Asherson’s syndrome is an extremely rare autoimmune disorder characterized by the development, over hours, days, or weeks, of rapidly progressive blood clots affecting multiple organ systems of the body. Conditions such as infections, immunizations, wounds caused due to physical trauma, and failure in the anticoagulation mechanism of the body usually act as “triggers”.
The syndrome is particularly common among patients with antiphospholipid syndrome who experience a cessation of the anticoagulation mechanism related to recurrent bleeding in the body. It is usually seen in patients who have previously suffered from a simple/classic episode of antiphospholipid syndrome. It is not known why patients of the antiphospholipid syndrome often tend to be “catapulted” into a serious or fatal multiorgan failure, while the same triggers in other individuals may only result in recurrent large vessel thrombosis. The symptoms are also aptly observed in patients during pregnancy or in the weeks after childbirth (puerperium) and may follow the HELLP syndrome or be associated with malignancies. Symptoms vary from case to case depending upon the specific organ systems involved. Asherson’s syndrome can rapidly result in life-threatening multiorgan failure.
Asherson’s syndrome is a severe variant of antiphospholipid syndrome (APS), an autoimmune disorder in which blood clots occur about the presence of antiphospholipid antibodies in the body. Antibodies are specialized proteins produced by the body’s immune system to fight infection. In autoimmune disorders, antibodies mistakenly attack healthy tissue. In APS and Asherson’s syndrome, antibodies mistakenly attack certain proteins that bind to phospholipids, which are fat molecules that are involved in the proper function of cell membranes. Phospholipids are found throughout the body. The reason these antibodies attack these proteins and the process by which they cause blood clots to form is not known.
Asherson’s syndrome may occur in individuals who have primary or secondary APS or in individuals with lupus or other autoimmune disorders. In some cases, no previous history of these disorders may be present. The exact cause of Asherson’s syndrome is unknown.
Symptoms
The symptoms of Asherson’s syndrome are caused by complications resulting from the development of multiple blood clots (thromboses) in the body. Multiple blood clots may form in a matter of hours, days, or weeks, potentially causing life-threatening multiorgan failure.
Specific symptoms vary depending upon what organ systems are involved. The kidneys, stomach, lungs, heart, skin, and central nervous system are commonly affected. Involvement of the kidneys may result in kidney dysfunction and associated symptoms such as low urine production and high blood pressure (hypertension).
Involvement of the lungs (pulmonary system) may result in adult respiratory distress syndrome, a severe lung disorder characterized by difficulties (dyspnea), excessively deep and rapid breathing (hyperventilation), and insufficient levels of oxygen in the circulating blood (hypoxemia). Additional pulmonary symptoms may include (pulmonary embolism).
Blotchy reddish patches of discolored skin, a condition known as livedo reticularis, bruising, and the loss of living tissue (gangrene) may develop. Central nervous system symptoms may include stroke (cerebral infarction), seizures, and a condition characterized by altered brain structure and function (encephalopathy).
If the heart is involved, symptoms may include inflammation and thickening of the valves of the heart (valvar heart disease) potentially resulting in complications such as mitral valve regurgitation (MVR). In MVR, the mitral valve does not shut properly allowing blood to flow backward into the heart. Affected individuals may also experience chest pain (angina) and the possibility of a heart attack (myocardial infarction).
Additional organ systems may be involved including the gastrointestinal system, resulting in abdominal pain and cramping; the adrenal and pituitary glands resulting in hormone imbalances and low blood pressure; and the bone marrow resulting in low levels of red blood cells (anemia) and platelets (thrombocytopenia).
Causes
Asherson’s syndrome is a rare autoimmune disorder. Autoimmune disorders are caused when the body’s natural defenses (antibodies, lymphocytes, etc.) against invading organisms suddenly begin to attack perfectly healthy tissue. Researchers believe that multiple factors including genetic and environmental factors play a role in the development of autoimmune disorders.
Asherson’s syndrome is a variant of antiphospholipid syndrome, which is characterized by the presence of certain antibodies in the body and the development of blood clots. The antibodies that are present in both antiphospholipid syndrome and Asherson’s syndrome are known as antiphospholipid antibodies. There are several different types of antiphospholipid antibodies. Two types are the most prevalent lupus anticoagulant and anticardiolipin antibodies. These antibodies were originally thought to attack phospholipids, fatty molecules that are a normal part of cell membranes found throughout the body. However, researchers now know that these antibodies mostly target certain blood proteins that bind to phospholipids. The two most common proteins affected are beta2-glycoprotein and prothrombin. The exact mechanism by which these antibodies eventually lead to the development of blood clots is not known.
Asherson’s syndrome may develop in individuals who already have primary or secondary antiphospholipid syndrome. It may also develop in individuals without a previous history of these disorders. The exact cause of Asherson’s is unknown. In some cases, researchers have identified a precipitating event or “trigger” that plays a role in the development of the multiple blood clots that characterize this disorder. The main trigger is infection. Additional triggers are trauma including trauma caused by invasive surgical procedures, withdrawal of anti-clotting medication, pregnancy, and certain underlying malignancies (cancers).
Diagnosis
A diagnosis of Asherson’s syndrome is made based upon a thorough clinical evaluation, identification of characteristic findings (e.g., multiple blood clots affecting at least three different organ systems that arise simultaneously within one week), and a variety of tests including simple blood tests that can detect antiphospholipid antibodies.
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).
Vascular Thrombosis
APLS can cause arterial and/or venous thrombosis involving any organ system. APLS-related thrombotic events can occur without preceding the 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 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%. [rx] 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.[rx] Severe thrombocytopenia leading to hemorrhage is rare. A 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 (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.[rx]
Preliminary criteria for the classification of CAPS were published in 2013. [rx] 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.
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 antibodies. 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. [rx]
Lupus Anticoagulant Test
The lupus anticoagulant test is the strongest predictor of 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’s 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 of more than 40 GPL units are associated with thrombotic events, while lower titers have a less proven association with thrombotic events.
Other Laboratory Findings
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 to 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 are 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, were published in 1999 and were updated in 2006. [rx] The revised Sapporo classification criteria for APLS require at least one laboratory and one clinical criterion to be met.
Clinical Criteria
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.
- 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.
- Superficial venous thrombosis shall not be included as a criterion.
Pregnancy Morbidity
- One or more unexplained fetal deaths of the morphologically normal fetuses (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.
A specialized blood test called a coagulation test is used to measure blood clotting and can indicate the presence of lupus anticoagulant in the blood. An Enzyme-Linked ImmunoSorbent Assay (ELISA) test can detect the presence of anticardiolipin antibodies in the blood. Positive tests may often need to be repeated because antiphospholipid antibodies can be present in short intervals (transiently) due to other reasons such as infection or drug use. Borderline negative tests may need to be repeated because individuals with APS have initially tested negative for the antiphospholipid antibodies.
Treatment
Because of the recent identification and a limited number of cases of Asherson’s syndrome, no standard therapy has been approved. Researchers who have studied the disease recommend a combination of therapeutic regimens including drugs that prevent clotting (anticoagulants), corticosteroids, specialized proteins known as immunoglobulins, and repeated plasma exchanges using a procedure called plasmapheresis.
Initial therapy for individuals is usually the anticoagulant, heparin, delivered intravenously. Corticosteroids may be given along with heparin. Steroids are given to minimize the effects of tissue loss (necrosis) that often accompanies Asherson’s syndrome. Specialized proteins called immunoglobulins have also been used to treat affected individuals.
Repeated plasma exchanges using fresh frozen plasma may be given using a procedure known as plasmapheresis. Plasmapheresis is a method for removing unwanted substances (e.g., antiphospholipid antibodies) from the blood. Blood is removed from the patient and blood cells are separated from plasma. The patient’s plasma is then replaced with other human plasma and the blood is transfused into the patient. This therapy is still under investigation to analyze side effects and effectiveness. Intensive antibiotic therapy may be used to treat the infection.
Pregnancy Management
All pregnant females with positive APLA should be kept under surveillance during their pregnancy to ensure fetal well-being and to avoid maternal complications. Treatment for pregnant females is aimed at reducing the risk of adverse fetal outcomes and is dictated by the clinical scenario. It must be noted that warfarin is teratogenic and shall not be used in pregnancy. Low-molecular-weight heparin (LMWH) or unfractionated heparin can be used; however, LMWH is preferred because of its better bioavailability, longer half-life, and convenience once a day dosing, and lower risk of thrombocytopenia and osteoporosis.
- For pregnant females with positive APLA but no history of arterial or venous thrombosis:
- First pregnancy: No treatment is indicated
- History of single pregnancy loss at gestation less than 10 weeks: No treatment is indicated
- History of multiple pregnancy losses at gestation less than 10 weeks: Low dose aspirin in combination with prophylactic dose unfractionated heparin or LMWH throughout pregnancy.
- History of one or more pregnancy losses at gestation more than 10 weeks: Low dose aspirin in combination with therapeutic dose unfractionated heparin or LMWH throughout pregnancy. Aspirin should be started before conception, and both aspirin and heparin/LMWH can be discontinued 6 to 12 weeks postpartum.
- For pregnant females with positive APLA and a history of arterial or venous thrombosis:
- Low dose aspirin in combination with therapeutic dose unfractionated heparin or LMWH throughout pregnancy. After delivery, these patients should be transitioned to warfarin, which should be continued lifelong with the INR goal of 2.0 to 3.0.
Catastrophic Anti-Phospholipid Syndrome (CAPS) Management
Early diagnosis is crucial in the management of CAPS due to the high mortality associated with it. There are no randomized controlled trials for the management of CAPS. Anticoagulation and high-dose corticosteroids are used in combination with IVIG, plasmapheresis, rituximab, cyclophosphamide, or eculizumab.
Management of Other Manifestations
The role of anticoagulation has not been established in other non-criteria manifestations of APLS. Thrombocytopenia with platelet count more than 50,000/mm3 does not require any treatment; however, corticosteroids with or without IVIG or rituximab can be used if platelet counts are less than 50,000/mm3. Splenectomy has also been proven to be beneficial in some patients with severe refractory thrombocytopenia. Renal involvement with thrombotic microangiopathy shall be confirmed with a renal biopsy, especially in patients with concomitant SLE to rule out lupus nephritis. Anticoagulation and corticosteroids can be used for thrombotic microangiopathy. For patients with cardiac valve nodules or deformity, there is no known effective treatment. However, if there is evidence of embolism or intracardiac thrombus, anticoagulation is recommended.
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
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 (RX).
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 apps and render them inactive (RX).
Low molecular weight heparin. Several LMWH products are now available for clinical use. Dosing requirements are individualized for each product (RX). 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 (RX). 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 is crucial for the APS management to succeed.
Antiplatelet agents
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 (RX). However, some studies suggest that aspirin (81 mg/day) reduces the risk of thrombosis in aPL- positive patients (RX). 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 (rx).
Retrospective and prospective observational studies and controlled trials of aspirin for the prevention of thrombotic events in people with aPL with no history of arterial or venous thromboembolism have had disparate results (rx, rx). The Antiphospholipid Antibody Acetylsalicylic Acid (APALA) study consisted of two separate investigations involving patients who were asymptomatic but persistently aPL-positive (rx). The conclusions of the APLASA trial were:
- Asymptomatic individuals who are persistently positive for aPL have a low annual incidence of acute thrombosis.
- These individuals do not benefit from low-dose aspirin.
- Thrombotic events in this population are unlikely in the absence of additional risk factors for thrombosis.
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 (rx).
Investigational Therapies
In 2020, the Catastrophic Antiphospholipid Syndrome (CAPS) Registry was created to document the clinical, laboratory, and therapeutic information on affected individuals. The registry is overseen by the European Forum on Antiphospholipid Antibodies. For more information visit: www.med.ub.es/MIMMUN/FORUM/CAPS.HTM
The drug Rituximab has been used successfully to treat individuals with Asherson’s syndrome who experience severe thrombocytopenia. Additional drugs have been used to treat Asherson’s syndrome including drugs that suppress the immune system (e.g., cyclophosphamide) or drugs that break down blood clots or prevent platelets or clots from forming (fibrinolytic drug) such as prostacyclin. More research is necessary to determine the long-term safety and effectiveness of these potential therapeutic agents for Asherson’s syndrome.
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