Antiphospholipid syndrome (APS) is a chronic condition that is associated with recurrent venous and/or arterial thrombosis, recurrent miscarriages, thrombocytopenia, and/or autoimmune hemolytic anemia, with positive results for antiphospholipid antibodies (aPL) and/or lupus anticoagulant (LA) tests. The syndrome can be primary (primary APS), occurring on its own, or secondary, associated with other autoimmune systemic diseases, particularly systemic lupus erythematosus (SLE). ICD-10 code: D68.
In less than 1/3 of patients with systemic lupus erythematosus (SLE), antiphospholipid antibodies (aPL) are present, and approximately 1/3 of them develop APS. Almost 1/3 of new cases of stroke in individuals under 50 years old, 15% of all patients with deep vein thrombosis, and nearly 10% of women with recurrent miscarriages may have APS.
The characteristic features of the disease are associated with the prothrombotic (or thrombogenic) effects of antiphospholipid antibodies. The exact cause of the production of these antibodies is unknown. Phospholipid antibodies usually recognize phospholipids complexed with a plasma coagulation inhibitor known as a2-glycoprotein I (a2-GPI). However, there is insufficient evidence to determine whether the potential antithrombotic effect of a2-GPI is clinically relevant.
Therefore, a number of pleiotropic effects of phospholipid antibodies on the coagulation cascade are considered: (a) direct endothelial injury and/or decreased production of prostacyclin; (b) endothelial activation to a procoagulant state through transient expression of adhesive molecules and tissue factor (TF), initiating the process of the exogenous coagulation cascade; (c) platelet activation, and (d) inhibition of the function of various phospholipid-binding proteins that regulate coagulation, such as protein C, protein S, antithrombin III, or annexin V.Thrombosis of veins and/or arteries of any size is possible.
Signs associated with venous thrombosis include:- Deep vein thrombosis or superficial vein thrombosis
- Pulmonary embolism/pulmonary infarction
- Nephrotic syndrome due to thrombosis of both renal arteries
- Budd-Chiari syndrome and ascites due to thrombosis of hepatic veins
- Thrombosis of the inferior vena cava
- Pulmonary hypertension due to microthrombi in pulmonary arterioles.
- Cerebral infarctions(ischemic stroke) manifesting as strokes, multi-infarct dementia, or brief episodes of altered consciousness
- Myocardial infarctions(heart attacks)
- Peripheral gangrene
- Intestinal infarction with clinical signs of peritonitis
- "Blind spots" due to occlusion of the ophthalmic artery
- Renal dysfunction due to occlusion of large, medium, and small renal arteries, resulting in tubular and glomerular dysfunction.
To establish a diagnosis, the patient must meet at least two criteria (one clinical and one laboratory) from the following:
Clinical criteria:- Arterial or venous thrombosis.
- Unexplained miscarriages.
- Lupus anticoagulant.
- Immunoglobulin G (IgG) and/or IgM anticardiolipin antibodies (aCL).
Antibodies to phospholipids are typically determined using enzyme-linked immunosorbent assay (ELISA) tests with phospholipid cardiolipin (aCL antibodies) as the antigen. It has been shown that cardiolipin is a factor that stabilizes the true antigen recognized by aPL antibodies in the ELISA test. This true antigen is a2-glycoprotein I (a2-GPI), as well as other phospholipid-binding proteins that are present in excess in the patient's serum and in bovine serum used as a "blocking factor" in the ELISA test. Recently, specific anti-a2-GPI ELISA tests have been proposed to detect specific anti-a2-GPI antibodies. High reactivity of serum in this test is more associated with APS than with aCL reactivity.
The lupus anticoagulant (LA) test measures the activity of aPL in blocking the in vitro conversion of prothrombin to thrombin, resulting in prolonged partial thromboplastin time (PTT). This result does not change when normal plasma is added. Prolongation of PTT is a measure of LA activity in the serum. Other tests measuring LA activity include kaolin clotting time or Russell's viper venom time. Antibodies of the LA type mainly recognize prothrombin.
- Avoid substances that can cause thrombosis.
- Initially, high cholesterol levels should be managed through diet, and if that is not effective, cholesterol-lowering medications may be prescribed.
- Maintain a weight as close to the ideal range as possible.
- Avoid estrogen-containing medications.
- Quit smoking.
- Diabetic patients should receive appropriate treatment for diabetes.
- If the patient is undergoing surgery, prophylactic doses of heparin should be prescribed, such as 5,000 IU twice a day, until the patient is able to walk.
- In cases of secondary APS associated with other systemic autoimmune diseases, the primary underlying condition should be monitored and managed.
- Initial treatment involves intravenous administration of 5,000 IU of heparin, followed by a continuous infusion of 1,000-1,200 IU/h.
- Partial thromboplastin time (PTT) is not a suitable test for assessing the intensity of therapy since it is prolonged in patients with APS. In this case, heparin levels in the plasma can be measured.
- Once these levels reach 0.4 IU/mL, usually 1-2 days after the start of initial treatment, warfarin therapy can be initiated. It should be taken concurrently with heparin for 2-3 days, and then continued separately.
- The dose of warfarin should be individually adjusted to achieve a target international normalized ratio (INR) >2.9. The INR is calculated as the patient's PTT divided by the mean normal PTT. The mean normal PTT is determined by various laboratories testing normal plasma using a thromboplastin reagent with the same international sensitivity index (ISI).
- Thrombotic recurrences can occur even with an INR of 2.5, while the risk of bleeding increases with an INR >3. Therefore, some authors recommend intensive treatment with INR values between 2.6 and 3.0, while others prefer higher INR values for intensive treatment (INR >3).
- Treatment of patients with APS for the prevention of thrombotic recurrences should be continued.
Treatment and prevention of arterial thrombotic events:
Warfarin is prescribed with a target INR range of 2.9-3.5. Some authors add 325 mg of aspirin daily, and this combination has been found to be slightly more effective than warfarin alone for the prevention of thrombotic recurrences. Treatment should be continued indefinitely.
Treatment of cutaneous manifestations:
"Marble-like" skin itself does not require treatment. However, this characteristic is closely associated with the syndrome. Patients with skin infarctions, transient ischemic attacks, or abdominal pain should be thoroughly evaluated for APS since early and vigorous treatment is strongly recommended in such cases. Skin ulcers and gangrene should be treated using intensive antithrombotic therapy.
Treatment of thrombocytopenia:
Mild thrombocytopenia (platelet count of 50,000-150,000 per microliter) does not require treatment. For platelet counts between 20,000 and 50,000 per microliter, there is a higher risk of developing severe thrombocytopenia, and we recommend prescribing prednisolone at a dose of 10 mg per day and azathioprine at a dose of 100-150 mg per day. At the beginning of azathioprine therapy, the dose is 50 mg per day for one week, followed by a complete blood count and platelet level assessment. If the platelet and hematocrit levels are within the normal range, the recommended azathioprine dose is increased to 100 mg, and then to 150 mg per day.
Therapeutic measures for idiopathic autoimmune hemolytic anemia:
For severe thrombocytopenia with purpura and/or bleeding, intravenous administration of 1 g of methylprednisolone for 3 days followed by oral prednisolone at a dose of 60 mg per day, which is gradually tapered according to the clinical presentation, is recommended. If treatment with methylprednisolone is ineffective, intravenous administration of immunoglobulin at a dose of 0.4 g/kg per day for 5 days is given. In cases of non-response to treatment, intravenous administration of cyclophosphamide at a dose of 0.35 g/m2 is recommended. Splenectomy may be necessary for patients with severe thrombocytopenia who do not respond to previous measures.
Treatment of pregnant women with APS for the prevention of fetal loss:
Prednisolone at a dose of 10 mg per day along with subcutaneous heparin at a dose of 5000 IU twice daily plus 80 mg of aspirin significantly reduced the risk of fetal loss. However, the group of women receiving prednisolone had a higher number of preterm births. Patients receiving heparin should also receive vitamin D (0.25 mcg of 1,25-dihydroxyvitamin D3) daily and calcium (500 mg daily).
Alternative and experimental treatment methods:
Intravenous immunoglobulin therapy: Although this therapy is a recognized treatment strategy for thrombocytopenia, it remains an experimental method used to prevent fetal loss. Oral intake of immunoglobulin at a dose of 0.4 g/kg per day in courses lasting 4-5 days is recommended throughout the pregnancy. Aspirin at a dose of 80 mg per day, with or without heparin, as described above, is also prescribed.
Azathioprine and cyclophosphamide: These immunosuppressive drugs can help treat thrombocytopenia, but there is no evidence that they can prevent thrombotic recurrences. Some authors recommend these drugs as an additional therapy alongside full antithrombotic treatment if recurrences continue to occur despite previous antithrombotic measures.