Introduction

• It is autoimmune production of antibodies against phospholipids and cell membrane substances (cardiolipin and beta-2 glycoprotein I)
• It presents with triad of 
  • Recurrent venous/ arterial thrombosis
  • Recurrentfetal loss
  • Antiphospholipid antibody in serum

Epidemiology

• 10% of patients with VTE have APLA
• 20% of women with 3 unexplained pregnancy losses before 12 weeks of gestation or atleast 1 intrauterine fetal demise after 12 weeks of gestation have APLA

Etiology:

• Primary antiphospholipid antibody syndrome- Autoimmune disorder with no apparent cause
• Autoimmune disorders- Systemic lupus erythematosus; other autoimmune and connective tissue diseases
• Drug induced – Phenytoin, procainamide, hydralazine, quinidine, phenothiazines, penicillin
• Malignancies- Leukemia, lymphoproliferative and plasmacytic disorders, solid tumors, essential thrombocytosis
• Infections: Viral, bacterial, protozoal, fungal
• Other associations: Neurological disorders, liver disease, valvular heart disease, peripheral arterial disease, chronic renal failure, sickle cell disease
• Ethylene diamine tetra acetic acid – dependent pseudothrombocytopenia

Pathogenesis:

• Antiphospholipid antibodies react with proteins, which are themselves complexed with negatively charged phospholipids
• Thrombosis due to 
  • Antibody induced concentration of prothrombin on phospholipid surface
  • Increased expression of tissue factor on moncytes and endothelial cells
  • Interference with protein C anticoagulant pathway
  • Acquired protein S deficiency
  • Inhibition of fibrinolysis by antibodies totissue type plasminogen activator
  • Inhibition of Annexin V binding to phospholipids
  • Activation of platelets due to binding to beta2 Glycoprotein I binding leading to platelet activation
• Pregnancy failure due to placental infarction and acute atherosis in maternal spiral arteries

Clinical Manifestations

• Asymptomatic
• Venous thromboembolism
  • Any site can be involved- DVT of lower extremities is common
  • Incidence is higher if additional risk factors exist
• Arterial thrombosis
  • Avascularosteonecrosis
  • Stroke
  • Coronary artery disease
• Hematological
  • Cytopenias ; thrombocytopenia, autoimmune hemolytic anemia, leucopenia
  • Coagulopathy : platelet dysfunction, prothrombin deficiency, Acquired haemophilia, acquired vWD
• Neurologic: Acute ischemia (cerebrovascular accident, transient ischemic attack, encephalopathy) ; severe migraine ; multiple infarct dementia ; seizures ; peripheral neuropathy ; myasthenia gravis; Retinal disease; Chorea, GBS
• Dermatologic: Livedoreticularis ; acrocyanosis (distal cutaneous ischemia, ulceration, gangrene) ; widespread cutaneous necrosis ; pyodermagangrenosum-like skin lesions 
• Cardiopulmonary: Maranticendocarditis ; myocardial ischemia and infarction ; intracardiac thrombotic mass ; peripheral artery disease ; thromboembolic and non thrombotic pulmonary hypertension; alveolar hemorrhage
• Obstetric: Recurrent spontaneous abortion (especially in 1^st trimester); intrauterine growth restriction ; still birth; pre-eclampsia; chorea gravidarum ;  placental abruption; Oligohydromnios; low Apgar scores; prematurity; development of DVT (APLA is not a cause for infertility, as implantation is not affected by presence of APLA antibodies)
• Others:Acute adrenal failure, acute sensoryneural hearing loss, occlusion of hepatic vessels, intestinal ischemia, pancreatitis, renal infarction, glomerulonephritis, APS nephropathy (due to vasoocclusion of small sized intrarenal vessels)
• Catastrophic antiphospholipid syndrome- See below

Investigations:

• Immunoassays for identification of anti-phospholipid antibodies
  • Anticardiolipin antibodies
    • High sensitivity but poor specificity
    • Positive in 3-10% of healthy population
    • Also positive in syphilis and Lyme’s disease, which is not related APLA
    • Higher levels are associated with higher risk of thrombosis
  • Anti-beta 2 glycoprotein antibodies- More specific but less sensitive
  • Anti-phosphatidyl serine antibodies
  • Anti prothrombin antibodies
• Coagulation tests for lupus anticoagulant
  • DRVVT with mixing incubations and neutralization with excess phospholipids
    • Russel viper venom directly activates Factor X, leading to formation of fibrin clot
    • LA prolongs DRVVT by interfering with assembly of prothrombinase complex
    • Prolongation is reversed by adding excess of phospholipids to the reaction (sometimes referred to as confirmatory test)
    • This is the most sensitive LA test
  • APTT with mixing incubation and neutralization with excess phospholipids
    • Some LA prolong APTT and it is not corrected by addition of normal plasma. Suspect LA when APTT is prolonged and patient does not have bleeding symptoms
  • Plasma containing Factor 8 antibodies show no prolongation of APTT immediately after mixing but show marked prolongation following incubation for 2 hrs at 37 degree C, where as LA prolongs APTT immediately after mixing with normal plasma.
  • APLA sensitive and insensitive reagents and platelet neutralization procedures. When frozen washed platelets are used as source of phospholipid, APTT becomes LA insensitive (This is called platelet neutralization procedure)
  • Kaolin clotting time
    • Depends on ability of APL antibodies to block thecoagulant activity of trace amounts of platelets present in centrifuged plasma.
  • Tissue thromboplastin inhibition test (Dilute prothrombin time)
  • PT is done with diluted tissue factor- phospholpid complex
    • Results are expressed as ratio of patient to control clotting times.
  • Hexagonal phase array test
    • It is based on the idea that APLA antibodies can recognize phosphatidyl ethanolamine in the hexagonal phase array configuration but not in the laminar phase
    • So incubation of plasma with hexagonal phase array adsorbs LA antibodies, if present, and therefore normalizes APTT that was prolonged because of LA.
  • Textarin/ ecarin test
    • Depends on the difference in phospholipid dependence of coagulation mechanisms triggered by 2 snake venoms
    • Textarin- Activates prothrombin via a phospholipid dependent pathway
    • Ecarin- Activates prothrombin directly without phospholipid.

Indications for APLA testing

• Unprovoked/ unexplained VTE
• Arterial thrombosis in young (<50 years)
• Thrombosis in unusual sites
• Late pregnancy loss
• Recurrent pregnancy loss
• Thrombosis/ pregnancy complication in patients with autoimmune disease such as SLE, RA, AIHA or ITP
• Prolonged APTT on routine evaluation 

Diagnostic Criteria: Both clinical and laboratory criteria must be met

• Clinical Criteria (Any one of the following must be present)
  • Thrombosis: Arterial, venous or microvascular thrombosis in any tissue or organ
  • Unexplained death of morphologically normal fetus at or beyond 10 weeks gestation
  • Three or more unexplained consecutive miscarriages before 10 weeks
  • One or more premature  births of a morphologically normal fetus before 34 weeks of gestation due to pre-eclampsia, eclampsia or severe placental insufficiency
• Laboratory Criteria- (2 LA tests must be done which are based on different assay principles. Tests must be consistently positive  on at least two occasions 6 weeks apart)
  • Anti cardioloipin/ Anti beta 2 glycoprotein 1 antibody- IgG and / or IgM
  • Detection of Lupus anticoagulant by coagulation test
• But these criteria are not very strict. One can have APLA without having any antibody test positive. They are called as sero-negative APLA.

Treatment

• All patients
  • Tab. Aspirin- 75mg- OD
  • Avoid modifiable risk factors such as smoking, obesity, exogenous female hormone use etc.
  • Tab. Hydroxychloroquine- 600-1200mg per day. It reverses APLA antibody mediated platelet activation.
  • Vitamin D- It has immunomodulatory function.
  • Anticoagulant prophylaxis in high risk situations
• Patient presentation with VTE/ arterial thrombosis: 
  • Lifelong anticoagulation with warfarin
  • INR target- 
    • Venous thromboembolism- 2-3- Aspirin is not required
    • Arterial thromboembolism- 2.5-3.5- Along with aspirin
  • Do PT before starting anticoagulation. If PT is prolonged due to LA, LA insensitive reagents such as Innovin/ thromborel must be used
  • Novel anticoagulants have been approved in APLA. They may be used if LA insensitive PT testing is not available/ recurrence of VTE while on VKA/ VKA allergy/ poor anticoagulant control.
• Patient presentation with pregnancy complications
  • Unfractionated heparin (5000 units-SC-BD) along with Aspirin (75mg-OD)
  • Start as soon as pregnancy is confirmed and continue throughout pregnancy and 6 weeks after delivery.
  • Use steroids/ IVIg if there is associated thrombocytopenia/ refractory to anticoagulant therapy/ contraindication to heparin
  • Routine screening for asymptomatic obstetric patients for APLA is not warranted due to high frequency of false positive tests.
• Associated ITP/ AIHA/ Skinulcers/ APLA nephropathy/ Underlying autoimmune disease such as SLE
  • Add Rituximab- 100mg- 2 doses- 2 weeks apart

Related disorders:

• Catastrophic APLA syndrome
  • Multiple simultaneous thromboses
  • Generally associated with multiorgan failure and death
  • Precipitating factors
    • Infections
    • Drugs- Sulphur containing diuretics, captopril, OCPs
    • Surgical procedures
    • Cessation of prior anticoagulant therapy
  • They can present with- Massive venous thromboembolism, respiratory failure, stroke, abnormal liver function, renal impairment, adrenal insufficiency, areas of cutaneous infarction
  • Criteria for diagnosis (All 4 must be met)
    • Involvement of at least 3 organs/ systems/ tissues
    • Development of manifestations simultaneously or within a week
    • Histopathological confirmation of small vessel occlusion
    • Laboratory confirmation of presence of APLA antibodies
  • Lab features of DIC are often present
  • Treatment
    • Plasma exchange
    • High dose methylprednisolone
    • IVIg
    • Immunosuppression with Rituximab/ Cyclophosphamide/ azathioprine
    • Anticoagulation with IV Heparin