Catastrophic Antiphospholipid Syndrome – Symptoms, Treatment

• Familial antiphospholipid syndrome;
• Antiphospholipid antibody syndrome;
• Lupus anticoagulant, familial;
• APS;
• Hughes 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

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.

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%. [10] 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.[11] 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.[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.

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. [rx]

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’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 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 (β2GP1) 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. [rx] 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.

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.