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{{Antiphospholipid syndrome}}
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==Overview==
==Overview==
The cornerstone of therapy for symptomatic antiphospholipid syndrome hinges on platelet inhibition with or without [[anticoagulation]]. Platelet inhibition is often achieved with [[aspirin]], while [[warfarin]] and [[heparin]] are the mainstays of anticoagulation. Generally there is no indication for primary prophylaxis. Immunosuppression, the use of [[intravenous immunoglobulin]], and [[plasmapheresis]] have also been used with modest success.
The mainstay of treatment in antiphospholipid syndrome(APS) is anticoagulation. Platelet inhibition is often achieved with [[aspirin]], while [[warfarin]] and [[heparin]] are the preferred drugs for anticoagulation. Typically, there is no indication for primary [[prophylaxis]]. [[Immunosuppression]], the use of [[intravenous immunoglobulin]], and [[plasmapheresis]] have also been used with modest success in patients with catastrophic antiphospholipid syndrome (APS).
 
==Medical Therapy==
==Medical Therapy==
===Anticoagulation===
===General principles and choice of anticoagulation===
When anticoagulation with warfarin is pursued, some authors recommend a goal INR of 3.0-4.0.<ref>{{cite journal |author=Horton JD, Bushwick BM |title=Warfarin therapy: evolving strategies in anticoagulation |journal=American family physician |volume=59 |issue=3 |pages=635-646 |year=1999 |pmid=10029789 |doi=}}</ref> However, the current standard of care targets a therapeutic INR of 2.0-3.0 following initial venous thromboembolism, and an INR >3.0 for an arterial event or venous thrombosis refractory to anticoagulation.<ref name="pmid18050167">{{cite journal |author=Ruiz-Irastorza G, Hunt BJ, Khamashta MA |title=A systematic review of secondary thromboprophylaxis in patients with antiphospholipid antibodies |journal=Arthritis and Rheumatism |volume=57 |issue=8 |pages=1487–95 |year=2007 |month=December |pmid=18050167 |doi=10.1002/art.23109 |url=http://dx.doi.org/10.1002/art.23109}}</ref> Khamashta et al in a study of 147 patients with usual antiphopholipid antibody syndrome showed a low rate of recurrent thrombosis in patients with INR >3, with a risk of 7.1% bleeding complications per patient year (a third of which were serious).
The mainstay of treatment in antiphospholipid syndrome(APS) is [[Anticoagulant|anticoagulation]]. The choice of anticoagulant is [[heparin]], which is given in overlap with [[warfarin]]. In cases where warfarin is contraindicated such as pregnancy, [[low molecular weight heparin]] ([[Low molecular weight heparin|LMWH]]) is used.<ref name="pmid27421221">{{cite journal| author=Khamashta M, Taraborelli M, Sciascia S, Tincani A| title=Antiphospholipid syndrome. | journal=Best Pract Res Clin Rheumatol | year= 2016 | volume= 30 | issue= 1 | pages= 133-48 | pmid=27421221 | doi=10.1016/j.berh.2016.04.002 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27421221  }} </ref><ref name="pmid28262233">{{cite journal| author=Cervera R| title=Antiphospholipid syndrome. | journal=Thromb Res | year= 2017 | volume= 151 Suppl 1 | issue=  | pages= S43-S47 | pmid=28262233 | doi=10.1016/S0049-3848(17)30066-X | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28262233  }} </ref><ref name="pmid24449256">{{cite journal| author=Nalli C, Andreoli L, Casu C, Tincani A| title=Management of recurrent thrombosis in antiphospholipid syndrome. | journal=Curr Rheumatol Rep | year= 2014 | volume= 16 | issue= 3 | pages= 405 | pmid=24449256 | doi=10.1007/s11926-013-0405-4 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24449256  }} </ref><ref name="pmid19559568">{{cite journal| author=Tuthill JI, Khamashta MA| title=Management of antiphospholipid syndrome. | journal=J Autoimmun | year= 2009 | volume= 33 | issue= 2 | pages= 92-8 | pmid=19559568 | doi=10.1016/j.jaut.2009.05.002 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19559568  }} </ref><ref name="LimCrowther2006">{{cite journal|last1=Lim|first1=Wendy|last2=Crowther|first2=Mark A.|last3=Eikelboom|first3=John W.|title=Management of Antiphospholipid Antibody Syndrome|journal=JAMA|volume=295|issue=9|year=2006|pages=1050|issn=0098-7484|doi=10.1001/jama.295.9.1050}}</ref>
 
{| class="wikitable"
! colspan="2" |Treatment regimens for different patient groups
|-
|'''Patient population'''
|'''Treatment regimen'''
|-
|Asymptomatic antiphospholipid antibody positive
|
* '''Low risk:''' Life-style changes
 
* '''High risk:''' Life-style changes plus consider [[aspirin]] 75mg daily
|-
|Secondary thrombosis prevention
|
* '''Venous event:''' Lifelong [[warfarin]] (INR range 2-3)
 
* '''Arterial event:''' Lifelong [[clopidogrel]] or warfarin (INR range 2-3)
|-
|Pregnant patients or patients who are considering becoming pregnant
|'''Clinical criteria obstetric:''' Consider [[aspirin]] 75mg daily, plus prophylactic unfractionated heparin/low molecular weight heparin
|}
 
===1.Treatment of acute thromosis in APS===
*The choice of treatment for acute thrombosis in APS is [[low molecular weight heparin]] (LMWH).
*It is overlapped with warfarin for a minimum of 4-5 days.
*It is continued as long as the International normalized ratio ([[INR]]) is in the therapeutic range that is 2-3.<ref name="pmid7885428">{{cite journal| author=Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ, Hughes GR| title=The management of thrombosis in the antiphospholipid-antibody syndrome. | journal=N Engl J Med | year= 1995 | volume= 332 | issue= 15 | pages= 993-7 | pmid=7885428 | doi=10.1056/NEJM199504133321504 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7885428  }} </ref>
 
===2.Anticoagulation in pregnancy===
The goals of treatment in pregnant women with antiphospholipid syndrome are as follows:
*Improvement of maternal and fetal-neonatal outcomes by managing the risk factors leading to complications.<ref name="pmid19284363">{{cite journal| author=Espinosa G, Cervera R| title=Thromboprophylaxis and obstetric management of the antiphospholipid syndrome. | journal=Expert Opin Pharmacother | year= 2009 | volume= 10 | issue= 4 | pages= 601-14 | pmid=19284363 | doi=10.1517/14656560902772302  | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19284363  }} </ref>
 
*During pregnancy, [[low molecular weight heparin]] and low-dose [[aspirin]] are used to avoid warfarin's teratogenicity.<ref name="pmid19954317">{{cite journal| author=Puente D, Pombo G, Forastiero R| title=Current management of antiphospholipid syndrome-related thrombosis. | journal=Expert Rev Cardiovasc Ther | year= 2009 | volume= 7 | issue= 12 | pages= 1551-8 | pmid=19954317 | doi=10.1586/erc.09.112 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19954317  }} </ref>
*The therapy is initiated at the beginning of pregnancy and continued until the time of delivery.
*Women with recurrent miscarriages are often advised to take low dose [[aspirin]] and to start low molecular weight [[heparin]] treatment after missing a menstrual cycle.
*For women with previous history of clots, higher dose of low molecular weight heparin is used.
====Treatment of refractory cases in pregnancy====
*Intravenous immunoglobulin(IgG) and [[Corticosteroid|corticosteroids]] are used for patients with refractory cases in pregnancy.
 
=== 3.Limited role of alternative therapies: ===
Following alternative therapies can be used for the treatment of APS:
 
==== Direct oral anticoagulants: ====
The rationale behind using direct oral anticoagulants such as [[dabigatran]], [[apixaban]] or [[rivaroxaban]] is as follows:
* They dont require laboratory monitoring of PT/aPTT.
* They have lower risk of bleeding.
* They are useful for patients who cannot tolerate [[warfarin]].
 
====Immunomodulatory agents:====
Immunomodulatory agents are proposed for the use of antiphospholipid syndrome as it is an autoimmune disease. The following drugs are preferred:
* [[Rituximab]]
* [[Hydroxychloroquine]]
 
===4.Treatment of catastrophic antiphospholipid syndrome:===
A small subset of patients develop catastrophic disease which is managed as follows:


====Anticoagulation in pregnancy====
=== Pearls of management: ===
{{main|Anticoagulation in pregnancy}}
Early diagnosis and timely management with addressing the [[Thrombotic lesion|thrombotic]] events and suppressing the [[cytokine]] cascade is essential for the treatment.


During pregnancy, [[low molecular weight heparin]] and low-dose [[aspirin]] are used to avoid warfarin's teratogenicity. Women with recurrent miscarriage are often advised to take aspirin and to start low molecular weight heparin treatment after missing a menstrual cycle.
=== Approach to treatment: ===
The steps of managing [[Catastrophic antiphospholipid syndrome|catastrophic]] APS are as follows:


===Platelet inhibition===
==== (a)Antibiotics: ====
Aspirin is frequently added to a regimen of chronic anticoagulation, particularly when patients experience recurrent thrombosis despite therapeutic aticoagulation. However data demonstrating additive benefit are lacking.
* Identify the underlying infection and administer appropriate antibiotics accordingly.


===Immunosuppression===
==== (b)Anticoagulation: ====
It is not clear that immunosuppression is beneficial, particularly in patients who do not have an underlying autoimmune process. Nevertheless, immunosuppression is often tried in patients who have failed usual anticoagulation. Steroids, for example [[prednisone]] 1 mg/kg (or equivalent), has been used with moderate success. Pulse solumedrol IV 1 g/d for 3 days is an alternative regimen. [[Cyclophosphamide]], either oral or pulse IV, has demonstrated modest utility.
* Anticoagulate with [[heparin]] in the acute setting.
* In hemodynamically stable patients and no evidence of bleeding, oral [[anticoagulant]] such as [[warfarin]] can be used.


Other, more desperate interventions include [[intravenous immunoglobulin]] and [[plasmapheresis]]. The latter has been shown via case reports to have efficacy in patients who have failed other interventions.
==== (c)Systemic glucocorticoids: ====
* Preferred regimen (1): [[Methylprednisolon]] 0.5-1g IV q12h for 3 days
This is followed by oral therapy with 1mg/kg of [[prednisone]] per day.


===Treatment of catastrophic disease===
==== (d)Plasma exchange or IVIG: ====
Optimal treatment has not been clearly defined in this condition.  We are limited to data from small case report studies. These patients often display a fulminant course with rapid multiorgan system failure, so multiple interventions are often desperately tried in hopes that the patient might respond to something and survive.
* Plasma exchange or [[Intravenous immunoglobulin|IVIG]] is used to remove antibodies from the plasma.
* Preferred regimen (1): [[IVIG]] 400 mg/kg per day for 5 days.


==References==
==References==

Latest revision as of 20:33, 24 April 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Feham Tariq, MD [2]

Overview

The mainstay of treatment in antiphospholipid syndrome(APS) is anticoagulation. Platelet inhibition is often achieved with aspirin, while warfarin and heparin are the preferred drugs for anticoagulation. Typically, there is no indication for primary prophylaxis. Immunosuppression, the use of intravenous immunoglobulin, and plasmapheresis have also been used with modest success in patients with catastrophic antiphospholipid syndrome (APS).

Medical Therapy

General principles and choice of anticoagulation

The mainstay of treatment in antiphospholipid syndrome(APS) is anticoagulation. The choice of anticoagulant is heparin, which is given in overlap with warfarin. In cases where warfarin is contraindicated such as pregnancy, low molecular weight heparin (LMWH) is used.[1][2][3][4][5]

Treatment regimens for different patient groups
Patient population Treatment regimen
Asymptomatic antiphospholipid antibody positive
  • Low risk: Life-style changes
  • High risk: Life-style changes plus consider aspirin 75mg daily
Secondary thrombosis prevention
  • Venous event: Lifelong warfarin (INR range 2-3)
  • Arterial event: Lifelong clopidogrel or warfarin (INR range 2-3)
Pregnant patients or patients who are considering becoming pregnant Clinical criteria obstetric: Consider aspirin 75mg daily, plus prophylactic unfractionated heparin/low molecular weight heparin

1.Treatment of acute thromosis in APS

  • The choice of treatment for acute thrombosis in APS is low molecular weight heparin (LMWH).
  • It is overlapped with warfarin for a minimum of 4-5 days.
  • It is continued as long as the International normalized ratio (INR) is in the therapeutic range that is 2-3.[6]

2.Anticoagulation in pregnancy

The goals of treatment in pregnant women with antiphospholipid syndrome are as follows:

  • Improvement of maternal and fetal-neonatal outcomes by managing the risk factors leading to complications.[7]
  • During pregnancy, low molecular weight heparin and low-dose aspirin are used to avoid warfarin's teratogenicity.[8]
  • The therapy is initiated at the beginning of pregnancy and continued until the time of delivery.
  • Women with recurrent miscarriages are often advised to take low dose aspirin and to start low molecular weight heparin treatment after missing a menstrual cycle.
  • For women with previous history of clots, higher dose of low molecular weight heparin is used.

Treatment of refractory cases in pregnancy

  • Intravenous immunoglobulin(IgG) and corticosteroids are used for patients with refractory cases in pregnancy.

3.Limited role of alternative therapies:

Following alternative therapies can be used for the treatment of APS:

Direct oral anticoagulants:

The rationale behind using direct oral anticoagulants such as dabigatran, apixaban or rivaroxaban is as follows:

  • They dont require laboratory monitoring of PT/aPTT.
  • They have lower risk of bleeding.
  • They are useful for patients who cannot tolerate warfarin.

Immunomodulatory agents:

Immunomodulatory agents are proposed for the use of antiphospholipid syndrome as it is an autoimmune disease. The following drugs are preferred:

4.Treatment of catastrophic antiphospholipid syndrome:

A small subset of patients develop catastrophic disease which is managed as follows:

Pearls of management:

Early diagnosis and timely management with addressing the thrombotic events and suppressing the cytokine cascade is essential for the treatment.

Approach to treatment:

The steps of managing catastrophic APS are as follows:

(a)Antibiotics:

  • Identify the underlying infection and administer appropriate antibiotics accordingly.

(b)Anticoagulation:

  • Anticoagulate with heparin in the acute setting.
  • In hemodynamically stable patients and no evidence of bleeding, oral anticoagulant such as warfarin can be used.

(c)Systemic glucocorticoids:

This is followed by oral therapy with 1mg/kg of prednisone per day.

(d)Plasma exchange or IVIG:

  • Plasma exchange or IVIG is used to remove antibodies from the plasma.
  • Preferred regimen (1): IVIG 400 mg/kg per day for 5 days.

References

  1. ↑ Khamashta M, Taraborelli M, Sciascia S, Tincani A (2016). "Antiphospholipid syndrome". Best Pract Res Clin Rheumatol. 30 (1): 133–48. doi:10.1016/j.berh.2016.04.002. PMID 27421221.
  2. ↑ Cervera R (2017). "Antiphospholipid syndrome". Thromb Res. 151 Suppl 1: S43–S47. doi:10.1016/S0049-3848(17)30066-X. PMID 28262233.
  3. ↑ Nalli C, Andreoli L, Casu C, Tincani A (2014). "Management of recurrent thrombosis in antiphospholipid syndrome". Curr Rheumatol Rep. 16 (3): 405. doi:10.1007/s11926-013-0405-4. PMID 24449256.
  4. ↑ Tuthill JI, Khamashta MA (2009). "Management of antiphospholipid syndrome". J Autoimmun. 33 (2): 92–8. doi:10.1016/j.jaut.2009.05.002. PMID 19559568.
  5. ↑ Lim, Wendy; Crowther, Mark A.; Eikelboom, John W. (2006). "Management of Antiphospholipid Antibody Syndrome". JAMA. 295 (9): 1050. doi:10.1001/jama.295.9.1050. ISSN 0098-7484.
  6. ↑ Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ, Hughes GR (1995). "The management of thrombosis in the antiphospholipid-antibody syndrome". N Engl J Med. 332 (15): 993–7. doi:10.1056/NEJM199504133321504. PMID 7885428.
  7. ↑ Espinosa G, Cervera R (2009). "Thromboprophylaxis and obstetric management of the antiphospholipid syndrome". Expert Opin Pharmacother. 10 (4): 601–14. doi:10.1517/14656560902772302. PMID 19284363.
  8. ↑ Puente D, Pombo G, Forastiero R (2009). "Current management of antiphospholipid syndrome-related thrombosis". Expert Rev Cardiovasc Ther. 7 (12): 1551–8. doi:10.1586/erc.09.112. PMID 19954317.

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