3. Antiphospholipid antibodies (aPLs) are acquired antibodies (IgG, IgM, and/or
IgA) react against negatively charged phospholipids:
cardiolipin (diphosphatidyl glycerol)
Phosphatidylserine
phosphatidylinositol
phosphatidylglycerol
associate with a slow progressive thrombosis and infarction in the placenta.
classified as thrombophilic factors and as autoimmune factors.
Antiphospholipid antibodies (aPLs)
dr. Mohamed Alajami
Am J Obstet Gynecol 1982;142: 829–34.
4. 1. inhibit the release of HCG from human placental explants;
2. block trophoblast migration, invasion, and multinucleated cell formation;
3. inhibit trophoblast cell adhesion molecules;
4. activate complement on the trophoblast surface, inducing an inflammatory
response.
dr. Mohamed Alajami
Biol Reprod 1995;53:905–10.
Biol Reprod 1997;56:50–8.
Fertil Steril 2005;83:691–8.
Circ Res 2002;11:29–37.
Antiphospholipid antibodies
5. an autoimmune condition characterized by the production of aPL combined
with certain clinical features.
Presence of aPL (including anticardiolipin [aCL] and lupus anticoagulant
[LAC]) during pregnancy is a major risk factor for adverse pregnancy
outcome.
֎ How aPLs arise in patients with APS??
Not yet understood
Genetic factors and infection may play a role.
Antiphospholipid syndrome (APS)
dr. Mohamed Alajami
Eur J Obstet Gynecol Reprod Biol 1991;41:179–86.
6. APS is a syndrome is defined based on both clinical and laboratory criteria.
(Sydney criteria)
At least 1 clinical and 1 laboratory criterion must be present for definite APS
DIAGNOSIS OF APS
dr. Mohamed Alajami
Clin Obstet Gynecol 2010;53: 617- 27
7. 1. Vascular thrombosis
1< clinical episodes of an arterial, venous, or small vessel thrombosis,
confirmed by imaging or Doppler studies or histopathology, without
significant evidence of inflammation in the vessel wall.
2. Obstetric morbidity
Sydney criteria - Clinical criteria
dr. Mohamed Alajami
8. 2. Obstetric morbidity
1) 1 > unexplained demise of a morphologically normal fetus at or beyond 10
weeks of gestation, or
2) 1 > premature births of a morphologically normal neonate at or before 34
weeks of gestation, caused by severe preeclampsia or severe placental
insufficiency, or
3) 3 > unexplained, consecutive miscarriages of less than 10 weeks of gestation.
ruled out known factors associated with recurrent miscarriage.
dr. Mohamed Alajami
Sydney criteria - Clinical criteria
9. ֎ Any one of:
1. aCL IgG and/or IgM in blood, in medium or high titers on 2 or more
occasions at least 12 weeks apart, measured by ELISA.
2. Anti-b2GP1 antibody of IgG and/or IgM in blood on 2 or more occasions at
least 12 weeks apart, measured ELISA.
3. Lupus anticoagulant (LAC) present in plasma, on 2 or more occasions at least
12 weeks apart.
dr. Mohamed Alajami
Sydney criteria - Laboratory criteria
Clin Obstet Gynecol 2010;53:617–27
10. APS
I. primary (Obstetric antiphospholipid syndrome)
without clinical or laboratory evidence of an underlying condition or
disease,
II. secondary when associate with other diseases or conditions
DIAGNOSIS OF APS
dr. Mohamed Alajami
Clin Obstet Gynecol 2010;53: 617- 27
11. II. Secondary APS
1. Autoimmune disease
SLE
Rheumatoid arthritis
Sjo¨gren syndrome
Systemic sclerosis
Diabetes mellitus
Crohn disease
Autoimmune thyroid disease
2. Drug-induced conditions
Oral contraceptives
DIAGNOSIS OF APS
dr. Mohamed Alajami
3. Malignancies
Carcinoma of ovary and cervix
Lymphoma
Leukemia
4. Infectious diseases
• Syphilis
• HIV infection
12. ֎ The clinical manifestations of primary and secondary APS are diverse and may
involve most organ systems.
֎ Vaso-occlusive disease is the pathologic basis for many of the complications
of primary and secondary APS.
Clinical Criteria OF APS
dr. Mohamed Alajami
J Am Med Assoc 1997;277:1549–54.
Medicine (Baltimore) 1989;68: 353–65.
Fertil Steril 1993;60:449–99.
J Thromb Haemost 2006;4:295–306.
Br J Rheumatol 1986;26:324–6.
13. ֎ In women with APS and histories of early loss, the prevalence of prior
thromboembolic events is low.
֎ Estrogen-containing oral contraceptive pills should be avoided in women with
repeated positive aPL.
֎ a single low-dose aspirin (81 mg) per day may decrease this future risk for
thromboembolic event.
Clinical Criteria OF APS
dr. Mohamed Alajami
Obstet Gynecol 2012;120:1514–21.
Obstet Gynecol 1994;83:372–7.
14. ֎ Indications to identify LAC and aPL in obstetric patients
1. RPL
2. Unexplained second-trimester or third-trimester loss
3. Fetal demise
4. Early-onset severe preeclampsia
5. Pregnancy-related thrombosis (venous or arterial)
6. Severe IUGR
7. Autoimmune or connective tissue disease
8. False-positive serologic test for syphilis (VDRL or rapid plasma reagin)
9. Prolonged coagulation studies
10. Positive autoantibody tests
Red flags OF APS
dr. Mohamed Alajami
15. ֎ Lupus anticoagulant
immunoglobulin (IgG, IgM, or both) interferes with one or more of the
phospholipid-dependent tests of coagulation.
The name is a misnomer in 2 ways.
1. Although it is called an anticoagulant, patients with LAC more frequently
have a hypercoagulable state.
2. LAC is frequently found in patients without SLE.
Laboratory Criteria OF APS
dr. Mohamed Alajami
16. ֎ The most common tests that have been used to identify the LAC include:
1. activated partial thromboplastin time (aPTT),
2. kaolin clot time (KCT),
3. dilute Russell viper venom time (dRVVT),
4. plasma clot time (PCT).
Laboratory Criteria OF APS
dr. Mohamed Alajami
17. Screening tests for lupus anticoagulants
dr. Mohamed Alajami Obstet Gynecol 1992;80:614–20.
18. Positive tests should ideally be confirmed in 6 to 8 weeks.
In general, aPLs decline during pregnancy.
aPLs may increase in as many as 20% of women during pregnancy.
dr. Mohamed Alajami
Laboratory Criteria OF APS
19. A major target molecule for aPL binding is beta-2 glycoprotein-1 (b2GP1).
b2GP1 is more specific indicator of APS.
b2GP1 is bound to phosphatidylserine exposed on the surface of
trophoblastic cell membranes undergoing syncytial formation.
b2GP1 inhibit thrombosis. by reducing the conversion of prothrombin to thrombin on
platelets and inhibiting the activation of the intrinsic coagulation cascade.
dr. Mohamed Alajami
Laboratory Criteria OF APS
Thromb Haemost 1995;73:798–804
20. I. Recurrent Miscarriage
II. Fetal Loss
III. Severe Preeclampsia Before 34 Weeks’ Gestation
IV. Severe Placental Insufficiency.
dr. Mohamed Alajami
OBSTETRIC COMPLICATIONS OF APS
Fertil Steril 1996;66:540–6.
Human Reprod 2002;17:2981–5.
Ann N Y Acad Sci 2010;1205:106–17
21. RPL defined as 2 or 3 or more consecutive losses before the 20th week of
gestation with the same partner.
affects up to 2% to 4% of pregnancies.
The risk of miscarriage in subsequent pregnancies is
30% after 2 losses
45% after 3 losses in patients without a history of live birth, therefore testing
after 2 consecutive losses.
dr. Mohamed Alajami
Recurrent Pregnancy Loss
Clin Obstet Gynecol 1994;37:625–34.
Fertil Steril 2012;98: 1103–11.
22. ASRM defined RPL as 2 or more failed clinical pregnancies as documented by
ultrasonography or histopathologic documentation of products of conception
and recommended a thorough evaluation of RPL after two or more clinical
losses.
dr. Mohamed Alajami
Recurrent Pregnancy Loss
Fertil Steril 2012;98:1103–11
23. Late fetal loss (after 10 weeks of pregnancy)
aCL antibodies and b2GP1 antibodies, but not LAC, strongly associated
with intrauterine fetal death.
more common as the number of aPL antibody tests become positive.
dr. Mohamed Alajami
Fetal loss
J Matern Fetal Neonatal Med 2011;24:606–9.
Br J Haematol 2006;132:171–96
Eur J Obstet Gynecol Reprod Biol 2002;101:6–14
24. Stillbirth (intrauterine fetal death > 20 weeks gestational age) the
association with APS less well defined.
Therapy for patients with a prior stillbirth and APS with low-dose aspirin and
heparin is commonly used but not supported by randomized controlled trials.
dr. Mohamed Alajami
Fetal loss
Clin Obstet Gynecol 2010; 53:617–27
25. Preterm birth resulting from severe preeclampsia < 34 weeks of gestation.
APS increase preeclampsia and eclampsia at any gestational age by 2.93
aCL antibodies alone with preeclampsia was 2.86, and for severe preeclampsia was
11.15
in severe preeclampsia < 34 weeks’ gestation, testing should be done for
LAC, aCL antibodies, and b2GP1 antibodies.
dr. Mohamed Alajami
Severe preeclampsia before 34 weeks
Obstet Gynecol 1992;80:614–20.
26. includes IUGR and abruptio placenta at or before 34 weeks’ gestation.
dr. Mohamed Alajami
Severe Placental Insufficiency
Obstet Gynecol 1992;80:614–20.
Clin Exp Rheumatol 1996;14:131–6
Eur J Obstet Gynecol Reprod Biol 2002;101:6–14
27. Thrombosis
Defective Placentation
Local Inflammatory Events
dr. Mohamed Alajami
PATHOPHYSIOLOGY OF APS
30. The primary hypothesis for the major pathogenic mechanism for aPL-induced
pregnancy loss and fetal growth restriction is placental thrombosis.
Thrombosis of vessels causes placental infarction with resultant impairment
of maternal-fetal nutrient and oxygen exchange.
dr. Mohamed Alajami
Thrombosis and aPLs
31. LAC cause a higher risk of thrombosis than aCL.
LAC-positive increase thromboxane activity producing a thrombophilic state.
aPL could promote thrombosis by interfering with protein C activation and
diminishing antithrombin activity.
aPL-mediated thrombosis may involve a disruption of the normal function of
a plasma protein called annexin V.
dr. Mohamed Alajami
Blood 2003;101:1827–32.
Am J Obstet Gynecol 1993;169:1403–6
N Engl J Med 1986;314:1193–4.
Lupus 2010;19:460.
Thrombosis and aPLs
32. aPLs may be pathogenic in obstetric APS by directly impairing normal
placentation via a mechanism independent of placental or decidual
thrombosis.
dr. Mohamed Alajami
Defective Placentation
33. aPLs in obstetric APS directly impairing normal placentation via a
mechanism independent of placental or decidual thrombosis.
1. Abnormalities of early trophoblast invasion caused by aPLs are a likely
pathogenic mechanism in obstetric APS.
2. aPLs can directly retard trophoblast invasiveness, impair trophoblastic
cellular differentiation and maturation, and diminish HCG
3. the histologic abnormality is defective decidual endovascular trophoblast
invasion, rather than intervillous thrombosis.
dr. Mohamed Alajami
Defective Placentation
Hum Reprod 2002;17:1067–71.
Hum Reprod 1999;14:489–95.
34. Exposure of trophoblastic cell monolayers to aPLs resulted in an increased
rate of programmed cell death (apoptosis) and inhibition of syncytial
formation.
The sequential expression of cell adhesion molecules between trophoblastic and
decidual cells is involved in trophoblastic invasion during normal placentation.
aPLs might affect placental invasion through an abnormal trophoblastic expression of
integrins and cadherins.
dr. Mohamed Alajami
Proc Natl Acad Sci U S A 1993;90:6464–7.
Fertil Steril 2002;77:805–11.
Defective Placentation
35. The maternal immune system is transformed during normal pregnancy to
prevent immune rejection of the fetoplacental unit.
Acute inflammatory responses generally promote adverse pregnancy
outcome and chemokine mediators favor a profile of T helper cells type 2
(Th2) responses in early pregnancy which block acute immune rejection.
Local Inflammatory Events
dr. Mohamed Alajami
Obstet Gynecol 1992;80:614–20.
36. Complement-mediated immune attack is suppressed in normal pregnancies,
resulting in viable delivery by complement inhibitory proteins expressed on
trophoblast cells.
inhibition of complement C3 activation and deficiencies of C5 and C5a protect
against pregnancy loss and fetal growth restriction.
Local Inflammatory Events
dr. Mohamed Alajami
J Clin Invest 2003; 112:1644–54.
J Exp Med 2002;195:211–20.
37. The binding of aPL to trophoblast cell membranes promotes complement
activation, specifically C3a and C5a, resulting in thrombosis and pregnancy
loss by:
increase in decidual TNF-a levels, putatively secondary to C5 activation.
increases tissue factor TF expression in neutrophils, which increase
generation of reactive oxygen species thus providing a novel mechanism
to explain fetal loss.
TF activate the coagulation pathway, leading to thrombosis.
Local Inflammatory Events
dr. Mohamed Alajami
Curr Dir Autoimmun 2004;7:133–48.
J Immunol 2005; 174:485–90.
Obstet Gynecol Surv 2010;65:39–45.
38. Relate to their anticoagulant properties.
dosage lower than is required to achieve clinical anticoagulation.
anticoagulants such as hirudin and fondaparinux are ineffective in the
treatment of aPL-induced pregnancy loss, despite having anticoagulant
effects similar to heparin.
Mechanism of Therapeutic Benefit of Heparin
dr. Mohamed Alajami
Nat Med 2004;10:1222–6
39. Several mechanisms of heparin independently of its anticoagulant action.
1. Low-molecular-weight heparin (LMWH) directly impedes aPL binding to
trophoblast cells
2. Reinstates normal trophoblast invasiveness and differentiation hindered by
aPL.
3. Heparin also can potentially regulate apoptosis in placental by increasing
levels of Bcl-2, an antiapoptotic protein.
Mechanism of Therapeutic Benefit of Heparin
dr. Mohamed Alajami
40. 4. heparins prevent complement activation, an action that would protect
normal placentation from inflammatory injury.
5. LMWH increase matrix metalloproteinases in trophoblastic cells, an action
that would promote trophoblastic invasiveness.
6. Heparin sulfate directly binds aPL, providing a novel and alternative
mechanism for its therapeutic benefit in treating obstetric APS.
Mechanism of Therapeutic Benefit of Heparin
dr. Mohamed Alajami
41. Overview of Proposed Treatments:
Only 20% to 30% of patients with LAC and/or positive levels of aPL who have
had unsuccessful previous pregnancies have a successful delivery without
treatment.
Several treatments have been proposed,
1. a single low-dose aspirin per day (81 mg),
2. aspirin and low-dose or high-dose prednisone,
3. aspirin and unfractionated heparin,
4. aspirin and LMWH,
5. intravenous immunoglobulin.
MANAGEMENT OF APS IN PREGNANCY
dr. Mohamed Alajami
42. Combination of unfractionated heparin with low-dose aspirin provide the
highest success rates.
Aspirin is thought to improve outcome by selective inhibition of
thromboxane production thus restoring the balance with prostaglandin.
Concomitant use of prednisone and heparin is generally not recommended
because this combination has not been shown to be better than either alone
and may increase the risk of fractures.
MANAGEMENT OF APS IN PREGNANCY
dr. Mohamed Alajami
43. aspirin alone versus aspirin and heparin,
• aspirin alone had a 44% live birth rate, whereas the group treated with
subcutaneous heparin and aspirin had a 78% live birth rate.
• The incidence of maternal complications was low and there were no
significant differences.
Unfractionated Heparin Compared with LMWH
dr. Mohamed Alajami
44. Low-dose heparin is the treatment of choice for RPL associated with
antiphospholipid syndrome.
1. initiated at 5000 to 7500 U twice a day when the pregnancy test is positive.
2. obtain a baseline platelet count and partial thromboplastin time.
3. heparin-induced osteopenia at total daily doses of more than 15,000 (IU)
4. calcium to 600 mg orally twice a day along with vitamin D 400 IU twice daily
to optimize absorption of calcium and to reduce the risk of osteopenia.
Unfractionated Heparin Compared with LMWH
dr. Mohamed Alajami
45. Heparin is associated with thrombocytopenia
During pregnancy, the normal platelet count > 100,000/mL compared with
the nonpregnant state, in which platelet counts are normally more than
150,000/mL.
If counts were normal before conception and decreased dramatically during
pregnancy, the heparin dosage should be reduced.
Unfractionated Heparin Compared with LMWH
dr. Mohamed Alajami
46. use of aspirin 81 mg daily in combination with LMWH during pregnancy for
the prevention of RPL in women with APS be as safe as unfractionated
heparin plus aspirin.
Unfractionated Heparin Compared with LMWH
dr. Mohamed Alajami
Fertil Steril 2005;83:684–90.
47. Antepartum testing based on the increased risk for poor obstetric outcome.
For who have had only first-trimester losses, perform serial ultrasonic
assessments weekly until progressed beyond the point of their prior losses.
If had a prior second-trimester or third-trimester fetal loss, serial
antepartum testing is recommended.
daily fetal kick counts
twice weekly nonstress tests, or
weekly biophysical profile.
Antepartum Surveillance
dr. Mohamed Alajami
48. Immediately Postpartum
Lifelong Consequences of APS
POSTPREGNANCY CONSIDERATIONS
dr. Mohamed Alajami
49. Immediately Postpartum
1. ambulate as soon as possible.
2. Reinitiate Aspirin 81 mg a day.
3. Thromboprophylaxis for 4 to 6 weeks with and without a prior history of thrombosis.
4. Supplemental calcium should be continued as long as the patient is taking heparin.
5. Breast-feeding is not contraindicated for women taking low-dose aspirin or
prophylactic heparin.
POSTPREGNANCY CONSIDERATIONS
dr. Mohamed Alajami
50. Lifelong Consequences of APS
The diagnosis of APS is for life.
POSTPREGNANCY CONSIDERATIONS
dr. Mohamed Alajami
51. 1. Baseline nonpregnant studies of aPLs:
complete blood count with platelets,
PT, PTT
lupus anticoagulant.
aPL assay should be confirmed before pregnancy.
2. Aspirin 81 mg:
initiated before conception
discontinued 4 weeks before the expected delivery date.
resumed postpartum and continued for life.
Guidelines for prophylactic heparin plus aspirin of patients
with RPL without a history of thromboembolism but with APS
dr. Mohamed Alajami
52. 3. Subcutaneous heparin (5000 units every 12 hours) should be initiated when
pregnancy is confirmed unless instructed otherwise.
When weigh > 80 kg should use heparin 7500 units every 12 hours.
Check platelets and PTT every week for 2 weeks initially, 1 week following
any adjustment in dose, and each trimester throughout pregnancy to
evaluate for heparin-induced thrombocytopenia
patients with prior thromboembolic events should be fully
anticoagulated.
dr. Mohamed Alajami
Guidelines for prophylactic heparin plus aspirin of patients
with RPL without a history of thromboembolism but with APS
53. 4. Calcium carbonate (1200–1500 mg) with vitamin D (800–1000 IU) should be
taken daily in divided doses once start heparin to decrease the bone loss
associated with pregnancy and heparin therapy.
5. Ultrasonography by 7 weeks for the detection of fetal heart motion.
Perform further sonography at 18 to 20 weeks.
dr. Mohamed Alajami
Guidelines for prophylactic heparin plus aspirin of patients
with RPL without a history of thromboembolism but with APS
54. 6. Antenatal testing should begin at 28 to 30 weeks, based on the possible
increased risk of fetal growth restriction and stillbirth.
kick counts, nonstress tests, and/or serial biophysical profiles.
Serial scans for growth rate may be indicated.
dr. Mohamed Alajami
Guidelines for prophylactic heparin plus aspirin of patients
with RPL without a history of thromboembolism but with APS
55. 7. Heparin should be continued until the patient initiates spontaneous labor or
until the night before any scheduled induction or operative delivery.
One heparin dose may be skipped the night before amniocentesis.
Heparin should be restarted postpartum at the lowest predelivery dosage
and continued for 4 weeks
in those with previous thromboembolic events, full anticoagulation should
continue for 6 weeks postpartum.
dr. Mohamed Alajami
Guidelines for prophylactic heparin plus aspirin of patients
with RPL without a history of thromboembolism but with APS
56. 8. For prolonged deliveries and operative deliveries, the use of pneumatic
sequential compression devices or hose should be considered until the
patient is ambulatory.
9. If the patient is fully anticoagulated and delivery is emergent,
administer 1% protamine sulfate IV over 10 minutes
if coagulation indicators are increased (2.5 mg protamine per 1000 U
heparin, maximum 50 mg protamine).
dr. Mohamed Alajami
Guidelines for prophylactic heparin plus aspirin of patients
with RPL without a history of thromboembolism but with APS
10. Don't use estrogen-containing birth control pills.
11. Stop smoking.
57. (1) In women who have a diagnosis of APS, the chance for successful pregnancy
is reduced; and treatment be a clear option, particularly in the case of
patients with prior thromboembolic events.
(2) use subcutaneous heparin and aspirin.
(3) This treatment should begin with a positive pregnancy test, continue
throughout pregnancy, and extend postpartum.
SUMMARY
dr. Mohamed Alajami