Antiphospholipid Syndrome (APLS), Catastrophic APLS (CAPS) 4.71/5 (17)

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Antiphospholipid syndrome is characterized by blood clots (thrombosis). Blausen gallery 2014. CC BY 3.0

Definition

Antiphospholipid syndrome (APLS) is one Autoimmune disease which entails blood clots (thrombosis) or miscarriages and special results in blood samples (antifosfolipid antibodies). Antiphospholipid syndrome can be an independent disease (primarily APLS) or part of a rheumatic disease, most often Systemic lupus (SLE) (secondary APLS). Spontaneous abortion is defined as fetal loss before week 22 of pregnancy, while later fetal loss is referred to as fetal death.

Occurrence

There are about two new cases of APLS per 100.000 inhabitants annually (incidence). A total of 40-50 cases are seen per 100.000 people (prevalence). This corresponds to approx. 100 new cases annually in Norway and that a total of 2400 people have antiphospholipid syndrome. A large proportion, 18-40% of cases, with antiphospholipid syndrome also have Systemic lupus (SLE) (references: Koniari I, 2010; Duarte-Garcia A, 2019). Conversely, 10-30% have SLE (secondary) APLS.

The distribution of antiphospholipid syndrome between women and men is 5: 1 in APS in total, 3,5: 1 in primary APS and 7: 1 in SLE association (secondary APS). APS antibody is detected among approx. 13% of patients with stroke, 11% with myocardial infarction, 9,5% with deep vein thrombosis and 6% with pregnancy complications (Gomez-Puerta J, Cervera R, 2014). APLS accounts for 5-15% of all people with deep vein thrombosis (DVT).

Symptoms

Livedo reticularis with marbling in the skin that can be seen in antiphospholipid syndrome.

Antiphospholipid antibodies in the blood and carries an increased risk of APLS causes, but few or no symptoms before complications occur. However, some (20%) have noticeable, visible blood vessel changes in the form of marbling that is visible through the skin. The phenomenon is also called livedo reticularis or livedo racemosa. However, skin changes are also common in the population without risk factors. Illustration: Sajjan VV, Lunge S, Swamy MB, Pandit AM - Indian dermatology online journal (2015 Sep-Oct)CC BY-NC-SA 3.0.

Blood clots (thrombosis) and organ complications

Blood clots are classic complications of APLS. Most (70%) occur in veins and are then usually less dramatic than when arteries / arteries are attacked (30%).

ARDS (Acute Respiratory Distress Syndrome) is acute lung failure, intralvular hemorrhagia (pulmonary edema), fibrosing alveolitis. These are rare complications.

Adrenal glands. Adrenal necrosis. Causes hormone production to be impaired (Adrenal / Addison-crisis)

Blood clots in arteries (arterial thrombosis) can cause stroke (apoplexy) or heart attack as the three most common arterial manifestations (reference: Cervera R, 2002).

Blood clots in veins (deep vein thrombosis, DVT) most often seen in one leg. Typically, the leg swells up, especially around the ankle and leg without much pain. Also arms, internal organs and brain can be attacked.

Blood clots in the lungs (lungembolism,) and may be characterized by sudden, stabbing pains in the chest. Reduced lung function with difficulty breathing can also be seen.

Heart. Heart valve disease (vegetation, thickening).

Skin. Marbling (livedo retikularis / racemosa), thrombophlebitisRaynaud's Pyoderma gangrenosum-like) leg ulcers (reference: Santos G, 2014).

Stomach area. Blood clot in portal vein (liver) Budd Chiari's Syndrome, mesentrial-vein (intestine).

The nervous system. Stroke 13%, TIA (temporary) 8%, migraines, headache (Sinus Venous thrombosis), papillary edema (eyes), (Sinus Venous thrombosis), transverse myelitis (spinal cord) (reference: D'Cruz, DP, 2004).

Kidneys. tissue death (necrosis) in kidneys, nephritis, microangiopathy.

Sinus vein thrombosis in the brain causes persistent headaches with radiation forward in the forehead and behind the eyes (reference: Biggioggero M, Meroini PL, 2010).

Abortions (miscarriages) and other complications in pregnancy

Pregnancy complications are characteristic of APS. Most common are early or late miscarriage, premature birth, preeclampsia (pre-eclampsia, eclampsia). Please see more about pregnancy with anti-phospholipid syndrome in a separate section below.

Catastrophic apL syndrome (CAPS)

The condition is characterized by rapid, dramatic development (within less than a week) and blood clots occur in several organs simultaneously (multi-organ affection). Catastrophic APL syndrome (CAPS) is also called Asherson syndrome and is a serious complication of antiphospholipid syndrome (APLS).

Criteria for CAPS (safe CAPS: all 4 points, 3 points: probable CAPS (reference: Ascherson R, 2003)):

  1. Three or more organs involved (kidney: s-creatinine more than 50% increased as a sign of renal failure. Blood pressure above 180/100 mmHg and / or proteinuria).
  2. Development (fast) in less than a week.
  3. Histologically (tissue sample) vasculitis is seen in small blood vessels with occlusion (blood clot) in at least one organ.
  4. Lupus anticoagulant or anti-cardiolipin Antibodies detected in the blood.

Treatment of CAPS usually takes place in an intensive care unit. One gives "blood-thinning" drugs (anticoagulation with Heparin and later Marevan). In some cases it is also done plasmapheresis (plasma replacement), dialysis. It can also be treated with cyclophosphamide (Sendoxan), immunoglobulins and frozen plasma. eculizumab is experimental treatment (for special cases).

Prognosis by CAPS. Severe condition. Deaths reported in 48%.

Literature for CAPS: (reference: Aquiar CL 2013)

Examination by Antifosfolipid syndrome

Medical history includes skin changes (marbling), blood clots and pregnancy complications. Signs of systemic lupus (SLE) should also be sought.

Clinical examinations may involve assessment of skin, any signs of blood clots and a general rheumatological examination if systemic lupus (SLE).

Blood tests. Antiphospholipid antibodies consist of lupus anticoagulant, Anti-cardiolipin and beta-2-glycoprotein antibody. High levels are more important than low values. When all three of the above tests fail, it is called "triple-positive" and clearly indicates an increased risk of blood clots. Blood tests must be performed on at least two occasions at intervals of more than three months (to rule out accidental, transient rash). Other rheumatic diseases with antiphospholipid antibody are SLE: 6-80%, Systemic sclerosis: 7-31%, Sjøgrens Syndrome: 2-32%, (Dermato- myositis: 6-14%. The results of Lupus anticoagulant tests are affected by "blood-thinning" drugs (anticoagulants). Marevan, Factor Xa inhibitor (Xarelto, Eliquis) or Factor IIa inhibitor (Pradaxa) thus affect the result and may cause false positive lupus anticoagulant. The blood sample should (ideally) be taken before starting the drug or at least one week after stopping treatment (literature: Kristoffersen AH, 2019). To rule out any other causes of blood clots can be considered: Protein S deficiency, protein C deficiency. Factor V Leiden, prothrombin gene mutation. hyperhomocysteinemia og MBL deficiency.

Low platelet count (thrombocytopenia) (most often moderate 75-100.000) is present in 22% with APLS. Among other causes to thrombocytopenia is SLE and Heparin-induced thrombocytopenia.

Urine sticks to exclude protein and traces of blood seen in SLE and other diseases with nephritis.

Diagnosed antiphospholipid syndrome

Criteria that can be used for the diagnosis (Sapporo / Sydney criteria 2006) (1 + 2);

  1. Clinical:
    1. Vascular thrombosis (venous 32%) or arterial
    2. Or miscarriage (8%) (after at least 10 weeks of pregnancy or less than 34 weeks of pregnancy at (pre-) eclampsia / placental insufficiency) or at least three unexplained spontaneous abortions before 10 weeks of pregnancy
  2. Serum antibodies against phospholipids (cardiolipin / beta2 glycoprotein / lupus anticoagulant) in medium-high titers IgG or IgM measured in significantly positive titers on at least two occasions by at least 12 weeks in the last 5 years.

More about criteria here (medicalcriteria.com)

Pregnancy and antifosfolipid syndrome

Risk Pregnancy. Patients with APLS are followed up as "risk pregnancies" where gynecologist / obstetrician and hematologist (blood diseases). By secondary APLS (if also SLE, Sjögren's syndrome or other rheumatic disease is present) one collaborates with a rheumatologist. Lupus anticoagulant, cardiolipin antibody and beta-2 glycoprotein (see more under "blood tests" above) increase the risk of blood clots (thrombosis) and complications related to pregnancy regardless of whether rheumatic disease is present or not. People with high levels of the antibodies, especially lupus anticoagulant or in the presence of all three antibodies (triple positive), are most at risk. One can divide these antibodies into IgG and IgM antibody, of which high level of IgG antibody is considered to be of greater importance than IgM level and high level is worse than low level.

Risk of blood clots (Thromboembolism) is increased in pregnancy and in the weeks after birth. The pregnant woman may have blood clots (thromboembolisms) such as deep vein thrombosis (DVT), pulmonary embolism or stroke. The fetus may be affected by blood clots in the placenta (placenta) and thus an increased risk of miscarriage or stillbirth. In APLS (see above), "blood-thinning" drugs (anticoagulants) are given which reduce the risk of blood clots. However, Marevan must not be used during pregnancy (increased risk of fetal harm when used after week 6 of pregnancy). Data suggest that Plaquenil (hydroxychloroquine) may also have some blood clot protective effect (and may reduce the level of SSA / B antibody), even during pregnancy (reference: Sciascia S, 2015).

More information about SLE and pregnancy here or can be obtained at National Center for Pregnancy and Rheumatic Disease, Trondheim.

Post partum syndrome (fever peaks, lung / pleural pain, breathing problems / dyspnea, pleural fluid (water on the lungs) + spotted infiltrates

Catastrophic antiphospholipid syndrome (CAPS) and pregnancy). CAPS can debut during pregnancy and is associated with an increased risk of death. The condition is characterized by rapid, dramatic development (within less than 1 week) and that several organs are attacked simultaneously (multi-organ affection). To save the mother's life, in some cases it may be necessary to provide treatment even with the risk of damaging the fetus. Unusually high doses of Fragmin or Klexane, IVIG (intravenous immunoglobulins), corticosteroids and / or Plaquenil may be used. Some also provide plasma replacement (plasmapheresis).

Similar conditions / differential diagnoses

False positive anti-phospholipid (APL) antibody tests (rash without APLS) occurs in up to 9,4% of healthy blood donors and is thus not a sign of disease in everyone. The diagnosis antiphospholipid syndrome (APLS) is therefore not only based on blood test results, and the test should show lasting changes over time. False negative tests (no results in the test even if APLS is present) also occur, but are rare: antibodies to phosphatidylserine, phosphatidylinositol and prothrombin can be causes in such cases.

Other causes of venous thrombosis are many: Blood diseases with blood clots (coagulopathies): Factor analyzes. Defects in the thrombolysis system. Cancer / leukemia diseases. Nephrotic syndrome with protein loss via urine. Hereditary factors: may be relevant for Protein S deficiency, protein C deficiency, Factor V Leiden, Prothrombin gene mutation, hyperhomocysteinemia og MBL deficiency.

Arterial thrombosis: Atrial fibrillation («flicker»). Myxoma. Endocarditis. Cholesterol embolism. Myocardial infarction. Diving disease (Caisson's disease). Thrombotic thrombocytopenic purpura / hemolytic uremic syndrome (Vaskulitt.no). Brain stroke in children: DaDa-2 (juvenil PAN). TIA / stroke

Combined vein and artery blood clots: Defective thrombolysis (dysfibrinogenemia or plasminogen activator deficiency). Homocysteineemia. Myeloproliferative blood diseases. Polycythemia vera (hyperviscosity). Paroxymal nocturnal hemoglobinuria.  Walden stream macroglobulinemia. Sickle cell disease. Vasculitis diseases. Paradoxical emboli. Cancer.

Literature. Emmi G 2014

Treatment

In the case of thrombosis (thrombosis), heparin preparations (injections) are most commonly used as Fragmin or Klexane. Dosage can be titrated based on measurement of anti-FXa activity in blood plasma. Transition to warfarin (INR 2.0-3.0). In case of repeated thromboembolism, lifelong treatment is relevant

Preventive treatment for antiphospholipid antibody. With persistently high levels of lupus anticoagulant, especially in combination with cardiolipin and beta-2 glycoprotein antibodies (triple-positive), there is an increased risk of blood clots. Preventive treatment is recommended (Tektonidou MG, 2019, EULAR). Acetylsalicylic acid 75-100mg / day (Albyl-E, ASA) can prevent arterial emboli (in arteries). More uncertain effect on venous thrombosis. ASA does not prevent blood clots in everyone (14% get a blood clot within 5 years, despite acetylsalicylic acid), but is recommended at high risk and especially if at the same time high risk of cardiovascular disease.

Heparin preparations (injections), most often Fragmin or Klexane is used in particularly vulnerable situations such as long journeys by plane, after operations and after births.

Estrogen contraceptives (common birth control pills) should not be used for APLS, as the risk of blood clots increases (reference: Sammaritano LR, 2014). Gestagen preparations can usually be used («mini-pill», contraceptive pill, hormonal IUD, contraceptive syringe, emergency contraception / attack pill). Smoking increases the risk of blood clots and can reduce the effect of the medication

Newer oral anticoagulants (Direct oral anticoagulants, DOAC). DOAC tablets (Pradaxa / dabigatran, Xarelto / rivaroxaban, Eliquis / apiksaban and Lixiana / edoxaban) are used to prevent blood clots, but none are approved for use in antiphospholipid syndrome. The reason is that both studies and reports indicate insufficient effect in antiphospholipid syndrome at least for «triple positive cases» (as of 2019) (reference Dufrost V, 2016 og Uthman I, 2019). If necessary, Marevan / warfarin is also recommended. Cases of new blood clots during treatment with DOAC are known, also from Norway (reference: Johnsen SJA, 2018).

Reference: TRAS study (rivaroxaban versus warfarin); Pengo V, 2018

Treatment guidelines

EULAR: Tektonidou, MG, 2019

Literature


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