Sindrome da anticorpi antifosfolipidi: clinica e terapia

Vittorio PengoClinical Cardiology, Padova, Italy

Clinical criteria

1. Vascular thrombosis

One or more clinical episodes of arterial, venous, or small vessel thrombosis, in anytissue or organ. Thrombosis must be confirmed by objective validated criteria (i.e.unequivocal findings of appropriate imaging studies or histopathology).For histopathologic confirmation, thrombosis should be present without significant evidenceof inflammation in the vessel wall.

Revised Classification Criteria for the Antiphospholipid Syndrome

J Thromb Haemost 2006;4:295-306

MC/ Male

18 yrs of age

Proximal DVT

LA (dRVVT) +

aCL + (high titre)

A-human-ß2GPI +

No risk factors

No associated autoimmune diseases

Pain in the right legLasting one month

Primary APS

MASSIVE POLMONARY EMBOLISM

atat presentationpresentation

PAPS MC/ Male18 yrs of age

PAPS MC/ Male18 yrs of age

after 6 months

Pulmonary artery pressure : 55 mmHg (CTPH)

APS most common features

38 .5

31 .3

27 .8

25 .3

23 .7

14 .2

14 .2

13

11 .8

9 .2

0 10 20 30 40 50

DVT

Fetal -loss

Thrombocytopenia

TIA /stroke

arthralgia

Livedo -reticularis

Migrain like headaches

Valvular Dysfunction

pulmonary embolism

epilepsy

Euro-APS, 538 patients

Other less common sites of venous thromboembolism in APS

•Venous thrombosis of the upper limbs •Retinal thrombosis •Cerebral vein thrombosis•Inferior vena cava thrombosis •Jugular vein thrombosis •Mesenteric vein thrombosis* •Budd-Chiari syndrome*•Portal vein*

*DD: myeloproliferative disorders (JAK2 mutation)

RAThrombus

Arterial Thrombosis and APS

Cerebral ischemia •Stroke/TIA•Dementia•Epilepsy

CEREBRAL ISCHEMIA White matter

CEREBELLAR ISCHEMIA (female patient with objective vertigo)

Small ischemic areas in 45 years old male (B. L.) with cognitive disability

Multiple cerebral infarctions in 48 years old female

( N. C.) with hemiparesis and epilepsy

LIVEDO RETICULARISCerebral ischemia + livedo reticularis: Sneddon’s syndrome

Pathogenesis

Numerous recent studies have stressed a link between cerebral ischemia and cardiac valvular lesions.

Cardiogenic stroke

CEREBRAL EMBOLUS

Marked focal thickening of the midportion of the posterior mitral valve leaflet

Farzaneh-Far A, Arthr Rheum 2006

Multiple mitral valve thickening

Clinical Cardiology, Padua

Libman-Sacks Endocarditis

Moyssakis I, American Journal of Medicine 2007Moyssakis I, American Journal of Medicine 2007

APS most common features

38 .5

31 .3

27 .8

25 .3

23 .7

14 .2

14 .2

13

11 .8

9 .2

0 10 20 30 40 50

DVT

Fetal -loss

Thrombocytopenia

TIA /stroke

arthralgia

Livedo -reticularis

Migrain like headaches

Valvular Dysfunction

pulmonary embolism

epilepsy

Euro-APS, 538 patients, in preparation

Other less common sites of arterial thromboembolism in APS

• Arterial thrombosis of the lower limbs • Myocardial infarction • Renal artery thrombosis • Retinal artery thrombosis • Mesenteric ischemia

THROMBOSIS IN THE LEFT RENAL ARTERY

PAPS

FP/ Female

13 yrs of age

Blood pressure 220/140 in the emergency room

LA (dRVVT) +

aCL + (high titre)

A-human-ß2GPI +

ANTERIOR DESCENDING CORONARY ARTERY THROMBOSIS NO ATHEROSCLEROSIS

All the previous slides referredto patients with triple positivity

Characteristics

Age –yrs 41.1 ±

15.0

Female––no.(%) 113 (70.6)

APS-related event at diagnosis—no.(%)

VTE 76 (47.5)

Arterial Thrombosis 69 (43.1)

Obstetric complications 11 (6.9)

Catastrophic APS 4 (2.5)

High risk triple positive APS patients (n=160)

Pengo V, JTH 2010

High risk triple positive APS patients (n=160)

Pengo V, JTH 2010

High risk triple positive APS patients (n=160)

Pengo V, JTH 2010

High risk triple positive APS patients (n=160)

Pengo V, JTH 2010

• Often idiopathic• Young subjects• Triple positivity• Often No risk factors• Recurrence

Vascular thrombosis in definite APS

CATASTROPHIC APS

•Term proposed in 1992

•Accelerated form of APS with multiorgan thrombotic failure

•Around 50% mortality, it may show up ‘ex novo’

•Trigger: infection in many cases

•1% prevalence in APS

CUTANEOUS NECROSIS

CUTANEOUS NECROSIS

Scansione TC: infarto surrenalico sinistro (freccia) della paziente n°2

Cutaneous biopsy of ear lobe showing a thrombus in dermal vessel (arrow)

Cutaneous lesions related to thrombi in microcirculation

Clinical criteria

2. Pregnancy morbidity

a) One or more unexplained deaths of a morphologicallynormal fetus at or beyond the 10th week of gestation

b) One or more premature births of a morphologicallynormal neonate at or before the 34th week of gestation(preeclampsia or eclampsia or severe placental insufficiency)

c) Three or more unexplained consecutive spontaneousabortions before the 10th week of gestation (other causesexcluded)

INTERVILLOUS PLACENTAL THROMBOSIS

PLACENTAL INFARCTION

APS treatment in pts with VTE

• VKA• Intensity (INR 2.0-3.0)• Duration of treatment ?

Canadian Trial on OAT in APS

114 pts with APL and thrombosis (76% venous)

Randomization

WarfarinINR 2-3 2.7 years follow-up

Bleeding*4+11 (19 %)

Bleeding*3+14 (25 %)

Rec. TE2 (3.4 %)

Rec. TE6 (10.7 %)

Crowther et al., NEJM 2003; 349: 1133

WarfarinINR 3.1-4

(mean INR 2.3) (mean INR 3.3)

*Major+minor

WAPS Trial

109 pts with APL and thrombosis (68% venous)

Randomization

WarfarinINR 2-3 3.6 years follow-up

Bleeding*14.6 %

Bleeding*27.8 %

Rec. TE5.5 %

Rec. TE11.1 %

Finazzi et al., JTH 2005

WarfarinINR 3-4

(mean INR 2.5) (mean INR 3.2)

*Major+minor

Duration of treatment

• Provoked/unprovoked• aPL profile and titer• Type of VTE (DVT/PE)• Other (permanent) risk factors

Duration of treatment

• Provoked/unprovoked• aPL profile and titer• Type of VTE (DVT/PE)• Other risk factors

• Unprovoked• aPL profile:triple positivity• VTE was PE• Other thrombophilia• Associated autoimmune

disease

Long term if:

Duration of treatment

• Type of VTE (DVT/PE)• aPL profile and titer• Provoked/unprovoked• Other risk factors

• VTE was Provoked• aPL profile: single positivity• Other thrombophilias are

absent• No associated autoimmune

disease

Possible short term if:

Arterial thrombosis in APS

• VKA/antiplatelet drugs• Intensity• Duration of treatment• VKA plus antiplatelet drugs• Type and Titer of aPL

Arterial thrombosis in APSRecommendations from observational studies

“Because of the high risk of recurrence and consequent disability or death, stroke in APS should be treated with long-term OAT, target INR 2.5 (range 2.0-3.0) (level III evidence) ...

… Whether additional therapy with aspirin is efficacious is not known …

… Extracerebral arterial thrombosis in APS will also warrant consideration for long-term OAT …”

Br Soc Haemat Guidelines on APS Br J Haemat 2000; 109:704

AORTIC ARCH SOFT PLAQUE

TREATMENT OF PREGNANT PATIENTS WITH APS ____________________________________

PATIENTS WITH PREVIOUSPREGNANCY MORBIDITY ALONE

ONE DAILY DOSE OF HEPARIN

+LOW DOSE ASPIRIN

PROPHYLAXIS OF PREGNANCY LOSS

Favourable outcomeKutteh et al, 1996UH + LDA vs LDA 80% vs 40%

(significant difference)

Rai et al, 1997UH + LDA vs LDA 71% vs 42%

(significant difference)

Farquharson et al, 2002LMWH + LDA vs LDA 78% vs 72%

(no significant difference)

TREATMENT OF PREGNANT PATIENTS WITH APS ____________________________________

PATIENTS WITH PREVIOUS VASCULAR THROMBOSIS ALONE OR ASSOCIATED

TO PREVIOUS PREGNANCY MORBIDITY

THROMBOSIS PROPHYLAXIS

+PROPHYLAXIS OF PREGNANCY LOSS

FULL DOSE HEPARIN±

LOW DOSE ASPIRIN

• No clinical trials• There is agreement on full

anticoagulation with UH or LMWH

• LDA is generally combined

• Tincani et al. Lupus. 2003;12: 524-9.

• Ruitz-Irastorza et al. Ann NY Acad Sci. 2005; 1051: 606-12.

“SECOND LINE” TREATMENT PROTOCOLS Triple positive patients

____________________________________

Intravenous immunoglobulins (IVIG)

Plasma exchange ± IVIG

Immunoadsorption + IVIG