Catastrophic

Antiphospholipid Syndrome
Antiphospholipid Antibodies

Ruiz-Irastorza et al. Lancet.

2010 Oct 30;376(9751):1498-
509.
Primary vs. Secondary
• Cervera et al. Ann Rheum Dis. 2015 Jun;74(6):1011-8.
• 10 year prospective multicentre study in Europe w/ 1000 patients

• Primary
• 53.1% of all patients

• Secondary: concomitant systemic autoimmune disease

• Most commonly SLE: 36.2% of all patients
Presentation
• Arterial + venous thrombosis
• Pregnancy-related complications

• Multiple other clinical manifestations:

• Hematological: hemolytic anemia, thrombocytopenia, TMAs
• Neurological: cognitive deficits, white matter lesions
• Cardiac: valvular heart disease
• Cutaneous: livedo reticularis
• Etc.
Diagnosis
• Sapporo Criteria (1999) -> Revised Sapporo/Sydney Criteria (2006)

Lim W. Hematology Am Soc Hematol Educ Program. 2013;2013:675-80.

Issues with Diagnosis
• Lupus anticoagulant testing affected by anticoagulation.

• Antiphospholipid antibodies fluctuate with clinical status.

• Lupus anticoagulant is a stronger risk factor. Anti-cardiolipin not

shown to be consistently associated with thrombosis in
prospective/retrospective studies.

• Patients with “non-criteria” manifestations. Patients with low titres.

Management
• Briefly summarized from EULAR recommendations:
• ASA 1o ppx:
• Asymptomatic, high risk antiphospholipid Ab profile
• Can consider if SLE, asymptomatic, low risk profile (isolated low-med +ve anti-cardiolipin or anti-beta 2
glycoprotein)
• Non-pregnant women with hx obstetric APS
• VKA 2o ppx:
• Definite APS, 1st venous thrombosis
• If provoked, tx for standard duration, assess for longer duration depending on RFs
• Can consider adding ASA or increasing INR target if recurrent thrombosis. Can consider
switching to LMWH if recurrent arterial thrombosis.
• Obstetric APS:
• Consider ASA during pregnancy if asymptomatic w/ high risk profile
• ASA + ppx heparin during pregnancy recommended. Can consider if clinical “non-criteria.”
DOACs in APS
• TRAPS 2018:
• Open label, non-inferiority RCT, n=120
• Rivaroxaban (n=59) vs. warfarin in triple +ve APS
• Thrombosis/major bleed/vascular deaths: 11 (rivaroxaban) vs. 2 (warfarin)
• Stopped prematurely
• ISTH recommendations:
• DOACs can be considered in discussion w/ pt for single/double +ve APS
• already on DOAC x several months w/ good adherence for VTE or
• intolerant to VKA.
• EULAR recommendations:
• DOACs can be considered in pts unable to achieve target INR despite
adherence or if VKA contraindicated.
• No rivaroxaban for triple +ve APS.
Hydroxychloroquine in APS
• Wang et al. Hematology Am Soc Hematol Educ Program. 2016 Dec
2;2016(1):714-716.
• 11 studies: 4 prospective, 6 retrospective, 1 meta-analysis. No RCTs.
• 9 assessed 1o prevention in pts w/ SLE. 5/9 showed significant
reduction in thrombosis.
• 2 remaining studies:
• Small sample size, retrospective design, unbalanced characteristics, combined
analysis of ASA w/ HCQ
• Prospective non-randomized trial: n = 40, 30% recurrent thrombosis w/
standard anticoagulation, 0% w/ anticoagulation + HCQ
• Ultimately recommended HCQ for 1o ppx in secondary APS w/ SLE
only
Catastrophic APS
• Triggers

• Presentation
• CNS involvement

• Diagnosis
• Should patients be biopsied?

• Management and evidence

• Management of refractory disease
Triggers of Catastrophic APS
• Cervera et al. J Autoimmun. 2009;32:240-245.

• CAPS Registry:
• 65.4% of cases attributable to trigger
• Infection: 46.7%
• Malignancy: 17.6%
• Surgery: 16.8%
• Sub-therapeutic anticoagulation: 10.9%
Presentation of Catastrophic APS
• Term proposed in 1992: “Widespread
coagulopathy, strongly antiphospholipid
antibody related, but totally distinct and
separate from any of the other
recognized inherited/acquired
coagulopathies”
• <1% of all APS pts, mortality ~50% (now
~40%)

• Bucciarelli et al. Autoimmune Rev

2006;6:72-5.
• Chart review. N=250 from CAPS Registry
until Feb 2005 for mortality.
• Huang et al. J Rheumatol. 2009 Mar;36(3):651.
• Case report of 28F with poorly controlled “schizophrenia”
• Initially admitted w/ fever + diarrhea. Developed limb weakness, AKI, PEs.
Antiphospholipid Abs confirmed on investigations.
• Initial MRI normal. LOC normal -> comatose in 1 day. Repeat MRI diffuse
marked cortical edema with herniation, attributed to ischemic change.
Diagnosis of Catastrophic APS
• Preliminary Criteria for Classification for the Catastrophic APS (2003)

Lim W. Hematology Am Soc Hematol Educ

Program. 2013;2013:675-80.
Should patients be biopsied to confirm the
diagnosis?
• McMaster RARE-Bestpractices project group recommendations (2018)
• Objective: Provide proof of principle that guidelines can be developed for rare
diseases.
• 10 recommendations made: all very low certainty of evidence, most are
conditional recommendations.
• No studies comparing biopsy vs. no biopsy. No articles documenting
sensitivity and specificity of biopsy.
• Adverse effects depending on organ involved
• Recommended using biopsy to diagnose in select cases
Management of Catastrophic APS
• Kazzaz et al. Curr Opin Rheumatol. 2016 May;28(3):218-227.
• Anticoagulation
• Antiplatelets
• Corticosteroids
• PLEX, IVIg
• Cyclophosphamide
• Refractory disease
• Rituximab
• Eculizumab
Anticoagulation
• Two studies w/ total n=325 pts from CAPS Registry
• Significantly lower mortality in anticoagulated patients
• OR 0.18, 95% CI 0.09-0.38
• Anticoagulation received: UFH, LMWH, warfarin
• No clear role for DOACs
• 3 studies on antiplatelets n=275 (262 from CAPS Registry) suggestive
of lower mortality
• OR 0.79, 95% CI 0.36-1.73
• Recommended as add on therapy by McMaster RARE-Bestpractices project
group
Corticosteroids
• Generally used in combination. Little data to support
independent use.
• Analysis of 242 pts from CAPS registry, 190/242 received
corticosteroids (pulse, 1-2mg/kg/d):
• Ignoring concomitant therapy: no difference in recovery (55.8% vs.
56.9%)
• 11 pts w/ corticosteroid monotherapy: 2 survived
• Used in combination w/ anticoagulation >99% of time
• No evidence-based dosing regimen, high doses per expert
consensus
PLEX + IVIg
• PLEX
• Retrospective data shows survival 77.8% for anticoagulation +
steroids + PLEX (n=18), survival 55.4% otherwise
• Separate series: PLEX in 21 pts, 16/21 complete control, 3/21
partial response

• IVIg
• Analysis of 342 pts: 160/342 w/ anticoagulation + steroids + PLEX
OR IVIg improved survival p=0.04
Cyclophosphamide
• Analysis of 103 pts w/ SLE, cyclophosphamide decreased
mortality (47%)
• OR 0.20, 95% CI 0.06-0.71, p=0.013

• 126 pts without SLE, cyclophosphamide associated w/

increased mortality (although given to pts w/ more severe
disease)
• OR 8.5, 95% CI 1.91-37.83, p=0.005
Refractory Disease
• Rituximab
• 2 studies:
• Rituximab n=1
• Non-comparative study: n=20, 13/20 recovered, 4/20 died
• CAPS Registry: n=30, 5/30 deaths. Comparative odds ratio w/
contemporaneous patients 0.41, 95% CI 0.15-1.11.

• Eculizumab
• Limited to case reports only
In Summary
• Catastrophic APS is rare with a high mortality
• Clinical manifestations can be varied
• Mainstays of therapy: anticoagulation (no role for DOACs) +
steroids + PLEX/IVIg
• Evidence is generally poor
• Cyclophosphamide can be considered for patients with SLE
• Rituximab and eculizumab can be considered in refractory
disease
Thank you!
References (not already cited)
• Chaturvedi et al. Hematology Am Soc Hematol Educ Program.
2015;2015:53-60.