Antiphospholipid

Syndrome
 Hypercoagulable states

efenition:
disrupted clotting system can
ad to life threatening thrombosis
 Hypercoagulable States
• Inherited:
– Factor V Leiden mutation
– Prothrombin gene mutation
– Protein S deficiency
– Protein C deficiency
– Antithrombin III deficiency
– Hyperhomocysteinemia
• Acquired:
– Malignancy
– Surgery/Trauma
– Pregnancy
– OCPs, HRT, Tamoxifen
– Antiphospholipid Sndrome
– Immobilization
– CHF
– Nephrotic Syndrome
– IBD
– HIT
– Myeloproliferative disorders:
• POLYCYTHEMIA VERA
• Essential thrombocythemia
• Paroxysmal nocturnal
hemoglobinuria
– Hyperviscosity: Waldenstrom's
macroglobulinemia, MM,
Marked leukocytosis in acute
leukemia, Sickle cell anemia
 Hypercoagulable states
Acquired:
*Pregnancy
*Antiphospholipid Syndromre
The antiphospholipid syndrome is an
autoimmune disease that is
characterized clinically by vascular
thrombosis and pregnancy morbidity,
and serologically by the presence of
antiphospholipid Abs
 EPIDEMIOLOGY
10% of normal population have transient low-titer
anticardiolipin; 1% have moderate-high titerspatients

50% of APS patients have SLE (defined as secondary

APS)

Upto 40% of SLE patients have positive aPL tests

and 10-20% have APS

Asymptomatic aPL-positive patients have a 0% to 4%

annual risk of thrombosis

14% of patients with recurrent venous thromboembolic

disease have aPLs
 ETHIOLOGY
The main Ag is ß2GPI a physiologic phospholipid-
binding plasma protein

ß2GPI binds to phosphatidylserine on activated or

apoptotic cell membranes and function in the
elimination of apoptotic cells, removal of oxidized
lipids, and is a natural anticoagulant

Drugs (chlorpromazine, procainamide, quinidine,

and phenytoin) and malignancies
(lymphoproliferatives) can also induce non-
autoimmune aPLs
 PROSES HEMOSTASIS
Robekan vaskuler
Gangguan endothel
Hemostasis sekunder Hemostasis primer

Prekalikrein Aktifasi KBMT Kontrol Tissue factor VCAM-1 Reflek

Fletcher Fitzgerald Hemostasis released ECAM vasokonstriksi

Sticky platelet
Kalikrein Jalur Intrinsik Jalur Ekstrinsik collagen
Trombin
t-PA ADP, TXA2
Fibrinogen FPA+FPB released
PAI-1
Aggregasi
Fibrin trombosit
Plasminogen Plasmin FDP X,Y,D,E
polimer
Trombosit plug
Fibrin FDP X,Y,E
Cross link D-Dimer semipermiable

Recanalisasi endothelial proliferation PD-ECGF, VEGF, FGF

 Hemostasis primer
Vascular injury
Expose
Tissue
Collagen, elastin & Vasokonstriksi
factor
Membrana basalis
vWF Retarded
ADP Tissue
bloodflow
thromboplastin

Adhesi
Release ADP TXA2
Platelet-collagen

Aktifasi KBMT Aggregasi

Aktifasi jalur
Fitzgerald PF-3 Platelet-primer ekstrinsik
ADP, Epinephrin,
PF-4 5OH-Tryptamine
Aktifasi jalur PF-2 Aggregasi
intrinsik Platelet-sekunder
Dense granule
Alfa granule
Fibrinogen Fibrin
PF-2 = aktifator fibrin dan inhibitor AT-III, PF-3  phospholipid procoagulan
PF-4 = anti-heparin
Coagulation and fibrinolysis
 Mechanism of platelet action
TXA2 GPIa-IIa MGDF
PAF ADP
ADP TXA2

Epinefrin
Ribosome
MGDF Aktifasi sintesis 5HT
TXA2
GPIIb-IIIa ADP
aktifasi
Tyrosin kynase COX
P47 P47PO4 5HT
PK-C ATP
Serin/treonin kinase Arachidonat

aktifasi MLC-PO4 DAG PLA2

Ca++ Ca++
MLC-K PL
Ca ++
MLC PI(PO4)2 I(PO4)3
PL-C myosin
dense granule
G protein
MLC = myosin light chain
Ca++
MLC-K = myosin light chain kinase GPIb-IX vWF
Dinding sel
I(PO4)3 = inositol trifosfat
PI(PO4)2 = Fosfatidilinositol bifosfat
P47 = protein sitoplasma adhesi Aktifasi kontraksi myofibril
PK-C = protein kinase C (Tyrosine, serine, treonine)
PLA2 = fosfolipase A2
MGDF= Megakaryocytes Growth Developing thombocytes Factors
PATHOGENESIS
PATHOGENESIS
Antiphospholipid Syndrome (APS)

• Most common acquired thrombophilia

• Described by Hughes (1983)

A syndrome characterized by the association of:

• thrombosis, obstetric complications and/or
thrombocytopenia
• Antiphospholipid antibodies (APA)
Antiphospholipid Antibodies
(APA)
• Anticardiolipin antibodies (ACA)
• Lupus Anticoagulant Antibodies (LA)
• Anti ß2GP1 Antibodies
 APS Pathophysiology Thrombosis
aPL

platelets Complement
system
Coagulation Placental
cascade tissue
Endothelial
Activate cells
platelet
Trophoblastic
aggregation
cell growth,
Inhibit Protein C,
Protein S, TF, adhesion apoptosis
thrombomodulin, molecules and IL-3
antithrombin III proinflammatory
fibrinolysis cytokines
Anti-Phospholipid Syndrome
(APS)
Primary APS
No other discernible autoimmune disease

Secondary APS
Combination with other autoimmune disease
(mostly SLE and Scleroderma)

Catastrophic APS
With multiple organ failure (rare)
 APS: syndrome of clotting
(thrombosis)
• The tendency to blood clotting
– Can affect individual of any age both male and
female
– Quick : central retinal vein/artery occlusion
– Chronic : migrain, headache
– Can affect artery / vein of any of the body
 MANIFESTATIONS: THROMBOSIS
Venous and/or arterial occlusion may occur in any organ

Thromboses may be sever, recurrent, and occur in unusual

sites and in young peoples

DVT and stroke are the most common clinical

manifestations of APS

Severe HTN, renal failure and proteinuria without casts may

occur due to renal microangiopathy, glomerular capillary
injury, and thrombosis of renal vessels
PREGNANCY COMPLICATIONS
Losses in patients with aPLs typically
occur after 10 weeks'

Fetal growth slows and amniotic fluid

volume decreases in second trimester

Severe, early preeclampsia or HELLP syndrome

may develop

Prior late pregnancy losses predict future losses

 NON-THROMBOTIC
MANIFESTATIONS
Livedo reticularis is common but is not specific
for APS

Cardiac valve disease (vegetations,

thickening), is a late manifestation

Accelerated atherosclerosis is not evident in

recent studies

Leg ulcers may develop

 MISCELLANEOUS
MANIFESTATIONS
Pulmonary hypertension may develop due to recurrent
pulmonary embolism or small vessel thrombosis

Nonfocal neurologic symptoms are lack of concentration,

forgetfulness, and dizzy spells

Multiple small, hyperintense lesions seen on MRI in the

periventricular do not correlate well with clinical symptoms

Antiprothrombin antibodies may cause hemorrhage during

lupus anticoagulant hypoprothrombinemia syndrome
 CATASTROPHIC ANTIPHOSPHOLIPID
SYNDROME (CAPS)
Multiple thromboses of medium and small
arteries occurring over a period of days

Stroke, cardiac, hepatic, adrenal, renal,

and intestinal infarction; acute adrenal failure, peripheral
gangrene occur

Thrombocytopenia is moderate; erythrocytes are less

fragmented than in the HUS or TTP, and fibrin splits are
not strikingly elevated

Tissue biopsies show noninflammatory vascular occlusion

 LABORATORY TESTS
Repeatable positive LA test or
a moderate- to high-titer aCL IgG
or IgM test is required

IgA aCL and ( IgG, IgM, or IgA anti-ß2GPI )are

helpful when LA and aCL tests are negative

LA test is more specific but less sensitive

predictor of thromboses
 LABORATORY TESTS
ANA and anti-DNA antibodies occur in 45% of
patients with primary APS

Hypocomplementemia, erythrocyte casts, and

pyuria imply lupus nephritis rather APS

ESR, Hb, and WBC count are normal in

uncomplicated primary APS, except during acute
thrombosis
 IMAGING
MRI shows CVA and other infarctions

Multiple small, hyperintense

white-matter lesions are
common and may not be infarcts

Occlusions usually occur in vessels below the

angiographic resolution

Echocardiography or cardiac MRI may show

Libman-Sacks endocarditis and thrombi
 PATHOLOGY
Noninflammatory occlusion of all caliber
arteries and veins, acute and chronic
endothelial injury is noted

Uteroplacental insufficiency may be due

to inflamation rather than thrombosis or
spiral artery vasculopathy

Necrotizing vasculitis
suggests concomitant SLE
DIAGNOSIS: CLINICAL CRITERIA
1-Vascular thrombosis:
A clinical episodes of arterial, venous, or small
vessel thrombosis in any organ
2-Pregnancy morbidity :
a) An unexplained fetal deaths beyond the 10th
week of gestation, or
b) One premature birth before the 34th week
because of eclampsia, severe preeclampsia or
placental insufficiency or
c) Three unexplained consecutive abortions
before the 10th week ( not with anatomic,
hormonal or chromosomal causes)
 DIAGNOSIS: LAB CRITERIA
1- LA on two or more occasions at least 12 weeks
apart
2- aCL of immunoglobulin Ig G or IgM in medium
or high titer, on two or more occasions at least
12 weeks apart, by ELISA
3- Anti– ß2GPI antibody of IgG or IgM on two or
more occasions at least 12 weeks apart,
measured by ELISA
Note: Definite APS is present if at least one of
the clinical and one of the lab criteria are
met
 DIAGNOSIS:SUGGESTING
FEATURES
Clinical: Laboratory:
 Livedoreticularis  IgA aCL antibody 
  Thrombocytopenia  IgA Anti– ß2GPI
(usually 50,000-
100,000 /mm3)
  Autoimmune
hemolytic anemia 
 Cardiac valve disease
 Multiple sclerosis–like
syndrome, chorea, or
other myelopathy
 DIAGNOSIS: CAPS
1.    involvement of three or more organs or
tissues
 2.    Development of in less than 1 wk
  
3.    Confirmation by histopathology of small
vessel occlusion in at least one organ or tissue
  
4.    Laboratory confirmation of the presence of
aPL (LA or aCL or Anti– ß2GPI

Definite Catastrophic APS: All 4 criteria

 TREATMENT: VASCULAR Dis.
Acute thrombosis is treated as usual patients

Moderate intensity ( INR 2 to 3) and high-intensity

warfarin (INR 3 to 4) are equally protective

Arterial thrombosis who are at high risk for

recurrence require high-intensity anticoagulation

Aspirin is an option for elderly with a single low-titer

aCL and one stroke

Positive LA may cause the INR to be unreliable, if

so, anti–factor Xa activity testing is helpful
TREATMENT: VASCULAR Dis.
Aspirin, HCQ, statins , IVIG, and plasmapheresis
have been used in refractory cases

GCs have are used for rheumatic symptoms,

High doses used empirically in severe
thrombocytopenia, hemolytic anemia, and CAPS

Discontinuing anticoagulation in highly selected

patients when the triggers are eliminated and full
remission of antibody observed
 TREATMENT: PREGNANCY
MORBIDITY
Unfractionated or LMWH is used but lower risk of
thrombocytopenia and osteoporosis with the later

Prior fetal losses are treated with

prophylactic doses, prior thromboses
must be fully anticoagulated

In women with prior thrombosis, warfarin is changed

to heparin before conception, or at the first missed
mense
 TREATMENT: PREGNANCY
MORBIDITY
Anticoagulation is continued
for 6 to 12 weeks post
partum
Conversion from heparin to warfarin is
done after the first or second postpartum
week

Breastfeeding is permissible with both

heparin and warfarin.
 TREATMENT: ASYMPTOMATIC
INDIVIDUALS
The probability to develop APS is low

Elimination of reversible risk factors and

prophylaxis during surgical procedures, are
crucial

Drugs that promote

thrombosis
(estrogen, etc.)
may not be safe
TREATMENT: AMBIGUOUS EVENTS
Dizziness, visual disturbance, very early
pregnancy loss are treated with ASA, HCQ, or
both
In livedo reticularis, thrombocytopenia, leg
ulcers, microangiopathy, or valvulopathy the
efficacy of anticoagulation is unknown

Rituximab can be effective for

refractory thrombocytopenia and skin ulcers
 TREATMENT REVIEW
Asymptomatic No treatment

Venous thrombosis Warfarin INR 2.5

indefinitely
Arterial thrombosis Warfarin INR 2.5
indefinitely
Recurrent Warfarin INR 3 to 4 +
thrombosis low-dose aspirin
 TREATMENT REVIEW
First pregnancy No treatment
Single pregnancy loss at No treatment
<10 wk
≥1 Fetal or ≥3 embryonic Prophylactic heparin +
loss low-dose ASA,
discontinue 6-12 wk
postpartum
Thrombosis regardless Therapeutic heparin or
of pregnancy Hx low-dose ASA
throughout
pregnancy, warfarin
postpartum
 TREATMENT REVIEW
Valve nodules or No known effective
deformity treatment; full
anticoagulation if emboli
or intracardiac thrombi
No treatment
Thrombocytopenia
>50,000/mm3
Thrombocytopenia Prednisone, IVIG
<50,000/mm3
Catastrophic APS Anticoagulation +
corticosteroids + IVIG or
plasmapheresis
 PROGNOSIS
Prognostic factors are: pulmonary hypertension, neurologic
involvement, myocardial ischemia, nephropathy, gangrene
of extremities, and CAPS

Renal failure due to microangiopathy is rare

Thrombosis may cause loss of a transplanted kidney or

other organ

Valvulopathy may need valve replacement

Perioperative complications may occur despite prophylaxis

Mortality is 50% in CAPS

Name:
The
anemic
lady
Painter:
Van
Hoogst
-traten
1640