Antiphospholipid syndrome D68.8

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 29.10.2020

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Synonym(s)

Anti-cardiolipin antibody syndrome; Antiphospholipid syndrome; Antiphospholipid Syndrome; APLA Syndrome; APS; Cadiolipin antibody syndrome; Hughes-Stovin Syndrome; lupus anticoagulant syndrome; Phospholipid antibody syndrome

History
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Harris, 1983; Hughes, 1983

Definition
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Systemic autoimmune disease occurring mainly in young women with evidence of phospholipid antibodies, recurrent venous and arterial thromboses(thrombophilia), thromboembolic complications, habitual abortions, cerebral symptoms and various skin conditions.

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Classification
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A distinction is made:

  • Primary APS without underlying disease (50%)
  • Secondary APS with underlying diseases such as SLE, AIDS, malignancies (50%)
  • Catastrophic APS with infestation of > 3 organ systems. This shows characteristics of a thrombotic microangiopathy anaemia.

Etiopathogenesis
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  • An autoimmune disease which produces acquired antibodies of the IgG or IgM type with affinity for negatively charged phospholipids such as phosphatidylserine, the active phospholipid of the endogenous system of prothrombin activation, and/or for cardiolipin, the antigen used in lues serology.
  • Pathogenetically, the antiphospholipid
    APAinterferes
    with the in vitro activation of prothrombin by the activator complex (Factor Xa, V, phospholipid, Ca). APA forms complexes with protein S, C and prothrombin. This leads to a prolongation of lipid-dependent coagulation tests (quick-value, partial thromboplastin time [ PTT]) as well as to a tendency to thrombosis and abortion. At the vascular endothelium, the antibody inhibits the release of prostacyclin (inhibitor of platelet aggregation). Furthermore, APA leads to an activation of the mTOR signaling pathway in renal involvement, which in turn triggers vasculopathy.

Manifestation
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Occurs mainly in young women; the average age of the disease is 42 +/- 14 years. Less frequent in infants and older adults.

w:m=8:2.

Clinical features
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In about 80% of the cases the GSP is primary. In 20% of cases it is partially manifested with underlying diseases such as lupus erythematosus or other autoimmune diseases.

Skin symptoms: livedo racemosa, purpura, ulcerations (also under the picture of an atypical ulcer localized e.g. at the calf), subcutaneous nodules, Raynaud's syndrome, nail fold leangiectasia as well as splinter hemorrhages of the nail matrix, necroses.

Extracutaneous manifestations: Deep vein thrombosis, arterial thrombi, transient ischemic attacks (TIA), apoplectic insults, ischemic disorders of the central arteries of the eye, renal vein thrombi and thrombotic occlusion of the glomerulus capillaries, pulmes with potential efficacy of complex hypertension, recurrent abortions, arterial hypertension, epileptic seizures, thrombocytopenia, progressive failure of heart valves. The uncontrolled thrombus formation of the catastrophic APS suggests an uncontrolled activation of the classical complement pathway.

Laboratory
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Diagnostic criteria of the Sapporo classification:

  1. Detection of IgG or IgM anticardiolipin AK (ACA > 40IE). Detection of IgG or IgM anti-beta2 glycoprotein 1-Ak = anti-beta2 GPI-Ak (both methods are more sensitive than the detection of lupus anticoagulant). The detection must be performed at least twice or several times at intervals of 12 weeks.
  2. Detection of lupus anticoagulant (LA) in plasma, twice or more at 12-week intervals. Note: the examination cannot be performed under anticoagulation with heparin or vitamin K antagonists!

Further laboratory values:

  • False positive syphilis reactions (about 45%).
  • Alternating other signs of autoimmunopathy: ANA or DNA-AK (70%), positive Coombs test (55%), rheumatoid factors.

Remarks:

  • 15% of APS patients are only LA positive, 25% are only ACA positive, 60% are ACA and LA positive.
  • 2-5% of the healthy population are ACA positive (mostly low titers).

Diagnosis
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The criteria developed in 1999 as Sapporo diagnostic criteria were revised in 2005 and published in 2006 (Miyakis S et al)

An antiphospholipid antibody syndrome exists if at least 1 clinical criterion and 1 laboratory criterion are met:

  1. Vascular occlusions:
    1. One or more episodes of arterial, venous or small-vessel thrombosis in any organ. The thrombosis must be controlled by objectifiable validated criteria.
  2. pregnancy complications:
    1. Single or multiple unexplained death of a morphologically unremarkable fetus during or after the 10th week of pregnancy.
    2. Single or multiple premature birth of a morphologically normal newborn before the 34th week of pregnancy due to eclampsia or a plant insufficiency.
    3. 3 or more unexplained consecutive spontaneous abortions before the 1st week of pregnancy. in which maternal anatomical or hormonal abnormalities and paternal and maternal chromosomal causes are excluded.
  3. Laboratory criteria: see below. Laboratory

General therapy
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  • The treatment strategy for the detection of antiphospholipid antibodies in blood depends primarily on whether "only" the antibodies are detectable in the blood, whether symptoms requiring treatment are present (e.g. infarcts or venous thromboses) or whether an underlying underlying disease indicates the need for treatment.
  • If AK is detected exclusively without clinical symptoms (in this case there is no anti-phospholipid syndrome in the narrower sense), there is no need for treatment.
  • In the case of a manifest phospholipid antibody syndrome, a distinction must be made as to whether a primary (without underlying underlying disease) or a secondary form (underlying disease) is present.
  • In the case of a primary phospholipid-antibody syndrome, therapy is directed solely at preventing further complications of thrombosis.
  • In secondary phospholipid antibody syndrome following an underlying disease, therapy has two goals:
    • effective treatment of the underlying disease (e.g. immunosuppressive drugs in SLE or vasculitis).
    • anticoagulant therapy (as in primary phospholipid antibody syndrome) to prevent the formation of thrombi.
  • For anticoagulation (Marcumar and Aspirin), an INR between 2.6 and 3.0 should be aimed for. With regard to an immunosuppressive therapy in patients with primary antiphospholipid syndrome, the data situation is insufficient. Anticoagulation must be carried out for the rest of the patient's life if a complicative anti-phospholipid syndrome is confirmed (e.g. deep vein thrombosis). The administration of aspirin alone is not sufficient.

Note(s)
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Remember! Mandatory pregnancy monitoring (risk birth) is required.

15% of APS patients are only LA positive, 25% are only ACA positive, 60% are ACA and LA positive

Case report(s)
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Medical history: The 52-year-old female patient developed within 8 weeks a rapidly size progressive, painful ulcer in the middle of the right lower leg. The local therapy was unsuccessful so far.

Two miscarriages, an arterial hypertension as well as 1 uneventful healed venous thrombosis of the saphenous vein are known as previous diseases. Autoimmune diseases or neurological complications could not be determined. No Raynaud's symptoms.

Findings: The 17x7 cm large, inhomogeneously fissured ulcer showed a greasy-purulent surface with an irregular frayed border and a broad, red-livid border. Clinical Doppler sonography showed no evidence of venous or arterial insufficiency.

Histology: distinct lumen limiting arteriosclerosis of medium sized vessels of the fatty tissue with reactive panniculitis. No evidence of vasculitis.

Laboratory: BSG: 65/95; CRP: 15mg/dl, neutrophil leucocytosis (11.300/ul), no eosinophilia, S-C3 complement: 1,5g/l (standard value:0,9-1,8g/l), S-C4 complement 0,2g/l (standard value: 0,1-0,4g/l), thrombocytopenia (80th percentile), and vasospasm (80th percentile).000 /ul), detection of autoantibodies against cardiolipin (IgG), beta2-glycoprotein I and phosphatidylserine (IgG and IgM). Lupus anticagulant neg. ANA and ENA neg. p-ANCA and c-ANCA neg.

Diagnosis: Primary APS without underlying disease

Therapy: Adjustment to anticoagulant therapy with enoxaparin (Clexane®), simultaneous dexamathasone pulse therapy: (1 cycle 100mg/day i.v. on 3 consecutive days; 6 x repetition every 4 weeks as well as azathioprine 150mg/day p.o. Azathioprine was reduced to 100mg after 12 weeks and completely discontinued after 60 weeks. After 24 weeks complete healing of the ulcer. After 60 weeks, further absence of recurrence under long-term anticoagulatory therapy.

Literature
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  1. Combemale P et al (2002) Cutaneous necrosis revealing the coexistence of an antiphospholipid syndrome with acquired protein S deficiency, factor V Leiden and hyperhomocysteinemia. Eur J Dermatol 12: 278-282
  2. Crowther MA et al (2003) A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med 349: 1133-1138
  3. Girardi G et al (2003) Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome. J Clin Invest 112: 1644-1654
  4. Grimm W et al (1992) The antiphospholipid syndrome. Z Hautkr 67: 800-803
  5. Guvenc BH et al (2004) Transient antiphospholipid syndrome in an infant with segmental small bowel infarction. J Pediatric Surgery 39: 124-127
  6. Harris EN et al (1983) Antiphospholipid antibodies in acute Guillain-Barre syndrome. Lancet 2: 1361-1362
  7. Harris EN et al (1983) Anticardiolipin antibodies: detection by radioimmunoassay and association with thrombosis in systemic lupus erythematosus. Lancet 2: 1211-1214
  8. Hodak E et al (2003) Primary anetoderma: a cutaneous sign of antiphospholipid antibodies. Lupus 12: 564-568
  9. Hughes GR (1993) The antiphospholipid syndrome: Ten years on. The Lancet 342: 341
  10. Hughes GR (1983) Thrombosis, abortion, cerebral disease and lupus anticoagulant. Br Med J 287: 1088-1089
  11. Meurer M et al (1992) Antiphospholipid antibodies. dermatologist 43: 111-113
  12. Nakano J et al (2003) A case of antiphospholipid syndrome with cutaneous ulcer and intrauterine fetal growth retardation. J Dermatol 30: 533-537
  13. Sparsa A et al (2003) Anetoderma and its prothrombotic abnormalities. J Am Acad Dermatol 49: 1008-1012
  14. Van Beek N et al (2013) Diagnosis of a primary antiphospholipid syndrome in leg ulcers under Marcumar therapy. Dermatologist 64: 666-670

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Last updated on: 29.10.2020