ANTIPHOSPHOLIPID

ANTIBODY SYNDROME

Dr.Praveen Nagula

A discovery is said to be an accident meeting a prepared mind.

A discovery is said to be an accident

meeting a prepared mind.

A discovery is said to be an accident meeting a prepared

mind

Case description in brief.

A young female was admitted in casualty with swelling of rt lower limb.

On examination pulses absent. USG showed thrombus. h/o revealed –marriage life 0f 18 months---2 months later had

an ischemic stroke---after 7 months became pregnant---6 months miscarriage,severe pl. insufficiency---after 2 months she had swelling of rt lower limb—DVT---on 1st june had abd pain—hemorrhagic cyst of ovary—stopped acitrom---DVT.

INR---3.3 at discharge Diagnosis suspected of APLS APL ab positive---Ig G ACL—90GPL,IgM ,IgA were positive. Patient was kept on warfarin----to be followed up.

INTRODUCTION

Also known as HUGHES SYNDROME.

LUPUS ANTI COAGULANT SYNDROME (misnomer)

Autoimmune disorder.----acquired thrombophilic disorder.

Mostly assosciated with SLE.

Responsible for frequent miscarriages in young females (15%).

CATASTROPHIC APS---Asherson’s syndrome.

MC thrombotic defect leading to fetal wastage.

Graham R.V. Hughes

DEFINITION

A patient with definite APS must have persistent high titer antiphospholipid antibodies(APL) assosciated with a history of arterial or venous thrombosis or both ,or recurrent pregnancy morbidity.—(clinical criteria) and laboratory criteria.

CAPS Asymptomatic antiphospholipid antibodies Probable antiphospholipid syndrome Seronegative antiphospholipid syndrome(SNAP) Microangiopathic antiphospholipid syndrome Drug induced Infection assosciated Malignancy assosciated.

CLINICAL CRITERIA—( SAPPORO CRITERIA)

APS is present if at least one of the clinical criteria and one of the laboratory criteria that follow are met….

Clinical criteria---1.vascular thrombosis One or more clinical episodes of arterial,venous or small

vessel thrombosis,occuring in any tissue or organ.to be confirmed by objective validated criteria.histopathologically thrombosis should be present without significant evidence of inflammation in the vessel wall.

2.pregnancy morbidity a.one or more unexplained deaths of morphologically normal

fetuses at or after the 10 week of gestation. b.one or more premature births of morphologically normal

neonates before the 34th week of gestation—ecclampsia,sev pl insufficiency

c.three or more unexplained consequtive sp abortions before the 10th week of gestation—anatomic,hormonal abn excluded.

Sapporo,JAPAN…SYDNEY

Laboratory criteria 1.lupus anticoagulant present in plasma. 2.aCL of IgG and or IgM isotype in serum or

plasma,present in medium or high titer(>40GPL,40MPL,>99TH percentile)

3.anti β2GP1IgG or IgM isotype in serum or plasma

On two or more occasions at least 12 weeks apart.

Diagnostic clues for individual patients but not as classification criteria for the purpose of clinical trials

Cardiac valve disease,livedo reticularis,thrombocytopenia,renal thrombotic microangiopathy,neurological manifestations-chorea

Non criteria antibodies—IgAaCL,IgAanti Β2gp1,antiphosphatidylserine ab,antiphosphatidyl ethanolamine ab,ab against prothrombin alone,ab to Ph.serine-PT complex.

criteria

Advances in criteria 1999---sapporo concensus conference 2004---sydney conference revised Numerous modifications were made to the initial statement.

Better defining of clinical criteria by confirmation. Stratification of patients with APS presence or absence of other

inherited or acquired contributing cause of thrombosis.

APS with or without assosciated rheumatic disease. CAPS Asymptomatic aPL Time interval increased to 12 weeks Transient positivity to be excluded Add of b2gp1 ab Diagnostic clues J thromb haemost

2006:4:295-306 Arthritis Rheum

1999;42:1309-11 JAPI,mar 2010—176-183

EPIDEMIOLOGY In young,app healthy people---for LA,antiCL is 1-5% Prevalence ↑ with age ,in elderly with chronic disease. Risk of thrombosis is 0.5-30% Women :men is 5:1 Mean age of onset-31 yrs Low age 8 months Females---arthritis,livedo,migraine Males—MI,epilepsy,lower extremity arterial thrombosis ACA ass with thrombosis>LA ---5:1 Acl in elderly More common in african americans.

Without rheumatic disease at younger age and with rh –older

Apl ab—30-40% in SLE---10% have APLS Idiopathically—ACL-24%,LA-4%

The clinical manifestation of thrombosis is similar whether the APL is primary or secondary.

Removed in 2006.

Common auto immune diseases ass with APL ab are 1.SLE-25-50% 2.sjogren’s –42% 3.RA-33% 4.AITP-30% 5.AIHA-unknown 6.PA-28% 7.SS-25% 8.MCD-22% 9.behcet-20% 10.PMR-20%

etiology

Unknown cause Possible triggers identified and stratified accordingly. Most of the autoimmune disorders ass with APLab WHETHER IT ITSELF INVOLVED IN PATHOGENESIS OR

IS AN EPIPHENOMENON IS ? Relatives of persons with known APS—33% freq have

APLab HLA –DRW53,DR7—HISPANIC,DR4 white.

PATHOGENESIS

Homeostatic regulation of blood coagulation is altered.

1.defect in cellular apoptosis---exposure of membrane phospholipids to the binding of various plasma proteins---b2gp1---complex—epitope---target for autoantibodies.

2.oxidized b2GP1---activates dendritic cells –autoantibodies are produced.

3.production of antibodies against prothrombin,proteinC,S annexins.

4.activation of platelets to enhance endothelial adherence.

5.activation of vascular endothelium—platelet and monocyte binding.

6.ab against oxidized LDL—atherosclerosis.

Complement activation has been increasingly recognised as a possible significant role in the pathogenesis of APS.

Blood. Jan 15 2007;109(2):422-30. 

Nat Med. Nov 2004;10(11):1222-6.

The family of APL ab are heterogenous and the targets vary.

APS can be caused by –LA,ACA,B2GP1 or other antibodies.

There are distinct clinical ,laboratory and biochemical differences between the disorders mediated by the different antibodies.

ACL---risk of stroke—arterial thrombosisLA-venousTNF alpha –pregnancy loss

Mechanism of thrombosis

Precise mechanism is unclear. Heterogenous---several mechanisms are responsible.

‘phospholipids are an integral part of platelet And endothelial cell surface membranes ,it is expected that these antibodies have a effect on them.’

How do they mediate????

Inhibition of endothelial cell prostacyclin production Clin Appl Thromb Hemost 1999;5;s76

Procoagulant effect on platelets Br J Haematol 2002:119;781

Impairement of fibrinolysis Interference with the thrombomodulin-proteinS-proteinC

pathway J Autoimmun 2007;28(2-3):129-33

Induction of procoagulant activity on endothelial cells and/or monocytes Clin Exp Immuno 2000;120:537

Disruption of the annexin Vcellular shield Fertil Steril 2002l;77:805

Abnormal cytotrophoblast expression of adhesion molecules in pregnancy NEJM2002;346 (10);752-63

Anionic phospholipids

pathology

pathogenesis

Coagulation pathway

Annexin V

In pregnancy

ACA– are directed against cardiolipin They may be b2 gp1 dependent or independent Independent—syphilis

B2 gp1-----apolipoprotein H Bind with cardiolipin ab --thrombosis

What do the animal models say???

Question the non inflammatory ,thrombotic state Evidence for complement activation is crucial for

complications in pregnancy. Inflammation mediated tissue injury in pregnancy Therapy should be against inflammation Ann N Y Acad Sci

2005 ;1051:413-20

Mouse model of APS---heparin prevents complement activation induced by APL.

Use of specific complement inhibitors in APS—future TNF alpha– as a critical effector in pregnancy loss—TNF

blockade

Risk factors for thrombosis

Age >55 in men,>65 in women Risk factor for CVD* Inherited thrombophilias Oral contraceptives Nephrotic syndrome Malignancy Immobilization Surgery

*htn,DM2,LDL,↓HDL,cigarette smoking,family h/o BMI>30kg/m2,microalbuminuria,GFR<60ml/min

CLINICAL FEATURES(SPECTRUM)

1.VENOUS THROMBOSIS Lower extremities 29-55% caes >50% have asymptomatic pulmonary embolism Seen at unsual sites Cerebral veins may be affected Superior sagittal sinus Semin Thromb Hemost

1999;25:333-50

Superficial thrombophlebitis

Retinal vein thrombosis

2.ARTERIAL THROMBOSIS Less common Males Present with TIA or stroke 50%,MI(25%) Presence of anti CL ab—risk factor Involvement of large and small vessels—unique Brachial,subclavian arteries Peripheral arteries

NEJM 2002;346;752-63Dis Mon 2003;49:696-741Semin Thromb Hemost 1999:25;333-50

gangrene

Retinal artery thrombosis

3. CARDIAC disorders Thrombotic or embolic Premature athreosclerosis—occlusion Apl inv in young age with no risk factors for CaVD Valvular thickening—M.,A Vegetations ----libmann sacks Premature coronary disease Myocardial infarction Diffuse cardiomyopathy CHF Pericardial effusion Pulmonary hypertension

In SLE---pericarditis is common,no valvular reg,with htn –HF,only epicardial ischemia.

J thromb thrombolysis 2005;20;105-12

endocarditis

4.NEUROLOGICAL disorders Thrombotic or embolic LA—venous,ACL—arterial---risk factor for stroke in young Recurrent strokes—multi infarct dementia No other risk factors are present “chorea is another clinical diosrder that has been strongly

linked to presence of APL” Migraine,TM,GBS,ON,ICH,psychosis Mimics multiple sclerosis—cognitive dysfunction Diff—chorea,migraine,seizure ,dysarthria mc in

apl,ON,bowel ,bladder ,gait—MS Non enhancing with gadolinium,strongly poisitive

ab---APLS

Dis Mon 2003;49(12):696-741,Thromb Res 2004;114;489-99,Ann N Y Acad Sci 2005

5.obstetrical disorders Recurrent miscarriages Fetal demise Ecclampsia IUGR Oligohydramnios HELLP syndrome

May be the prsenting feature of APLS

MC thrombotic defect leading to fetal demise---15% of miscarriages

Haemtol Oncol Clin North Am 2008;22;33-52

miscarriages

6.DERMATOLOGICAL May be the presenting feature Noninflammatory vascular thrombosis Livedo reticularis is more common Cutaneuos ulcerations Subungual splinter hemorrhages Anetoderma

Patients with livedo reticularis and APS frequently have cardiac and cerebral thrombotic events,epilepsy,migraine headaches

Cerebral---SNEDDON’S syndrome Clin Exp Rheumatol

2005;23;499-504

Livedo reticularis

Splinter hemorrhages

anetoderma

Subungual splinter hemorrhage

7.PULMONARY Most frequent arterial complication Thromboembolism of lung arteries ARDS Diffuse alveolar hemorrhage—non thrombotic manifestation of APS High mortality

8.ABDOMINAL Hepatic involvement is common Acalculous cholecystitis Giant gastric ulceration

9.ENDOCRINE Adrenal insufficiency Thyroid 10.RETINAL---CRAO,CRVO,ON,CiRAO 11.HEMATOLOGY-----thrombocytopenia<1,00,000. Severe—CAPS,TTP <50,000—bleeding

12.RENAL APLN---renal manifestation of APLS Thrombosis at any site. Non thrombotic –glomerulonephritis 25% patients have renal ---mostly IgG ab Nil/membranous nephropathy Patient—with flank pain,RVT,proteinuria---check for APL Urine analysis---mod proteinuria,hematuria Ischemic mesangiolysis,vessel hyperplasia <10%--ARF—recurrence Warfarin,steroids,plasmapheresis Lupus

2006,15;485-9

Catastrophic Antiphospholipid Syndrome(CAPS)

A syndrome of multisystem involvement . <1% of patients. Multiple small vessel occlusions---multi organ failure. Acute onset 3 different organ systems Acute microangiopathy is characteristic ARF,ARDS,CEREBRAL INJURY,MYOCARDIAL ischemia. Potentially lethal Trigger factors involved---

infections,trauma,neoplasia,pregnancy,lupus flares. ICU SLE-higher mortality.

PPts of CAPS

Catastrophic antiphospholipid syndrome

A note on other syndromes Asymptomatic---??? Apl---risk factor,requires other trigger for APLS—double hit

theory. h/o thrombosis,LA,acl IgG---FIVE FOLD Probable– Lack the clinical criteria of vascular thrombosis or pregnancy

loss. Livedo,chorea,thrombocytopenia. Livedo reticularis the first manifestation—41% Seronegative Clinical manifestations but no identifiable ab Repeat testing---positive. Microangiopathic Microvascular---TTP,HELLP,CAPS Drug induced Infection assosciated malignancy

DRUG induced Cardiac---procainamide,quinidine,propanolol,hydralazine. Neuroleptic or psychiatric—phenytoin,chlorpromazine. Other-interferon alpha,quinine,amoxicillin

Infection— Syphilis HCV HIV HTLV type 1 Malaria Septicemia.

LAB DIAGNOSIS

APA---IgG,IgA,IgM SEVERAL antibodies are recognised Recently—antibodies against annexin V,protein C

IgM acl---HEMOLYTIC ANEMIA. IgG ACL –thrombosis False positive test result for syphilis ACL—membrane phospholipids LA-plasma coagulation molecules Elongates APTT,Kaolin clotting time,dilute russells viper

venom time.

Kaolin clotting test

Lab assessment

INR

The ISI—1.0-2.0 INR—5 high chance of bleeding 0.5--- clot formation Normal range is 0.9-1.3 Warfarin ---2.0-3.0 Prosthetic valves—3.0-4.0

LUPUS ANTICOAGULANT

LABORATORY artifact. Interferes with the action of phospholipid cofactors in the

coagulation cascade in lab assays—prolongation of time to clot—mimics anticoagulant response.

Misnomer—ass with thrombosis. Inhibits the formation of prothrombinase complex within

the coagulation cascade. It blocks the binding of prothrombin and factor Xa to

phospholipids---thrombin formation inhibited. It can be Ig G,A,M 10%of SLE Venous thrombosis

How you diagnose LA

Normal Platelets-- poor plasma is mixed with patient’s plasma

If a clotting factor is deficient,the addition of normal plasma corrects the prolonged clotting time.

If the clotting time does not normalize ,an inhibitor is present.

The absence of a specific clotting factor inhibitor confirms that LA is present.

What if LA,ACL are negative

If patient experiencing thrombosis or recurrent miscarriages

Order Antibodies to b2 gp1 Ab to phosphatidyl serine,ethonalamine,glycerol,inositol Annexin V Phosphatidyl choline.

DRVVT

Detection of LA In vitro test ---ability of venom of russells viper to induce

thrombosis. Coagulant in venom directly activates factor X—turns

prothrombin to thrombin in presence of factor V and phospholipid.

In drvvt assay time is set to 23-27 sec A prolonged clotting time of 30 sec or greater that does not

correct with addition of an equal volume of normal plasma suggests the presence of LA.

Excess phospholipid is added. Normalised Both the tests are determined to a ratio. >1.2---may have.1.6 ---confirm. More sensitive than APTT for LA

Diluted Russells viper venom test

Imaging studies

For confirmation USG COLOR DOPPLER CT SCAN MRI 2D ECHO

Histology----non inflammatory bland thrombosis with no signs of perivascular inflammation or leukocytoclastic vasculitis.

DVT

DIFFERENTIAL DIAGNOSIS

Think of any other thrombophilic states before making a diagnosis of APLS.

Malignancy OCP Homocysteinemia Antithrombin 111 def Protein C,S def Factor V leiden mutation

TREATMENT

Asymptomatic individuals in whom blood test findings are positive do not requires specific treatment.

In pregnancy---use heparin and aspirin Previously prednisolone was used—no benefit as per trials Increases premnaturity,hypertension. No beneficial role of immunoglobulins in pregnancy. 1.with one fetal loss or mulitple abortions---aspirin plus

heparin. Warfarin only after organogenesis is complete Nursing is safe

Prophylactic therapy— Eliminate other risk factors Low dose aspirin,clopidogrel SLE—hydroxychloroquine—intrinsic antithrombotic

properties. Statins may be used—fluvastatin.

Thrombosis--- IV /sc heparin---warfarin Reasonable INR is 2.0-3.0 for venous,3.0 for

arterial,recurrent—3.0-4.0---think of bleeding if >5.0 Life long anticoagulation

Obstetric--- Prophylaxis for with no h/o thrombosis Full anticoagulation with h/o thrombosis. Sc heparin,low dose aspirin With held at the time of delivery.

CAPS—steroids

Recurrent DVT ---ivc filter.

Patient education Avoid prolonged immobilization.

Current recommendations

Primary thrombosis prevention---lack of evidence based approach. Arthritis Rheum 2004;50;s640-1

for sec prevention—life long warfarin. Duration,intensity ---still debate.

In case of fetal loss h/o-low dose aspirin+LMWH-----fail-----Ivig effective only in reports. Curr Rheumatol Report2002(4);379-86

CAPS—anticoagulation,steroids,IVIG,plasma exchange. Arthritis Rheumat 2003;48(12);3320-7

Elimination of reversible risk factorsProphylaxis during high risk periods are crucial

How much warfarin should be used?

Both moderate INR 2-3 and high intensity anticoagulation (INR 3-4) are similar protective in APS patients after the first thrombosis---NEJM 2003;349;1133-8,J Thromb Haemost 2005;3:848-53

Excess of minor bleeding in high intensity group. target of INR 2.5 High target in case of recurrence.

Intensity in case of arterial events is still deabte?????///

No data to support primary prevention of stroke in asymptomatic carriers of APL.

Risk factors—use low dose aspirin. Anticoagulate patients with INR 3.0 Long term warfarin therapy.

How long should we use warfarin???/ Lifelong Recurrence may not be higher in APL patients on

discontinuation of warfarin—10% What is the effect of discontinuation—trials are going on..

Is warfarin complete treatment?

Efficacy in microangiopathic nephropathy,valvular heart disease ,livedo reticularis, leg ulcers is not supported by data.

In asymptomatic patients???????///

178 persistently positive patients---thrombosis free were followed for three years witrhout anticoagulation---no patient developed thrombosis.

J Rheuma 2004,31;1560-7

Alternatives to warfarin

Dipyridamole,ticlopidine,clopidogrel---sec prevention of non cardio embolic strokes---only clopidogrel effective.

Recurrence rate is 5-10% with these agents.

Direct thrombin inhibitors role ??? But can be used in HIT

CAPS---rituximab,an anti CD20 MONOCLONAL AB HYDROXYXHLOROQUINE Statins—fluvastatin decreases thrombus size.

Ximelagatran—first oral thrombin inhibitor. Neutralises clot bound thrombin. Melgatran—rapid onset of action,shorter half life. No interaction Superior to warfarin after TKRS. Cause LFT changes Not approved by FDA in 2004-----www.astrazeneca.com

doses

Warfarin---5-15mg/day qd for 2-5 days INR 2.5-3.5 LMWH—low dose 20-40mg/day SC,1 mg/kg SC bid –high

dose. Unfractionated—SC 5000-10,000u q12h IV—5,000 U ---1000-2000U/Hr Weight based 80U/Kg ---18U/Kg/h iv APTT 2 times baseline----factor Xa assays in case of LA. aspirin 81mg/day Hydroxychloroquine—6-7mg/kg/d---200-400mg/d Cyclophosphamide 2-3 mg/kg/d PO OD, Steroids—prednisolone 1 mg/kg bw IV ig---400mg/kg/d iv for 5 days Statins ---atorva 10mg,pravastatin 40m g,fluvastatin 5 mg

New drugs

Rituximab 1000mg iv for 2 doses.seperated by 2 weeks. Rate at 50mg/h

eculizumab

FOLLOW UP

Frequent check ups Adequate patient education Avoidance of smoking Strict control with anticoagulants. In case of bleeding –hospital.

Normal healthy life

TRIALS

Eculizumab to Enable Renal Transplantation in Patients With History of Catastrophic Antiphospholipid Antibody Syndrome

by john hopkins university,nov 2009.

Genetic Risk Factors Associated With Antiphospholipid Antibody Syndrome---JUNE 2006---JULY 2009---Individuals with APL and family h/o APL compared with APL patients with h/o of only othr rheumatic disorders.—observational

Pilot Study of Cyclophosphamide in Patients With Life-Threatening Systemic Lupus Erythematosus orAntiphospholipid Antibody Syndrome----

Reliability of Point-of-Care INR Measurements in Patients With Antiphospholipid-Antibody SyndromeTreated With Warfarin----comparing with venupuncture

Predictors of Pregnancy Outcome in Systemic Lupus Erythematosus (SLE) and Antiphospholipid Syndrome (APS) (PROMISSE)

Antiphospholipid Syndrome Collaborative Registry (APSCORE)

effects of Fluvastatin on Proinflammatory and Prothrombotic Markers in Antiphospholipid SyndromePatients

Hematopoietic Stem Cell Transplantation in Patients With Antiphospholipid Syndrome

A Pilot Study of Rituximab for the Anticoagulation Resistant Manifestations of Antiphospholipid Syndrome(RITAPS)

Low-molecular-weight Heparin (LMWH) Versus Unfractionated Heparin (UFH) in Pregnant Women With History of Recurrent Abortion Secondary to Antiphospholipid Syndrome.

Steroids and Antiphospholipid Syndrome- Related Pregnancy Loss

Low Molecular Weight Heparin and Aspirin in the Treatment of Recurrent Pregnancy Loss: A RCT (HepASA)

Pharmacokinetics of Low Molecular Weight and Unfractionated Heparin in Pregnancy

LOG on to clinicaltrials.gov

future

Target based treatment

Specific complement inhibitors

Using anticoagulation in times of need.

Primary prevention drug

Alternative effective drug to warfarin.

TAKE HOME MESSAGE

Think of APLS in a young female with thrombosis,fetal wastage.

Recurrent migraine headaches in a young female –do APL

INR to be individualized and mainatined at 2.0-3.0 Recurrent –3.0-4.0 LA—DRVVT HEPARIN –FACTOR XA IgG ACL –THROMBOSIS Ig M ACL—HEMOLYTIC ANEMIA LIVEDO RETICULARIS –THINK OF APLS CHOREA IN YOUNG –THINK OF APLS ACL –INCREASES WITH AGE ACL—ARTERIAL,LA—VENOUS LIFE LONG ANTICOAGULATION CAPS—ICU CARE

SUMMARY

An autoimmune disease ,acquired, assosciated with heterogenous antibodies which act through various mechanisms—leading to thrombosis---diagnosis by sapporo criteria—confirmation on thrombosis for diagnosis---seperation of lab tests by 12 weeks---warfarin life long therapy—heparin in pregnancy----CAPS– acute emergency---INR to be monitored----risk to be explained.---future trends of target therapy awaited.

References,sites www.emedicine.com

www.lupus.org

www.wikipedia.com

www.lupusawarenessandresearch.com

www.japi.org

www.clinicaltrials.gov

HARRISON’S PRINCIPLES OF INTERNAL MEDICINE,17 ED.

Thank you SAGITTARI

AN

discussion

1.what you do in a case of a female who is diagnosed as having APLS,was kept on warfarin –had previous miscarriage—now wants to conceive----?

Ans—stop warfarin if the patient wants to conceive.and put her on heparin.again shift her to warfarin postpartum.

You said after she diagnosed as pregnant

2.what you will do in 2 cases with status epilepticus---patient treated,both being young was advised—CT scan brain—one had infarct,other normal,both APL being positive .with no h/o of previous thrombosis or APL postivity

Ans—the APL positivity to be confirmed again after 12 weeks.if they are positive then attribute it to APLS.the false positivty of APL ab are high---the drugs used for the treatment of status epilepticus—phenytoin –may also cause an increase in APL ab.in both the test to be confirmed after 12 weeks.and treatment of thrombosis to be started at that time

You said treatment for the one having thrombosis to be taken.

queries

Your vocabulary is not appropriate,adequate. You were stopping in the middle. You could not explain the drvvt. You could not explain CAPS adequately.

Read about

What is the one causing LA to lead to thrombosis or per se it causes thrombosis?

Normally coagulation takes place on exposure of the endothelium—how is the endothelium exposed in case of APLS?

What were the patients with pregnancy using in case of PROMISSE trial?

Normally complement activation leads to hemolysis—how is it causing thrombosi?

Annexin v ab to be explained? Pathogenesis to be explained? LA is a coagulant not an anticoagulant.

All were present during my presentation. Juniors were present

Total duration was 42 min.—exhaustive. I lost the tempo. Date of presentation—23-06-2010.