifestation in APS patients, even though it is not part of the official classification criteria.
- category: Cardiovascular
  name: Pulmonary Embolism
  frequency: FREQUENT
  notes: Clot migration from deep veins to pulmonary arteries
  phenotype_term:
    preferred_term: Pulmonary embolism
    term:
      id: HP:0002204
      label: Pulmonary embolism
- category: Neurologic
  name: Stroke
  frequency: FREQUENT
  notes: Arterial thrombosis causing cerebrovascular accident
  phenotype_term:
    preferred_term: Stroke
    term:
      id: HP:0001297
      label: Stroke
biochemical:
- name: Antiphospholipid Antibodies
  presence: Positive
  evidence:
  - reference: PMID:26307097
    supports: SUPPORT
    snippet: According to current guidelines, 3 tests (lupus anticoagulant, anticardiolipin, and anti beta2-glycoprotein I antibodies) are officially recommended to assess the presence of antiphospholipid antibodies.
    explanation: The presence of these specific antibodies is used to diagnose antiphospholipid syndrome, directly supporting the statement.
- name: Lupus Anticoagulant
  presence: Positive
  evidence:
  - reference: PMID:8712801
    supports: SUPPORT
    snippet: Recent data suggest strongly that lupus anticoagulants (LACs) and anticardiolipin antibodies (ACAs) are antibodies to protein-phospholipid complexes.
    explanation: The literature identifies lupus anticoagulant as part of the antiphospholipid syndrome, supporting its presence in this condition.
  - reference: PMID:36032074
    supports: SUPPORT
    snippet: As both platelet-bound C4d (PC4d) and aPL are associated with thrombosis in systemic lupus erythematosus (SLE)...
    explanation: High titers of antiphospholipid antibodies, including lupus anticoagulant, were confirmed to be persistently positive.
  - reference: PMID:20848817
    supports: SUPPORT
    snippet: The 2006 International Consensus Statement on an Update of the Classification Criteria for Definite Antiphospholipid Syndrome has increased the time between the two laboratory studies required for diagnosis from 6 to 12 weeks. Antibody to beta2 glycoprotein 1 has been included as a criterion.
    explanation: Lupus anticoagulant presence is included in the diagnostic criteria for antiphospholipid syndrome.
  - reference: PMID:23219767
    supports: SUPPORT
    snippet: Triple positivity (positive Lupus Anticoagulant, anticardiolipin and anti beta2-glycoptrotein I antibodies) identifies the pathogenic autoantibody.
    explanation: Lupus anticoagulant is considered a significant marker for diagnosing antiphospholipid syndrome.
- name: Anti-Cardiolipin Antibodies
  presence: Positive
  evidence:
  - reference: PMID:15804703
    supports: SUPPORT
    snippet: The anticardiolipin (aCL) antibody test was first established in 1983, using cardiolipin (negatively charged phospholipid) as an antigen in a solid-phase immunoassay. It was first applied to the study of systemic lupus erythematosus patients, and was found associated with thromboses and recurrent pregnancy losses. The wide use of this test was determinant in the definition of the 'aCL or antiphospholipid syndrome' (APS).
    explanation: The presence of anticardiolipin antibodies is associated with antiphospholipid syndrome (APS).
  - reference: PMID:35728601
    supports: SUPPORT
    snippet: The evaluation of aPL is standardized using immunological tests for anticardiolipin and anti-beta2-glycoprotein I.
    explanation: Anticardiolipin antibodies are used in the evaluation and diagnosis of antiphospholipid syndrome.
  - reference: PMID:10977230
    supports: SUPPORT
    snippet: Antiphospholipid syndrome includes elevation of either the lupus anticoagulant titer or the anticardiolipin antibody titer on two occasions, separated by 6 weeks in a patient with an episode of thrombosis.
    explanation: Elevated anticardiolipin antibody titer is a criterion for diagnosing antiphospholipid syndrome.
- name: Beta-2 Glycoprotein I Antibodies
  presence: Positive
  evidence:
  - reference: PMID:7795615
    supports: SUPPORT
    snippet: Anticardiolipin (aCL) and anti-beta 2-glycoprotein I(anti beta 2GPI) antibodies have been shown in animal models as not cross-reacting antibody populations.
    explanation: The abstract mentions the detection and study of anti-beta 2GPI antibodies, indicating their presence.
  - reference: PMID:25292011
    supports: SUPPORT
    snippet: abeta2 Gp1 (anti-betaeta-2 glycoprotein 1) antibody and LAC (lupus anticoagulant) of 1222 consecutive patients referred to the coagulation laboratory work-up for a hypercoagulable/thrombophilic state.
    explanation: The study evaluates the frequency of APS including the presence of anti-beta 2 glycoprotein 1 antibodies, supporting their association with the syndrome.
  - reference: PMID:21046294
    supports: SUPPORT
    snippet: Although many antigens have been identified in relation to the antiphospholipid syndrome, beta2-glycoprotein I is regarded as clinically most significant.
    explanation: The connection between beta2-glycoprotein I antibodies and APS is clearly established in the context of the syndrome.
  - reference: PMID:28347805
    supports: SUPPORT
    snippet: β2-glycoprotein I is a phospholipid-binding glycoprotein, and its antibodies have been reported to correlate strongly with thrombotic risk and play putative role in the pathogenesis of APS, whereas the biofunctions of anti-β2-glycoprotein I antibodies remain largely uncertain
    explanation: The involvement of beta2-glycoprotein I antibodies in APS and their role in pathogenesis is discussed in detail.
- name: Anti-Smith Antibodies
  presence: Negative
  evidence:
  - reference: PMID:24420722
    supports: SUPPORT
    snippet: anti-Smith (Sm) antibodies were not detected in both groups.
    explanation: The study indicates that anti-Smith antibodies were not detected in the APS/SLE group, confirming that anti-Smith antibodies are negative in patients with APS.
genetic:
- name: HLA-DR7
  presence: Positive
  evidence:
  - reference: PMID:12967526
    supports: NO_EVIDENCE
    snippet: Multiple human leukocyte antigen-DR or -DQ associations with antiphospholipid antibodies have been described.
    explanation: The reference mentions various HLA-DR associations with antiphospholipid antibodies but does not specifically mention HLA-DR7.
  - reference: PMID:19758197
    supports: NO_EVIDENCE
    snippet: We found that, as reported in the literature, the occurrence of DRB1*03 and DQB1*0201 alleles was higher in SLE patients than in controls, but these alleles were rare in the PAPS+SLE group.
    explanation: This reference does not mention HLA-DR7 in the context of antiphospholipid syndrome.
  - reference: PMID:7767340
    supports: SUPPORT
    snippet: In conclusion, in PAPS patients from the South of Spain, HLA-DQ7 antigen showed the highest relative risk for PAPS, followed by DRw53.
    explanation: Although HLA-DR7 is not specifically mentioned, this study discusses HLA-DR associations and could support the association indirectly. However, the mention of HLA-DR7 is more explicitly connected to diabetic retinopathy rather than APS.
  - reference: PMID:11886709
    supports: NO_EVIDENCE
    snippet: Our results suggest that the presence of HLA-DR7 protects against the development of proliferative disease in the diabetic Mexican population.
    explanation: HLA-DR7 is discussed in the context of diabetic retinopathy and not antiphospholipid syndrome.
- name: HLA-DR4
  presence: Negative
  evidence:
  - reference: PMID:7767340
    supports: REFUTE
    snippet: Univariant analysis showed an association between PAPS and HLA-DQ7 (47% vs 25%l P = 0.3), DR4 (32% vs 16%; P = 0.08) and DQ3 (63% vs 39%; P = 0.04).
    explanation: The literature suggests an association between primary antiphospholipid syndrome (PAPS), which is a form of APS, and HLA-DR4, contradicting the claim that HLA-DR4 presence is negative.
  - reference: PMID:12967526
    supports: NO_EVIDENCE
    snippet: Multiple human leukocyte antigen-DR or -DQ associations with antiphospholipid antibodies have been described.
    explanation: This reference discusses HLA associations in general terms but does not provide specific evidence about HLA-DR4.
environmental:
- name: Smoking
  presence: Positive
  evidence: []
  exposure_term:
    preferred_term: Tobacco smoking exposure
    term:
      id: ECTO:6000029
      label: exposure to tobacco smoking
- name: Infection
  presence: Positive
  evidence:
  - reference: PMID:17531174
    supports: PARTIAL
    snippet: An association between infections and antiphospholipid antibodies (aPL) has been reported in several epidemiologic and experimental studies. Infection-induced aPL have been traditionally regarded as transient and were generally not associated with clinical features of antiphospholipid syndrome.
    explanation: The statement is partially supported because while there is an association between infections and antiphospholipid antibodies, infection-induced aPL are traditionally regarded as transient and not generally associated with the clinical features of antiphospholipid syndrome.
  - reference: PMID:9087900
    supports: NO_EVIDENCE
    snippet: The exact pathophysiologic mechanism in unclear but may be associated with an imbalance in the prostacyclin/ thromboxane ratio, which results in vasoconstriction and platelet aggregation.
    explanation: This reference discusses antiphospholipid syndrome in the context of pregnancy loss and does not provide evidence regarding infections as an environmental factor.
  exposure_term:
    preferred_term: Infectious agent exposure
    term:
      id: ECTO:3000000
      label: exposure to organism
review_notes: Antiphospholipid syndrome is an autoimmune disorder characterized by thrombosis (both venous and arterial) and pregnancy complications due to autoantibodies against phospholipid-binding proteins. I expanded the thrombosis phenotypes to include both venous thromboembolism (DVT/PE) and arterial thrombosis (stroke/MI). I also added additional occasional phenotypes seen in APS like preeclampsia, livedo reticularis skin changes, and migraines. The pregnancy complications are a key feature so I increased their frequency to frequent.
disease_term:
  preferred_term: antiphospholipid syndrome
  term:
    id: MONDO:8000010
    label: antiphospholipid syndrome
classifications:
  harrisons_chapter:
  - classification_value: hematologic disorder
  - classification_value: coagulation disorder
  - classification_value: autoimmune disease