Antiphospholipid Syndrome – Causes, Symptoms, Treatment

Antiphospholipid syndrome (APS) is a systemic autoimmune, hypercoagulable, thrombo inflammatory, and thrombosis and/or pregnancy complications syndrome caused by the persistent presence of antiphospholipid antibodies (aPL) in plasma of patients with vascular thrombosis and/or pregnancy morbidity along with persistent anti-phospholipid antibodies (APLA), including lupus anticoagulant (LA), anti-ő≤2-glycoprotein I (anti-ő≤2GPI) and/or anti-cardiolipin (aCL) antibodies. Signs and symptoms vary, but may include blood clots, miscarriage, rash, chronic headaches,¬†dementia, and¬†seizures.[rx]¬†These antibodies are often referred to by different terms, including anticardiolipin antibody, lupus¬†anticoagulant, and antiphospholipid antibody. APS can be primary or secondary, and also can be referred to by the name Hughes syndrome or ‚Äústicky blood‚ÄĚ.

Antiphospholipid syndrome is an acquired autoimmune disorder characterised by recurrent arterial or venous thrombosis and/or pregnancy losses, in the presence of persistently elevated levels of anticardiolipin antibodies and/or evidence of circulating lupus anticoagulant (these abnormalities are detected by blood tests). Antiphospholipid syndrome can be primary or secondary.

Other Names

  • Familial antiphospholipid syndrome;
  • Antiphospholipid antibody syndrome;
  • Lupus anticoagulant, familial;
  • APS;
  • Hughes syndrome
  • antiphospholipid antibody syndrome
  • APLS
  • lupus anticoagulant syndrome
  • primary antiphospholipid syndrome
  • secondary antiphospholipid syndrome
  • catastrophic antiphospholipid syndrome
  • Categories: Blood Diseases
  • Subtypes: Catastrophic antiphospholipid syndrome

Causes of Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is caused by the body’s immune system producing abnormal antibodies called antiphospholipid antibodies. Antiphospholipid syndrome is an autoimmune disorder of unknown cause. Autoimmune disorders are caused when the body natural defenses (antibodies, lymphocytes, etc.) against invading organisms attack perfectly healthy tissue. Researchers believe that multiple factors including genetic and environmental factors play a role in the development of APS. In rare cases, APS has run in families suggesting that a genetic predisposition to developing the disorder may exist.

This increases the risk of blood clots developing in the blood vessels, which can lead to serious health problems, such as:

  • deep vein thrombosis (DVT)
  • strokes
  • heart attacks

It’s not clear why these abnormal antibodies are produced, or why many people have antiphospholipid antibodies but don’t develop blood clots. A combination of genetic and environmental factors is thought to be responsible.

Antiphospholipid antibodies

Antibodies are proteins produced by the immune system to help fight off infection and illness. They’re part of the body’s defense system and are produced to help protect against “foreign invaders”, such as bacteria and viruses. Antibodies signal the immune system to release chemicals to kill these bacteria and viruses, and to prevent infection from spreading. In APS, the immune system produces abnormal antibodies that rather than attacking bacteria and viruses, mistakenly attack proteins found on the outside of cells in the blood and blood vessels.

It’s not known how this causes the blood to clot more easily. But most experts believe that keeping your blood at the correct consistency (not too runny and not too sticky) is a delicate balancing act that relies on different types of proteins and fats working together. This balance may be disrupted by the abnormal antibodies in people with APS.

Genetic factors

Research into the genetics around APS is still at an early stage, but it seems the genes you inherit from your parents may play a role in the development of abnormal antiphospholipid antibodies. APS¬†isn’t passed down directly from parents to children in the same way as other conditions, such as¬†hemophilia¬†and¬†sickle cell anemia.

But having a family member with antiphospholipid antibodies increases the chance of your immune system also producing them. Studies have shown that some people with APS have a faulty gene that plays a role in other autoimmune conditions, such as lupus. This may explain why some people develop APS alongside another immune system condition.

Environmental factors

It’s thought that one or more environmental triggers may be needed to trigger APS in some people.Environmental factors that may be responsible include:

  • viral infections, such as the¬†cytomegalovirus (CMV)¬†or¬†parvovirus B19
  • bacterial infections, such as E. coli (a bacteria often associated with¬†food poisoning) or¬†leptospirosis¬†(an infection usually spread by certain animals)
  • certain medications, such as anti-epileptic medicine or the¬†oral contraceptive pill

Another theory is that many people with abnormal antiphospholipid antibodies only go on to develop APS if they have a higher risk of developing blood clots.

For example, if they:

  • eat an unhealthy diet, leading to¬†high cholesterol¬†levels in the blood
  • don’t do enough¬†exercise
  • take the contraceptive pill or¬†hormone replacement therapy (HRT)
  • smoke
  • are¬†obese

But this doesn’t explain why some children and adults who don’t have any of these risk factors still develop APS.

Symptoms of Antiphospholipid Syndrome

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO). The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Signs and symptoms of the antiphospholipid syndrome can include:

  • Blood clots in your legs (DVT).¬†Signs of a¬†DVT¬†include pain, swelling and redness. These clots can travel to your lungs (pulmonary embolism).
  • Repeated miscarriages or stillbirths.¬†Other complications of pregnancy include dangerously high blood pressure (preeclampsia) and premature delivery.
  • Stroke.¬†A stroke can occur in a young person who has antiphospholipid syndrome but no known risk factors for cardiovascular diseases.
  • Transient ischemic attack (TIA).¬†Similar to a stroke, a¬†TIA¬†usually lasts only a few minutes and causes no permanent damage.
  • Rash.¬†Some people develop a red rash with a lacy, net-like pattern.
  • Neurological symptoms. Chronic headaches, including migraines; dementia, and seizures are possible when a blood clot blocks blood flow to parts of your brain.
  • Cardiovascular disease.¬†Antiphospholipid syndrome can damage heart valves.
  • Bleeding.¬†Some people have a decrease in blood cells needed for clotting. This can cause episodes of bleeding, particularly from your nose and gums. You can also bleed into your skin, which will appear as patches of small red spots.
  • Stroke. A clot in your brain can cause sudden numbness, weakness, or paralysis of your face, arm, or leg. You may have difficulty speaking or understanding speech, visual disturbances, and a severe headache.
  • Pulmonary embolism. If a clot lodges in your lung, you may experience sudden shortness of breath, chest pain, and coughing up blood-streaked mucus.
  • Deep vein thrombosis (DVT).¬†Signs and symptoms of¬†DVTs include swelling, redness, or pain in a leg or arm.
  • sudden pain, warmth, and swelling in one leg or arm
  • shortness of breath
  • chest pain
  • coughing up blood-streaked mucus
  • numbness, paralysis, or weakness in your face or limbs
  • slurred speech
  • problems with your vision.
Medical Terms Other Names
Learn More:
HPO ID
Percent of people who have these symptoms is not available through HPO
Arterial thrombosis
Blood clot in artery
0004420 
Autoimmune thrombocytopenia 0001973 
Autosomal dominant inheritance 0000006 
Blurred vision 0000622 
Central retinal artery occlusion 0025342 
Iritis
Inflammation of iris
0001101 
Keratitis
Corneal inflammation
0000491 
Lupus anticoagulant 0025343 
Retinal detachment
Detached retina
0000541 
Retinal vasculitis 0025188 
Scleritis 0100532 
Venous thrombosis
Blood clot in vein
0004936 
Visual loss
Loss of vision

[ more  ]

0000572 
Vitritis 0011531 

To classify as antiphospholipid syndrome a patient must have at least one of the two following clinical manifestations in addition to the presence of certain laboratory abnormalities.

  1. Venous or arterial thrombosis: this may involve the cerebral vascular system, coronary arteries, pulmonary emboli or thromboses, hepatic or renal veins, ocular veins or arteries
  2. Recurring miscarriages or premature births: patients may have pre-eclampsia in pregnancy and babies may be unexpectedly small
Skin disorders in antiphospholipid syndrome

Livedo reticularis affects up to 80% of people with antiphospholipid antibodies. Other features include:

  • Splinter¬†haemorrhage¬†(one or more red or black streaks on a¬†nail)
  • Leg¬†ulcers, both¬†arterial¬†and¬†venous ulcers
  • Superficial thrombophlebitis
  • Blue toe syndrome
  • Vasculitis¬†involving medium-sized and¬†small vessels
Neurological defects in antiphospholipid syndrome
  • Migraine headaches
  • Seizures
  • Stroke
  • Multi-infarct¬†dementia
Cardiac abnormalities in antiphospholipid syndrome
  • Heart murmur
  • Cardiac valve vegetations
Eye disorders in antiphospholipid syndrome
  • Blindness
Blood abnormalities in antiphospholipid syndrome
  • Thrombocytopenia¬†(low¬†platelet¬†count)
  • Hemolytic¬†anemia¬†(low red cell count due to the destruction of the cells by antibodies)

The catastrophic antiphospholipid syndrome refers to the blockage of blood vessels in multiple organs, which may occur over days or weeks. The condition is serious and often lethal.

Diagnosis of Antiphospholipid Syndrome

History and Physical

The clinical features vary significantly and can be as mild as asymptomatic APLA positivity, or as severe as catastrophic APLS. Arterial and venous thrombosis and pregnancy-related complications are the hallmarks of the disease. However, several other organ systems may be involved (non-criteria manifestations).

Specific blood tests

To diagnose APS, the blood needs to be tested for the abnormal antiphospholipid antibodies that increase the risk of blood clots.

This requires a blood test specifically designed to look for these antibodies. A diagnosis of APS can only be made after 2 abnormal blood test results, with at least a 12-week gap between them. This is because harmless antiphospholipid antibodies can sometimes develop in the body for short periods of time.  Usually, this is the result of an infection or a side effect of medication, such as antibiotics. If antiphospholipid antibodies are identified during the first blood test, another test will be needed at a later date to confirm whether the abnormal antibodies are still present.

Vascular Thrombosis

APLS can cause arterial and/or venous thrombosis involving any organ system. APLS related thrombotic events can occur without preceding risk of thrombosis. They can be recurrent and can involve vessels unusual for other-cause-thrombosis (such as upper extremity thrombosis, Budd-Chiari syndrome, and sagittal sinus thrombosis). Venous thrombosis involving the deep veins of lower extremities is the most common venous involvement and may lead to pulmonary embolism resulting in pulmonary hypertension. Any other site may be involved in venous thrombosis, including pelvic, renal, mesenteric, hepatic, portal, axillary, ocular, sagittal, and inferior vena cava.

Arterial thrombosis may involve any sized arteries (aorta to small capillaries). The most common arterial manifestation of APLS is transient ischemic events (TIAs) or ischemic stroke, and the occurrence of TIA or ischemic stroke in young patients without other risk factors for atherosclerosis shall raise suspicion for APLS. Other sites for arterial thrombosis may include retinal, brachial, coronary, mesenteric, and peripheral arteries. The occurrence of arterial thrombosis carries a poor prognostic value, given the high risk of recurrence in these cases.

Pregnancy Morbidity

Pregnancy loss in patients with APLS is common, especially in the second or third trimester. While genetic and chromosomal defects are the most common cause of early (less than 10-week gestation) pregnancy loss, they may also occur in patients with APLS. Tripple positivity (lupus anticoagulant, anticardiolipin and anti-beta-2-glycoprotein-I antibodies), previous pregnancy loss, history of thrombosis, and SLE are risk factors for adverse pregnancy-related outcomes and pregnancy losses in APLS. Besides pregnancy losses, other pregnancy-related complications in APLS include pre-eclampsia, fetal distress, premature birth, intrauterine growth retardation, placental insufficiency, abruptio placentae, and HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelet count).

Cutaneous Involvement

Several cutaneous manifestations have been reported, although all are non-specific for APLS. Livedo reticularis is the most common cutaneous manifestation seen in APLS. However, it can also be seen in the healthy population and in other disorders such as SLE, other connective tissue diseases, vasculitides, sepsis, multiple cholesterol emboli, and Sneddon syndrome. Skin ulcerations, especially in lower extremities ranging from small ulcers to large ulcers resembling pyoderma gangrenosum, have been reported in APLS. Other cutaneous manifestations include nail-fold infarcts, digital gangrene, superficial thrombophlebitis, and necrotizing purpura.

Valvular Involvement

Cardiac valve involvement is very common in APLS, with some studies noting a prevalence as high as 80%.  Mitral and aortic valves are most commonly involved with thickening, nodules, and vegetations evident on echocardiography. This may lead to regurgitation and/or stenosis.

  • Hematological Involvement – Thrombocytopenia has been seen in more than 15% of APLS cases. Severe thrombocytopenia leading to hemorrhage is rare. Positive Coomb test is frequently seen in APLS, although hemolytic anemia is rare.
  • Neurological Involvement – The most common neurological complication of APLS includes TIAs and ischemic stroke, which may be recurrent, leading to cognitive dysfunction, seizures, and multi-infarct dementia. Blindness secondary to the retinal artery or vein occlusion can occur. Sudden deafness secondary to sensorineural hearing loss has been reported.
  • Pulmonary Involvement – Pulmonary artery thromboembolism from deep vein thrombosis is common and may lead to pulmonary hypertension. Diffuse pulmonary hemorrhage resulting from pulmonary capillaritis has been reported.
  • Renal Involvement – Hypertension, proteinuria, and renal failure secondary to thrombotic microangiopathy is the classic renal manifestation of APLS, although this is not specific to APLS. Other renal manifestations reported include renal artery thrombosis leading to refractory hypertension, fibrous intimal hyperplasia with organized thrombi with or without recanalization, and focal cortical atrophy.
  • Catastrophic Anti-Phospholipid Syndrome (CAPS) – CAPS is a rare but life-threatening complication of APLS, with less than 1% of patients with APLS developing CAPS. Mortality is very high (48%), especially in patients with SLE and those with cardiac, pulmonary, renal, and splenic involvement. It is characterized by thrombosis in multiple organs over a short period of time (a few days). Small and medium-sized arteries are most frequently involved. Clinical presentation varies depending on the organ involved and may include peripheral thrombosis (deep vein, femoral artery or radial artery), pulmonary (acute respiratory distress syndrome, pulmonary embolism, pulmonary hemorrhage), renal (thrombotic microangiopathy, renal failure), cutaneous (livedo reticularis, digital ischemia, gangrene, skin ulcerations), cerebral (ischemic stroke, encephalopathy), cardiac (valve lesions, myocardial infarction, heart failure), hematological (thrombocytopenia), and gastrointestinal (bowel infarction) involvement.

Preliminary criteria for the classification of CAPS were published in 2013.  The four criteria are:

  • Involvement of three or more organs/systems/tissues
  • Manifestations developing simultaneously or within less than one week
  • Histopathological confirmation of small vessel occlusion in at least one organ/tissue
  • Laboratory confirmation of the presence of APLA

Definite CAPS can be classified by the presence of all four criteria, while probable CAPS can be classified if 3 criteria are present and the fourth is incompletely fulfilled.

Evaluation

In addition to clinical criteria, the diagnosis of APLS requires the presence of lupus anticoagulant or moderate-high titers of IgG or IgM anticardiolipin or anti-beta-2-glycoprotein I antibodies. The criteria also require a repeat APLA test to be positive 12 weeks after the initial positive test to exclude clinically unimportant or transient antibody. If that duration is less than 12 weeks, or the gap between two separate clinical manifestations and positive laboratory tests is more than 5 years, the diagnosis of APLS is questionable. 

Lupus Anticoagulant Test

Lupus anticoagulant test is the strongest predictor for adverse pregnancy-related events. It is more specific but less sensitive than anticardiolipin antibodies in predicting thrombosis. A positive lupus anticoagulant test is seen in 20% of patients with anticardiolipin antibodies, and anticardiolipin antibodies are seen in 80% of patients with a positive lupus anticoagulant test.  A false-positive syphilis test does not fulfill the criteria for a diagnosis of APLS, but one should always check APLA in patients with previous thrombotic or adverse pregnancy-related events. The presence of a lupus anticoagulant indicates the presence of a coagulation inhibitor of phospholipid-dependent coagulation reactions. It does not react directly with coagulation factors and is not associated with bleeding complications. False-positive and false-negative results can be seen in patients on heparin or warfarin.

It is a four-step test:

  • Prolonged¬†phospholipid-dependent coagulation screening test (activated partial thromboplastin time or¬†dilute Russell viper venom time)
  • Inability to¬†correct the prolonged screening test despite mixing the patient‚Äôs plasma with normal platelet-poor plasma. This indicates the presence of an inhibitor
  • Correction or improvement in the prolonged screening test after the addition of excess phospholipid. This indicates¬†phospholipid dependency
  • Exclusion of other inhibitors.

Anticardiolipin and Anti-beta-2-glycoprotein I Antibodies

Anticardiolipin antibodies and anti-beta-2-glycoprotein I antibodies are assessed by enzyme liked immunosorbent assay (ELISA), and common assays include tests for IgG and IgM isotypes. IgG antibodies correlate better with clinical manifestations than IgM or IgA. Titers more than 40 GPL units are associated with thrombotic events, while lower titers have a less proven association with thrombotic events.

Other Laboratory Findings

  • aCL antibodies
  • Anti-beta-2¬†glycoprotein¬†I antibodies
  • Activated partial thromboplastin time (aPTT)
  • LA tests such as dilute Russell viper venom time (DRVVT)
  • Syphilis (false-positive¬†serology)
  • Complete blood cell count (thrombocytopenia, Coombs-positive haemolytic anaemia)

Blood tests that are used to detect the presence of autoantibodies include:

  • Lupus anticoagulant testing¬†(e.g., dilute Russell viper venom test or DRVVT and hexagonal phase phospholipid neutralization test)
  • Cardiolipin antibodies
  • Beta2 glycoprotein I (ő≤2GP1) antibodies
  • Partial thromboplastin time (PTT)
  • Prothrombin time (PT)
  • Complete blood count (CBC), to evaluate blood cells and platelets
  • A variety of additional tests to evaluate other causes of a person’s symptoms, such as 1:1 Mix study (dilute PTT) to screen for lupus anticoagulant in the blood

Thrombocytopenia or anemia can be seen in APLS frequently. Renal failure and proteinuria may indicate renal involvement with thrombotic microangiopathy. Erythrocyte sedimentation rate may be high during the acute thrombotic event. However, markers of inflammation are usually normal otherwise. Patients with SLE may have positive serologies specific for SLE, such as ANA, anti-Ds-DNA, Anti-smith, etc. Hypocomplementemia is not usually seen in APLS, and when present with renal involvement, it indicates lupus nephritis. Notably, positive ANA and even anti-Ds-DNA is frequently seen in primary APLS without associated SLE, and the presence of these antibodies alone does not imply a diagnosis of SLE in patients without any clinical features of SLE. It may also be important to test a patient with multiple thrombotic events or pregnancy losses for other hypercoagulable states (hyperhomocysteinemia, Factor V Leiden and prothrombin mutations, deficiency of protein C, protein S, or antithrombin III) when indicated.

Classification Criteria

The initial classification criteria, known as the Sapporo criteria, was published in 1999, which was updated in 2016. The revised Sapporo classification criteria for APLS require at least one laboratory and one clinical criterion to be met. One of the following clinical findings should be confirmed to diagnose antiphospholipid antibody syndrome.

Vascular Thrombosis

  • One or more events of arterial, venous, or small-vessel thrombosis of any organ. Thrombosis must be objectively confirmed with appropriate¬†imaging or histopathology. For histopathology, thrombosis shall be present without significant vessel wall inflammation.
  • Superficial venous thrombosis shall not be included as a criterion.
  • A thrombotic episode in the past can be included as a criterion as long as it was appropriately confirmed by appropriate diagnostic means, and there was no other cause of thrombosis.

Pregnancy Morbidity 

  • One or more unexplained fetal deaths of the morphologically normal fetus (normal fetal morphology confirmed by ultrasound or direct examination) at or beyond 10 weeks of gestation.
  • One or more premature births of morphologically normal neonates before the 34th week of gestation. Prematurity must be secondary to eclampsia, severe preeclampsia, or placental insufficiency.
  • Three or more consecutive spontaneous abortions before the 10th week of gestation after ruling out any anatomic or hormonal abnormalities in the mother and parental chromosomal causes.

Laboratory Criteria

One of the following laboratory findings should be confirmed to diagnose antiphospholipid antibody syndrome.

  • Detection of lupus anticoagulant in plasma on two or more occasions, 12 or more weeks apart.
  • Detection of IgG or IgM anticardiolipin antibodies in serum or plasma in moderate to high titers (more than 40 GPL or more than 99th percentile) measured by standard ELISA on two or more occasions, twelve or more weeks apart.
  • Detection of IgG or IgM anti-beta-2-glycoprotein I antibody in serum or plasma in moderate to high titers (more than 99th percentile) measured by standard ELISA, on two or more occasions, 12 or more weeks apart.

Anticardiolipin antibodies

  • Anti-cardiolipin antibodies¬†can be detected using an¬†enzyme-linked immunosorbent assay¬†(ELISA)¬†immunological test, which screens for the presence of ő≤2glycoprotein 1 dependent anticardiolipin antibodies (ACA). A low platelet count¬†and positivity for antibodies against ő≤2-glycoprotein 1 or phosphatidylserine may also be observed in a positive diagnosis.
  • 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.[rx]¬†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 ‚ÄĒ other than superficial venous thrombosis ‚ÄĒ in any tissue or organ by objective validated criteria with no significant evidence of inflammation in the vessel wall
  • 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

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 titer (i.e., > 40 GPL or MPL,[rx]¬†or > the 99th percentile)
  • Anti-ő≤2 glycoprotein I IgG and/or IgM measured by standardized ELISA on 2 or more occasions, not less than 12 weeks apart; medium or high titer (> the 99th percentile)
  • 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).

According to a 2016 consensus statement,[rx] 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-ő≤2 glycoprotein I IgG and/or IgM present alone in a titer greater than 99th percentile

The International Consensus Statement is commonly used for Catastrophic APS diagnosis.[rx] Based on this statement, a 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.

VDRL, which detects antibodies against syphilis, may have a false-positive result in aPL-positive patients (aPL bind to the lipids in the test and make it come out positive), although the more specific test for syphilis, FTA-Abs, that use recombinant antigens will not have a false-positive result

Treatment of Antiphospholipid Syndrome

APS is characterized by recurrent thrombotic events that have not been properly managed. Thus anti-thrombotic medication is necessary for long-term management to reduce thrombotic risk or pregnancy morbidity. Choosing the type of pharmacological treatment and the intensity and duration of anticoagulation depends on the clinical type, comorbidities, severity of the APS, and the risk of bleeding. Change of life habits that are known to increase the risk of thrombotic events has to be stressed in addition to avoiding estrogens and cigarette smoking. When present, the active control of elevated serum LDL-cholesterol and triglycerides, arterial hypertension, and blood sugar, is recommended.

Patients with APS may be evaluated in an outpatient setting. In patient evaluation is required if the patient presents with a significant clinical event. Patients with CAPS require intense observation and treatment, often in the intensive care unit.

Venous thromboembolism

  • Venous thromboembolism is the most common initial clinical manifestation in APS and occurs in 32% of patients who meet consensus conference diagnostic criteria ().
  • Initial treatment consists of unfractionated or low molecular-weight heparin for at least 5 days overlapped with warfarin therapy ().
  • The use of warfarin with an international normalized ratio (INR) of 2.0- 3.0 reduces the risk of recurrent venous thrombosis by 80% to 90% irrespective of the presence of aPL (). For long-term treatment of venous thromboembolism, retrospective case series have suggested that high-intensity warfarin (INR 3.0) is more effective than either aspirin or warfarin administered with an INR < 3.0 (, ).
  • Some studies have found that high-intensity warfarin is better than moderate-intensity warfarin for the prevention of recurrent thrombosis. However, a significant excess of minor bleeding was evident in patients who were given high-intensity warfarin ().

Arterial thromboembolism

  • Arterial events in APS most commonly involve the cerebral circulation with stroke being the initial clinical manifestation in 13% and a transient ischemic attack in 7% of patients. () The association between APS and another arterial thrombosis, including myocardial infarction, is less certain.
  • Warfarin and aspirin appear to be equivalent for the prevention of thromboembolic complications in patients with a first ischemic stroke and aPL. Patients with a first ischemic stroke and a single positive antiphospholipid antibody test result who do not have another indication for anticoagulation may be treated with aspirin (325 mg/d) or moderate-intensity warfarin (INR, 1.4 – 2.8) (). Aspirin is likely to be preferred because of its ease of use and lack of need for laboratory monitoring.
  • It is known that aPL may persist in the serum of APS patients for long periods of time, but thrombotic events occur only occasionally. It has been suggested that aPL (‚Äėfirst hit‚Äô) raises the thrombophilic threshold (i.e., induces a prothrombotic/proinflammatory phenotype in endothelial cells), but that clotting only takes place in the presence of a ‚Äėsecond hit‚Äô or triggering event (i.e., an infection, a surgical procedure, use of estrogens, prolonged immobilization, etc.) ().
  • In general, treatment regimens for APS must be individualized based on the patient‚Äôs current clinical status, presence of co-morbidities, and history of thrombotic events. Asymptomatic individuals in whom blood test findings are positive do not require specific treatment in addition to avoidance of known risk factors.

Prophylactic therapy

  • Eliminate other risk factors such as oral contraceptives, smoking, hypertension, hyperhomocysteinemia, or hyperlipidemia.
  • Low-dose aspirin is usually used. Clopidogrel may be useful in patients allergic to aspirin.
  • In patients with SLE, consider HQC, which may have intrinsic antithrombotic properties.
  • Consider the use of statins, especially in patients with hyperlipidemia.

Initial therapies

  • Corticosteroids, such as prednisone – Prednisone¬†is used to treat conditions¬†such¬†as arthritis, blood disorders, breathing problems, severe allergies, skin diseases, cancer, eye problems, and immune system disorders.¬†Prednisone¬†belongs to a class of drugs known as¬†corticosteroids.
  • Hydroxychloroquine – Hydroxychloroquine (HCQ) is an important disease-modifying agent for the treatment of systemic autoimmune diseases, particularly SLE. In animal models of APS, treatment with HCQ leads to smaller thrombi and less durable persistence.[]¬†HCQ may also mediate a reduction of aPL-ő≤2GPI complex binding to phospholipid bilayers and human monocytes.[]
  • Low molecular weight heparin –¬†Several LMWH products are now available for clinical use. Dosing requirements are individualized for each product (). The advantages of LMWH over unfractionated heparin are reviewed separately.
  • Unfractionated heparin – Unfractionated heparin is preferred to LMWH in certain circumstances. The major potential advantage of unfractionated heparin over LMWH is in the setting of hemorrhage (a rare complication of the APS). Unfractionated heparin can be reversed quickly with protamine while LMWH is not completely reversible with this approach. The major condition in which hemorrhage is due to APS is when antibodies to prothrombin are present.
  • Warfarin – Following stabilization of the patient, warfarin is begun. Warfarin is the standard of care for the chronic management of patients with APS who are not pregnant. INR should be maintained between 2.0 and 3.0 (). However, aPL may create problems in monitoring the INR. A monotonous diet with only slight variations in the amount of vitamin K intake, intensification of monitoring when a different medication has to be used, and above all, patient education on the importance of close monitoring are crucial for the APS management to succeed.
  • Statins – Statins, which function as 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors, have been widely used for primary and secondary cardiovascular disease prevention due to their cholesterol lowering, anti-inflammatory, and anti-thrombotic effects.[]¬†Fluvastatin-treated APS mice have significantly smaller thrombi, decreased inflammatory molecules (intercellular cell adhesion molecule [ICAM]-1), and reduced leukocyte adhesion to endothelial cells compared with controls.[]
  • Vitamin K antagonists – Vitamin K antagonists such as warfarin have historically been the primary treatment for thrombotic APS. Their efficacy in preventing recurrent thrombosis has been supported by multiple studies. One systemic review suggested that anticoagulation with moderate intensity warfarin (INR between 2.0 and 3.0) reduced the risk of recurrent venous thrombosis by 80% to 90%.[]
  • Aspirin. Aspirin is of minimal or no benefit for the prevention of thrombotic APS manifestations in patients who have experienced previous events according to retrospective series (). However, some studies suggest that aspirin (81 mg/day) reduces the risk of thrombosis in aPL- positive patients (). In addition to its antiplatelet effects, low dose aspirin (ASA) (50 to 100 mg) enhances leukocyte-derived interleukin-3 production, which stimulates normal trophoblast growth and hormone expression ().
  • Clopidogrel – It has anecdotally been reported to be helpful in patients with APS and may be useful in those allergic to aspirin. Its use is not advised for the treatment of APS ().
  • Heparin – The initial approach to thrombosis in APS is identical to that of many other thromboses. For acute thrombotic events, the first therapy is heparin. Low molecular weight heparin (LMWH) has replaced unfractionated heparin as the standard of care for most thrombotic events.
  • Full dose LMWH (1mg/Kg twice daily) is usually given simultaneously with warfarin and is overlapped with warfarin for a minimum of four to five days until the International Normalized Ratio (INR) has been within the therapeutic range (2.0 to 3.0) for two consecutive days ().

Some characteristics of heparin

  • The antithrombotic effects include potentiating the anti-thrombin effects of antithrombin and other endogenous antithrombin effectors, increasing the levels of factor Xa inhibitor, and inhibiting platelet aggregation.
  • Heparin may also bind to aPLs and render them inactive ().
  • Heparin may also block tissue factor-mediated placental bed immunopathology (, ).

GPIIbIIIa inhibitors

  • Platelet glycoproteinsIa/IIa and IIb/IIIa – aPL-enhanced thrombosis in vivo can be abrogated by infusions of a GPIIb/IIIa antagonist monoclonal antibody. Recently, it has been reported that heterozygosity for platelet glycoproteinsIa/IIa and IIb/IIIa increase arterial thrombosis in patients with APS (). These data indicate that GPIIb/IIIa antagonists or platelet membrane glycoprotein IIb/IIIa receptor inhibitors may prove to be useful in the treatment of an acute thrombotic event, particularly an arterial event, in patients with APS. In addition, the combination of GPIIb/IIIa antagonists and an ADP receptor antagonist, e.g., ticlopidine, is an attractive therapeutic strategy. It provides fast and continuous platelet inhibition since pre-stimulation of platelets by agonists leads to the exposure of phosphatidylserine on the outer membrane of the cell. As a result, it produces an anti-ő≤2GPI/ő≤2GPI complex on the exposed phosphatidylserine before interacting with a specific platelet receptor to potentiate activation ().
  • B cell directed therapy – Anecdotal reports have reported a beneficial effect of Rituximab on APLA titers. A recent open-label pilot study of Rituximab in primary APS reported that Rituximab had some efficacy in controlling non-criteria manifestations such as thrombocytopenia, hemolytic anemia and skin ulcers though it did not substantially change the APLA profile.
  • Hydroxychloroquine (HCQ) – HCQ inhibits the aPL-induced expression of platelet GPIIb/IIIa receptor (platelet activation) dose-dependently and also reverses the binding of aPL‚Äďő≤2GPI complexes to phospholipidbilayers (). In SLE patients, those receiving HCQ experienced fewer thrombotic events and results from the Baltimore Lupus Cohort showed a decreased risk of arterial thrombosis (). HCQ could be used in patients with APS and thrombosis as a second-line agent together with anticoagulation therapy. We still do not have a study result for a consistent recommendation for HCQ in APS although, in SLE, it is known to reduce the thrombotic risk, including during pregnancy.
  • Rituximab (RTX) – RTX has been shown to be a good treatment for life-threatening CAPS in a few patients and case reports suggest it may be successful in patients with aPL, autoimmune-mediated thrombocytopenia, and hemolytic anemia. Statkute et al. demonstrated normalization of aCL antibody titer after autologous hematopoietic stem-cell transplantation in patients with APS secondary to SLE (). Recently, an uncontrolled and nonrandomized pilot study suggested that the safety of rituximab in aPL-positive patients with non-criteria manifestations of APS is consistent with the safety profile of rituximab. Despite causing no substantial change in aPL profiles, rituximab may be effective in controlling some but not all non-criteria manifestations of APS ().
  • Eculizumab – Complement activation plays an important role in APS pathogenesis. For example, murine studies have shown that complement activation is required for aPL-mediated fetal loss.[]¬†In these models, complement inhibition prevents fetal growth restriction and can also reduce aPL-mediated thrombus formation.[,]¬†Eculizumab is a humanized monoclonal antibody currently approved for treatment of atypical hemolytic uremic syndrome and paroxysmal nocturnal hematuria.[]
  • Defibrotide – is a mixture of oligonucleotides derived from the controlled depolymerization of porcine intestinal mucosal DNA with antithrombotic, anti-ischemic, and anti-inflammatory activities. It binds to the vascular endothelium, modulates platelet activity, promotes fibrinolysis, decreases thrombin generation and activity, and reduces circulating levels of plasminogen activator inhibitor type 1 (PAI-1).[‚Äď] It may also act
  • Coenzyme Q10 (CoQ10) – plays an important role in the electron transport chain of the mitochondrial membrane, while adequate CoQ10 levels protect cells from protein oxidation and lipid peroxidation. Supplementation of CoQ10 has been trialed in patients with coronary artery disease, where it decreases the production of proinflammatory cytokines.[]

Exercise

  • Though there aren‚Äôt any exercises that can help specifically with the condition, regular exercise keeps you fit, keeps your heart healthy and helps prevent blood clots.
  • Yoga, walking, swimming and Tai Chi are good low-impact types of exercise that can help you physically and mentally. Tai Chi also helps with any problems you have with your balance.
  • Speak to a member of your healthcare team before you make any changes to your regular exercise routine.

Diet

You should aim to routinely stick to a healthy, balanced diet, containing a good mix of carbohydrates, proteins, fruit, vegetables and low-fat dairy products.

It’s important to make sure your diet has food containing vitamin K in it. Vitamin K affects your blood’s ability to clot and can affect how warfarin works. Too little vitamin K in your diet can increase your INR levels, while too much decreases them. Vitamin K is mostly found in leafy green vegetables, such as:

  • spinach
  • kale
  • broccoli
  • asparagus
  • lettuce.
  • chickpeas
  • liver
  • egg yolks
  • wholegrain cereals
  • mature cheese and blue cheese
  • avocado
  • olive oil.

While it’s important to make sure you have these vegetables in your diet, you need to balance the amount you eat each day. Too much could increase your risk of clotting and affect your INR levels, but too little is unhealthy. Speak to your doctor about the amount of vitamin K in your diet and how it could affect your warfarin dose. Some herbs and spices also affect your blood flow and the time it takes to clot.

The anticoagulant effect of warfarin can also be affected by:

  • cranberry juice
  • grapefruit juice
  • pomegranate juice
  • garlic
  • dong Quai
  • danshen (red sage)
  • devil‚Äôs claw
  • Korean ginseng
  • green tea.

A member of your healthcare team should be able to advise you on a good healthy diet that won’t interfere with your treatment. Increasing the amount of essential fatty acids in your diet, particularly omega-3 fatty acids, could help reduce the risk of clots. These are found in oily fish. However, there are no clinical trials to support this. If you’re trying for a baby, it may be best to avoid fish liver oil supplements, as they contain large amounts of vitamin A, which can be harmful.

Complementary and alternative treatments

At present, there are no complementary medicines that have been shown to help with APS. Besides vitamin K, supplements such as vitamin C, vitamin E, coenzyme Q10 and the remedies devil’s claw and St John’s wort can also alter the body’s reaction to warfarin. Speak to your doctor, pharmacist or healthcare team before trying any new treatment.

Current treatment of thrombosis

Treatments in APS are directed at modulating the final event or second hit. Treatments that modulate the early effects of aPL on target cells ‚Äď that is monocytes or endothelial cells (first hit) ‚Äď would be more beneficial and potentially less harmful than current treatments.

The current antithrombotic approach to aPL-positive patients may be replaced by an immunomodulatory approach in the future as our understanding of the mechanisms of aPL-mediated thrombosis improves. Understanding the molecular mechanisms triggered by aPL and identifying biomarkers released as a consequence of cell activation may help us design new ways to treat clinical manifestations in APS.

The main target recognized by aPL binds to endothelial cells and monocytes through its fifth domain. aPL/anti-ő≤2GPI antibodies then bind to domain I of ő≤2GPI, and upon clustering and formation of complexes, they trigger cell activation ().

Therefore, blocking the binding of aPL or inhibiting the binding of ő≤2GPI to target cells may be the most specific approach to ameliorate their pathogenic effects without interrupting any important physiologic mechanisms. Recently, Ioannou¬†et al. demonstrated that the soluble recombinant domain I of ő≤2GPI abrogates, in a dose-dependent fashion, the in vitro and in vivo effects of anti-ő≤2GPI antibodies. This underscores the possibility of utilizing decoy peptides that are part of ő≤2GPI to abrogate the binding of pathogenic aPL to target cells in the treatment of patients with APS. Nevertheless, human studies are needed to establish the safety and efficacy of such a treatment (, ).

References

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