APS2011 osama
-
Upload
usama-sayed-abou-sehly -
Category
Documents
-
view
236 -
download
0
Transcript of APS2011 osama
-
8/4/2019 APS2011 osama
1/89
Dr. Osama Sayed Daifallahabosehly
Assisstant lecturer
-
8/4/2019 APS2011 osama
2/89
the antiphospholipid antibodies syndrome is
defined as:
Vascular thromboses and\or pregnancy morbidity
occurring in persons with anti-phospholipid
antibodies(APL) most commonly anti-cardiolipin
antibodies(aCL), +ve results for lupus
anticoagulant(LA) test, and anti-B2 glycoprotien-I (B2-
GPI) antibodies.
The origin of APL antibodies is unknown but ishypothesized to be an incidental exposure to
environmental agents inducing APL in susceptible
individuals.
-
8/4/2019 APS2011 osama
3/89
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
Epidemiology of antiphospholipid antibodies
-
8/4/2019 APS2011 osama
4/89
Epidemiology of antiphospholipid antibodies
in the normal population: 2 - 5 %
prevalence increases with age and chronic disease
in SLE: 12 - 40 %
LAC: 11-30% aCL: 24-86%
in first Stroke: 10 - 26 %
in recurrent fetal loss: 15 %
-
8/4/2019 APS2011 osama
5/89
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
-
8/4/2019 APS2011 osama
6/89
-
8/4/2019 APS2011 osama
7/89
Bleeding and Thrombosis
Defects in primary
hemostasis
Thrombocytopenia
Defects in secondary
hemostasis
Clotting factor deficiencies Prethrombotic
(hypercoagulable) states
-
8/4/2019 APS2011 osama
8/89
Prethrombotic disorders
Inherited
Acquired
-
8/4/2019 APS2011 osama
9/89
-
8/4/2019 APS2011 osama
10/89
Acquired prethrombotic disorders
Conditions associated with a hypercoagulablestate:
- pregnancy and postpartum
- major surgery
- obesity and immobility- malignancy
- congestive heart failure
- nephrotic syndrome
Estrogen treatment
Antiphospholipid syndrome
-
8/4/2019 APS2011 osama
11/89
APS
Venous thrombosis are more common thanarterial thrombosis
The most common site of DVT is the calf
The most common site of arterial thrombosisis the cerebral circulation
The initial and long-term manifestations of
the disease are similar: in most, but not allthe initial arterial thrombosis tends to befollowed by an arterial event and the initialvenous thrombosis by a venous event
-
8/4/2019 APS2011 osama
12/89
The Antiphospholipid Syndromeis characterized by:
Arterial or Venous Thrombosis
Recurrent Fetal Loss
Serum Anti-phospholipid antibodies (aPL)
-
8/4/2019 APS2011 osama
13/89
The Antiphospholipid Syndromemay be:
Primary:
an isolated condition
Secondary:secondary to SLE or other connective
tissue diseases
-
8/4/2019 APS2011 osama
14/89
Clinical Presentations of APS
Venous thromboembolism:
Deep Vein Thrombosis
Pulmonary Embolism
-
8/4/2019 APS2011 osama
15/89
ThromboThrombo--embolic diseaseembolic disease
-
8/4/2019 APS2011 osama
16/89
Pulmonary embolismPulmonary embolism
-
8/4/2019 APS2011 osama
17/89
-
8/4/2019 APS2011 osama
18/89
-
8/4/2019 APS2011 osama
19/89
Clinical Presentations of APS
Arterial Occlusion:
Stroke and TIAs are the most common
-
8/4/2019 APS2011 osama
20/89
Cerebrovascular accidents
-
8/4/2019 APS2011 osama
21/89
-
8/4/2019 APS2011 osama
22/89
-
8/4/2019 APS2011 osama
23/89
-
8/4/2019 APS2011 osama
24/89
Clinical presentations of APSPregnancy morbidity
Recurrent fetal loss
In women with recurrent miscarriage due to APS fetal loss rate: as high as 90%
antiphospholipid abs are associated with:- placental insufficiency
- early preeclamapsia
- IUGR- intrauterine growth restriction
-
8/4/2019 APS2011 osama
25/89
Antiphospholipid antibodies (aPL)
anti-Cardiolipin IgG
anti-Cardiolipin IgM
Lupus anticoagulant (LAC)
* false positive VDRL
-
8/4/2019 APS2011 osama
26/89
Antiphospholipid Syndrome
Aclinicopathologicdiagnosis
-
8/4/2019 APS2011 osama
27/89
Antiphospholipid Syndrome CriteriaSydney revision of Sapporo criteria 2006
CLINICALCRITERIA
Vascular Thrombosis:
-arterial, venous, in any organ
or tissue Pregnancy Morbidity:
a) death of normal fetus
at > 10 wksb) premature birth at < 34
wks due to preeclampsia
c) >3 consecutive abortions
at
-
8/4/2019 APS2011 osama
28/89
Sydney Revision of Sapporo criteria
(2006)
Clinical Criteria
- Thrombosis:
exclude other causes : male > 55 yrs
female > 65 yrs
- Pregnancy:
placental insufficiency < 34 wksexclude other causes
-
8/4/2019 APS2011 osama
29/89
Sydney Revision of Sapporo criteria
(2006)
Laboratory Criteria
- medium/high titerIgG or IgM aCL on 2
occasions
12 wks apart
- LAC on 2 occasions 12 wks apart
-
8/4/2019 APS2011 osama
30/89
Sydney Revision of Sapporo criteria
(2006)
aPL associated manifestations (individual diagnosis)
Thrombocytopenia ( occurs in up to 50%)
Cardiac valve disease
Livedo reticularis
Nephropathy ( late manifestation: proteinuria,
hypertension and creatinine clearance) Non-thrombotic neurologic manifestations, including
multiple sclerosis-like syndrome, chorea, or migraine
headaches.
-
8/4/2019 APS2011 osama
31/89
Cardiovascular disease
-
8/4/2019 APS2011 osama
32/89
Libman-Sacks Vegetation
PrevalenceTTE; 10%, TEE; 30%
Mitral and aortic valves < 1 cm2 in size
Irregular borders
Heterogenous echo density No independent motion Associated with thickening or
regurgitation
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
(CardiolClin 1998;16;531)
-
8/4/2019 APS2011 osama
33/89
Libman-Sacks Vegetation and MR
-
8/4/2019 APS2011 osama
34/89
-
8/4/2019 APS2011 osama
35/89
Myocardial infarction
-
8/4/2019 APS2011 osama
36/89
Hematologic manifestations
-
8/4/2019 APS2011 osama
37/89
-
8/4/2019 APS2011 osama
38/89
Cutaneous manifestations
-
8/4/2019 APS2011 osama
39/89
Livedo reticularis:
a lattice like pattern of superficial veins.
-
8/4/2019 APS2011 osama
40/89
-
8/4/2019 APS2011 osama
41/89
Livedo reticularis with necrotic finger tips
in Antiphospholipid syndrome
-
8/4/2019 APS2011 osama
42/89
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.
-
8/4/2019 APS2011 osama
43/89
-
8/4/2019 APS2011 osama
44/89
Antiphospholipid antibodiesantibodies 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
-
8/4/2019 APS2011 osama
45/89
Beta 2 Glycoprotein-I (F2GPI)
F2GPI = a plasma protein with affinity for
negatively charged phospholipids
anti- F2GPI:
are probably the major cause of APS
-
8/4/2019 APS2011 osama
46/89
Antibodies and antigens
Anticardiolipn abs recognize in most assays:
F2 GPI
Lupus Anticoagulant activity is caused byautoantibodies to:
- F2 GPI - prothrombin
-
8/4/2019 APS2011 osama
47/89
Laboratory Testing for antiphospholipid
antibodies
Solid phase assays
usually anti-Cardiolipin abs
Lupus Anticoagulant (LAC)
MUST USE BOTH TESTS
-
8/4/2019 APS2011 osama
48/89
N LAC h 100%
-
8/4/2019 APS2011 osama
49/89
Tests for LAC
APTT:- variability in reagents result in inconsistent sensitivity.
- acute phase reaction and pregnancy may shorten APTT andmask a weak LAC
A normalAPTT doesnotexclude LAC
KCT- Kaolin clotting time
more sensitive to presence of anti-II
DRVVT- Dilute Russells viper venom timemore sensitive to presence of F2 GPI
TTI - Tissue thromboplastin inhibition test
No LAC shows 100%
specificity and sensitivity
because aPLs are
heterogeneous.
More than 1 test system is
needed
-
8/4/2019 APS2011 osama
50/89
Possible mechanisms of aPL induced
thrombosis
Endothelial-aPL interactionendothelial cell damage or activation, coexisting anti-endothelial abs, aPL induced monocyte adhesion,
increased tissue factor expression
Platelet-aPL interactionplatelet activation, stimulation of thromboxane production
Coagulation system-aPL interaction
inhibition of activation of protein C , interaction between aPLand substrates of activated protein C: factors Va VIIIa;
interaction between aPL and annexin V anticoagulant shield
Complement activation
-
8/4/2019 APS2011 osama
51/89
Occurrence of antiphospholipid antibodies
in other conditions:
Infection:
- Syphilis, TB, Q-fever, Spotted Fever, Klebsiella, HCV,
Leprosy,HIV.
- The abs are usually transient, not F2 GPI dependent
Malignancy:
Lymphoma, paraproteinemia
Drug induced:
phenothiazines, procainamide, quinidine, phenytoin,
hydralazine
I di ti f L b t t ti f ti h h li id
-
8/4/2019 APS2011 osama
52/89
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 < 50yrs
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
-
8/4/2019 APS2011 osama
53/89
APSTreatment
-
8/4/2019 APS2011 osama
54/89
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
-
8/4/2019 APS2011 osama
55/89
Venous or Arterial thrombosis
1. Initial treatment with Heparin
2. Start Warfarin
3. Stop Heparin when therapeutic INR achieved
-
8/4/2019 APS2011 osama
56/89
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 high-intensity VKA therapy (Grade 1A).
We recommendtreatment for 12 months
(Grade 1C+).
We suggest indefinite anticoagulanttherapy for these patients (Grade 2C).
-- Buller, et al., Chest, 2004; 126 (Supplement):
-
8/4/2019 APS2011 osama
57/89
-
8/4/2019 APS2011 osama
58/89
-
8/4/2019 APS2011 osama
59/89
Current Recommendations
Asymptomatic aPL no treatment (Aspirin?)
Venous thrombosis Warfarin INR 2.0-3.0
Arterial thrombosis Warfarin IN
R 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
-
8/4/2019 APS2011 osama
60/89
Potentially usable
Non-aspirin antiplatelet agents
Hydroxychloroquine
Statins
Thrombin inhibitors
Rituximab
Recombinant activated protein C
Prostaglandin and prostacyclin Anti-cytokine
-
8/4/2019 APS2011 osama
61/89
Thrombocytopenia
Mild to moderate- Platelets > 50,000:
No treatment
Severe-
-
8/4/2019 APS2011 osama
62/89
Management of aPL positive patients with
adverse pregnancy history
Poor obstetric history - the most importantpredictor
The risk of fetal loss is related to aCL ab titer
Presence of aPL are a marker for a high riskpregnancy
Once APS is diagnosed, serial aPL testing isnot useful
-
8/4/2019 APS2011 osama
63/89
Current Recommendations
Pregnancy Fetal protection Asymptomatic aPL no treatment
Single loss
-
8/4/2019 APS2011 osama
64/89
Heparin and aspirin for recurrent
miscarriage without history of thrombosis
for recurrent miscarriage :
improved live birth rate from 40% to 70-80%
for late losses or intrauterine death:
results in 70-75% live birth
-
8/4/2019 APS2011 osama
65/89
Other therapies for aPL associated
pregnancy loss
Corticosteroids :
- associated with significant maternal and fetalmorbidity
- ineffective
Immunosuppression:
azathioprine, plasmapheresis:
numbers treated too small for conclusion
IVIG:
may be salvage therapy in women who fail on
Heparin + Aspirin
-
8/4/2019 APS2011 osama
66/89
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
-
8/4/2019 APS2011 osama
67/89
-
8/4/2019 APS2011 osama
68/89
How long should patients with
APS and venous thrombosis betreated 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.
-
8/4/2019 APS2011 osama
69/89
Do any of the clinical laboratory
tests identify patients at risk for
thromboembolic problems?
-
8/4/2019 APS2011 osama
70/89
Risk factors for recurrent vascular
events despite anticoagulation
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%)
-
8/4/2019 APS2011 osama
71/89
Anticardiolipin Antibodies and Recurrent
Venous Thromboembolism
A A positi e
A A ne ati e
onths
umulatie
robabilito
Recurrence
-- Schulman, et al, Am J ed, 99 ; :
-
8/4/2019 APS2011 osama
72/89
What about patients with
recurrent thromboembolismdespite therapeutic warfarin?
Th ti ti f
-
8/4/2019 APS2011 osama
73/89
Therapeutic options for
recurrent thromboembolism in
APS
Warfarin with a higher target INR (>
3.0).
Addition of an antiplatelet agent to
warfarin.
Change to an alternative anticoagulant(e.g., low molecular weight heparin).
Immunomodulatory therapy.
-
8/4/2019 APS2011 osama
74/89
British Society of Haematology
Guidelines
For patients with APS and venous thrombosis,
treatment for 6 months with a target INR of 2.5
is reasonable. Recurrent venous thrombosis should be treated
by long-term oral anticoagulation.
Recurrence while the INR is between 2.0 and
3.0 should lead to more intensive warfarin
therapy, target INR 3.5, but this is uncommon.
-- Greaves, et al., Br.J.Haematol., 2000; 109: 70
-
8/4/2019 APS2011 osama
75/89
Because of the high risk of recurrence and
likelihood of consequent permanentdisability or death, stroke due to cerebral
infarction in APS should be treated with
long-term oral anticoagulant therapy,
target INR 2.5 (optimal range 2.0-3.0)(level III evidence, grade B
recommendation).
British Society of Haematology
Guidelines
-- Greaves, et al., Br.J.Haematol., 2000; 109: 70
-
8/4/2019 APS2011 osama
76/89
ACCP Guidelines
Prevention of noncardioembolic cerebral
ischemic events.
For most patients, we recommend antiplateletagents over oral anticoagulation (Grade 1A).
For patients with well-documented
prothrombotic disorders, we suggestoral
anticoagulation over antiplatelet agents
(Grade 2C).
-- Albers, et al., Chest, 2004; 126 (Supplement):
-
8/4/2019 APS2011 osama
77/89
Treatment of cardiac involvement
-
8/4/2019 APS2011 osama
78/89
Treatment of cardiac involvement
Asymptomatic valve thickening: low
dose aspirin (81 mg/d)
Embolic disease: Heparin followed by
warfarin
MI: Heparin followed by warfarin +aspirin
-
8/4/2019 APS2011 osama
79/89
Case description
35 year old male, single
Presented with:
- sudden vision loss- rt eye:
due to Central retinal vein occlusion
- Chronic leg ulcer
-
8/4/2019 APS2011 osama
80/89
Past Medical History
S\P Lt lower Leg DVT
S\P CVA with Lt. hemiparesis
Hypertension
-
8/4/2019 APS2011 osama
81/89
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
-
8/4/2019 APS2011 osama
82/89
Laboratory work-up ANA- negative
Anti-DNA- negative
Anticardiolipid IgG > 120 GPLU (N 100 (N
-
8/4/2019 APS2011 osama
83/89
Diagnosis
Primary Antiphospholipid syndrome with:
- recurrent arterial thrombosis: CVA
leg ulcer
- recurrent venous thrombosis: DVT
CRV occlusion
- High titer antiphospholipid antibodies: anticardiolipin IgGanti-F2 GPI
-
8/4/2019 APS2011 osama
84/89
Management and course
Coumadin: INR = 3.0
Gradual complete healing of leg ulcer
No further thrombotic episodes
Some improvement in gait and cognition
-
8/4/2019 APS2011 osama
85/89
And what lies ahead?
-
8/4/2019 APS2011 osama
86/89
Future Directions
Can we predict which patients with
antiphospholipid antibodies will developthromboembolic complications?
Is there an inherited predisposition to
developing antiphospholipid antibodysyndrome?
F ili l A ti h h li id
-
8/4/2019 APS2011 osama
87/89
Familial Antiphospholipid
Syndrome Family members of patients with APS
have an increased incidence of
autoimmune disorders.
Genetics of APS is a clinical trial being
developed by the Rare Thrombotic
Diseases Clinical Research Consortium. For more information:
http://rarediseasesnetwork.epi.usf.edu/rtdc /
-
8/4/2019 APS2011 osama
88/89
Antiphospholipid Antibody Syndrome
Venous or arterial thrombosis, recurrent fetal loss,or thrombocytopenia accompanied by an increasedlevels of antiphospholipid Ab (aPLs)
Primary or secondary (SLE)
Valvular lesions Vegetation, thickening, or regurgitation
Prevalence
32% to 38% in primary APS
A significantly higher prevalence of valvulardefects in SLE pts with aPLs
TherapyLong-term, high intensity oral anticoagulation
(INR2.5-3)
-
8/4/2019 APS2011 osama
89/89
Thank you