Suradi Maryono
Hematology Medical Oncology Division .
Dr. Moewardi . Regional Ceneral Hospital
Surakarta.
Antiphospholipid syndrome (APL
syndrome)(APS)
- Autoimmune disorder with clinical & laboratoryfeatures :
- vascular thrombosis,
- pregnancy loss, and
- persistent antiphospholipid antibodies (aPLs).
* The pathophysiology is, The activation :
- endothelial cells
- monocytes,
- platelets, and
- complement
- Disease can range from asymptomatic to rapidly
fatal ( catastrophic APS ).
Antiphospholipid Syndrome: Needed. U.I. and Shiksha K. ET et al. . Staten Island, NY 10305, USA. 2017
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Antiphospholipid Syndrome: U. Ibrahim and Shiksha K.. Dep.Hematology/Oncology, Island
University Hospital,, Staten Island, , USA .
Laboratory studies elevated :
- LDH, bilirubin and ferritin, decreased haptoglobin, and positive Coombs test.
- ANA test was negative
- Antiphospholipid antibody positivity: anti-cardiolipin IgG and IgM,
antiphosphatidylserine IgG, and anti-𝛽2-glycoprotein IgG.
- Pancytopenia relatively rare in primary APS and is more often seen in secondary APS.
- Involvement of multiple organ systems as well as livedo reticularis and autoimmune-
related , such as Raynaud phenomenon and Coombs positive hemolytic anemia.
Primary : APS . in the absence of any other autoimmune disorder, such as SLE .
Secondary : When APS is seen in conjunction with other autoimmune diseases :
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Antiphospholipid Syndrome: Needed. U.I. and Shiksha K. ET et al. . Staten Island, NY 10305, USA. 2017
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II. Thrombocytopenia
III. Other system involvements
- The endocrine system may be involved in the form of Addison’s
disease and hypopituitarism ;
while common ,
- GIT manifestations : Budd-Chiari syndrome, oesophageal
necrosis, intestinal ischaemia, and hepatic necrosis.
- Skin manifestations: livedo reticularis, skin ulceration,
cutaneous necrosis & infarction, gangrene digits, and splinter
haemorrhages.
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IV. Obstetrical manifestations :
* Obstetric complications are the hallmark of APL syndrome:
* Recurrent pregnancy losses within the foetal period, i.e., 10 or more weeks of
gestation. ( general population, first 9 weeks ).
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Table . Clinical manifestations of Antiphospholipid Syndrome.
Activation of coagulation
Dr.Robert Virchow
(Q J Med, 95 : 199-210,
2002)
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* CLINICAL MODEL FOR PREDICTING PRETEST PROBABILITY FOR DVT:
(WELLS CRITERIA ):
ITEM. SCORE
-------------------------------------------------------------------------------------------------------------------
Pressure stockings
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Pregnant
› LMWH
Monitor anti-factor Xa levels q 4 weeks (4 hrs after dose)
Goal: 0.6 – 1.0 IU/ml (bid dosing) or 1-2 IU/ml for q day dosing
› Heparin bridge
Stop LMWH 2 weeks before delivery. No epidural within 24 hrs
of LWMW.
Start Unfractionated Heparin with goal PTT 1.5-2.3 X normal
Hold for delivery with restart 6 hours after vaginal delivery or 12
hours after C-section.
› Coumadin in the post-partum period
› Three to Six months
› Need to cover at least six weeks post-partum
› Ok for breast-feeding.
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LMWH
Enoxaparin (Lovenox), dalteparin (Fragmin), and tinzaparin
(Innohep) have received US Food and Drug Administration
(FDA) approval for the treatment of DVT in the United States.
Enoxaparin: Approved for inpatient and outpatient treatment of
DVT.
No monitoring
>90% bioavailable
Minimal protein binding
Levels are predictable
No heparin-induced thrombocytopenia (HIT)(1%)
No anti-heparin antibodies
In plasma for 12-16h
Allows for BID dosing
Associated with less major bleeding compared with UFH in
acute venous thromboembolism.
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LMWH Dosages
Lovenox: 1 mg/kg q 12h or 1.5 mg/kg/d SC
Max.: 180 mg/d
Fragmin: 100U/kg q 12h or 200 U/kg/d SC
Max.: 18,000U/d
Innohep: 175U/kg/d SC
Max.: 18,000U/d
Table . Potential future therapies for antiphospholipid syndrome.
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Deep vein thrombosis prophylaxis :
* Use either low-dose UFH or LMWH, unless
contraindicated
* Use a mechanical prophylactic device, such as
compression stockings or an intermittent
compression device, when heparin is
contraindicated.
* Use a combination of pharmacologic and
mechanical therapy for patients who are
at very high risk for DVT.
In patients at very high risk, LMWH should be
used rather than UFH .
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Preventive Strategies
(Donald H Jenkins 2009)
Mechanical
Early ambulation: not possible in OR; not possible for many
of highest risk patients
Sequential compression devices (inflatable stockings worn
on legs): essentially risk free; can’t be used for all patients
(leg injury or surgery); used during and after operations;
fairly effective
Vena Cava (main abdominal and chest vein) filters: small
wire cages in vena cava to prevent PE; inserted by
radiologists or surgeon in special x-ray suite; latest
technology allows removal of filter once risk of PE minimal
(~3 weeks after injury or surgery); does not prevent DVT;
controversial due to long term complication risk but
effective in PE prevention Umbrella.
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(Kendall TED, 2005)
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Inferior Vena Cava Filters
Indications
Contraindication to anticoagulation
Anticoagulation failure
Effectiveness
2-3 % PE rate with fatal complication of 0.1%
Complications
2 fold increased risk for lower extremity DVTs within 2 years
of placement
5% filter dislodgement
16% filter thrombosis
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Tabel . Dosis pemberian heparin . (Bates SM and Jaeschke R. Et al. 2012.)
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Tabel . Regimen LMWH dalam penatalaksanaan DVT.
(Bates SM and Jaeschke R. Et al. 2012.)
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II. Obstetrical manifestations :
* Obstetric complications are the hallmark of APL syndrome:
- Recurrent miscarriage, early delivery, oligohydramnios, prematurity, intrauterine
growth restriction, fetal distress, fetal or neonatal thrombosis, pre-eclampsia/
eclampsia, HELLP syndrome, arterial or venous thrombosis and placental
insufficiency are the most severe APS-related complication for pregnant
women .
* Recurrent pregnancy losses within the foetal period, i.e., 10 or more weeks of
gestation. ( general population, first 9 weeks ). APLAs may also impair
trophoblastic invasion and hormone production, by this means
promoting not only pre-embryonic and embryonic loss but also foetal loss and
uteroplacental insufficiency .
* Mechanisms of Pregnancy Loss in APL Syndrome .
Intervillous thrombosis, intravillous infarctions, and decidual vasculopathy
disturbing placental circulation were proposed as the pathobiologic basis of
recurrent miscarriages in women with APL syndrome.
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- Future therapies: Clopidogrel, rivaroxaban, statins, rituximab, and other new
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Figure 1. Treatment algorithm for the thrombotic and obstetric complications associated with persistently
positive antiphospholipid antibodies. Readers are referred to current evidence-based consensus guidelines60
for the management of the various acute coronary syndromes, with and without coronary artery stenting, and
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myocardial infarction.
Mosby items and derived items © 2006 by Mosby, Inc. How I treat the antiphospholipid syndrome .
Bill Giannakopoulos and Steven A. Krilis. Et al. (Blood. 2009;114: 2020-2030)
Table . Suggested regimens for the treatment of antiphospholipid syndrome in pregnancy .
Data from Am. College of Chest Physicians Evidence-Based Clinical Practice Guidelines
(8th edition). 31
Mosby items and derived items © 2006 by Mosby, Inc. Antiphospholipid Syndrome: U. Ibrahim and Shiksha K.. Dep.Hematology/Oncology, Island
University Hospital,, Staten Island, , USA .
2. Immunomodulation - Prednisone and other .
- Immunomodulating therapies are seldom
- prednisone is appropriate for secondary APS with clinically active SLE
- intravenous immunoglobulin is beneficial. from 0.4 g/kg body weight per
trimester to 2.0 g/kg body weight monthly .
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Mosby items and derived items © 2006 by Mosby, Inc. Antiphospholipid Syndrome: U. Ibrahim and Shiksha K.. Dep.Hematology/Oncology, Island
University Hospital,, Staten Island, , USA .
III. Treatment of thrombocytopenia
- In a patient of APS, thrombocytopenia could be caused by preeclampsia, HELLP
syndrome, placental insufficiency, active SLE, idiopathic thrombocytopenic purpura, or
worsening maternal APS. Late onset thrombocytopenia, a common phenomenon during
normal pregnancies, occurs frequently in pregnant. patients with APS and could signal an
increased risk of foetal injury. Heparin-induced thrombocytopenia , is rare as compared to
other causes .
* Thrombocytopenia
- Thrombocytopenia rarely causes clinical problem of hemorrhage in APL syndrome.
However, it is essential to achieve a platelet count above 50,000 per mm3 (54) before
warfarin therapy to reduce the risk of hemorrhage.
- Prednisone is the most common approach for management of autoimmune
thrombocytopenia
- Intravenous immunoglobulin (IVIG), chloroquine, low-dose heparin, cyclosporin A,
dapsone, and danazol have been used to correct thrombocytopenia in APL syndrome in
selected cases.
- Aspirin administration should be given with caution for the damaged function of already
low-count platelets in thrombocytopenic APL syndrome.
- Splenectomy might be indicated, but is occasionall
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Figure 2. A case of catastrophic APS with involvement of the ampulla of Vater. (A) Morphologic
appearance (on endoscopic examination) of ampulla of Vater, which is grossly edematous and unusual
in appearance. (B) Ampullary biopsy showing small-vessel thrombosis.. (C) Resolution of changes after
treatment with intravenous anticoagulation, corticosteroids, antibiotics, plasma exchange, and intravenous
immunoglobulin.
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Mosby items and derived items © 2006 by Mosby, Inc. How I treat the antiphospholipid syndrome .
Bill Giannakopoulos and Steven A. Krilis. Et al. (Blood. 2009;114: 2020-2030)
Table. Major cause of death of patients with catastrophic
antiphospholipid syndrome.
Which are the main causes of mortality of
patients with catastrophic APS .
Among the first 250 patients included in the
website-based internationalregistry of patients
with catastrophic APS (CAPS) Registry;
,114 (46%) died at the time of the catastrophic
APS event, which was identified as the cause of
death in 80 of them. Cerebral involvement was
the most frequent cause of death (27.2%),
followed by cardiac involvement (19.8%),
infection(19.8%) and multiorgan failure
(17.3%).
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The current treatment of CAPS
(catastrophic APS) is based on
this empirical pathogenic basis.
Besides identification and
treatment of any precipitating
factor, first-line therapies should
always include the combination of
anticoagulation against thrombosis
plus glucocorticoids against
manifestations of SIRS plus
plasma exchange and/or
intravenous immunoglobulins
(IVIG) to remove or block the aPL
and the cytokines involved in the
SIRS (Figure .) .
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Hydroxychloroquine protects the annexinA5 anticoagulant
shield from disruption by antiphospholipid antibodies: evidence
for a novel effect for an old antimalarial drug .
Jacob H. R and Xiao-Xuan Wu. Etal. (Blood. 2010; 115:2292-2299) .
- AnnexinA5 (AnxA5) is a potent anticoagulant protein that crystallizes over
phospholipid bilayers (PLBs), blocking their availability for coagulation reactions. -
- Antiphospholipid antibodies disrupt AnxA5 binding, thereby accelerating
coagulation reactions. This disruption may contribute to thrombosis and
miscarriages in the antiphospholipid syndrome (APS). We investigated whether the
antimalarial drug, hydroxychloroquine (HCQ), might affect this prothrombotic
mechanism.
Hydroxychloroquine (HCQ) is a synthetic antimalarial, has proven to be an effective
immunosuppressive treatment of systemic lupus erythematosus (SLE).
Hopkins Lupus Cohort reported that the presence of aPL antibodies is an independent predictor of
thrombosis in SLE, and that treatment of SLE patients with HCQ was associated with a reduced risk
of thrombosis.
In conclusion, these data demonstrate that an antimalarial drug, HCQ, can protect the AnxA5
anticoagulant from disruption by aPL antibodies on phospholipid bilayers, on the apical membranes of
cultured HUVECS and STCs, APS patient plasmas.
These results demonstrate that it may be possible to target earlier steps in the APS disease process than
those addressed by anticoagulant therapy.
DABIGATRAN
Dabigatran etexilate (Pradaxa) is the
first oral direct thrombin inhibitor to be
approved by
the US Food and Drug Administration
(FDA).
RIVAROXABAN
Rivaroxaban (Xarelto) is the first oral
direct coagulation factor Xa inhibitor
approved for clinical use in the United
States.
APIXABAN
Apixaban (Eliquis) is an oral direct
coagulation factor Xa inhibitor
approved for clinical use in the United
States..
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TABLE 5. Effects of the New Oral Anticoagulants on Routine and Special Coagulation Assay .
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Rivaroxaban in antiphospholipid syndrome (RAPS) protocol: a prospective,
randomized controlled phase II/III clinical trial of rivaroxaban versus
warfarin in patients with thrombotic antiphospholipid syndrome, with or
without SLE .
H .Cohen and CJ Dore´. Et al. Lupus (2015) 24, 1087–1094 .
Introduction: The current mainstay of the treatment of thrombotic antiphospholipid syndrome
(APS) is long-term anticoagulation with vitamin K antagonists (VKAs) such as warfarin.
Non-VKA oral anticoagulants (NOACs), which include rivaroxaban, have been shown to
be effective and safe compared with warfarin for the treatment of venous thromboembolism
(VTE) in major phase III prospective, randomized controlled trials (RCTs), but the results
may not be directly generalizable to patients with APS .
Prospective, randomized controlled trials (RCTs) support the current recommendation of
anticoagulation at a target international normalized ratio (INR) of 2.5 (range 2.0–3.0) for patients
with APS, with or without SLE, presenting with a first venous thromboembolism (VTE) event, or a
recurrent VTE event which occurred whilst off anticoagulation.7–10 However, warfarin, the most
widely used VKA in the United Kingdom (UK), has a slow onset of action (three to five days), a
narrow therapeutic window, numerous drug and dietary interactions, and potential for variation of
action with alcohol, intercurrent illness, exercise and smoking, and regular INR monitoring is
required. VKAs present particular problems in patients with APS.
First, VKA monitoring in patients with aPL can be complicated by the variable responsiveness of
thromboplastin reagents to lupus anticoagulant (LA), which may in turn potentially influence the
validity of the INR in patients with APS.
Secondly, LA detection in patients on warfarin may be problematic because of the prolonged basal
clotting time.11 This potentially limits the ability to diagnose APS in patients on VKAs and also to 47
monitor aPL status in those with an established diagnosis. The limitations of warfarin and other
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conventional anticoagulants have driven a search for new alternative anticoagulants.
Conclusion 1.
- Obstetricians and gynecologists have the means to prevent thrombosis
related pregnancy complications .with APS .
- Attaining the ability to identify patients at risk, determine who is a
candidate for thrombophilia screening, and thromboprophylaxis .
- In addition, it is fundamental to understand variousthromboprophylaxis
regimens and peripartum anticoagulant management.
- Other the optimal treatment of patients with antiphospholipid
antibodies and APS, especially the detailed and well standardized
recommendations precise intensity and duration of anticoagulation .
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CONCLUSION 2 .
The advent of NOAs represents a major development in the field of medicine. After more
than half a century in which warfarin was the only oral anticoagulant available, the
discovery of these agents has provided uswith more options. Several more oral
anticoagulants are in the development pipeline (Supplemental Table; available online
at http://www.mayoclinicproceedings.org), and their use will only increase in the years to
come. As we accumulate more experience with these agents, we will need to have a better
understanding of the appropriate selection of therapy in given clinical situations and the
management of their adverse effects, particularly bleeding complications.
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Conclusion 3.
- It is clear from the above discussion that the presence of aPLA has an adverse effect on
many systems of the body because of its thrombophilic effect.
- In pregnancy, apparent in the first trimester, presenting as recurrent pregnancy loss, or
may be associated with the later development of PET, IUGR, placental abruption, preterm
delivery, and intrauterine death. It seems that the presence of aPL may impair
trophoblastic invasion, thus interfering with implantation and subsequent placental
development.
- Role of an inflammatory process has been documented..
- Dramatic improvements in pregnancy outcome can be achieved by a combination of
heparin and aspirin.
- However, although the live birth rate is increased, it should be acknowledged that these
births are associated with an increased rate of prematurity and possible neonatal
complications. The increased incidence of pregnancyrelated complications necessitates
the need for careful antenatal surveillance, and for delivery to be conducted in a unit with
facilities for operative interventions and neonatal intensive care. For the women
themselves, the significance of aPLA outside pregnancy is far from clear, and the ideal
management for optimising long-term health still remains a dilemma..
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Future perspective
The future management of catastrophic APS is based on two points:
- to improve the knowledge of pathologic processes leading to multiple
thrombosis in patients carriers of aPL,
- also to improve the knowledge of intracellular mechanisms of aPL-mediated
thrombosis.
Better understanding of how aPL promotes thrombosis will help us to design
more specifically targeted antithrombotic or immunomodulatory therapies.
Regarding the second point, some of these new proposed potential therapies are
statins (fluvastatin diminished thrombus size in aPLtreated mice and was able to
reverse the expression of inflammatory proteins in a pilot proteomics analysis of
APS patients , rituximab (effective for treating thrombocytopenia, hemolytic
anemia, and recurrent thrombosis in aPL-positive patients , antagonists of IIb/IIIa
platelet membrane glycoproteins, p38 mitogen-activated protein kinase
inhibitors, and anticytokine agents. However, no human data are available yet to
support these three last therapeutic modalities.
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