Antiphospholipid antibody syndrome

ANTIPHOSPHOLIPID ANTIBODY
SYNDROME
Ajay Kumar Yadav
2075/05/15
PGY3,Medicine

LAYOUT
• Introduction
• Historical background
• Classification criteria for APS
• Types of APS
• Clinical presentations
• Management

INTRODUCTION
• The antiphospholipid syndrome (APS)is a systemic autoimmune disease defined by thrombotic or
obstetrical events that occur in patients with persistent antiphospholipid antibodies(APLA)
• Thrombosis may be venous , arterial or microvascular.
• The deep veins of the lower extremities and the cerebral circulation are the most common sites of
venous and arterial thrombosis respectively.
• Obstetrical APLA is characterized by fetal loss after 10th week of gestation, recurrent early
miscarriages, intrauterine growth restriction, or severe preeclampsia.
• A definite diagnosis of APS requires the presence of at least 1 clinical and 1 laboratory criterion.
• The term APS is not synonymous with APLA.

When do we suspect APS?
• Clinical suspicion for APS should be raised in the following settings:
 Occurrence of one or more otherwise unexplained thrombotic or
thromboembolic events
 One or more specific adverse outcomes related to pregnancy
 Otherwise unexplained thrombocytopenia or prolongation of a test of blood
coagulation (eg. aPTT)

HISTORICAL BACKGROUND
• Aka “Hughes syndrome”.
• Graham R.V. Hughes linked major cerebral disease (e.g. recurrent strokes) with abortions and the
LA in an editorial published in the British Medical Journal in late 1970s and early 1980s.
• In the Third International Antiphospholipid Conference in 1994 in Leuven, Belgium, his colleagues
honored him by naming the syndrome, Hughes syndrome.

APS is not synonymous with APLA
• APLA may also be detected in
 Healthy individuals
 Advancing age
 Lymphoproliferative disease
 Infection : Syphilis ,HIV , Lyme disease , IMN ,TB
 Drugs : AED(phenytoin , valproate ) , Procainamide , Chlorpromazine , Hydralazine

• Recently, the APS ACTION group (AntiPhospholipid Syndrome Alliance For Clinical Trials and
International Networking) published a literature review focused in the prevalence of aPL in the
general population.
• APLA are positive in approx.
• 13% of all Stroke,
• 11% of all MI,
• 9.5% of DVT and
• 6% of pregnancy morbidity
• 9% of pregnancy loss
Gezer S. Antiphospholipid syndrome. Dis Mon 2003;49(12):696–741.

EPIDEMIOLOGY
• Prevalence of the APLA in the general population ranges between 1 and 5%.
• However, only a minority of these individuals develop the APS.
• The prevalence of the catastrophic APS is scarce (less than 1% of all cases of APS)
• Prevalence increases with age ,in elderly with chronic disease
• F: M = 5:1
• Age : Young and middle age adults, mean age- 31 yrs.
• APLA in 30-40% of SLE pts.

PATHOGENESIS
• Phospholipids are an integral part of platelet and endothelial cell surface membranes.
• APLA are directed against phospholipid binding proteins. B2GPI is the primary antigenic target of
APLA.
• Under physiologic conditions B2GPI act as elimination of apoptotic cells and as natural
anticoagulant
• 2 hit hypothesis-
• 1st hit : aPL antibody thrombophilic state
• 2nd hit : thrombophilic state  cloting episodes.

Revised Sapporo Classification Criteria for APS
• Clinical Criteria
• Vascular thrombosis
 One or more clinical episodes of arterial, venous or small vessel thrombosis in any tissue or organ
• Pregnancy morbidity
 One or more unexplained deaths of a morphologically normal fetus at or beyond 10th week of gestation
 One or more premature births of a morphologically normal neonate before 34th wk of gestation because of
recognized features of placental insufficiency or
 3 or more unexplained consecutive spontaneous abortions before 10th wk of gestation, with maternal
anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded

Sydney Criteria Cont..
• Laboratory Criteria
 Lupus Anticoagulant present in plasma
 Anti Cardiolipin antibody of IgG or IgM isotype in serum or plasma, present in medium or high
titer(> 40GPL or MPL or more than 99th percentile)by ELISA
 Anti ß2 glycoprotein I antibody of IgG or IgM isotype in serum or plasma(in titre > 99th
percentile) by ELISA
(detection of 1 of the above antibodies on 2 or more occasions at least 12 wks apart)

ISTH criteria for diagnosis of LA

• ACLA causes more arterial thrombosis
• LA causes more venous thrombosis

APLA PROFILE
• High risk
• Defined as a positive LA test with or without a moderate to-high-titer of aCL
or anti-β2GPI IgG or IgM.
• Moderate risk
• Defined as a negative LA test with a moderate-to high titer of aCL or anti-
β2GPI IgG or IgM.
• Low risk
• Defined as a negative LA test with a low titer of aCL or anti-β2GPI IgG or IgM.

CLINICAL FEATURES
CNS Obstetric Renal (25% 0f pts)
 Young stroke
 Cortical sinus thrombosis
 Multi-infarct dementia,
 Migraine headache,
 GBS,
 Transverse Myelitis
 Idiopathic Intracranial HTN
 Chorea
 Cognitive decline
 Optic neuritis.
 Recurrent fetal losses
usually after 10th week of
gestation,
 Early eclampsia,
 HELLP syndrome,
 IUGR,
 IUFD,
 Thrombocytopenia.
 Proteinuria, ( esp in primary
APS)
 Hematuria,
 Acute thrombotic micro-
angiopathy
 Glomerulonephritis(25%)
 RAS and/or severe HTN,
 Renal vein thrombosis,
 Renal failure or ESRD

Cont..
Cardiac Pulmonary Skin
 Valvular thickening,
 Valvular regurgitation,
 Valvular stenosis,
 Myocardial infarction,
 Intracardiac emboli.
 Pulmonary embolism,
 Chronic pulmonary
thromboembolism,
 ARDS,
 Diffuse alveolar hemorrhage
 Pulmonary hypertension.
 Livedo reticularis,
 Ulcerations,
 Digital gangrene,
 Subungual splinter hemorrhages,
 Superficial thrombophlebitis and DVT

Cont..
• Endocrine manifestation
• Adrenal insufficiency
• Autoimmune thyroid disease
• Hypopituitarism( Sheehan’s syndrome)
• Hematological
• Immune hemolytic anemia
• Thrombocytopenia : usually mild ( < 1 lakh )
• If severe ( < 20,000)  CAPS /TTP-HUS

MICROVASCULOPATHY
Gangrene of toes
Livedo reticularis Digital infarct

VENOUS THROMBOSIS
• DVT in the lower extremities : 29% to 55% of pts
• More than 50% with symptomatic DVT have asymptomatic Pulmonary embolism.
• Unusual sites of venous thrombosis includes
• The upper extremities
• Intracranial veins – acute cerebral infarction
• Inferior and superior vena cava
• Hepatic veins (Budd-Chiari syndrome),
• Portal vein
• Renal vein and retinal vein.

ARTERIAL THROMBOSIS
• Less common than venous thromboses
• Most commonly present with TIA or stroke (50%) or MI(23%)
• Presence of ACLA : risk factor for stroke
• Involvement of large and small vessels—unique feature.
NEJM 2002;346;752-63 Dis Mon 2003;49:696-74 Semin Thromb Hemost 1999:25;333-50

VALVULAR HEART DISEASE(VHD)IN APS
• Between 15% - 30% of patients with APS have VHD, k/a Libman-Sacks
endocarditis or nonbacterial thrombotic endocarditis(NBTE)
• Criteria include
• Valve thickness >3 mm,
• Localized thickening of the proximal or middle portion of the valve leaflet,
• Irregular nodules on the atrial aspect of the mitral valve or the vascular
surface of the aortic valve, and/or
• Moderate-to-severe valvular regurgitation or stenosis

Primary APS
• Genetic predisposition
• HLA associations: certain HLA genes a/w APS
• DRw53, DR7 : mostly people of Hispanic origin
• DR4 : mostly whites
• Familial association: Relatives of persons with known APS are more likely to have APLA

Secondary APS
• Systemic autoimmune diseases:
• SLE(most common cause of secondary APS), RA, Systemic sclerosis,
• Primary Sjogren’s syndrome,
• Dermato- and polymyositis,
• Vasculitis (PAN, microscopic polyarteritis, giant cell arteritis, Behçet’s disease, relapsing
polychondritis, leucocytoclastic vasculitis).
• Infections:
• Viral (HIV ,IMN, rubella, parvovirus, hepatitis A,B, C, mumps),
• Bacterial (syphilis, Lyme disease, tuberculosis, leprosy, infective endocarditis, rheumatic fever,
Klebsiella),
• Protozoal (malaria, toxoplasmosis).
• Drugs: Procainamide, phenothiazines, ethosuximide, chlorothiazide, quinine,OCP, anti-TNFa therapies

Cont..
• Malignancies:
• Solid tumors (lung, colon, cervix, prostate, liver, kidney, thymus, esophagus, maxilla, ovary, breast),
• Hematologic (myeloid and lymphatic leukemias, PV , myelofibrosis),
• Lymphoproliferative diseases (HL, NHL, lymphosarcoma, cutaneous T cell lymphoma/Sezary
syndrome),
• Paraproteinemias (MGUS,WM,MM).
• Non-malignant hematologic conditions:
• ITP
• Sickle cell disease,
• Pernicious anemia.
• Other conditions: DM, autoimmune thyroid disease, IBD, Ehlers danlos syndrome.

Additional risk factors for thrombosis
• Age >55 in men and >65 in women
• Risk factors for CVD
• Inherited thrombophilias
• Oral contraceptives
• Nephrotic syndrome
• Malignancy
• Immobilization
• Surgery

CATASTROPHIC APS
• Preliminary criteria for the classification of catastrophic APS .
1. Evidence of involvement of three or more organs, systems and/or tissues.
2. Development of manifestations simultaneously or in less than a week.
3. Confirmation by histopathology of small vessel occlusion in at least one organ or
tissue.
4. Laboratory confirmation of the presence of antiphospholipid antibodies (lupus
anticoagulant and/or anticardiolipin antibodies).

CAPS cont..
• Definite catastrophic APS: All 4 criteria.
• Probable catastrophic APS:
• All 4 criteria, except for only two organs, systems and/or tissues involvement.
• All 4 criteria, except for the absence of laboratory confirmation at least 6 weeks
apart due to the early death of a patient never tested for aPL before the catastrophic
APS.
• 1, 2 and 4.
• 1, 3 and 4 and the development of a third event in more than a week but less than a
month, despite anticoagulation.
• Renal involvement is defined by a 50% rise in serum creatinine, severe systemic
hypertension (>180/100 mmHg) and/or proteinuria (>500 mg/24 h).

D/D of CAPS
• Factor V Leiden mutation
• Homocysteinemia
• Vasculitis e.g. Classical PAN
• Infective Endocarditis with embolic phenomena
• TTP
• Cholesterol embolism
• Malignancy
• HUS
• Sepsis
• DIC

Approach to a patient with asymptomatic
positive APLA

Primary Thromboprophylaxis in APS
Primary Thromboprophylaxis in Antiphospholipid Syndrome
General measures for all antiphospholipid
positive pts
 Assessment and management of traditional
cardiovascular risk factors
 In high-risk situations (puerperium, surgery,
prolonged immobilization), use usual doses of
LMWH for thromboprophylaxis
Antiphospholipid-positive non-SLE patients
(obstetric APS and asymptomatic carriers)
 Low-dose aspirin (75–100 mg/day) in those
with a high-risk APLA profile ,esp. in the
presence of other thrombotic risk factors
Patients with SLE and positive APLA  Hydroxychloroquine (200–400 mg/day) +
low-dose aspirin (75–100 mg/day)

Secondary Thromboprophylaxis in APS
Secondary Thromboprophylaxis in Antiphospholipid Syndrome
Definite APS and a first venous event Indefinite oral anticoagulant therapy to a target
INR of 2.0–3.0
Definite APS and arterial thrombosis Indefinite oral anticoagulant therapy to a target
INR >3.0 or combined antiaggregant-
anticoagulant (INR 2.0–3.0) therapy
Patients with venous or arterial thrombosis who
do not fulfill criteria for APS
Treatment as per usual recommendations for
arterial or venous thrombosis

Alternative and Adjunctive Therapeutic
Options for Specific Clinical Scenarios in APS
Alternative and Adjunctive Therapeutic Options for Specific Clinical Scenarios in Antiphospholipid Syndrome
Known warfarin allergy, warfarin intolerance, or
poor anticoagulant control on warfarin despite
therapeutic target
 Treatment with, or addition of, NOAC: direct
thrombin inhibitor dabigatran or direct anti–
factor Xa inhibitors rivaroxaban, apixaban, or
edoxaban
Heparin-induced thrombocytopenia  Treatment with fondaparinux or argatroban
Refractory APS despite adequate
anticoagulation
 Consider starting statin therapy
 Consider adding rituximab therapy
 Consider adding glucocorticosteroids and IVIG
/plasma exchange

Cont..
Alternative and Adjunctive Therapeutic Options for Specific Clinical Scenarios in Antiphospholipid
Syndrome
CAPS  Heparin anticoagulation + glucocorticoids +
IVIG and/or plasma exchange reduces
mortality
 Eculizumab reduces mortality
Renal transplant pts with CAPS  Sirolimus decreases recurrent vascular lesions
and vascular proliferation
 Eculizumab for treatment and prevention of
thrombotic microangiopathy in patients with
history of CAPS

Management of Obstetric APS
Obstetric APS
 Heparin (unfractionated or LMWH) + low dose aspirin (75–100 mg/day)
 Patients on warfarin should be switched to heparin (unfractionated or LMWH)
immediately upon pregnancy confirmation to avoid teratogenicity
 Extended thromboprophylaxis (up to 6 weeks after delivery) for high-risk patients
 Indefinite anticoagulation for APS patients with prior thrombotic events

Summary of the drug usage in APS
• Low-dose aspirin (<100 mg per day)
 Primary thrombosis prevention for CVD prevention in the general population;
 Secondary arterial thrombosis prevention, if patient has other risk factors for
CVD ;
 Prevention of pregnancy complications in pregnant patients with obstetrical or
thrombotic APS or both;
 Potential add-on treatment for recurrent thrombosis despite therapeutic-dose
anticoagulant therapy

Summary cont..
• Hydroxychloroquine (200–400 mg per day)
anticoagulant therapy.
• Statins
anticoagulant therapy.
• Warfarin
 Secondary thrombosis prevention (INR, 2–3);
 Target INR of 3–4 is a possible strategy for recurrent thrombosis despite therapeutic dose
anticoagulant therapy

Summary cont..
• Low-molecular-weight heparin
 Thrombosis prevention during high-risk periods (e.g., perioperative or
postpartum period);
 Prevention of thrombosis and pregnancy complications in pregnant patients with
obstetrical APS (e.g., enoxaparin, 40 mg daily) and thrombotic APS (e.g.,
enoxaparin, 1.5 mg/kg of body weight daily or 1 mg/kg twice daily);
 Potential alternative treatment for recurrent thrombosis despite therapeutic dose
warfarin (e.g., enoxaparin, 1.5 mg/kg daily or 1 mg/kg twice daily)

Summary cont..
• Unfractionated heparin
 Part of first-line combination treatment for catastrophic APS;
 Prevention of thrombosis and pregnancy complications in pregnant patients with
obstetrical APS (5000 units subcutaneously twice daily) and thrombotic APS (e.g.,
250 units/kg subcutaneously twice daily)
• Direct oral anticoagulants
 More data needed

Summary cont..
• Glucocorticoids (e.g., IV methylprednisolone,250–1000 mg for 3 days)
 Part of first-line combination treatment for catastrophic APS;
 First-line treatment for severe thrombocytopenia, hemolytic anemia, or both.
• Intravenous immune globulin
 Part of first- or second-line combination treatment for catastrophic APS (1–2
g/kg, given over a period of 3–5 days);
 First- or second line treatment for severe thrombocytopenia (1 g/kg; can repeat
once, usually 1–2 days after first dose)

Summary cont..
• Plasma exchange
 Part of first- or second-line combination treatment for catastrophic APS; for acute
thrombotic micro-angiopathy in patients with aPL related nephropathy
• Traditional immunomodulatory agents (e.g., azathioprine, 100–150 mg per day,
or MMF, 1000–3000 mg per day)
 An option for severe thrombocytopenia, hemolytic anemia, or both;
 An option for aPL nephropathy

Summary cont..
• Rituximab (e.g., 1000 mg on days 0 and 15, repeated every 6 mo)
 An option for thrombocytopenia, hemolytic anemia, livedoid vasculopathy, and aPL
nephropathy;
 An option for catastrophic APS that is refractory to standard treatment
• Eculizumab
 An option for catastrophic APS that is refractory to standard treatment;
 An option for acute thrombotic microangiopathy in patients with aPL-related
nephropathy
• Defibrotide
 More data needed

Reference
Wintrobes clinical hematology 13th edition
Harrison 19th edition
N Engl J Med 2018; Diagnosis and Management of the Antiphospholipid Syndrome
ASH hematology APS 2015
Journal of ACG 2017 APS

NETosis
• Upon activation, neutrophils release fibers composed of chromatin and
neutrophil proteins termed neutrophil extracellular traps (NETs).
• NETs trap and kill microbes, activate dendritic cells and T-cells, and are
implicated in auto-immune and vascular diseases.

DEFIBROTIDE
• Adenosine receptor agonist
• Approved for hepatic veno-occlusive disease (also known as the sinusoidal
obstruction syndrome) after hematopoietic stem-cell transplantation.
• Adenosine 2A receptor agonism triggers cAMP formation in neutrophils
• Lower thrombotic risk by reducing antiphospholipid antibody–mediated
NETosis

Antiphospholipid antibody syndrome

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