ANTI PHOSPHOLIPID SYNDROME (APS )

Dr.A.P.Naveen KumarChief Specialist (Gen. Med. )Visakhapatnam Steel Plant

HISTORY

•Unusual clotting inhibitor in SLE- 1952•BFP-STS - false positive test for syphilis•1976- Johannsen – recurrent thrombi•Nelson et al first reported with recurrent

abortions•1984 – concept of APS

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• Substances in the blood, called phospholipids, are required for the blood to clot.

• In some people, the body mistakenly identifies phospholipids, or proteins bound to the phospholipids, as foreign substances and forms antibodies against them.

• • This reaction can be viewed as a confusion of the

immune system, called an autoimmune process

• Certain substances, such as phospholipids, must also be present in the blood for the clotting proteins to function properly and form a clot.

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INCIDENCE

•1-5% of general population have positive APLA

•10% of DVT and PE

•12 – 34 % of LUPUS

•Typically are not inherited but acquired

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DEFINITIONAPS is the commonest acquired prothrombotic

state and it is associated with one or more of the antiphospholipid antibodies namely

• anti cardiolipin antibody ( ACLA),• Lupus anticoagulant ( LA ) or• anti β2 glycoprotein 1 antibody

Plus

One of the clinical manifestations namely arterial thrombosis, venous thrombosis and recurrent foetal loss. Thrombocytopenia and autoimmune hemolytic anemia are also strong

clinical associations.

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CLASSIFICATION

•Primary•Secondary• SLE – other CVD• Auto immune hypothyroidism• Infections• Drugs

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•Secondary APS is classified as Autoimmune and Alloimmune

•Alloimmune are usually transient and not associated with clinical complications

•Infections are alloimmune

•Drugs maybe allo or autoimmune

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INFECTIONS

• HIV• TB• Syphilis• Lyme disease• Infectious Mononucleosis• Hep. C

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DRUGS

•Phenothiazines•Procainamide•Chlorpromazine•Hydralazine•Phenytoin•Valproate

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Sapporo criteria ( 8th International Symposium on APA ,Sapporo-Japan )

•The Sapporo criteria for definite APS are the presence of at least one of the listed clinical criteria and at least one of the two listed laboratory criteria.

•Two clinical criteria include vascular thrombosis and pregnancy morbidity

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•Vascular thrombosis consists of one or more clinical episodes of arterial, venous or small vessel thrombosis in any tissue or organ.

•The thrombosis must be confirmed by imaging or doppler or histopathology with the exception of superficial venous thrombosis.

•If HPE is performed there should be thrombosis with no significant e/o inflammation in the vessel wall

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•Three categories of pregnancy morbidity

Category –A

•consists of one or more unexplained deaths of a morphologically normal foetus at or beyond the 10 th week of gestation.

•Ultrasound or direct examination of the foetus must document normal fetal morphology

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Category –B

• consists of one or more premature births of a morphologically normal neonate at or before the 34 th week of gestation due to severe pre-eclampsia or eclampsia, or severe placental insufficiency

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Category –C

•Consists of three or more unexplained consecutive spontaneous abortions before the 10th week of gestation ,following exclusion of both maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal abnormalities

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• According to a 2006 consensus statement,(Sydney-2006 ) it is advisable to classify APS into one of the following categories for research purposes:

• I: more than one laboratory criterion present in any combination;

• IIa: lupus anticoagulant present alone

• IIb: anti-cardiolipin IgG and/or IgM present alone in medium or high titers

• IIc: anti-β2 glycoprotein I IgG and/or IgM present alone in a titer greater than 99th percentile

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LABORATORY CRITERIA

•Anticardiolipin antibody of the Ig G or Ig M type present in medium or high titre on 2 or more occasions 6 weeks apart

•Lupus anticoagulant present in plasma on 2 or more occasions at least 6 weeks apart detected by aPTT , KCT (kaolin clotting time ) ,dilute Russell’s viper venom time (DRVVT ),dilute prothrombin time (PT )

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•ACLA is 6 times more common than LA•80 % of APA have ACLA•20% have LA only•Both are positive in 60%•Anti β2GP1 assay in SLE patients is useful

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• 20 yr. girl-hypothyroid and anemic, past h/o ATT

• Presented with convulsions

• MRI brain – large bleed

• Thrombocytopenia

• Persistant headache

• Drowsy and not improving

• MR Venogram – Sup. Saggital sinus thrombosis

• LMWH given

• APLA workup positive

CNS• Stroke in young Singh K, Shome DK et al - 18.8 %

• Sneddon ‘s syndrome – livedo reticularis ,stroke and CVA

• Non thrombotic neurologic symptoms like focal neurologic manifestations

• Multiple hyperintense lesions in a MRI in young ind. < 40

• Siezures

• CSVT , Multi infarct dementia , migraine headache,GB Syndrome ,chorea and optic neuritis

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• 24 yr. old boy –hematuria and rt. Loin pain

• u/s abd. Grossly enlarged rt. Kidney –carcinoma

• CT abd. –renal vein thrombosis

• Investigations – N

• Hypercoagulable states workup done

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RENAL

•Severe HTN, proteinuria ,hematuria ,nephrotic syndrome ,ESRD and renal failure

•Post transplant renal thrombosis

•Renal artery stenosis ,malignant HTN,renal infarction, renal vein thrombosis ,thrombotic microangiopathy and glomerulonephritis

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CARDIAC•Myocardial infarctions ,premature and

accelerated atherosclerosis

•Valve thickening , regurgitation , stenosis and vegetations

•Valvular abnormalities – 30-50%•MR - 25% , AR – 6-10 %

•Recurrent re-stenosis

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PULMONARY

•Lung syndrome –

pulmonary microthrombosis, PTE , PAH, ARDS intra alveolar hemorrhage and

postpartum syndrome

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• 22 yr. old girl• Polyarthritis and rash• Gangrene of tips of fingers• Treated with LMWH and

then acitrom• Recovered completely• ANA , DsDNA , Anti

Cardiolipin positive• On follow up

• 35 yr. female• Fever , rash and polyarthritis

• Gangrene of fingers and toes• Started on steroids , LMWH

and HCQS

• Workup for SLE and APA was positive

• Acitrom started steroids tapered off

SKIN•Livedo reticularis•Digital gangrene•Subungal splinter

hemorrhages•Superficial venous

thrombosis•Thrombocytopenic purpura•Pseudovasculitic

manifestations•Generalised vasculopathy

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•28 yr. female•Recurrent abortions•Anti cardiolipin antibodies positive•Started on anticoagulants•Delivered a female baby with LMWH

OBSTETRIC

•Spontaneous miscarriages•Maternal thrombocytopenia

•Placental insufficiency•Annexin -5 markedly reduced

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• 15 yr. boy asymptomatic earlier• Presented with fever and abdominal pain• Developed blurring of vision ,headache and altered

sensorium• MRI –bilateral cortical hemorrhages• Thrombocytopenia and hypokalemia• Went into septicemia and MODS -ventilated• Recovered completely with steroids except for

thrombocytopenia

• ANA positive – treated with steroids• After 1 yr. developed swelling of abdomen• U/S s/o Budd Chiari

• Investigations confirmed APLA

GIT

•Budd-chiari syndrome•Intestinal ischemia and infarction•Colonic ulceration•Esophageal necrosis and perforation•Hepatic infarction•Mesentric and portal vein thrombosis

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• 12 yr. girl• Recurrent abdominal pain

• Confirmed as pancreatitis

• Later symptoms of rash and arthritis• Investigations for SLE and APLA pos

• On immunomodulants and acitrom• Developed CNS lupus and recovered

•34 yr. female•Polyarthritis and skin rash•Developed swelling of leg•Doppler showed DVT•ANA,DsDNA,Smith and Anti cardiolipin

Ab. positive

ACA SYNDROME

OTHERS

•Autoimmune sensorineural hearing loss•Bleeding complications secondary to

acquired hypo prothrombinemia –venous end occlusion by thrombus can lead to capillary bleeding

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CLINICAL TYPES

•Type – 1 Retinal / CNS / Major organs•Type - 2 Arterial•Type - 3 Venous•Type - 4 Arterial and venous•Type - 5 Obstetrical•Type - 6 Asymptomatic antibody

positivity

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MALIGNANCY ASSOCIATION

•B cell Lymphoma•CML•NHL•Renal cell carcinoma•Lung adenocarcinoma•Breast carcinoma•Melanoma

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CATASTROPHIC APS

• Serious form of APS with MOD• Histopathological e/o multiple occlusions of large or

small vessels

• Kidney ,lung ,CNS ,heart,adrenal and skin are involved usually in that order

• Gut maybe involved resulting in gut ischemia and abd. pain

• Thrombotic storm - multiple microemboli • Precipit. factors are infections , surgical procedures

and drugs• Very high mortality

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VASCULITIS AND APS

•Strong association between vasculitis and thrombosis and the cause effect relationship is not clear

•Vasculitis has been reported as a complication of APS itself

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DDDD

•Factor V Leiden mutation•Hyperhomocystenemia •Classic PAN•Infective endocarditis•Cholesterol embolism•TTP•Infections

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PRIMARY PROPHYLAXIS

• Low dose aspirin is the first logical option

• Physician Health Study did not show any protection in men

• HCQS -protective against thrombosis in SLE pts. with APLA

• Aspirin with low intensity warfarin therapy under study in UK

• Treatment of HTN,DM,DLD and stop smoking

• Prophylaxis with heparin in high risk conditions

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TREATMENT

• Anticoagulation -INR between 3-4• INR - 2-3 – venous thrombosis• INR – 3-4 - recurrent thrombosis and arterial

thrombosis• Recent trials suggest that a INR of 2-3 is as good

for the prevention of future thrombosis

• HCQS – 200-400 mgs.

• Role of steroids and immunosuppressives is ?• Definite role in Lupus and APA• Steroids in catastrophic APS and repeated

thrombosis

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PREGNANCY AND APS

• For pregnancy loss low dose aspirin plus heparin• IVIG – in women with pregnancy loss despite

treatment with aspirin and heparin

• Planned pregnancy – stop warfarin before conception and start heparin to prevent warfarin embryopathy

• Continue heparin both antepartum and postpartum until warfarin is re introduced

• Monitor fetal growth and uteroplacental blood flow• Timely delivery

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• Recommendations suggest lifelong anticoagulation• One study showed abnormal d dimer test one month

after discontinuation of anticoagulation can be used as an indicator for continuation of anticoagulation

• Study – 223 /608 (36.7% ) test was positive• 18 events in 120 pts. who stopped (15%)• 3 events in 103 pts. who resumed (2.9%)

•Study concluded that pts, with abnormal D dimer level at 1 month after discontinuation have a significant incidence of thrombosis,which is reduced by resumption of anti coagulation

(NEJM- 2006 –Cosmi ,Legani et al )

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TREATING OTHER COMPLICATIONS

•Thrombocytopenia - Steroids is the choice, danazol ,dapsone ,HCQS, Splenectomy

•Headache – aspirin ,warfarin

•Heart valve lesions – replacement

•ESRD – Transplant – prognosis not good

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COMMON CLUES

•Cerebrovascular accidents•Myocardial infarction•Pulmonary thromboembolism•DVT•Recurrent foetal loss•Non healing ulcer•Livedo reticularis

WITHOUT ANY KNOWN RISK FACTOR

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Recognize the condition early,at the same time avoiding overdiagnosing this condition, as the treatment in unwarranted situations can be hazardous

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Sensitizing the physician’s mind for

diagnosis of APS is important , especially because of its varied manifestations and because, it is treatable on the other hand it can lead to significant morbidity, disability and mortality if left untreated.

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THANK YOUTHANK YOU

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