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10-20% of idiopathic thromboembolic disease are due to APS 50% of patients younger than 50 years and affected with strokes (without evident etiology) are due to APS
in SLE:
LAC: 11-30% aCL: 24-86%
12 - 40 %
10 - 26 % 15 %
Normal hemostasis
Disruption of vascular endothelial lining allows exposure of blood to subendothelial connective tissue: Primary hemostasis (seconds) - Platelet plug formation at site of injury - Stops bleeding from capillaries, small arterioles and venules Secondary hemostasis (minutes) - Fibrin formation by reactions of the plasma coagulation system
Prethrombotic disorders
Inherited Acquired
APS
Venous thrombosis are more common than arterial thrombosis The most common site of DVT is the calf The most common site of arterial thrombosis is the cerebral circulation The initial and long-term manifestations of the disease are similar: in most, but not all the initial arterial thrombosis tends to be followed by an arterial event and the initial venous thrombosis by a venous event
Arterial or Venous Thrombosis Recurrent Fetal Loss Serum Anti-phospholipid antibodies (aPL)
Primary: an isolated condition Secondary: secondary to SLE or other connective tissue diseases
ThromboThrombo-embolic disease
Pulmonary embolism
Cerebrovascular accidents
Antiphospholipid Syndrome
A clinicopathologic diagnosis
Vascular Thrombosis: -arterial, venous, in any organ or tissue Pregnancy Morbidity: a) death of normal fetus at > 10 wks b) premature birth at < 34 wks due to preeclampsia c) >3 consecutive abortions at <10wks d) placental insufficiency at < 34 wks
Cardiovascular disease
Libman-Sacks Vegetation
Cauliflower-like or flat, red multiple spreading masses of 2 4 mm in diameter present on the free margins or line of closure of the heart valve
Echo findings
Prevalence
TTE; 10%, TEE; 30% Mitral and aortic valves < 1 cm2 in size Irregular borders Heterogenous echo density No independent motion Associated with thickening or regurgitation
Myocardial infarction
Hematologic manifestations
Cutaneous manifestations
CAPS is a rare, lifethreatening complication of apl which occure in multiple organs over a short period of days. Multiple thromboses of medium sized and small vessels may occur despite of adequate anticoagulation. Mortality may reach up to 50% with therapy.
Antiphospholipid antibodies
antibodies and antigens Most of the abs are NOT directed against phospholipids Most of the antiphospholipid abs recognize phospholipid binding proteins: - beta 2 glycoprotein I (F2 GPI) - prothrombin
Beta 2 Glycoprotein-I
(F2GPI)
F2GPI = a plasma protein with affinity for negatively charged phospholipids anti- F2GPI: are probably the major cause of APS
APTT: - variability in reagents result in inconsistent sensitivity. - acute phase reaction and pregnancy may shorten APTT and mask a weak LAC A normal APTT does not exclude LAC KCT- Kaolin clotting time more sensitive to presence of anti-II DRVVT- Dilute Russells viper venom time more sensitive to presence of F2 GPI
No LAC shows 100% specificity and sensitivity because aPLs are heterogeneous. More than 1 test system is needed
Platelet-aPL interaction
platelet activation, stimulation of thromboxane production
Complement activation
Malignancy:
Lymphoma, paraproteinemia
Drug induced:
phenothiazines, procainamide, quinidine, phenytoin, hydralazine
Indications for Laboratory testing for antiphospholipid abs Spontaneous venous thromboembolism Recurrent VT, even in presence of other risk factors Stroke or peripheral arterial occlusive event at < 50 yrs In all SLE patients In women with > 3 consecutive pregnancy losses
loss of morphologically normal fetus at II-III trimester early severe preeclampsia severe placental insufficiency
APS
Treatment
Incidental finding of antiphospholipid antibodies Anti-thrombotic therapy not usually indicated Low threshold for thromboprophylaxis at times of high risk Some suggest low dose Aspirin prophylaxis Reduce other risk factors for thrombosis
ACCP Guidelines
Treatment of venous thromboembolism in patients with antiphospholipid antibodies. We recommend a target INR of 2.5 (INR range, 2.0 and 3.0) (Grade 1A). We recommend against highintensity VKA therapy (Grade 1A).
We recommend treatment for 12 months (Grade 1C+). We suggest indefinite anticoagulant therapy for these patients (Grade 2C).
Current Recommendations
Asymptomatic aPL no treatment (Aspirin?) Venous thrombosis Warfarin INR 2.0-3.0 Arterial thrombosis Warfarin INR 3.0 Recurrent thrombosis Warfarin INR 3.0-4.0 + low dose Aspirin Thrombocytopenia>50000 no treatment Thrombocytopenia50000 cs, i.v Ig CAPS Anticoagulation + CS + IVIg or plasmapheresis
Potentially usable
Non-aspirin antiplatelet agents Hydroxychloroquine Statins
Thrombin inhibitors Rituximab Recombinant activated protein C Prostaglandin and prostacyclin Anti-cytokine
Thrombocytopenia
Mild to moderate- Platelets > 50,000: No treatment Severe- <50,000: - corticosteroids - corticosteroid resistant cases: HCQ , IVIG, Immunosuppressive drugs, Splenectomy
Current Recommendations
Pregnancy Asymptomatic aPL Single loss <10wks Recurrent loss* <10wks after(?) Fetal protection no treatment no treatment prophylactic heparin +ASA up to 6-12 wks postpartum, ASA
therapeutic heparin + ASA, warfarin postpartum therapeutic heparin + ASA warfarin postpartum
Immunosuppression:
azathioprine, plasmapheresis: numbers treated too small for conclusion
IVIG:
may be salvage therapy in women who fail on Heparin + Aspirin
Fetal Monitoring
US monitoring of fetal growth and amniotic fluid every 4 weeks US monitoring of uteroplacental blood flow: uterine artery waveforms assessed at 20-24 wks If early diastolic notch seen: do 2 weekly growth scans due to high risk of IUGR
How long should patients with APS and venous thrombosis be treated with warfarin?
Schulman, et al., 1998.
Prospective study. 412 patients with 1st episode of venous thrombo-embolism treated for 6 months with warfarin. 68 patients (17%) with elevated antibody levels when warfarin therapy stopped.
Do any of the clinical laboratory tests identify patients at risk for thromboembolic problems?
More than one prior thrombotic event aCL levels: the risk of recurrence is twice as high among pts with aCL compared to those without such antibodies (29#14%)
A positi e
A ne ati e
onths
-- Schulman, et al , Am J ed, 99 ; :
ACCP Guidelines
Prevention of noncardioembolic cerebral ischemic events.
For most patients, we recommend antiplatelet agents over oral anticoagulation (Grade 1A). For patients with well-documented prothrombotic disorders, we suggest oral anticoagulation over antiplatelet agents (Grade 2C).
-- Albers, et al., Chest, 2004; 126 (Supplement): 48
Asymptomatic valve thickening: low dose aspirin (81 mg/d) Embolic disease: Heparin followed by warfarin MI: Heparin followed by warfarin + aspirin
Case description
35 year old male, single Presented with: - sudden vision loss- rt eye: due to Central retinal vein occlusion - Chronic leg ulcer
Physical examination
Marked cognitive impairment Unstable gait Lt. mild spastic hemiparesis Rt. blind eye Edematous left calf with venous stasis Large chronic leg ulcer- lt calf
ANA- negative
Laboratory work-up
Anti-DNA- negative Anticardiolipid IgG > 120 GPLU (N<10) Anticardiolipin IgM - normal Anti-F2 glycoprotein I > 100 Lupus anticoagulant negative (N<8)
(x2) (x2)
Diagnosis
Primary Antiphospholipid syndrome with:
- recurrent arterial thrombosis: CVA leg ulcer - recurrent venous thrombosis: DVT CRV occlusion - High titer antiphospholipid antibodies: anticardiolipin IgG anti-F2 GPI
Future Directions
Can we predict which patients with antiphospholipid antibodies will develop thromboembolic complications? Is there an inherited predisposition to developing antiphospholipid antibody syndrome?
Thank you