Antifosfolipid Syndrome (APLS) (Hughes Syndrome) (ICD-10: D68.8)

Definition

Antiphospholipid syndrome (APLS) is an Autoimmune disease which entails blood clots (thrombosis) or miscarriages and special results in blood samples (antifosfolipid antibodies).

APLS can be a primary, independent disease or part of a rheumatic disease, most often as Systemic lupus (SLE) (about 40%, reference: Koniari I, 2010). Conversely, about 10-30% have SLE (secondary) APLS (Reference: EULAR compendium).

Occurrence

There are approximately 5 new cases per 100.000 population per year (incidence). Together, 40-50 cases / 100.000 persons (prevalence) are seen.

• This corresponds to 265 new cases annually in Norway and that 2400 people have antiphospholipid syndrome

Clinical symptoms

• Blood clots (70% in veins, 30% in arteries)
  • Deep vein thrombosis (DVT)
    • APLS constitutes 5-15% of all deep venous thrombosis (DVT)
    • Portal vein (liver) Budd Chiari's Syndrome
    • Mesenterial-vene (intestinal)
    • Kidney vein
    • Sinus cavernosum (brain), (Sinus Venous thrombosis) see below
  • Pulmonary embolism
• Miscarriages
• Livedo reticularis (20%)
  

  Blood clot in right leg Illustration: James Heilman, MD. CC BY SA 3.0 https://commons.wikimedia.org

• Leg wound (reference: Santos G, 2014)
• Renal disease (renal necrosis, renal inflammation, microangiopathy)
  • At the same time SLE: reference: Tektonidou M, 2004
  • For primary APLS (reference: Abeysekera RA, 2015)
• Neurological symptoms
  • Stroke 13%
  • TIA (transient) 8%
  • Migraine
  • Headache (Sinus Venous thrombosis)
  • Papille edema (eyes) (Sinus Venous thrombosis)
  • Transverse myelitis (spinal cord) (reference: D'Cruz, DP, 2004)
• Heart disease (vegetation, thickening)
• Adrenal necrosis (Adrenal / Addison-crisis)
• Budd Chiari's Syndrome
• Skin (thrombophlebitis, Raynaud's , Pyoderma gangrenosum-like)
• Lung (embolism, Micro thrombosis, ARDS (Acute Respiratory Distress Syndrome), intralvular hemorrhagia (pulmonary edema)Fibrosing alveolitis)
• Post partum syndrome (fever peaks, lung / pleural pain, breathing problems / dyspnea, pleural fluid (water on the lungs) + spotted infiltrates

Catastrophic apL syndrome (CAPS)

• CAPS is described on a separate page, please read here

Blood tests in antifosfolipid syndrome

• Lupus anticoagulant (Coagulation laboratory)
  • High level is of greater significance than low values
• Anti-cardiolipin and beta-2 glycoprotein antibody
• When all three of the above mentioned tests are positive, it is called "Triple-positive" and clearly indicates an increased risk of blood clots.
• Blood tests must be performed on at least two occasions more than three months apart (to rule out accidental, transient rash)
• Thrombocytopenia (low platelet count) (moderate 75-100.000) present at 22%
  • Other causes: SLE, Heparin-induced thrombocytopenia, other causes
• Hemolysis (7%)
  • LD (lactate dehydrogenase) in blood is high, haptoglobin low

Anticoagulation treatment and lupus anticoagulant

Always inform the laboratory of any anticoagulation use

• Acetylsalicylic acid (ASA) does not affect the result
• If using Low molecular weight heparin (Fragmin, Klexane), the blood sample should be taken just before a new dose is given (bottom concentration)
• Heparin in regular doses does not usually affect the result, but high doses can
• With warfarin (Marevan), false positive often causes lupus anticoagulant. The laboratory can reduce the problem by mixing analysis where normal plasma is added
• Direct-acting oral anticoagulants (DOAK) often cause false positive lupus anticoagulants
• Literature: Kristoffersen AH, 2019

Disease Criteria

• More about classification criteria for antiphospholipid syndrome, please read here

Pregnancy and antifosfolipid syndrome

Risk of blood clots (thromboembolism) is nevertheless increased during pregnancy and in the weeks after birth. This can be before birth attack fetus via blood clots in placenta and thus increased risk of abortion, or the pregnant woman may develop thromboembolism (deep vein thrombosis, pulmonary embolism, stroke).

• Abortions
  • In general, in recurrent miscarriages, 10-15% of women have aPL antibodies
  • By SLE and aPL antibody recurrent abortions is seen in 38-59% of pregnancies, versus 16-20% at SLE without these antibodies.
• Therefore, APLS is given drugs that reduce the risk of thromboembolism. Most commonly, Albyl-E (acetylsalicylic acid) is 75 mg / day (from week 12 of pregnancy to week 37) and Fragmin, Klexane or Heparin injections.
  • Fragmin or Klexane is continued for 6 weeks after birth
• Albyl-E is given prophylactically in case of high antiphospholipid antibody responses (without established antiphospholipid syndrome). In some cases (other risk factors, high titers, triple positive), you will choose Fragmin / Klexsane or a combination
• Plaquenil tablets (hydroxychlorokine) may also have a blood clotting protecting effect during pregnancy
• Controls are performed as in the case of "high risk pregnancies" where gynecologist / obstetrician and hematologist (blood disorders) or rheumatologist cooperate
• A separate page about pregnancy at ApLs, please read here
• More information about SLE and pregnancy here or can be obtained at National Center for Pregnancy and Rheumatic Disease, Trondheim.
• More about pregnancy and rheumatic disease, please read here

Incorrect diagnosis? (Similar diseases / differential diagnoses)

• Read more about differential diagnosis of antifosfolipid syndrome here

APL antibody associated diseases

SLE: 6-80%, Systemic sclerosis: 7-31%, Sjøgrens Syndrome: 2-32%, (Dermato- myositis: 6-14%

• Diabetes mellitus, Crohn's disease, Ulcerative colitis, Thyroiditis. Hues / syphilis, HIV, Epstein Barr virus infection (Mononucleosis), Lyme disease, Tuberculosis, Malaria, Hepatitis C
• The results of Lupus anticoagulant tests are affected by "blood-thinning" drugs (anticoagulants).
  • Marevan, Albyl-E, Factor Xa inhibitors (Xarelto, Eliquis) or Factor IIa inhibitors (Pradaxa) affect the outcome
  • The test should (ideally) be taken before drug start or at least one week after stopping treatment

Problems with INR Quick Test

INR (measured at warfarintreatment) may show (“false”) high values ​​in rapid tests at the doctor's office or at home with CoaguCek at APLS because the antibodies interfere with the measurements

• The major hospital laboratories usually use other and less sensible methods

Treatment

In the case of thrombosis (thrombosis), heparin preparations (injections) are most commonly used as Fragmin or Klexane. Dosage can be titrated from measurement of anti-FXa activity in blood plasma.

• • Transition to warfarin (INR 2.0-XNUM)
  • In case of repeated thromboembolism, life-long treatment is relevant
• In some cases with particularly high blood clot risk, Marevan may be dosed higher so that INR becomes 3.0-3.5 or an option to combine with acetylsalicylic acid (Albyl-E)
• Hydroxychlorokine (Plaquenil) probably has preventive effect against thromboembolism (blood clots) and is used especially at the same time SLE and in pregnancy
• In pregnancy (see above) special attention is required ("risk pregnancy"). Marevan should not be used during pregnancy, but Fragmin and Albyl-E (75mg) should be considered early in pregnancy or in advance (reference: Di Prima FAF, 2011)
• Eculizumab (Soliris) which inhibits complement C5a has shown effect at Catastrophic Antifosfolipid Syndrome (CAPS) Most often handled in an intensive care unit
  • The drug is very expensive
• Literature: Erkan D, 2014 (Task Force Report)

Preventive treatment for antiphospholipid antibody

Persistent high rash in lupus anticoagulant, especially in combination with cardiolipin and beta-2 glycoprotein antibody (triple positive) is at increased risk of blood clots. Preventative treatment is recommended (Tektonidou MG, 2019, EULAR).

• Acetylsalicylic acid 75-100mg / day (Albyl-E)
  • Can prevent arterial embolism (in arteries). More uncertain effect on vein thrombosis.
  • Does not prevent blood clots in everyone (14% Get Blood Clot Within 5 Years, Despite Acetylsalicylic Acid)
  • Recommended at high risk and especially if at the same time high risk of cardiovascular disease
  • Albyl-E is usually dosed 75 mg daily
• Plaquenil (hydroxychlorokine)
  • Should be considered when coexcisting Systemic lupus (SLE)
  • Supposed to have a preventive effect against blood clots and related miscarriage during pregnancy (Plaquenil can be used during pregnancy)
  • Considered at high blood clotting risk, especially if at the same time high risk of cardiovascular disease
• Heparin preparations (injections), most often Fragmin or Klexane
  • In particularly vulnerable situations such as long journeys by plane, after operations and after birth
• Statins (Lescol, Fluvastatin 20-40mg / day)
  • Some studies suggest some blood clotting preventive action in antiphospholipid syndrome. However, there is too little data to recommend beyond high cholesterol use
• Immune supressing anti-rheumatic drugs
  • A number of drugs, including corticosteroids (prednisolone), rituximab, belimumab and immunoglobulins are under consideration, but data on general benefit at antiphospholipid syndrome have not been shown to date (per 2019) (reference; Uthman I, 2019)
• Contraceptives with estrogens (common oral contraceptives) should not be used because the blood clotting risk 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 blood clotting risk and can reduce the effectiveness of the drugs

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 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

Referral to specialist

• Key words and checklist useful when referring to a specialist here

Literature

• Tektonidou MG, 2019 (EULAR Recommendations)
• Jackson WG, 2017
• Uthman I, 2019 ′
• Grans Compendium in Rheumatology
• Great Norwegian encyclopedia

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