Antiphospholipid syndrome

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Antiphospholipid syndrome
Other namesHughes syndrome, [1] aCL syndrome, anticardiolipin antibody syndrome, antiphospholipid syndrome, lupus anticoagulant syndrome [2]
Thrombotic microangiopathy - very high mag.jpg
Micrograph showing an advanced thrombotic microangiopathy, as may be seen in APLA syndrome. Kidney biopsy. PAS stain.
Specialty Immunology, hematology, rheumatology

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. [3]

Contents

Diagnosis is made based on symptoms and testing, but sometimes research criteria are 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. [4]

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 generalised 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.

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. [4] [5] 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. [6] People with a blot clot in their extremities may experience swelling, pain, or redness in the affected area. [7] 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. [8] 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. [5]

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). However, a person can develop a provoked blood clot while having APS due to APS causing an increased risk of blood clot development. [5]

In pregnant people affected by APS, there is an increased risk of recurrent miscarriage, preterm birth, intrauterine growth restriction, pre-eclampsia, eclampsia. [9] [10] 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. [10] 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. [11]

Other 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. [5] There are also associations between antiphospholipid antibodies and different neurologic manifestations [12] including headache, [13] migraine, [14] epilepsy, [15] and dementia [16] 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. [17]

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 (primary APS) of other diseases. [18] While the exact functions of the antibodies are not known, the activation of the coagulation system is evident.

Anti-ApoH and a subset of anti-cardiolipin antibodies bind to ApoH. 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. [19] [20]

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. [9]

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 antiphospholipid antibodies (aPL) is needed to establish a diagnosis because false positives can occur. [4] [21] [22]

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: [5]

In their report, they acknowledge that some individuals may qualify for more than one category based on symptoms. [5]

Research criteria

Because there are no agreed upon diagnostic criteria for APS, research classification criteria are sometimes used to aid in diagnosis. [5] The Sapporo APS classification criteria (1998, published in 1999) [23] were replaced by the Sydney criteria in 2006. [10] The Sydney criteria requires one clinical (thrombosis or pregnancy related) manifestation and persistent presence of one or more APS antibody. [10] 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. [4] 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. [4] [5] 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: [24]

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. [22] 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 for lupus anticoagulant/antiphospholipid antibodies of the International Society on Thrombosis and Haemostasis 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. [21]

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 phosphatidylserine may also be observed in a positive diagnosis.[ citation needed ]

False results

The presence of antiphospholipid antibodies 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: [21]

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. [21] 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. [21]

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 ]

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.

Treatment

Treatment depends on a person's APS symptoms. [25] 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. [25] [26] For those people with APS who have had a blood clot (venous or arterial), anticoagulants such as warfarin are used to prevent future clots. [25] [26] If warfarin is used, the INR is kept between 2.0 and 3.0. [26] 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 [27] [28] or are "triple positive" with all types of antiphospholipid antibody (lupus anticoagulant, anticardiolipin antibody and anti-β2 glycoprotein I antibody). [25] [26] [29] [30] 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. [27] [28]

In pregnant women 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. [25] [26] Heparin and aspirin together appears to make miscarriage less likely in pregnant women with APS. [26] Women with recurrent miscarriages are often advised to take aspirin and to start low molecular weight heparin treatment after missing a menstrual cycle.[ citation needed] 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:

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. [31] Outside of people with APS having an increased risk of blood clots and pregnancy complications, people with APS generally have increased risk of atherosclerotic disease. [6] [32]

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. [5]

Epidemiology


References:

History

Antiphospholipid syndrome was described in full in the 1980s, by E. Nigel Harris and Aziz Gharavi. They published the first papers in 1983. [33] [34] 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.[ citation needed ]

Research

According to a 2006 Sydney consensus statement, [10] it is advisable to classify APS into one of the following categories for research purposes:

Related Research Articles

<span class="mw-page-title-main">Venereal Disease Research Laboratory test</span> Blood test for syphilis

The Venereal Disease Research Laboratory test (VDRL) is a blood test for syphilis and related non-venereal treponematoses that was developed by the eponymous US laboratory. The VDRL test is used to screen for syphilis, whereas other, more specific tests are used to diagnose the disease.

<span class="mw-page-title-main">Deep vein thrombosis</span> Formation of a blood clot (thrombus) in a deep vein

Deep vein thrombosis (DVT) is a type of venous thrombosis involving the formation of a blood clot in a deep vein, most commonly in the legs or pelvis. A minority of DVTs occur in the arms. Symptoms can include pain, swelling, redness, and enlarged veins in the affected area, but some DVTs have no symptoms.

<span class="mw-page-title-main">Bleeding diathesis</span> High tendency to bleed due to a blood clotting disorder

In medicine (hematology), bleeding diathesis is an unusual susceptibility to bleed (hemorrhage) mostly due to hypocoagulability, in turn caused by a coagulopathy. Therefore, this may result in the reduction of platelets being produced and leads to excessive bleeding. Several types of coagulopathy are distinguished, ranging from mild to lethal. Coagulopathy can be caused by thinning of the skin, such that the skin is weakened and is bruised easily and frequently without any trauma or injury to the body. Also, coagulopathy can be contributed by impaired wound healing or impaired clot formation.

<span class="mw-page-title-main">Partial thromboplastin time</span> Test for coagulation of blood

The partial thromboplastin time (PTT), also known as the activated partial thromboplastin time, is a blood test that characterizes coagulation of the blood. A historical name for this measure is the Kaolin-cephalin clotting time (KCCT), reflecting kaolin and cephalin as materials historically used in the test. Apart from detecting abnormalities in blood clotting, partial thromboplastin time is also used to monitor the treatment effect of heparin, a widely prescribed drug that reduces blood's tendency to clot.

Mixing studies are tests performed on blood plasma of patients or test subjects to distinguish factor deficiencies from factor inhibitors, such as lupus anticoagulant, or specific factor inhibitors, such as antibodies directed against factor VIII. Mixing studies are screening tests widely performed in coagulation laboratories. The basic purpose of these tests is to determine the cause of prolongation of Prothrombin Time (PT), Partial Thromboplastin Time, or sometimes of thrombin time (TT). Mixing studies take advantage of the fact that factor levels that are 50 percent of normal should give a normal Prothrombin time (PT) or Partial thromboplastin time (PTT) result.

Lupus anticoagulant is an immunoglobulin that binds to phospholipids and proteins associated with the cell membrane. Its name is a partial misnomer, as it is actually a prothrombotic antibody in vivo. The name derives from their properties in vitro, as these antibodies increase coagulation times in laboratory tests such as the activated partial thromboplastin time (aPTT). Investigators speculate that the antibodies interfere with phospholipids used to induce in vitro coagulation. In vivo, the antibodies are thought to interact with platelet membrane phospholipids, increasing adhesion and aggregation of platelets, which accounts for the in vivo prothrombotic characteristics.

<span class="mw-page-title-main">Protein S deficiency</span> Medical condition

Protein S deficiency is a disorder associated with increased risk of venous thrombosis. Protein S, a vitamin K-dependent physiological anticoagulant, acts as a nonenzymatic cofactor to activate protein C in the degradation of factor Va and factor VIIIa.

<span class="mw-page-title-main">Thrombophilia</span> Abnormality of blood coagulation increasing the risk of blood clotting (thrombosis)

Thrombophilia is an abnormality of blood coagulation that increases the risk of thrombosis. Such abnormalities can be identified in 50% of people who have an episode of thrombosis that was not provoked by other causes. A significant proportion of the population has a detectable thrombophilic abnormality, but most of these develop thrombosis only in the presence of an additional risk factor.

<span class="mw-page-title-main">Dilute Russell's viper venom time</span> Laboratory test

Dilute Russell's viper venom time (dRVVT) is a laboratory test often used for detection of lupus anticoagulant (LA). It is an assessment of the time for blood to clot in the presence of a diluted amount of venom from Russell's viper, a highly venomous snake native to the Indian subcontinent and named after the herpetologist Patrick Russell.

<span class="mw-page-title-main">Renal vein thrombosis</span> Medical condition

Renal vein thrombosis (RVT) is the formation of a clot in the vein that drains blood from the kidneys, ultimately leading to a reduction in the drainage of one or both kidneys and the possible migration of the clot to other parts of the body. First described by German pathologist Friedrich Daniel von Recklinghausen in 1861, RVT most commonly affects two subpopulations: newly born infants with blood clotting abnormalities or dehydration and adults with nephrotic syndrome.

<span class="mw-page-title-main">Hypoprothrombinemia</span> Medical condition

Hypoprothrombinemia is a rare blood disorder in which a deficiency in immunoreactive prothrombin, produced in the liver, results in an impaired blood clotting reaction, leading to an increased physiological risk for spontaneous bleeding. This condition can be observed in the gastrointestinal system, cranial vault, and superficial integumentary system, affecting both the male and female population. Prothrombin is a critical protein that is involved in the process of hemostasis, as well as illustrating procoagulant activities. This condition is characterized as an autosomal recessive inheritance congenital coagulation disorder affecting 1 per 2,000,000 of the population, worldwide, but is also attributed as acquired.

Steven Krilis is Professor of Immunology Allergies and Infectious diseases at the University of New South Wales and St George Hospital in Sydney, Australia. He is a Fellow of the Royal Australasian College of Physicians.

Catastrophic antiphospholipid syndrome (CAPS), also known as Asherson's syndrome, is a rare autoimmune disease in which widespread, intravascular clotting causes multi-organ failure. The syndrome is caused by antiphospholipid antibodies that target a group of proteins in the body that are associated with phospholipids. These antibodies activate endothelial cells, platelets, and immune cells, ultimately causing a large inflammatory immune response and widespread clotting. CAPS was first described by Ronald Asherson in 1992. The syndrome exhibits thrombotic microangiopathy, multiple organ thromboses, and in some cases tissue necrosis and is considered an extreme or catastrophic variant of the antiphospholipid syndrome.

<span class="mw-page-title-main">Apolipoprotein H</span> Protein-coding gene in humans

β2-glycoprotein 1, also known as beta-2 glycoprotein 1 and Apolipoprotein H (Apo-H), is a 38 kDa multifunctional plasma protein that in humans is encoded by the APOH gene. One of its functions is to bind cardiolipin. When bound, the structure of cardiolipin and β2-GP1 both undergo large changes in structure. Within the structure of Apo-H is a stretch of positively charged amino acids, Lys-Asn-Lys-Glu-Lys-Lys, are involved in phospholipid binding.

Hypercoagulability in pregnancy is the propensity of pregnant women to develop thrombosis. Pregnancy itself is a factor of hypercoagulability, as a physiologically adaptive mechanism to prevent post partum bleeding. However, when combined with an additional underlying hypercoagulable states, the risk of thrombosis or embolism may become substantial.

<span class="mw-page-title-main">Anti-cardiolipin antibodies</span> Type of autoantibody

Anti-cardiolipin antibodies (ACA) are antibodies often directed against cardiolipin and found in several diseases, including syphilis, antiphospholipid syndrome, livedoid vasculitis, vertebrobasilar insufficiency, Behçet's syndrome, idiopathic spontaneous abortion, and systemic lupus erythematosus (SLE). They are a form of anti-mitochondrial antibody. In SLE, anti-DNA antibodies and anti-cardiolipin antibodies may be present individually or together; the two types of antibodies act independently. This is in contrast to rheumatoid arthritis with systemic sclerosis (scleroderma) because anti-cardiolipin antibodies are present in both conditions, and therefore may tie the two conditions together.

In autoimmune disease, anti-apolipoprotein H (AAHA) antibodies, also called anti-β2 glycoprotein I antibodies, comprise a subset of anti-cardiolipin antibodies and lupus anticoagulant. These antibodies are involved in sclerosis and are strongly associated with thrombotic forms of lupus. As a result, AAHA are strongly implicated in autoimmune deep vein thrombosis.

<span class="mw-page-title-main">Lupus</span> Autoimmune disease in which the immune system attacks healthy tissue

Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Common symptoms include painful and swollen joints, fever, chest pain, hair loss, mouth ulcers, swollen lymph nodes, feeling tired, and a red rash which is most commonly on the face. Often there are periods of illness, called flares, and periods of remission during which there are few symptoms.

Lupus and pregnancy can present some particular challenges for both mother and child.

Blood clots are a relatively common occurrence in the general population and are seen in approximately 1-2% of the population by age 60. Typically, blood clots develop in the deep veins of the lower extremities, deep vein thrombosis (DVT) or as a blood clot in the lung, pulmonary embolism. A very small number of people who develop blood clots have a more serious and often life-threatening condition, known as thrombotic storm (TS). TS is characterized by the development of more than one blood clot in a short period of time. These clots often occur in multiple and sometimes unusual locations in the body and are often difficult to treat. TS may be associated with an existing condition or situation that predisposes a person to blood clots, such as injury, infection, or pregnancy. In many cases, a risk assessment will identify interventions that will prevent the formation of blood clots.

References

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