a case of antiphospholipid antibody syndrome

Physician’s Meet

March 17 2010

Dr Jishanth M

Prof. Dr A Gowrishankar’s Unit, M4

An Interesting Hypercoagulable State

• Manikandan, 19 yr, Male

• Admitted on 26 Dec 2009

• Presenting Complaints:

1. Breathlessness- 1 year

2. Fever 1 week

3. Pain and discoloration of toes 3days

• H/o Present Illness:

• Breathlessness- Insidious onset, slowly progressive , Gr I-III

No h/o palpitation/ pedal edema

• H/o fever for last 1 week, high grade continuous fever without chills or rigors

• H/o cough with expectoration +, mucopurulent, non foulsmelling

• H/o Loss of appetite+ with loss of weight

• H/o pain both lower limbs+, R>L,

with brownish black discoloration of 2nd & 3rd toes of R leg

H/o Cramps +, H/o claudication pain+

• H/o thinning of both UL&LL +

• No h/o joint pain/swelling/deformities/morning stiffness

• Past Medical history:• Treated for Pulmonary tuberculosis with ATT

twice over the past 2 ½ years

• On treatment for breathlessness and cough with expectoration…? Bronchiectasis

• Family History:• No history of similar illness

• 2nd of non-consanguinous marriage.

• On Examination:• Patient conscious,• Oriented• Emaciated• Pallor+• Grade II clubbing +• Right forefoot gangrene+(2nd & 3rd toe)• Skin of lower limbs dry, scaly and atrophic.• No rashes• No deformities of joints

• PR: 70/min, regular• Absent in R LL(femoral, popliteal, dorsalis pedis and posterior tibial)• Feeble in L LL• BP: 130/80 mmHg(RUL)

System Examination:• CVS:

S1S2 heard, P2 loud

no murmers• Abd:

Soft, no organomegaly• CNS:

Higher functions normal

Generalised wasting of all muscles (UL and LL)

DTR exaggerated bilaterally

Plantar B/L flexor

No meningial signs• RS:

Trachea central,

NVBS+

B/L coarse late inspiratory leathery creps + in lower lung fields

B/lL Rhonchi+

PROVISIONAL DIAGNOSIS

• Bronchiectasis

• Old treated tuberculosis

• Gangrene ® 2nd & 3rd toe/? Cause

INVESTIGATIONS

• Hb :10.8 g%• TC :8400• DC :P66L33E1• ESR :10/22• PCV :30%• Platelets :1.1L• MCV :90 fl• RBS : 102 mg%• BU :44 mg%• SCr :1.0 mg%

• Urine RoutineAlb-nilSugar-nilDeposits-1-3

pc/hpf• ECG: SR/70 per min

‘p’ pulmonale +

CXR PA VIEW

Investigation contd…

• Ultrasound abdomen:

Liver size and echotexture normal., no cysts

Kidneys normal, CMD+

• ECHO: RVH+, Mild PHT, Valves normal, No PE

• Sputum C/s: Pseudomonas s/to cipro; norflox; gentamicin

• Sputum AFB : Negative

• PT : 14.1 s

• INR : 1.0

• aPTT : 54 s

• RA factor: 80 positive• ASO : 200 positive • CRP : 96 positive• ANA : Negative• Anti dsDNA: Negative• S Homocysteine : 11.17• Anti Phospholipid(aCL) Ig M : 40.30 (N<15)

IgG : 54.96 (N<15)

Protein C: 35(normal)

Protein S: 32( normal)

• Started on Inj LMWH s/c BD

• Tab Aspirin 150 mg ½ OD

• Inj Deriphylline IV BD

• Inj Ampicillin 1 g IV TDS• Changed to Ciprofloxacin 200 mg BD and

Gentamicin 80 mg IV BD (Rpt RFT normal)

• Vascular Opinion:

Primary Hypercoagulable state,

Right Iliac artery occlusion

Left Temporal artery occlusion

• Continue LMWH

• Sugg: CT Angiogram

Cardiology opinion

• Patient had symptomatic improvement(fever& breathlessnes), but developed R LMN VII N palsy during in hospital stay associated with head ache.

• He was started on Tab Prednisolone 1mg/kg/day

• Patient developed multiple cranial nerve palsy( lower cranial nerves) over next 2 days

Neurophysician Opinion:

• B/L VI,

• R VII, VIII

• B/L IX, X, XI, XII

• Generalised Wasting +

• B/L Brisk reflexes

• Impression: Miliary Tuberculosis with Basal Meningitis; small fibre neuropathy

• Chest Physician Opinion:

?Rheumatoid related ILD with reactivation of Tuberculosis

• Sugg: HRCT, USG Abdomen

CT ANGIOGRAM

• Short segment stenosis(30-40%) of proximal coeliac artery

• Short segment stenosis(60-70%) of right common iliac artery

• Long segment high-grade stenosis/ occlusion of right distal external iliac artery extenting into common femoral artery

• Occlusion of right popliteal artery with reconstituted flow distally.

VASCULAR REVIEW:

• Sugg: Improve general condition for arterial revascularisation.

• Contnue LMWH

• T Acitrom 4 mg OD

• Monitor PT/INR (2-3)

Further investigations

• p ANCA: negative

• c ANCA: negative

• HBsAg : negative

• Anti HCV: negative

• HIV (I & II): negative

HRCT Chest

Interlobular septal thickeningB/l cystic spaces with peribrochial fibrosis

FINAL DIAGNOSIS

• ?Reactivated CNS tuberculosis with multiple CN palsy

• Secondary Antiphospholipid Syndrome

• Rheumatoid related ILD with bilateral bronchiectasis

Antiphospholipid Syndrome

• Multisystem autoimmune disease• Most common acquired thrombophilia• Described by Hughes (1983)

A syndrome characterized by the association of:• thrombosis, obstetric complications and/or

thrombocytopenia• antibodies against phospholipids or against proteins

bound to phospholipids.

• History• 1906: antiphospholipid antibody discovered in patients with syphilis,

complement-fixing antibody that reacted with extracts from bovine hearts

• 1952: Conley and Hartmann described circulating anticoagulant in patients with Lupus

• 1963: Bowie associated the anticoagulant with thromboembolic events• 1983: First description of syndrome with thrombosis, recurrent

miscarriage and thrombocytopenia by Hughes

• Epidemiology• Most common in young to middle-age adults• Can occur in children and elderly• More common in females

TWO TYPES

• Primary

• Secondary - Associated with other autoimmune or rheumatic diseases

Antiphospholipid Syndrome - Etiology

• Combination of

1. genetic background and

2. environmental factors: infection, trauma, drugs• Infections – molecular mimicry with B2GPI

Disease associations

Drug Induced aPLs

• Mediations reported• Phenothiazines• Phenytoin• Hydralazine• Procainamide• Quinidine• Dilantin• Ethosuximide• Alpha-interferon• Amoxicillin• Chlorothiazide• Oral contraceptives• Propranolol

• Usually transient• Associated with IgM• Rarely associated with

thrombosis

• Mechanism unknown

Antiphospholipid antibodies

• Antibodies are directed against phospholipids, plasma proteins bound to phospholipids, or unique antigens revealed during the interaction of the two.

• Antiphospholipid antibodies present in upto 10% of healthy donors

• Incidence increases with age and coexisting chronic disease

• Among patients with thrombosis, prevalence of antiphospholipid antibodies is 4 to 21%

• Increasing risk of thrombosis among those with higher antibody titers

Antiphospholipid Antibodies

• LA antibodies are directed against plasma proteins bound to anionic phospholipids

• aCL antibodies are directed against phospholipids bound to proteins– Can be IgA, M, or G (subclasses 1-4)– IgG (esp G2) associated with a greater risk of APS

• Anti 2GPI antibodies are directed against a plasma protein that binds phospholipid with high affinity

• Other antibodies of unclear significance: – prothrombin, annexin V, phosphatidylserine,

phosphatidylinositol, phosphatidylcholine

Antiphospholipid Antibodies

• Lupus Anticoagulant (LA) Antibodies• Prolonged coagulation in phospholipid-dependent in vitro tests

(aPTT, PT, dRVVT)• Failure to correct with 50:50 mix• Correction of coagulation time by adding phospholipid• Higher thrombotic potential than aCL when each are present

alone

• Anticardiolipin (aCL) Antibodies• ELISA assay in the presence of bovine B2GPI

• Anti-Beta 2 Glycoprotein I Antibodies (2GPI) • ELISA assay using human B2GPI coated plates• most specific

Beta 2 Glycoprotein I

• Natural inhibitor of coagulation and platelet aggregation

• Inhibits contact activation of coagulation cascade

• Inhibits conversion of prothrombin to thrombin

• Most aPL antibodies recognize domain I of b2gp

• Binding of antibody increases binding affinity for phospholipids

Significance of aPLs

• No history of thrombosis and positive aPL: Risk of new thrombosis <1%

• History of thrombosis and positive aPL: Risk of new thrombosis >10% in first year if anticoagulation stopped within 6 months

APS PathophysiologyaPL

platelets

Coagulation cascade

Endothelial cellsActivate

platelet aggregation

Inhibit Protein C, Protein S,

thrombomodulin, antithrombin III

fibrinolysis

TF, adhesion molecules and

proinflammatory cytokines

Placental tissue

Trophoblastic cell growth,

apoptosis

IL-3

Complement system

APS Pathophysiology

Pathogenesis

• Activation of platelets• Activation of vascular endothelium• Enhanced monocyte expression of Tissue Factor• Inhibition of Prot C ,Prot S and other coagulation

factors• A/B against other proteins involved in coagulation

– Heparin– Prothrombin– Platelet activating factor etc.

• Complement activation

• Diagnosis• At least one antiphospholipid antibody

• At least one clinical manifestation

REVISED SAPPORO CRITERIA, SYDNEY 2006

Clinical Criteria

• Vascular thrombosis: arterial, venous, or small vessel, in any tissue or organ, confirmed by objective validated criteria

• Pregnancy morbidity:

- Unexplained fetal death at or beyond 10 weeks gestation

- Premature birth before 34 weeks gestation because of

eclampsia, severe pre-eclampsia, or placental insufficiency

- Three or more consecutive spontaneous abortions before

10 weeks gestation

Laboratory criteria • Lupus anticoagulant, present on at least 2 occasions, at

least 12 weeks apart

• Anticardiolipin antibodies (ACA), IgG or IgM >30 units for both, present on at least 2 occasions, at least 12 weeks

apart

• Anti-beta-2-glycoprotein I antibodies (anti-B2GPI), IgG or IgM >20 units for both, present on at least 2 occasions, at least 12 wks apart

A diagnosis of APS should not be made if a period of greater

than five years separates the clinical event and positive

laboratory test.

Clinical Manifestations

• Vascular thrombosis: arterial and venous• Skin: Levido reticularis• Recurrent pregnancy loss• Neurologic: TIA, stroke, migraine, chorea, seizures, optic neuritis

– SNEDDON SYNDROME: stroke, levido reticularis, hypertension• Cardiac: Coronary artery disease, premature atherosclerosis,

vegetations• Renal: thrombotic microangiopathy, renal vein thrombosis, renal

infarction, renal artery stenosis with hypertension, increased allograft vascular thrombosis, and reduced survival of renal allografts

• Pulmonary: PE, pulmonary hypertension• GI: Budd-Chiari syndrome, intestinal ischemia and infarction, colonic

ulceration, esophageal necrosis and perforation, hepatic infarction, acalculous cholecystitis with gallbladder necrosis, and mesenteric and portal vein thrombosis

• Hematologic: thrombocytopenia, TTP/HUS, hemolytic anemia

Catastrophic APS• Multiple, simultaneous vascular occlusions throughout body

– Widespread microthrombi in multiple vascular bedsMassive thromboembolism

– Clinical involvement of at least 3 organ systems over days to weeks– Histopathologic evidence of occlusions of small and large blood

vessels– Most common organs:

kidney>lung>CNS>heart>skinmultiorgan failure– DIC in 25%– Respiratory failure, stroke, abnormal liver enzymes, renal

insufficiency/failure, adrenal insufficiency, cutaneous infarcts• Precipitating factor in 55%: Most common is infection• Usually primary APS• Mortality > 50%

Treatment-General

• Anti-thrombotic therapy– Heparin– Wafarin

• Pregnancy – controversial– SC heparin and/or Aspirin

• Immunosuppresion – rarely used• Treat associated condition eg.SLE• Risk factor modification eg.smoking , OCP

Anticoagulation

• Initial therapy – same as those without APS– Wafarinisation (INR 2-3)

• Recurrent events – greatest benefit with high intensity Wafarin (INR 3-4) with or without aspirin

Treatment-Other

• Plasmapharesis

• IVIG

• Experimental – fibrinolytics, prostacyclin anti-cytokines

Treatment of Catastrophic APS

• Treatment– Treat precipitating factor if present– Anticoagulation– Steroids– IVIG– Plasma exchange– Cyclosphosphamide

– Rituximab

– Prostacyclin

– Other fibrinolytics

Future directions of treatment of APS

• Peptide-specific therapy: peptide with B2GPI epitopes recognized by aPL or B2GPI blocking Ab

• Inhibitors of intracellular signaling triggered by aPL

• Complement activation inhibitors

• Anti-TNFα agents

• Anti CD20 agents

• Primary prophylaxis…?????

Summary• APS – under-recognized autoimmune disease that accounts for

a significant proportion of thromboembolic disease and recurrent pregnancy loss

• The etiology and pathophysiology involves aPL as “first hit” and environmental factors, including infection as “secondary hit”

• APS - complex disorder with evolving diagnostic criteria

• Anticuagulation rather than immunosuppresion is the current mainstay of therapy

• Well-designed prospective studies are required to complete the understanding of the optimal treatment.

Uniqueness of the case under discussion….

….THANK YOU….