User:Mhowiki/Antiphospholipid syndrome

Article Evaluation
-Overall: there is a good amount of information; however, I think it uses a lot of jargon and is written more for those with medical degree to understand compared to a lay person. It is underdeveloped in the sense that it has many sentences marked with "citation needed" (17 need citations), and there is recent literature that could be added to update the page.

-Lead section: has good flow and organization but I think a few more details could be added and removed to summarize it better. Some errors in how its conveyed.

-Treatment section: this could be expanded upon and updated. There is new research out there and while I have not read the articles yet, I am curious if it changes or supports what is written.

-Prognosis is only one section and does not mention pregnancy. I think that since this disease affects pregnancy, which this article also mentions, it should talk about prognosis for pregnancy given this disease there.

-Talk page: It has much discussion and some articles but those are old suggestions although its unclear if it was added or changed. Article is rated a c-class and mid-importance by physiology and medicine but low importance in terms of women's health.

-Grammar and organization: has most broad sections and no grammar errors I found on first glance. Organization of information within sections could improve. I feel it does not flow smoothly and subheaders for the antibodies can be confusing at times (especially in diagnosis section).

-Inconsistent time intervals between testing of lupus anticoagulant in the diagnosis section (12 weeks in criteria vs 6 weeks subheading section)

Sources

16-narrative review

Link to filtered pubmed search: https://pubmed.ncbi.nlm.nih.gov/?term=antiphospholipid+syndrome&filter=pubt.meta-analysis&filter=pubt.systematicreview&filter=datesearch.y_5

Article Plan

 * Lead section:
 * There may be in error when they talk about using heparin to treat APL. This is not discussed in treatment section and also problematic with falsely elevated PTT in some APL patients. Maybe put warfarin there or do not specify.
 * Made symptom list more nuanced
 * Epidemiology:
 * Add section and include information of race, sex, and age from risk factors section
 * Symptoms
 * removed " In patients with psychological symptoms, APS antibodies may be present in the blood and spinal fluid. " because it is primary literature
 * removed "In some cases, APS seems to cause intellectual and/or developmental disabilities in the newborn. [citation needed]." because could not find supporting secondary source to support this claim and did not have citation
 * consider adding incidental prolonged aPTT to this section (reference is https://www.jthjournal.org/article/S1538-7836(22)03725-4/fulltext )
 * Causes:
 * Add this section header and include risk factors
 * Include part of false positives antibodies after exposure
 * Pathogenesis section
 * change section name to "Mechanisms"
 * article talks about it being more common in women and during the age of 30-40. I think this demographic information should be moved to risk factor section or a new section for demographics.
 * this section may benefit from some reorganization and condensing in regards to the activation of certain parts of the cascade. I think this may be jargony and over the head of most readers. I think grouping talks about what are the antibodies implicated, what they do, and then how it relates to pregnancy could help with flow. Current research may contribute since some of the claims do not have sources
 * Diagnosis section
 * randomly talks about thrombophilia being a part of the differential but nothig else and then mentions the testing that would be done. I don't think this adds and just maybe confuse. I need to look more closely if differential diagnosis lists are included (if yes, add more; if no, take away).
 * consider adding more reasons for why lupus anticoagulant can have false positive tests. They only list infection currently.
 * Has 2006 Sydney criteria been updated since? This is the last criteria that the article is based on.
 * Consider splitting pregnancy criteria into separate bullets. As a paragraph its very dense and hard to read.
 * Correct inconsistencies in time intervals between testing of lupus anticoagulant in the diagnosis section (12 weeks in criteria vs 6 weeks in subheading section)
 * Diagnosis section should start with the three subcaterogies of antiphospholipid syndrome (primary, secondary, ect..) or at least flow better into the section if it comes after the criteria. I feel like this is also mentioned elsewhere in the article.
 * Research categories by antibody listed in this section should be moved to the research subcategory for consistency. It doesn't really have anything to do with diagnosis. Also these are from 2006, are there updated guidelines?
 * The talk on VDLR being falsely positive in the presence of lupus anticoagulant antibodies (at end of diagnosis section), should be moved to another section. Potentially either in the discussion of the antibodies themselves or their tests themselves earlier in the diagnosis section.
 * APS/PT is a new test apparently that is starting to be run. This may be interesting to mention
 * Treatment
 * Add more updated information from recent articles.
 * Talk more about DOACs vs warfarin
 * Interestingly heparin is discussed in the lead section but in this treatment section
 * Prognosis Section
 * This section is short and could be expanded if literature addresses.
 * Interestingly this section does not include prognosis for pregnancy in patients with APL. I think that may be interesting to include here. Information from another section may provide this information or I may need to find an article.
 * Removed "The long-term prognosis for APS is determined mainly by recurrent thrombosis, which may occur in up to 29% of patients, sometimes despite antithrombotic therapy.[ citation needed]" because could not find source to back up claim
 * History
 * Consider putting history as first section
 * Citations:
 * flagged: 14 (on actual doc)

Lead
Antiphospholipid syndrome, or antiphospholipid antibody syndrome (APS or APLS), is an autoimmune, hypercoagulable state caused by antiphospholipid antibodies. APS can lead to blood clots (thrombosis) in both arteries and veins, pregnancy-related complications, and other symptoms like low platelets, kidney disease, heart disease, and rash. Although the exact etiology of APS is still not clear, genetics is believed to play a key role in the development of the disease. Diagnosis is made based on symptoms and testing, but sometimes research criteria is used to aid in diagnosis. The research criteria for definite APS requires one clinical event (i.e. thrombosis or pregnancy complication) and two positive blood test results spaced at least three months apart that detect lupus anticoagulant, anti-apolipoprotein antibodies, and/or anti-cardiolipin antibodies.

Antiphospholipid syndrome can be primary or secondary. Primary antiphospholipid syndrome occurs in the absence of any other related disease. Secondary antiphospholipid syndrome occurs with other autoimmune diseases, such as systemic lupus erythematosus. In rare cases, APS leads to rapid organ failure due to generalized thrombosis; this is termed "catastrophic antiphospholipid syndrome" (CAPS or Asherson syndrome) and is associated with a high risk of death.

Antiphospholipid syndrome often requires treatment with anticoagulant medication to reduce the risk of further episodes of thrombosis and improve the prognosis of pregnancy. The anticoagulant medication used for treatment may differ depending on the circumstance, such as pregnancy.

History
Antiphospholipid syndrome was described in full in the 1980s, by E. Nigel Harris and Aziz Gharavi. They published the first papers in 1983. The syndrome was referred to as "Hughes syndrome" among colleagues after the rheumatologist Graham R.V. Hughes (St. Thomas' Hospital, London, UK), who brought together the team.

Epidemiology
Epidemiologic factors associated with APS include:


 * Genetic Markers: HLA-DR4, HLA-DR7, and HLA-DRw53
 * Race: Blacks, Hispanics, Asians, and Native Americans
 * Sex: female
 * Age: 30-40s

Signs and Symptoms
Antiphospholipid syndrome is known for causing arterial or venous blood clots, in any organ system, and pregnancy-related complications. While blood clots and pregnancy complications are the most common and diagnostic symptoms associated with APS, other organs and body parts may be affected like platelet levels, heart, kidneys, brain, and skin. Also, people with APS may have symptoms associated with other autoimmune diseases like Lupus erythematosus that are not caused by APS because APS can occur at the same time as other autoimmune diseases.

Blood clots
In APS patients, the most common venous event is deep vein thrombosis of the lower extremities, and the most common arterial event is stroke. People with a blot clot in their extremities may experience swelling, pain, or redness in the affected area. People experiencing a stroke can experience a variety of symptoms depending on what blood vessel in the brain is affected. Symptoms include but are not limited to trouble speaking, loss of sensation, or weakness in one side of the face or body. Blood clots can also occur in the lungs, which may cause trouble breathing or chest pain, and they can occur in the heart, which could lead to a heart attack.

Blood clots in patients with APS are often considered unprovoked, which means they occur in the absence of conditions that typically cause blood clots (i.e. prolonged sedentary behavior, immoblization, infection, cancer). Although, a person can develop a provoked blood clot while having APS due to APS causing an increased risk of blood clot development.

Pregnancy-related complications
In pregnant women affected by APS, there is an increased risk of recurrent miscarriage, preterm birth, intrauterine growth restriction, pre-eclampsia, eclampsia. Recurrent miscarriages associated with APS typically occur prior to 10th week of gestation, but miscarriage associated with APS can also occur after the 10th week of gestation. Certain causes must be excluded prior to attributing these complications to APS. Also, in pregnant individuals with lupus and antiphospholipid syndrome, antiphospholipid syndrome is responsible for most of the miscarriages in later trimesters.

Other signs and symptoms
Other common findings that suggest APS are low platelet count, heart valve disease, high blood pressure in the lungs, kidney disease, and a rash called livedo reticularis. There are also associations between antiphospholipid antibodies and different neurologic manifestations including headache, migraine, epilepsy, and dementia although more research is needed to prove that these symptoms are indicative of APS. Cancer is also observed to occur at the same time in some patients with APS.

Mechanisms
Antiphospholipid syndrome is an autoimmune disease, in which "antiphospholipid antibodies" react against proteins that bind to anionic phospholipids on plasma membranes. Anticardiolipin antibodies, β2glycoprotein 1, and lupus anticoagulant are antiphospholipid antibodies that are thought to clinically cause disease. These antibodies lead to blood clots and vascular disease in the presence (secondary APS) or absence of other diseases (primary APS). While the exact functions of the antibodies are not known, the activation of the clotting system is evident.

Antiphospholipid antibodies do not recognize isolated cardiolipin, but bind to a cardiolipin-β2GPI (apolipoprotein H) complex. Anti-ApoH and a subset of anti-cardiolipin antibodies bind to ApoH. [MH1] ApoH inhibits protein C, a glycoprotein with important regulatory function of coagulation (inactivates Factor Va and Factor VIIIa). Lupus anticoagulant antibodies bind to prothrombin, thus increasing its cleavage to thrombin, its active form.[ citation needed]

Other antibodies associated with APS include antibodies against protein S and annexin A5. Protein S is a co-factor of protein C, which is one of the body’s own anti-clotting factors. Annexin A5 forms a shield around negatively charged phospholipid molecules, which reduces the membrane's ability to participate in clotting. Thus, antibodies against protein S and anti-annexin A5 decrease protein C efficiency and increase phospholipid-dependent coagulation steps respectively, which leads to increased clotting potential.

The lupus anticoagulant antibodies are those that show the closest association with thrombosis; those that target β2glycoprotein 1 have a greater association with thrombosis than those that target prothrombin. Anticardiolipin antibodies are associated with thrombosis at moderate to high titres (over 40 GPLU or MPLU). Patients with both lupus anticoagulant antibodies and moderate or high titre anticardiolipin antibodies show a greater risk of thrombosis than with one alone.[ citation needed]

The increased risks of recurrent miscarriage, intrauterine growth restriction and preterm birth by antiphospholipid antibodies, as supported by in vitro studies, include decreased trophoblast viability, syncytialization and invasion, deranged production of hormones and signalling molecules by trophoblasts, as well as activation of coagulation and complement pathways.undefined due to an aPL-induced inhibition of trophoblast differentiation. A frequent cause of such complications is placental infarctions. [MH1]these conflict. read the sources and see what is correct or if somethings as lost in translation per se

Diagnosis
Diagnosis of antiphospholipid syndrome is often made through the combination of symptoms and testing. Repeat antibody testing 12 weeks after discovering the presence of APS antibodies is needed to establish a diagnosis because false positives can occur.

While APS was previously categorized into primary and secondary APS based on the absence or presence of concurrent autoimmune disease respectively, the 16th International Congress on Antiphospholipid Antibodies Task Force categorizes APS into 6 categories:


 * no symptoms in the presence of antiphospholipid antibodies
 * pregnancy related
 * blood clot (venous or arterial) related
 * microvascular (small blood vessel)
 * catastrophic
 * non-blood clot (i.e. kidney, low platelets, heart valve disease) related

In their report, they acknowledge that some individuals may qualify for more than one category based on symptoms.

Since there is no agreed upon diagnostic criteria for APS, research classification criteria is sometimes used to aid in diagnosis. The Sapporo APS classification criteria (1998, published in 1999) were replaced by the Sydney criteria in 2006. The Sydney criteria requires one clinical (thrombosis or pregnancy related) manifestation and persistent presence of one or more APS antibody. In the 2023 American College of Rheumatology and European League Against Rheumatism joint criteria they added heart related symptoms and low platelet levels as clinical criteria and changed some thresholds and specifics for antibody testing. However, all previously proposed research criteria are meant to create a standardized group of individuals with APS in order to increase accuracy in statistical analysis, so the criteria are not be representative of all individuals with APS. Thus, people who do not meet all of the criteria could still have APS.

In terms of Catastropic APS, the International Consensus Statement is commonly used for diagnosis. Based on this statement, Definite CAPS diagnosis requires:


 * Blood clot in three or more organs or tissues and
 * Development of manifestations simultaneously or in less than a week and
 * Evidence of small vessel blood clot in at least one organ or tissue and
 * Laboratory confirmation of the presence of aPL.

Differential diagnosis
For people with blood clot related APS, other conditions that can cause blood clots should be considered including but not limited to acquired blood clots, genetic thrombophilia, and paroxysmal nocturnal hemoglobinuria. Genetic thrombophilia can coexist in some patients with APS.[ citation needed]  For people with pregnancy related APS, other causes of recurrent miscarriage should be considered before the diagnosis of APS, such as genetic, structural, or immune abnormalities.

Lab testing
Antiphospholipid antibody tests are either liquid-phase coagulation assays to detect lupus anticoagulant or solid phase ELISA (enzyme-linked immunosorbent assay) to detect anti-cardiolipin antibodies and β2 glycoprotein 1. The use of testing for antibodies specific for individual targets of aPL such as phosphatidylserine is currently under debate.[ citation needed]

Lupus anticoagulant

This is tested for by using two coagulation tests that are phospholipid-sensitive, due to the heterogeneous nature of the lupus anticoagulant antibodies. A patient with lupus anticoagulant antibodies on initial screening will typically have been found to have a prolonged partial thromboplastin time (PTT) that does not correct in an 80:20 mixture with normal human plasma (50:50 mixes with normal plasma are insensitive to all but the highest antibody levels). The PTT (plus 80:20 mix), dilute Russell's viper venom time, silica clotting time and prothrombin time (using a lupus-sensitive thromboplastin) are the principal tests used for the detection of lupus anticoagulant. The Scientific and Standardization Committee (SSC) for lupus anticoagulant/antiphospholipid antibodies of the International Society on Thrombosis and Haemostasis (ISTH) no longer recommends the kaolin clotting time, dilute thromboplastin time, and Taipan/Ecarin snake venom based assays due to implementation issues from a variety of factors.

Distinguishing a lupus anticoagulant antibody from a specific coagulation factor inhibitor (e.g.: factor VIII) is normally achieved by differentiating the effects of a lupus anticoagulant on factor assays from the effects of a specific coagulation factor antibody. The lupus anticoagulant will inhibit all the contact activation pathway factors (factor VIII, factor IX, factor XI and factor XII). Lupus anticoagulant will also rarely cause a factor assay to give a result lower than 35 iu/dl (35%) whereas a specific factor antibody will rarely give a result higher than 10 iu/dl (10%). Monitoring IV anticoagulant therapy by the PTT ratio is compromised due to the effects of the lupus anticoagulant and in these situations is generally best performed using a chromogenic assay based on the inhibition of factor Xa by antithrombin in the presence of heparin.[ citation needed]

Anticardiolipin and β2glycoprotein 1 antibodies

Anti-cardiolipin antibodies can be detected using an enzyme-linked immunosorbent assay (ELISA) immunological test, which screens for the presence of β2glycoprotein 1 dependent anticardiolipin antibodies. A low platelet count and positivity for antibodies against β2-glycoprotein 1 or phosphatidylserine may also be observed in a positive diagnosis.[citation needed]

False results
The presence of antiphospholipid antibodies (aPL) may not indicate APS, which is why considering the symptoms present and retesting antibody levels is essential. People may be transiently positive, incorrectly positive, or incorrectly negative if they are tested when the following is occurring:


 * infection
 * pregnancy
 * blood clot
 * states in which acute-phase proteins, bilirubin, or fats are elevated
 * anticoagulation (i.e warfarin, heparin)

It is recommended to generally re-test people 12 weeks after the first positive test to confirm that it was correct, except for those who test positive during pregnancy. For that group, it is recommend to wait 3 months to re-test if possible. Re-testing is more nuanced if the person is taking an anticoagulant, which may require not taking the medication for a certain period of time or specifically timing the test.

Also, patients who have certain antiphospholipid antibodies may have false positive VDRL test, which aims to detect a syphilis infection. This occurs because the aPL bind to the lipids in the test and make it come out positive. A more specific test for syphilis, FTA-Abs will not have a false-positive result in the presence of aPL.[citation needed [MH1]check this because this doesn’t seem right

Treatment
Treatment depends on a person's APS symptoms. Typically a medication that decreases the body's ability to form blood clots is given to prevent future clots. Low dose aspirin can be given to people who have APS antibodies but no symptoms, high risk individuals with lupus erythematosus and APS antibodies but no symptoms of APS, and non-pregnant people who had APS during pregnancy. For those people with APS who have had a blood clot (venous or arterial), anticoagulants such as warfarin are used to prevent future clots. If warfarin is used, the INR is kept between 2.0 and 3.0. Direct-acting oral anticoagulants may be used as an alternative to warfarin, but not in people with APS who had a previous arterial blood clot or are "triple positive" with all types of antiphospholipid antibody (lupus anticoagulant, anticardiolipin antibody and anti-β2 glycoprotein I antibody). In people with arterial blood clot related APS, using direct-acting oral anticoagulants has shown to increase the risk of future arterial blood clots and should not be used.

In pregnant people with only pregnancy related APS or only past blood clot related APS, low molecular weight heparin and low-dose aspirin are used instead of warfarin because of warfarin's ability to cause birth defects. Heparin and aspirin together appears to make miscarriage less likely in pregnant women with APS. Women with recurrent miscarriages are often advised to take aspirin and to start low molecular weight heparin treatment if they become pregnant. In refractory cases plasmapheresis may be used.[ citation needed]

Prognosis
Factors that increase likelihood of developing APS related future blood clots and pregnancy complications include:


 * presence of all three antibodies (β2 glycoprotein 1, lupus anticoagulant, and anticardiolipin)
 * moderate to high titer levels of an antibody
 * presence of IgG APS antibodies

Also, a history of previous blood clots in someone with APS increases the risk for certain pregnancy complications, such as death of the child, smaller sized baby, and blood clots during and after pregnancy. Outside of people with APS having an increase risk of blood clots and pregnancy complications, people with APS generally have increase risk of atherosclerotic disease.

Other risk stratification criteria for predicting blood clots and pregnancy complications have been proposed, such as the aPL Score and the Global APS score, but further data is needed to validate these tools.

Research
APS ACTION (the AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking), is the first-ever international research network that has been created to design and conduct large-scale, multicenter clinical trials in persistently antiphospholipid antibody (aPL) positive patients. The network consists of a multidisciplinary group of physicians and investigators from around the world who are interested in antiphospholipid syndrome (APS) research. The primary mission of APS ACTION is to prevent, treat, and cure antiphospholipid antibody (aPL) associated clinical manifestations through high quality, multicenter, and multidisciplinary clinical research.[ citation needed]

According to a 2006 consensus statement, it is advisable to classify APS into one of the following categories for research purposes:

·       I: more than one laboratory criterion present in any combination;

·       IIa: lupus anticoagulant present alone

·       IIb: anti-cardiolipin IgG and/or IgM present alone in medium or high titers

·       IIc: anti-β2 glycoprotein I IgG and/or IgM present alone in a titer greater than 99th percentile