Antiphospholipid syndrome
Encyclopedia
Antiphospholipid syndrome or antiphospholipid antibody syndrome (APS or APLS or), often also Hughes syndrome, is an autoimmune, hypercoagulable
state caused by antibodies
against cell-membrane phospholipids that provokes blood clots (thrombosis
) in both arteries
and vein
s as well as pregnancy-related complications such as miscarriage
, stillbirth
, preterm delivery
, or severe preeclampsia. The syndrome occurs due to the autoimmune production of antibodies
against phospholipid
(aPL), a cell membrane
substance. In particular, the disease is characterised by antibodies against cardiolipin
(anti-cardiolipin antibodies
) and β2 glycoprotein I
. The term "primary antiphospholipid syndrome" is used when APS occurs in the absence of any other related disease. APS however also occurs in the context of other autoimmune diseases, such as systemic lupus erythematosus
(SLE), in which case the term "secondary antiphospholipid syndrome" is used. In rare cases, APS leads to rapid organ failure due to generalised thrombosis; this is termed "catastrophic antiphospholipid syndrome
" (CAPS) and is associated with a high risk of death.
Antiphospholipid syndrome is diagnosed with blood test
s. It often requires treatment with anticoagulant
medication such as warfarin
or heparin
to reduce the risk of further episodes of thrombosis and improve the prognosis of pregnancy.
Antiphospholipid syndrome can cause (arterial
/venous
) blood clots (in any organ system) or pregnancy
-related complications. In APS patients, the most common venous event is deep vein thrombosis
of the lower extremities (blood clot of the deep veins of the legs) and the most common arterial event is stroke
. In pregnant women affected by APS, miscarriage
can occur prior to 20 week of gestation, while pre-eclampsia
is reported to occur after that time. Placental infarction
s, early deliveries and stillbirth
are also reported in women with APS.
In some cases, APS seems to be the leading cause of mental and/or development retardation in the newborn, due to an aPL-induced inhibition of trophoblast
differentiation. The antiphospholipid syndrome responsible for most of the miscarriages in later trimesters seen in concomitant systemic lupus erythematosus and pregnancy
.
Other common findings, although not part of the APS classification criteria, are thrombocytopenia
(low platelet
count), heart valve disease, and livedo reticularis (a skin
condition). Some patients report headache
s, migraine
s, and oscillopsia
.
Very few patients with primary APS go on to develop SLE
.
, in which "antiphospholipid antibodies" (anticardiolipin antibodies and lupus anticoagulant) react against proteins that bind to anionic phospholipid
s on plasma membranes. Like many autoimmune disease
s, it is more common in women than in men. The exact cause
is not known, but activation of the system of coagulation is evident. Clinically important antiphospholipid antibodies (those that arise as a result of the autoimmune process) are associated with thrombosis and vascular disease. The syndrome can be divided into primary (no underlying disease state) and secondary (in association with an underlying disease state) forms.
Anti-ApoH and a subset of anti-cardiolipin antibodies bind to ApoH, which in turn inhibits Protein C
, a glycoprotein
with regulatory function upon the common pathway of coagulation (by degradating activated factor V
).
LAC antibodies bind to prothrombin, thus increasing its cleavage to thrombin
, its active form.
In APS there are also antibodies binding to:
Protein S
, which is a co-factor of protein C. Thus, anti-protein S antibodies decrease protein C efficiency;
Annexin A5
, which forms a shield around negatively-charged phospholipid molecules, thus reducing their availability for coagulation. Thus, anti-annexin A5 antibodies increase phospholipid-dependent coagulation steps.
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 (>40 GPLU or MPLU).
Patients with both Lupus anticoagulant antibodies and moderate/high titre anticardiolipin antibodies show a greater risk of thrombosis than with one alone.
using both liquid phase coagulation assays (lupus anticoagulant
) and solid phase ELISA
assays (anti-cardiolipin antibodies
).
Genetic thrombophilia is part of the differential diagnosis of APS and can coexist in some APS patients. Presence of genetic thrombophilia may determine the need for anticoagulation therapy. Thus genetic thrombophilia screening can consist of:
The testing of antibodies to the possible individual targets of aPL such as β2 glycoprotein 1
and antiphosphatidyl serine is currently under debate as testing for anticardiolipin appears to be currently sensitive and specific for diagnosis of APS even though cardiolipin
is not considered an in vivo
target for antiphospholipid antibodies.
antibodies. The patient on initial screening will typically have been found to have a prolonged APTT 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 APTT (plus 80:20 mix), dilute Russell's viper venom time
(DRVVT), the kaolin clotting time (KCT), dilute thromboplastin time (TDT/DTT) or prothrombin time
(using a lupus sensitive thromboplastin
) are the principal tests used for the detection of lupus anticoagulant
. These tests must be carried out on a minimum of two occasions at least 6 weeks apart and be positive on each occasion demonstrating persistent positivity to allow a diagnosis of antiphospholipid syndrome. This is to prevent patients with transient positive tests (due to infection etc.) being diagnosed as positive.
Distinguishing a lupus antibody from a specific coagulation factor inhibitor (e.g.: Factor VIII
). This 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%) where as a specific factor antibody will rarely give a result higher than 10 iu/dl (10%).
Monitoring IV anticoagulant therapy by the APTT 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
.
(ELISA) immunological test
, which screens for the presence of β2glycoprotein 1 dependent anticardiolipin antibodies (ACA).
A Low platelet count
and positivity for antibodies against β2-glycoprotein 1 or phosphatidylserine
may also be observed in a positive diagnosis.
There are 3 distinct APS disease entities: primary (the absence of any comorbidity), secondary (when there is a pre-existing autoimmune condition, most frequently systemic lupus erythematosus, SLE), and catastrophic (when there is simultaneous multi-organ failure with small vessel occlusion).
The International Consensus Statement is commonly used for Catastrophic APS diagnosis. Based on this statement, Definite CAPS diagnosis requires:
Some serological tests for syphilis may be positive in aPL-positive patients (aPL bind to the lipids in the test and make it come out positive) although the more specific tests for syphilis that use recombinant antigens will be negative.
to inhibit platelet activation, and/or warfarin
as an anticoagulant
. The goal of the prophylactic treatment is to maintain the patient's INR
between 2.0 - 3.0. It is not usually done in patients who have not had any thrombotic symptoms. During pregnancy
, low molecular weight heparin
and low-dose aspirin
are used instead of warfarin because of warfarin's teratogenicity. Women with recurrent miscarriage are often advised to take aspirin and to start low molecular weight heparin
treatment after missing a menstrual cycle
. In refractory cases plasmapheresis
may be used.
, which may occur in up to 29% of patients, sometimes despite antithrombotic therapy.
as "Hughes syndrome", after the rheumatologist
Dr. Graham R.V. Hughes (St. Thomas' Hospital, London
, UK
) who worked at the Louise Coote Lupus Unit at St Thomas' Hospital
in London and played a central role in the description of the condition.
House Md, 6:4 Instant karma
Coagulation
Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...
state caused by antibodies
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
against cell-membrane phospholipids that provokes blood clots (thrombosis
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
) in both arteries
Artery
Arteries are blood vessels that carry blood away from the heart. This blood is normally oxygenated, exceptions made for the pulmonary and umbilical arteries....
and vein
Vein
In the circulatory system, veins are blood vessels that carry blood towards the heart. Most veins carry deoxygenated blood from the tissues back to the heart; exceptions are the pulmonary and umbilical veins, both of which carry oxygenated blood to the heart...
s as well as pregnancy-related complications such as miscarriage
Miscarriage
Miscarriage or spontaneous abortion is the spontaneous end of a pregnancy at a stage where the embryo or fetus is incapable of surviving independently, generally defined in humans at prior to 20 weeks of gestation...
, stillbirth
Stillbirth
A stillbirth occurs when a fetus has died in the uterus. The Australian definition specifies that fetal death is termed a stillbirth after 20 weeks gestation or the fetus weighs more than . Once the fetus has died the mother still has contractions and remains undelivered. The term is often used in...
, preterm delivery
Premature birth
In humans preterm birth refers to the birth of a baby of less than 37 weeks gestational age. The cause for preterm birth is in many situations elusive and unknown; many factors appear to be associated with the development of preterm birth, making the reduction of preterm birth a challenging...
, or severe preeclampsia. The syndrome occurs due to the autoimmune production of antibodies
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
against phospholipid
Phospholipid
Phospholipids are a class of lipids that are a major component of all cell membranes as they can form lipid bilayers. Most phospholipids contain a diglyceride, a phosphate group, and a simple organic molecule such as choline; one exception to this rule is sphingomyelin, which is derived from...
(aPL), a cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
substance. In particular, the disease is characterised by antibodies against cardiolipin
Cardiolipin
Cardiolipin is an important component of the inner mitochondrial membrane, where it constitutes about 20% of the total lipid composition. The only other place that cardiolipin can be found is in the membranes of most bacteria. The name ‘cardiolipin’ is derived from the fact that it was first...
(anti-cardiolipin antibodies
Anti-cardiolipin antibodies
Anti-cardiolipin antibodies 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. They...
) and β2 glycoprotein I
Apolipoprotein H
Apolipoprotein H , previously known as , is a multifunctional apolipoprotein. One of its functions is to bind cardiolipin. When bound the structure of cardiolipin and Apo-H both undergo large changes in structure...
. The term "primary antiphospholipid syndrome" is used when APS occurs in the absence of any other related disease. APS however also occurs in the context of other autoimmune diseases, such as systemic lupus erythematosus
Systemic lupus erythematosus
Systemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage...
(SLE), in which case the term "secondary antiphospholipid syndrome" is used. In rare cases, APS leads to rapid organ failure due to generalised thrombosis; this is termed "catastrophic antiphospholipid syndrome
Catastrophic antiphospholipid syndrome
Catastrophic antiphospholipid syndrome, CAPS, also Asherson’s syndrome, is an acute and complex biological process that leads to occlusion of small vessels of various organs. It was first described by Ronald Asherson in 1992...
" (CAPS) and is associated with a high risk of death.
Antiphospholipid syndrome is diagnosed with blood test
Blood test
A blood test is a laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a needle, or via fingerprick....
s. It often requires treatment with anticoagulant
Anticoagulant
An anticoagulant is a substance that prevents coagulation of blood. A group of pharmaceuticals called anticoagulants can be used in vivo as a medication for thrombotic disorders. Some anticoagulants are used in medical equipment, such as test tubes, blood transfusion bags, and renal dialysis...
medication such as warfarin
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...
or heparin
Heparin
Heparin , also known as unfractionated heparin, a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule...
to reduce the risk of further episodes of thrombosis and improve the prognosis of pregnancy.
Signs and symptoms
The presence of antiphospholipid antibodies (aPL) in the absence of blood clots or pregnancy-related complications does not indicate APS (see below for the diagnosis of APS).Antiphospholipid syndrome can cause (arterial
Artery
Arteries are blood vessels that carry blood away from the heart. This blood is normally oxygenated, exceptions made for the pulmonary and umbilical arteries....
/venous
Vein
In the circulatory system, veins are blood vessels that carry blood towards the heart. Most veins carry deoxygenated blood from the tissues back to the heart; exceptions are the pulmonary and umbilical veins, both of which carry oxygenated blood to the heart...
) blood clots (in any organ system) or pregnancy
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
-related complications. In APS patients, the most common venous event is deep vein thrombosis
Deep vein thrombosis
Deep vein thrombosis is the formation of a blood clot in a deep vein. Deep vein thrombosis commonly affects the leg veins or the deep veins of the pelvis. Occasionally the veins of the arm are affected...
of the lower extremities (blood clot of the deep veins of the legs) and the most common arterial event is stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
. In pregnant women affected by APS, miscarriage
Miscarriage
Miscarriage or spontaneous abortion is the spontaneous end of a pregnancy at a stage where the embryo or fetus is incapable of surviving independently, generally defined in humans at prior to 20 weeks of gestation...
can occur prior to 20 week of gestation, while pre-eclampsia
Pre-eclampsia
Pre-eclampsia or preeclampsia is a medical condition in which hypertension arises in pregnancy in association with significant amounts of protein in the urine....
is reported to occur after that time. Placental infarction
Infarction
In medicine, infarction refers to tissue death that is caused by a local lack of oxygen due to obstruction of the tissue's blood supply. The resulting lesion is referred to as an infarct.-Causes:...
s, early deliveries and stillbirth
Stillbirth
A stillbirth occurs when a fetus has died in the uterus. The Australian definition specifies that fetal death is termed a stillbirth after 20 weeks gestation or the fetus weighs more than . Once the fetus has died the mother still has contractions and remains undelivered. The term is often used in...
are also reported in women with APS.
In some cases, APS seems to be the leading cause of mental and/or development retardation in the newborn, due to an aPL-induced inhibition of trophoblast
Trophoblast
Trophoblasts are cells forming the outer layer of a blastocyst, which provide nutrients to the embryo and develop into a large part of the placenta. They are formed during the first stage of pregnancy and are the first cells to differentiate from the fertilized egg...
differentiation. The antiphospholipid syndrome responsible for most of the miscarriages in later trimesters seen in concomitant systemic lupus erythematosus and pregnancy
Systemic lupus erythematosus and pregnancy
For women with systemic lupus erythematosus , pregnancy can present some particular challenges for both mother and child.While most infants born to mothers who have SLE are healthy, pregnant mothers with SLE should remain under medical care until delivery...
.
Other common findings, although not part of the APS classification criteria, are thrombocytopenia
Thrombocytopenia
Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
(low platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
count), heart valve disease, and livedo reticularis (a skin
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
condition). Some patients report headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
s, migraine
Migraine
Migraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...
s, and oscillopsia
Oscillopsia
Oscillopsia is a visual disturbance in which objects in the visual field appear to oscillate. The severity of the effect may range from a mild blurring to rapid and periodic jumping...
.
Very few patients with primary APS go on to develop SLE
Systemic lupus erythematosus
Systemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage...
.
Risk factors
Risk factors for developing antiphospholipid syndrome include:- Primary APS
- genetic markerGenetic markerA genetic marker is a gene or DNA sequence with a known location on a chromosome that can be used to identify cells, individuals or species. It can be described as a variation that can be observed...
HLA-DR7HLA-DR7HLA-DR7 is a HLA-DR serotype that recognizes the DRB1*0701 to *0705 gene products.-Serology:The serological reaction of DR7 is excellent for *0701. The serology of *0703 to *0705 to *0709, and *0711 to *0714 serotypes is unknown. DRB1*0710N is a null allele. DRB1*0702 nomenclature has been...
- genetic marker
- Secondary APS
- SLESLE-Medicine:* Systemic lupus erythematosus, an autoimmune disease affecting multiple systems in the body* Slit lamp examination, as used to examine the eye during an eye examination* St...
or other autoimmune disorders - Genetic markers: HLA-B8HLA-B8HLA-B8 is an HLA-B serotype. The serotype identifies the HLA-B*08 gene products. HLA-B8, previously known as HL-A8 was one of the first identified of the HLA antigens. It coined the "Super B8" haplotype, also called the ancestral European haplotype because of its common occurrence in Europe,...
, HLA-DR2HLA-DR2HLA-DR2 of the HLA-DR serotype system, is a broad antigen serotype that is now preferentially covered by HLA-DR15 and HLA-DR16 serotype group...
, HLA-DR3HLA-DR3HLA-DR3 is composed to the HLA-DR17 and HLA-DR18 split 'antigens' serotypes. DR3 is a component gene-allele of the AH8.1 haplotype in Northern and Western Europeans. Genes between B8 and DR3 on this haplotype are frequently associated with autoimmune disease.... - RaceRaceRace is classification of humans into large and distinct populations or groups by factors such as heritable phenotypic characteristics or geographic ancestry, but also often influenced by and correlated with traits such as appearance, culture, ethnicity, and socio-economic status...
: BlacksBlacksBlacks may refer to:* All Blacks, New Zealand rugby union team* Black people* Blacks Leisure Group, owner of Blacks and Millets in the United Kingdom* The Blacks , a play by Jean Genet* Zamora, California, formerly called Blacks...
, Hispanics, Asians, and Native AmericansIndigenous peoples of the AmericasThe indigenous peoples of the Americas are the pre-Columbian inhabitants of North and South America, their descendants and other ethnic groups who are identified with those peoples. Indigenous peoples are known in Canada as Aboriginal peoples, and in the United States as Native Americans...
- SLE
Mechanism
Antiphospholipid syndrome is an autoimmune diseaseAutoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
, in which "antiphospholipid antibodies" (anticardiolipin antibodies and lupus anticoagulant) react against proteins that bind to anionic phospholipid
Phospholipid
Phospholipids are a class of lipids that are a major component of all cell membranes as they can form lipid bilayers. Most phospholipids contain a diglyceride, a phosphate group, and a simple organic molecule such as choline; one exception to this rule is sphingomyelin, which is derived from...
s on plasma membranes. Like many autoimmune disease
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
s, it is more common in women than in men. The exact cause
Etiology
Etiology is the study of causation, or origination. The word is derived from the Greek , aitiologia, "giving a reason for" ....
is not known, but activation of the system of coagulation is evident. Clinically important antiphospholipid antibodies (those that arise as a result of the autoimmune process) are associated with thrombosis and vascular disease. The syndrome can be divided into primary (no underlying disease state) and secondary (in association with an underlying disease state) forms.
Anti-ApoH and a subset of anti-cardiolipin antibodies bind to ApoH, which in turn inhibits Protein C
Protein C
Protein C, also known as autoprothrombin IIA and blood coagulation factor XIV, is a zymogenic protein, the activated form of which plays an important role in regulating blood clotting, inflammation, cell death and maintaining the permeability of blood vessel walls in humans and other animals...
, a glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
with regulatory function upon the common pathway of coagulation (by degradating activated factor V
Factor V
Factor V is a protein of the coagulation system, rarely referred to as proaccelerin or labile factor. In contrast to most other coagulation factors, it is not enzymatically active but functions as a cofactor...
).
LAC antibodies bind to prothrombin, thus increasing its cleavage to thrombin
Thrombin
Thrombin is a "trypsin-like" serine protease protein that in humans is encoded by the F2 gene. Prothrombin is proteolytically cleaved to form thrombin in the first step of the coagulation cascade, which ultimately results in the stemming of blood loss...
, its active form.
In APS there are also antibodies binding to:
Protein S
Protein S
Protein S is a vitamin K-dependent plasma glycoprotein synthesized in the endothelium. In the circulation, Protein S exists in two forms: a free form and a complex form bound to complement protein C4b. In humans, protein S is encoded by the PROS1 gene...
, which is a co-factor of protein C. Thus, anti-protein S antibodies decrease protein C efficiency;
Annexin A5
Annexin A5
Annexin A5 is a cellular protein in the annexin group. The function of the protein is unknown; however, annexin A5 has been proposed to play a role in the inhibition of blood coagulation by competing for phosphatidylserine binding sites with prothrombin and also to inhibit the activity of...
, which forms a shield around negatively-charged phospholipid molecules, thus reducing their availability for coagulation. Thus, anti-annexin A5 antibodies increase phospholipid-dependent coagulation steps.
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 (>40 GPLU or MPLU).
Patients with both Lupus anticoagulant antibodies and moderate/high titre anticardiolipin antibodies show a greater risk of thrombosis than with one alone.
Diagnosis
Antiphospholipid syndrome is tested for in the laboratoryLaboratory
A laboratory is a facility that provides controlled conditions in which scientific research, experiments, and measurement may be performed. The title of laboratory is also used for certain other facilities where the processes or equipment used are similar to those in scientific laboratories...
using both liquid phase coagulation assays (lupus anticoagulant
Lupus anticoagulant
Lupus anticoagulant is an immunoglobulin that binds to phospholipids and proteins associated with the cell membrane. It is important to note that this disease name is actually a misnomer...
) and solid phase ELISA
ELISA
Enzyme-linked immunosorbent assay , is a popular format of a "wet-lab" type analytic biochemistry assay that uses one sub-type of heterogeneous, solid-phase enzyme immunoassay to detect the presence of a substance in a liquid sample."Wet lab" analytic biochemistry assays involves detection of an...
assays (anti-cardiolipin antibodies
Anti-cardiolipin antibodies
Anti-cardiolipin antibodies 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. They...
).
Genetic thrombophilia is part of the differential diagnosis of APS and can coexist in some APS patients. Presence of genetic thrombophilia may determine the need for anticoagulation therapy. Thus genetic thrombophilia screening can consist of:
- Further studies for Factor V LeidenFactor V LeidenFactor V Leiden is the name given to a variant of human factor V that causes a hypercoagulability disorder. In this disorder the Leiden variant of factor V cannot be inactivated by activated protein C. Factor V Leiden is the most common hereditary hypercoagulability disorder amongst Eurasians...
variant and the prothrombin mutationThrombinThrombin is a "trypsin-like" serine protease protein that in humans is encoded by the F2 gene. Prothrombin is proteolytically cleaved to form thrombin in the first step of the coagulation cascade, which ultimately results in the stemming of blood loss...
, Factor VIIIFactor VIIIFactor VIII is an essential blood clotting factor also known as anti-hemophilic factor . In humans, Factor VIII is encoded by the F8 gene...
levels, MTHFR mutation. - Levels of protein CProtein CProtein C, also known as autoprothrombin IIA and blood coagulation factor XIV, is a zymogenic protein, the activated form of which plays an important role in regulating blood clotting, inflammation, cell death and maintaining the permeability of blood vessel walls in humans and other animals...
, free and total protein SProtein SProtein S is a vitamin K-dependent plasma glycoprotein synthesized in the endothelium. In the circulation, Protein S exists in two forms: a free form and a complex form bound to complement protein C4b. In humans, protein S is encoded by the PROS1 gene...
, Factor VIIIFactor VIIIFactor VIII is an essential blood clotting factor also known as anti-hemophilic factor . In humans, Factor VIII is encoded by the F8 gene...
, antithrombinAntithrombinAntithrombin is a small protein molecule that inactivates several enzymes of the coagulation system. Antithrombin is a glycoprotein produced by the liver and consists of 432 amino acids. It contains three disulfide bonds and a total of four possible glycosylation sites...
, plasminogen, tissue plasminogen activatorTissue plasminogen activatorTissue plasminogen activator is a protein involved in the breakdown of blood clots. It is a serine protease found on endothelial cells, the cells that line the blood vessels. As an enzyme, it catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for clot breakdown...
(TPA) and plasminogen activator inhibitor-1Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 also known as endothelial plasminogen activator inhibitor or serpin E1 is a protein that in humans is encoded by the SERPINE1 gene....
(PAI-1)
The testing of antibodies to the possible individual targets of aPL such as β2 glycoprotein 1
Apolipoprotein H
Apolipoprotein H , previously known as , is a multifunctional apolipoprotein. One of its functions is to bind cardiolipin. When bound the structure of cardiolipin and Apo-H both undergo large changes in structure...
and antiphosphatidyl serine is currently under debate as testing for anticardiolipin appears to be currently sensitive and specific for diagnosis of APS even though cardiolipin
Cardiolipin
Cardiolipin is an important component of the inner mitochondrial membrane, where it constitutes about 20% of the total lipid composition. The only other place that cardiolipin can be found is in the membranes of most bacteria. The name ‘cardiolipin’ is derived from the fact that it was first...
is not considered an in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
target for antiphospholipid antibodies.
Lupus anticoagulant
This is tested for by using a minimum of two coagulation tests that are phospholipid sensitive, due to the heterogeneous nature of the lupus anticoagulantLupus anticoagulant
Lupus anticoagulant is an immunoglobulin that binds to phospholipids and proteins associated with the cell membrane. It is important to note that this disease name is actually a misnomer...
antibodies. The patient on initial screening will typically have been found to have a prolonged APTT that does not correct in an 80:20 mixture with normal human plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
(50:50 mixes with normal plasma are insensitive to all but the highest antibody levels). The APTT (plus 80:20 mix), dilute Russell's viper venom time
Dilute Russell's viper venom time
Dilute Russell's viper venom time is a laboratory test often used for detection of lupus anticoagulant .Variations in the test can affect the results.-Mechanism:...
(DRVVT), the kaolin clotting time (KCT), dilute thromboplastin time (TDT/DTT) or prothrombin time
Prothrombin time
The prothrombin time and its derived measures of prothrombin ratio and international normalized ratio are measures of the extrinsic pathway of coagulation. This test is also called "ProTime INR" and "INR PT". They are used to determine the clotting tendency of blood, in the measure of warfarin...
(using a lupus sensitive thromboplastin
Thromboplastin
Thromboplastin is a plasma protein aiding blood coagulation through conversion of prothrombin to thrombin.Although sometimes used as a synonym for tissue factor, this is a misconception. Historically, thromboplastin was a lab reagent, usually derived from placental sources, used to assay...
) are the principal tests used for the detection of lupus anticoagulant
Lupus anticoagulant
Lupus anticoagulant is an immunoglobulin that binds to phospholipids and proteins associated with the cell membrane. It is important to note that this disease name is actually a misnomer...
. These tests must be carried out on a minimum of two occasions at least 6 weeks apart and be positive on each occasion demonstrating persistent positivity to allow a diagnosis of antiphospholipid syndrome. This is to prevent patients with transient positive tests (due to infection etc.) being diagnosed as positive.
Distinguishing a lupus antibody from a specific coagulation factor inhibitor (e.g.: Factor VIII
Factor VIII
Factor VIII is an essential blood clotting factor also known as anti-hemophilic factor . In humans, Factor VIII is encoded by the F8 gene...
). This 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 VIII
Factor VIII is an essential blood clotting factor also known as anti-hemophilic factor . In humans, Factor VIII is encoded by the F8 gene...
, Factor IX
Factor IX
Factor IX is one of the serine proteases of the coagulation system; it belongs to peptidase family S1. Deficiency of this protein causes hemophilia B. It was discovered in 1952 after a young boy named Stephen Christmas was found to be lacking this exact factor, leading to...
, Factor XI
Factor XI
Factor XI or plasma thromboplastin antecedent is the zymogen form of factor XIa, one of the enzymes of the coagulation cascade. Like many other coagulation factors, it is a serine protease. In humans, Factor XI is encoded by the F11 gene....
and Factor XII
Factor XII
Coagulation factor XII also known as Hageman factor is a plasma protein. It is the zymogen form of factor XIIa, an enzyme of the serine protease class. In humans, factor XII is encoded by the F12 gene.- Function :...
). Lupus anticoagulant will also rarely cause a factor assay to give a result lower than 35 iu/dl (35%) where as a specific factor antibody will rarely give a result higher than 10 iu/dl (10%).
Monitoring IV anticoagulant therapy by the APTT ratio
Partial thromboplastin time
The partial thromboplastin time or activated partial thromboplastin time is a performance indicator measuring the efficacy of both the "intrinsic" and the common coagulation pathways...
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
Antithrombin
Antithrombin is a small protein molecule that inactivates several enzymes of the coagulation system. Antithrombin is a glycoprotein produced by the liver and consists of 432 amino acids. It contains three disulfide bonds and a total of four possible glycosylation sites...
in the presence of heparin
Heparin
Heparin , also known as unfractionated heparin, a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule...
.
Anticardiolipin antibodies
These can be detected using an enzyme-linked immunosorbent assayELISA
Enzyme-linked immunosorbent assay , is a popular format of a "wet-lab" type analytic biochemistry assay that uses one sub-type of heterogeneous, solid-phase enzyme immunoassay to detect the presence of a substance in a liquid sample."Wet lab" analytic biochemistry assays involves detection of an...
(ELISA) immunological test
Immunology
Immunology is a broad branch of biomedical science that covers the study of all aspects of the immune system in all organisms. It deals with the physiological functioning of the immune system in states of both health and diseases; malfunctions of the immune system in immunological disorders ; the...
, which screens for the presence of β2glycoprotein 1 dependent anticardiolipin antibodies (ACA).
A Low platelet count
Thrombocytopenia
Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
and positivity for antibodies against β2-glycoprotein 1 or phosphatidylserine
Phosphatidylserine
Phosphatidylserine is a phospholipid component, usually kept on the inner-leaflet of cell membranes by an enzyme called flippase...
may also be observed in a positive diagnosis.
Criteria
Classification with APS requires evidence of both one or more specific, documented clinical events (either a vascular thrombosis and/or adverse obstetric event) and the confirmed presence of a repeated aPL. The Sapporo APS classification criteria (1998, published in 1999) were replaced by the Sydney criteria in 2006. Based on the most recent criteria, classification with APS requires one clinical and one laboratory manifestation:- Clinical:
- A documented episode of arterial, venous, or small vessel thrombosis—other than superficial venous thrombosis in any tissue or organ by objective validated criteria with no significant evidence of inflammation in the vessel wall and/or
- 1 or more unexplained deaths of a morphologically normal fetus (documented by ultrasound or direct examination of the fetus) at or beyond the 10th week of gestation and/or 3 or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded or at least 1 premature birth of a morphologically normal neonate before the 34th week of gestation due to eclampsia or severe pre-eclampsia according to standard definitions, or recognized features of placental insufficiency plus
- Laboratory:
- Anti-cardiolipin IgG and/or IgM measured by standardized, non-cofactor dependent ELISA on 2 or more occasions, not less than 12 weeks apart; medium or high titre (i.e., > 40 GPL or MPL, or > the 99th percentile) and/or
- Anti-β2 glycoprotein I IgG and/or IgM measured by standardized ELISA on 2 or more occasions, not less than 12 weeks apart; medium or high titre (> the 99th percentile) and/or
- Lupus anticoagulant detected on 2 occasions not less than 12 weeks apart according to the guidelines of the International Society of Thrombosis and Hemostasis.
There are 3 distinct APS disease entities: primary (the absence of any comorbidity), secondary (when there is a pre-existing autoimmune condition, most frequently systemic lupus erythematosus, SLE), and catastrophic (when there is simultaneous multi-organ failure with small vessel occlusion).
The International Consensus Statement is commonly used for Catastrophic APS diagnosis. Based on this statement, Definite CAPS diagnosis requires:
- a) Vascular thrombosis in three or more organs or tissues and
- b) Development of manifestations simultaneously or in less than a week and
- c) Evidence of small vessel thrombosis in at least one organ or tissue and
- d) Laboratory confirmation of the presence of aPL.
Some serological tests for syphilis may be positive in aPL-positive patients (aPL bind to the lipids in the test and make it come out positive) although the more specific tests for syphilis that use recombinant antigens will be negative.
Treatment
Often, this disease is treated by giving aspirinAspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
to inhibit platelet activation, and/or warfarin
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...
as an anticoagulant
Anticoagulant
An anticoagulant is a substance that prevents coagulation of blood. A group of pharmaceuticals called anticoagulants can be used in vivo as a medication for thrombotic disorders. Some anticoagulants are used in medical equipment, such as test tubes, blood transfusion bags, and renal dialysis...
. The goal of the prophylactic treatment is to maintain the patient's INR
Prothrombin time
The prothrombin time and its derived measures of prothrombin ratio and international normalized ratio are measures of the extrinsic pathway of coagulation. This test is also called "ProTime INR" and "INR PT". They are used to determine the clotting tendency of blood, in the measure of warfarin...
between 2.0 - 3.0. It is not usually done in patients who have not had any thrombotic symptoms. During pregnancy
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
, low molecular weight heparin
Heparin
Heparin , also known as unfractionated heparin, a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule...
and low-dose aspirin
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
are used instead of warfarin because of warfarin's teratogenicity. Women with recurrent miscarriage are often advised to take aspirin and to start low molecular weight heparin
Low molecular weight heparin
In medicine, low-molecular-weight heparin is a class of medication used as an anticoagulant in diseases that feature thrombosis, as well as for prophylaxis in situations that lead to a high risk of thrombosis....
treatment after missing a menstrual cycle
Menstrual cycle
The menstrual cycle is the scientific term for the physiological changes that can occur in fertile women for the purpose of sexual reproduction. This article focuses on the human menstrual cycle....
. In refractory cases plasmapheresis
Plasmapheresis
Plasmapheresis is the removal, treatment, and return of blood plasma from blood circulation. It is thus an extracorporeal therapy...
may be used.
Prognosis
The long-term prognosis for APS is determined mainly by recurrent thrombosisThrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
, which may occur in up to 29% of patients, sometimes despite antithrombotic therapy.
History
Antiphospholipid syndrome was described in full in the 1980s, after various previous reports of specific antibodies in people with systemic lupus erythematosus and thrombosis. The syndrome is sometimes referred toEponym
An eponym is the name of a person or thing, whether real or fictitious, after which a particular place, tribe, era, discovery, or other item is named or thought to be named...
as "Hughes syndrome", after the rheumatologist
Rheumatology
Rheumatology is a sub-specialty in internal medicine and pediatrics, devoted to diagnosis and therapy of rheumatic diseases. Clinicians who specialize in rheumatology are called rheumatologists...
Dr. Graham R.V. Hughes (St. Thomas' Hospital, London
London
London is the capital city of :England and the :United Kingdom, the largest metropolitan area in the United Kingdom, and the largest urban zone in the European Union by most measures. Located on the River Thames, London has been a major settlement for two millennia, its history going back to its...
, UK
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
) who worked at the Louise Coote Lupus Unit at St Thomas' Hospital
St Thomas' Hospital
St Thomas' Hospital is a large NHS hospital in London, England. It is administratively a part of Guy's & St Thomas' NHS Foundation Trust. It has provided health care freely or under charitable auspices since the 12th century and was originally located in Southwark.St Thomas' Hospital is accessible...
in London and played a central role in the description of the condition.
External links
- APS Foundation of America, Inc.
- Hughes Syndrome Foundation
- Interview with Hughes The Daily TelegraphThe Daily TelegraphThe Daily Telegraph is a daily morning broadsheet newspaper distributed throughout the United Kingdom and internationally. The newspaper was founded by Arthur B...
February 2, 2009. Accessed February 3, 2009.
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