Pp. Penatalaksanaan Aps.o.k.ok ..

ANTIPHOSPHOLIPID
SYNDROME ( APS ) , MANAGEMENT
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
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 .
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.
Antiphospholipid antibody syndrome (APAS)

VN Mishra*, Nalini Mishra**, Devanshi***. JIACM 2012; 13(4): 303-10

3
APL syndrome (APS) designates the presence:
- APL antibodies : Lupus anticoagulants (LA) , Anticardiolipin antibodies(ACA)
, and Beta2 glycoprotein- 1 (β2GP-1) and prothrombin. β2GP-1
- Thrombotic manifestations
- and/or recurrent fetal loss and/or thrombocytopenia (Fig. )..

University Hospital,, Staten Island, , USA . 4
APS could be classified into two main classes:
Primary : APS . in the absence of any other autoimmune disorder, such as SLE .
Secondary : When APS is seen in conjunction with other autoimmune diseases :
- systemic lupus erythematosus (SLE).

- In rare cases, APS leads to rapid organ failure due to generalised
thrombosis and a high risk of death; this is termed as Catastrophic
antiphospholipid syndrome (CAPS).
- These include:
- Infections - Syphilis, HIV infection, hepatitis C and malaria .
- Medications - Consumption of certain drugs, such as hydralazine,
quinidine, phenytoin, and antibiotics such as amoxicillin .
- Genetic predispositions
5
Clinical features .
I. Vascular thrombosis
These include:
1. Cerebrovascular manifestations: Arterial thrombosis involves the brain up to 35%
cases.
2. Cardiac manifestations: Valvular heart disease (most commonly mitral
regurgitation) affects 10 - 35% of the patients. CAD is an important life-threatening
manifestation, up to 15% of young myocardial infarction cases may be due to APS
3. Pulmonary embolism .
4. Renal manifestations: Renal vein and/or artery thrombosis .
5. Peripheral vascular disease: Vein thrombosis (VT) is the most common
affection in venous circulation; recurrent superficial thrombosis is also seen.
Venous thrombosis particularly of the lower limbs occurs in up to 50% .
6
Antiphospholipid Syndrome: Needed. U.I. and Shiksha K. ET et al. . Staten Island, NY 10305, USA. 2017
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.
7
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 ).
V .Catastrophic antiphospholipid syndrome (CAPS)

- Acute and complex biological process with multiorgan venous or arterial thrombosis
with rapid onset and high mortality.
- The dramatic nature of the clinical presentation. involves at least three
different organ
- Histopathological evidence of multiple occlusions of large or small vessels.
- The kidney is the most commonly affected organ (78%) , lungs (66%), central
nervous system (56%), heart (50%), and skin (50%). - DIC , occurs in
approximately 25% of patients .
8
Table . Clinical manifestations of Antiphospholipid Syndrome.


University Hospital,, Staten Island, , USA . 9
Hirsh et al., Blood, 1 May 2002
Thrombosis is the basic pathologic process in the APL syndrome, the spectrum of
clinical findings is extremely wide (Fig. ).
FIG. Schematic representation of the clinical manifestations in antiphospholipid antibody syndrome .

10
Mosby items and derived items © 2006 by Mosby, Inc. Antiphospholipid Syndrome: U. Ibrahim and Shiksha K.. Dep.Hematology/Oncology, Island
Management :
I. Management of thrombosis
- Acute management of arterial or venous thrombosis is the same as with other.
- Heparin dose of 1,000 units/hour. Prophylactic treatment should be long term after
venous thrombosis since to recurrent thrombosis;
-Warfarin with an INR of 2.0- 3.0 reduces the risk of recurrent VT by 80% to 90% .
- Most physicians now use LMWH .as effective as, and less dangerous than (UFH).
- Enoxaparin is prophylactic. twice daily at doses of 0.5 mg/kg body weight
and therapeutic dose. 1.0 mg/kg body weight..
- In patients of SLE because lupus anticoagulant causes a prolonged this APTT
cannot be used; instead, the heparin dose can be monitored by measurement of the
activity of antifactor Xa.
- If lupus anticoagulant is not present and the baseline clotting time is normal, the
APTT , 2 to3 times that of normal at peak and at least 1.5 times that of normal
immediately before the next dose.

11
Hirsh et al., Blood, 1 May 2002
VENOUS THROMBOEMBOLISM.
Virchow's Triad :
 Vessel damage (Vessel wall)
 Stasis (Blood flow)
 Activation of coagulation
(Blood constituents) (Haemorheology)
Dr.Robert Virchow
(Q J Med, 95 : 199-210,
2002)
12
* CLINICAL MODEL FOR PREDICTING PRETEST PROBABILITY FOR DVT:
(WELLS CRITERIA ):
ITEM. SCORE
-------------------------------------------------------------------------------------------------------------------
-Active cancer (treatment ongoing or within previous 6 mo or palliative) 1

-Paralysis, paresis or recent plaster immobilization of the lower extremities 1
-Recently bedridden > 3 d or major surgery within 4 wk 1
-Localized tenderness along the distribution of the deep venous system 1
-Entire leg swollen 1
-Calf swelling 3 cm > asymptomatic side (measured 10 cm below
tibial tuberosity) 1
- Pitting edema confined to the symptomatic leg 1
-Collateral superficial veins (nonvaricose) 1
-Alternative diagnosis as likely or greater than that of DVT -2
--------------------------------------------------------------------------------------------------------
* In patients with symptoms in both legs, the more symptomatic leg is used.
Pretest probability calculated as the total score: high 3; moderate 1 or 2; low 0. 13
Mosby items and derived items © 2006 by Mosby, Inc. Hirsh et al., Blood, 1 May 2002
Treatment of DVT
 Not Pregnant
 Low Molecular Weight Heparin (LMWH)
 1 mg/kg q 12 hrs or 1.5 mg/kg q 24 hrs
 Coumadin x 3 months (Goal INR 2-3)
 LMWH should be overlapped until both of the following
conditions are met:
 INR >2 x days
 At least five days of LMWH given
 Pressure stockings
Westly Bailey, 2009
14
 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.
15
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.
16
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.
17
18
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 .
19
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.
20
(Kendall TED, 2005)
21
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
 Evaldas Giedrimas, MD ,Duane Pinto, MD
22
Tabel . Dosis pemberian heparin . (Bates SM and Jaeschke R. Et al. 2012.)
23
Tabel . Regimen LMWH dalam penatalaksanaan DVT.
(Bates SM and Jaeschke R. Et al. 2012.)
24
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.

* Management of pregnancy in patients with APS
1. Anticoagulation .
Combined heparin and low-dose aspirin :
Reduce the risk of spontaneous pregnancy loss by 54%, resulting in a live birth
rate of 70 - 80% .
The Evidence-Based Clin.Prac.Guidelines of Am.Coll.of Chest Physicians,

Women with APL antibodies , with 2 or more early pregnancy losses or 1 or
more late pregnancy losses, no prior historyof thrombosis.
Teatment with :
- Combination aspirin and heparin (UFH/ LMWH ) during pregnancy:
- Aspirin (81 mg/d) started with attempted conception; or recommend,
preconceptional because possible beneficial on early stages.
- Heparin (5000-10 000 units / 12 h.) or lLMWH , (Enoxaparin 40 mg SC/
24 h) be started when a viable intrauterine until late in the third trimester.
26
* Patients with a history of thrombosis should be fully anticoagulated with an
adjusted-dose UFH or LMWH regimen (UFH SC every 12 h or Enoxaparin
1 mg/kg SC every 12 h) for at least 6 months of VTE. .
* Women with warfarin should discontinue before 6 weeks of gestation
Some clinicians discontinuing the warfarin on initiates attempting to conceive,
replacing it with UFH or LMWH.
- Following delivery, the UFH or LMWH be restarted and bridged to warfarin..
- Recommendations for thromboprophylaxis .
- with prophylactic LMWH or UFH, or by mechanical prophylaxis with lower
extremity compression devices while hospitalized.
- Patients suspect spontaneous labor, heparin should be discontinued.
- For induction or scheduled cesarean, adjusted- dose heparin and intermediate-dose
LMWH should be discontinued 24 hours before the scheduled admission.
27
Antiphospholipid Syndrome during pregnancy: The state of the art .

- For prophylactic LMWH, regional anesthesia can be placed 10 to 12 hours’
duration from the last dose of LMWH heparin. The neuraxial catheter should be
removed 2 hours before the first LMWH dose.
- Vitamin K antagonists are teratogenic and should be avoided between 6 and 12
weeks’ of gestation.
* Probably there is a relationship of aPL to infertility but it has been controversial
until now. Although prevalence of aPL antibodies is increased in patients
undergoing in vitro fertilization (IVF), a recent prospective study found that
aspirin and heparin treatment of IVF patients with positive aPL antibodies and
history of failed IVF cycles does not improve IVF cycle outcome .
28
- Future therapies: Clopidogrel, rivaroxaban, statins, rituximab, and other new
anticoagulant drugs, are for non-pregnant patients.

- The new drugs for APS that pregnant women can use pyridamole and
hydroxychloroquine.
- Combination Aspirin plus dipyridamole have higher efficacy than aspirin alone.
- Hydroxychloroquine have antithrombotic effect of in patients aPL , mostly SLE.
- Hydroxychloroquine directly inhibits the binding of antiphospholipid antibody-β2-
glycoprotein-1 complexes to phospholipid surfaces.
- An additional and previously thatt hydroxychloroquine in prevention of pregnancy
loss is suggested by the description of its protective effect of the annexin A5
- Hydroxychloroquine should be considered for an adjuvant antithrombotic role in
Antiphospholipid Syndrome during pregnancy: The state of the art .
Fosca A. F. D P. and Oriana. Et al. Dep. of Obstetrics and Gynecology, University of Palermo, Italy . Journal of Prenatal Medicine 2011; 5 (2): 41-53
patients with SLE
29
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
30
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
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 .
32
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

IV.Treatment of Catastrophic Antiphospholipid Syndrome
(CAPS ) .
* CAPS is an acute and complex biological process that presents with multiorgan
venous or arterial thrombosis with rapid onset and high mortality.
- Clinical presentation. usually involves at least three different organ systems
- APS to rapid development of multi-organ failure because multiple vascular occlusions.
- Treatment with anithrombin III prevents the continuation of unchecked coagulation.
- Another possible therapy is the use of tissue plasminogen activator (t-PA). Pentoxifylline is
useful in improving erythrocyte flexibility and increases blood flow by decreasing blood
viscosity.
- One of the most successful approaches is the use of plasmapheresis.
- Other aggressive supportive therapies, immunoglobulin, haemodialysis, inotropic support,
intubation, and mechanical ventilation . The mortality rate is 50%; death is usually due to
multi-organ failure .
-The current treatment of catastrophic APS is based on this empirical pathogenic basis.
- first-line therapies , combination of anticoagulation against thrombosis plus glucocorticoids
against manifestations of SIRS plus plasma exchange and/or was related to a lower rate of
recovery (18.2 vs 58.1% of episodes not treated with glucocorticoids; p = 0.01); more
interestingly, the mortality rate decreased from 53% in the patients diagnosed before 2000 to
33.3% in those diagnosed from 2001 to February 2005 (p = 0.005; odds ratio [OR]: 2.25; 95%
CI: 1.27–3.99) 34
(CAPS) : variant of antiphospholipid syndrome (APS) the most severe form.
Characteristics:
- 1% of patients with APS .
- multiple organ involvement on very short period of time (< a week) histopathological
- small vessel occlusions
- laboratory antiphospholipid antibodies (aPL) . Described by Ronald A Asherson in
1992 ( Asherson’s syndrome).
- High mortality > 30% in the acute event.
- The majority of patients with multiorgan failure.
- From a histopathological a thrombotic microangiopathic condition.
- Recurrent thromboses of medium/large vessels /occlusions of small vessels
- Two possible explanations include: extensive thromboses , responsible by generating
thrombin, and Depressing fibrinolysis and consuming the natural anticoagulant proteins;
- Manifestations of the systemic inflammatory response syndrome ( SIRS ) , due to
excessive cytokine release from ischemic and necrotic tissues.
Current management of catastrophic antiphospholipid syndrome .

Gerard E. & Ricard C. Int. J. Clin. Rheumatol. (2011) 6(3), 297–303
Diagnosing catastrophic antiphospholipid syndrome (CAPS): Also known as Ashersons syndrome .
Ricard Cervera and Gerard Espinosa. Int. J. Clin. Rheumatol. (2014) 9(1), 1–3 .
35 35
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.
36
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%).

Gerard E. & Ricard C. Int. J. Clin. Rheumatol. (2011) 6(3), 297–303
37
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 .) .
Figure . Treatment of catastrophic antiphospholipid syndrome focused on their

pathogenic mechanisms.
38
Mosby items and derived items © 2006 by Mosby, Inc. Gerard E. & Ricard C. Int. J. Clin. Rheumatol. (2011) 6(3), 297–303
Management of , CatastrophicAPS (CAPS) .
Until now, there is an absence of prospective and randomized therapeutic studies in CAPS .
In fact, the evidence-based information about the current treatment of patients with CAPS
comes from three retrospective studies. From the information extracted from the first two
studies an International consensus on guidelines for the management of catastrophic APS was
proposed .
Glucocorticoids
- Glucocorticoids used in 79% of episodes of catastrophic APS ,IV pulses of 500–
1000 mg/day
for 1–3 days ( 34%) and as oral or intravenous dosages of 1–2 mg/kg/day ( 34% ) .
- The rationale for the use of based on their anti-inflammatory properties inhibiting
the theoretical excessive cytokine response related to SIRS via reduction of the
transcription of pro-inf lammatory genes by inhibiting the NF-kB..
In fact, NF-kB is recognized as the principal driver of the inflammatory response
and is responsible for the transcription of more than 100 genes, including TNF-a, IL-
1b, and IL-6 .Early use of glucocorticoids daily intravenous pulses of
methylprednisolone for 3 or 5 days are advised, followed by prednisone at doses of
1 mg/kg/day. The best practice for tapering
possibly, a dose of 7.5–10 mg/day of prednisone at 6 months after acute episode of
CAPS .
39
Plasma exchange
- Therapeutic plasma exchange was used as treatment CAPS .
- The usefulness of plasma exchange is based on the removal of pathological aPL and
mediators of SIRS development such as: Cytokines, TNF-a and complement activation
products .
- The recommendation is to start plasma exchange as soon as possible. In fact, the recently
published guidelines on the use of therapeutic apheresis .
- in clinical practice evidence-based approach from the American Society for Apheresis
suggests plasma exchange as a treatment of catastrophic APS with a category II (that is,
as disorder for which apheresis is accepted as second-line therapy, either as a standalone
treatment or in conjunction with other modes of treatment) .
* Which is the best replacement fluid for plasma exchange? Based on CAPS registry data,
the majority of the studies that specified the type of replacement fluid used fresh frozen
plasma (FFP), while few studies used albumin solution . In fact, the 2003 international
consensus statement on catastrophic APS and the American Society for Apheresis 2010
guidelines recommended FFP as a replacement fluid for plasma exchange in patients
with catastrophic APS.
However, these indications were designed taking into account the microangiopathic
involvement overlapping with other microangiopathic conditions such as thrombotic
thrombocytopenic purpura (TTP).
In fact, plasma exchange with FFP as replacement fluid is indicated for all patients with
suspected TTP, and is the most important component of treatment.
Current management of catastrophic antiphospholipid syndrome . 40
Intravenous immunoglobulins
Iv. Immunoglobulins were used in 21% of episodes of catastrophic APS.
They have pleiotropic and beneficial effects such as:
- the blockade of autoantibodies,
- the increased clearance of pathologic IgG and
- the modulation of complement.
Additionally, they protect against autoantibody-mediated pathology by
upregulating an inhibitory Fcg receptor on macrophages and suppress pathogenic
cytokines .
* In our therapeutic protocol, plasma exchange are started as early as possible and
performed every other day with a minimum of six sessions.
The day after each plasma exchange session, we administer IVIG (200 mg/kg/day)
in order to prevent the removal of IVIG by plasma exchange.
Identification & treatment of precipitating factors .
The most frequent precipitating factor in patients with catastrophic APS is infection, present
in 22% [25]. Therefore, the recommendation in patients with a suspected episode of
catastrophic APS is to look for the existence of a septic process and use antibiotic therapy if
appropriate. However, the diagnosis of infection may be difficult. Frequently, fever and acute
phase reactants, such erythrocyte sedimentation rate or leukocytosis, may be present in both
catastrophic .APS and infection.. The etiology of infection may be diverse and includes viral
41
infections of upper respiratory
tract, bacterial infections such as typhoid fever, urinary
infections, malaria, dengue and sepsis .
Cyclophosphamide
Cyclophosphamide was used in 31% of episodes (30.9%) and was given as an
intravenous pulse in 40 episodes (53.3%) and as an oral dose (50–100 mg/day)
in ten (13.3%). Route of administration was not specified in the remaining 25
episodes. There was no statistically significant difference between patients who
died and those
who survived with regard to the administration of cyclophosphamide, either in
its dosages or routes of administration. Moreover, the addition of
cyclophosphamide to the combined treatment showed no benefit .
42
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.
Hydroxychloroquine protects the annexinA5.

Jacob H.R and Xiao-Xuan Wu. Etal. (Blood. 2010; 115:2292-2299) . 43
The New Oral Anticoagulants in Clinical Practice
Wilson I. And . Gonsalves . Et al. Mayo Clin Proc. n May 2013;88(5):495-511
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..
44
45
TABLE 5. Effects of the New Oral Anticoagulants on Routine and Special Coagulation Assay .
46
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
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 .
48
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.
49
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..
50
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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