Critical Care Medicine

Catastrophic Antiphospholipid Antibody Syndrome

Catastrophic Antiphospholipid Syndrome

Synonyms

CAPS

Asherson's Syndrome

Microangiopathic APS

Related Conditions

Systemic Lupus Erythematosus

Primary Antiphospholipid Syndrome

1. Description of the problem

What every clinician should know

Catastrophic antiphospholipid syndrome (CAPS) is a life-threatening complication of antiphospholipid antibody syndrome with (a) clinical evidence of multi-organ involvement developing over a short period of time; (b) histopathologic evidence of small vessel occlusions; and (c) laboratory confirmation of antiphospholipid antibodies (aPL): lupus anticoagulant (LA) test; anticardiolipin antibody (aCL) by enzyme-linked immunosorbent assay (ELISA) and anti-B2 glyoprotenin 1 antibody (aB2GP1) by ELISA.

Clinical features

  • Multi-organ system involvvement (three or more organs) with evidence of either arterial or venous thrombosis developing with 1 week (or so).

  • Precipitating factors include infection, oral contraceptives, surgery, although not required.

  • Also known as "thrombotic storm."

  • Most common organ systems involved: renal>respiratory>CNS>heart>skin.

  • Associated thrombocytopenia.

  • Half of the patients will not have had a previous thrombotic event before presentation.

  • Requires tissue & laboratory confirmation.

  • Mortality rate 50%.

Key management points

  • Identification of CAPS (distinguish from other multi-organ thrmbotic processes such as disseminated intravascular coagulation [DIC] orthrombotic thrombocytopenia [TTP]).

  • Treatment of the underlying or precipitating factors.

  • Anticoagulation with heparin.

  • High-dose glucocorticoids (1 gram/day x 3) followed by 1 mg/kg orally or parenterally.

  • Therapeutic plasma exchange (approximately 5).

  • There is no prospective study on plasma exchange for CAPS. However, a review of the first 250 patients entered into a CAPS registry noted that the combination of plasma exchange, anticoagulation and steroids resulted in an overall 78% survival.

2. Emergency Management

  • Stabilize a-b-c's.

  • Identification of CAPS (distiguish from other multi-organ thrmobotic processes such as DIC or TTP).

  • Treatment of the underlying or precipitating factors.

  • Anticoagulation with heparin.

  • High-dose glucocorticoids (1 gram/day x 3) followed by 1 mg/kg orally or parenterally.

  • Therapeutic plasma exchange (approximately 5).

  • There is no prospective study on plasma exchange for CAPS. However, a review of the first 250 patients entered into a CAPS Registry noted that the combination of plasma exchange, anticoagulation and steroids resulted in an overall 78% survival.

3. Diagnosis

Establishing the diagnosis

CAPS is a clinical diagnosis made by the presence of multi-organ thrombosis with the presence of antiphospholid Ab.

Preliminary criteria for the classification of CAPS

  1. Evidence of involvement of three or more organs systems or tissues.

  2. Development of manifestations simultaneously or in less than a week.

  3. Confirmation of histopathology of small vessel occlusion in at least one organ or tissue.

  4. Laboratory confirmation of the presence of antiphospholipid Ab (lupus anticoagulant or anticardiolipin Ab).

Definite CAPS

  • All 4 criteria

Probable CAPS

  • All four criteria except for only two organs and/or tissue involvement.

  • All four criteria except for the laboratory confirmation at least 6 weeks apart due to the early death of a patient never previously tested for aPL prior to CAPS.

  • Criteria 1, 2, 4.

  • Criteria 1, 3, 4 and the development of a third event in more than a week but less than a month, despite anticoagulation.

Laboratory testing for antiphospholipid Ab

Activation (functional) assays: lupus anticoagulant

  1. Prolonged phospholipid-dependent coagulation on more than two different screening tests (e.g the dilute Russell viper venom time (dRVVT) and the aPTT).

  2. Failure to correct prolonged screening test mixing patient's plasma with normal platelet-poor plasma.

  3. Shortening or correction of prolonged screening test by addition of excess phospholipid.

  4. Exclusion of other coagulopathies.

Antigen assays (anticardiolipin Ab [IgG or IgM] by ELISA)

  1. See Sapporo criteria (below) for Ab titers

Other features

  • Thrombocytopenia is common (platelet count below 100,000).

  • Schistocytes with hemolytic anemia can be present; therefore, a peripheral smear should be evaluated.

Sapporo criteria for antiphospholipid antibody syndrome (APS)

Definite APS if at least one clinical and one laboratory criteria are met.

Clinical critieria

  • Vascular throbosis - one or more episodes of arterial, venous or small vessel thromboses.

  • Pregnancy morbidity - an unexplained fetal death occuring at or beyond the 10th week of gestation or one or more premature births before the 34th week of gestation-due to either eclampsia, pre-eclampsia or placental insufficiency-or at least three consecutive unexplained embryonic (before 10th week) losses.

Laboratory criteria

  • Lupus anticoagulant positivity on at least two occasions at least 12 weeks apart.

  • Anticardiolipin Ab (IgG or IgM in medium or high titer [ie, at least 40 or above 99th percentile] on at least two occasions at least 12 weeks apart).

  • Anticardiolipin B2 GP1 Ab (IgG or IgM in medium or high titer [i.e. above 99th percentile] on at least two occasions at least 12 weeks apart).

Normal lab values

See above.

Differential diagnosis

Acute thrombotic microangiopathic conditions, with or without schistocytic hemolytic anemia and thrombocytopenia, have a broad differential diagnosis. The diagnosis can be difficult to dissect because of overlapping features of the various conditions. Simultaneous consideration of other diagnoses such as heparin-induced thrombocytopenia (HIT), DIC, TTP and hemolytic uremic syndrome (HUS) should be done.

There are numerous diagnotic challenges:

  • A positive aPL test can be associated with infections (usually low titer). Thus at times it can be difficult to exclude the possibility that positive aPL tests are occurring as bystander to the underlying infectious process and are not pathologic to the process.

  • False-negative aPLs may occur during acute APS events, especially CAPS, presumably because the Ab is consumed in the process of widespread thrombosis. Therefore the absence of aPLs does not exclude the diagnosis.

  • Sepsis and CAPS share many similarities and can co-exist. Severe sepsis (sepsis with systemic inflammatory response [SIRS]) can have common complications.

  • HIT and CAPS share similarities and may overlap. They both have thrombosis despite thrombocytopenia, and thrombosis is more commonly venous than arterial. The thrombocytopenia tends to be mild to moderate (100,000-150,000).

If the patient has received either unfractionated or low-molecular-weight heparin, more commonly occurring post-surgical procedure and within 1 week of starting heparin, HIT should be seriously considered. Leg ischemia is more common in HIT, and stroke is a more common manifestation of antiphospholipid syndrome, but both can have any venous or arterial complications.

Special confirmatory tests

  • Lupus anticoagulant positivity on at least two occasions at least 12 weeks apart.

  • Anticardiolipin Ab (IgG or IgM in medium or high titer [i.e. at least 40 or above 99th percentile] on two or more occasions at least 12 weeks apart).

  • Anticardiolipin B2 GP1 Ab (IgG or IgM in medium or high titer [i.e. above 99th percentile] on two or more occasions at least 12 weeks apart).

4. Specific Treatment

  • Identification of CAPS (distinguish from other multi-organ thrmbotic processes such as DIC or TTP).

  • Treatment of the underlying or precipitating factors.

  • Anticoagulation with heparin.

  • HIgh-dose glucocorticoids (1 gram/day x 3) followed by 1 mg/kg orally or parenterally.

  • Therapeutic plasma exchange (approximately 5).

  • There is no prospective study on plasma exchange for CAPS. However, a review of the first 250 patients entered into a CAPS registry noted that the combination of plasma exchange, anticoagulation and steroids resulted in an overall 78% survival.

  • Once stabilized, patients should be transitioned to warfarin to maintain INR of 3.0 for lifetime.

  • If patient is not responding to above regimen, in addition to therapeutic plasma exchange one can consider appropriately timed IVIG.

5. Disease monitoring, follow-up and disposition

Expected response to treatment

Prognosis is poor, but as noted above the combination of anticoagulation, steroids and therapeutic plasma exchange has improved mortality. If patients survive CAPS, there is no specific risk for recurrence. Lifetime treatment with warfarin anticoagulation is recommended.

Monitoring

Continuous monitoring of patient for new thromboses and the development of worsening throbocytopenia or hemolytic anemia is very important. In addition, continued evaluation to exclude other causes of microangiopathy should be performed.

Follow-up

Patients will need long-term follow-up with a hematologist or rheumatologist if the underlying disease is lupus.

Pathophysiology

Presumed mechanism (not well understood)

  • Antiphospholipid antibody interference with endogenous anticoagulant mechanisms:

  1. Disruption of the annexin A5 anticoagulant shield.

  2. Inhibition of protein C pathway.

  3. Inhibition of antithrombin.

  • Binding and activation of platelets.

  • Interacting with endothelial cells, inducing expression of adhesion molecules and tissue factor.

  • Activation of complement cascade.

Epidemiology

Half of the patients have not had a previous thrombosis prior to the presentation of CAPS. Therefore, the absence of a history of previous thrombotic events does not preclude the diagnosis. Patients with systemic lupus erythematosus have the highest risk of having underlying antiphospholipid antibodies. Other precipitating factors for CAPS include infection, oral contraceptive use and surgery.

Prognosis

N/A

Special considerations for nursing and allied health professionals.

N/A

What's the evidence?

Erkan, D. "Catastrophic antiphospholipid syndrome: Updated diagnostic algorithms". Autoimmun Rev. 2010.

(A comprehensive, up-to-date discussion of the diagnostic challenges associated with CAPS and a proposed diagnostic algorithm. This paper reviews the new criteria for CAPS and lists the new Sapporo criteria for APS. There are three very nice algorithms for the diagnosis of CAPS based on clinical and laboratory findings.)

Asherson, RA, Cervera, R, Piette, JC. "Catastrophic antiphospholipid syndrome. Clinical and laboratory features of 50 patients". Medicine (Baltimore). vol. 77. 1998. pp. 195-207.

Asherson, RA, Cervera, R, Piette, JC. "Catastrophic antiphospholipid syndrome: clues to the pathogenesis from a series of 80 patients". Medicine (Baltimore). vol. 80. 2001. pp. 355-77.

(The 1998 paper is a landmark paper in the history of characterization of this syndrome, and the 2001 paper is a follow-up.)

Lockshin, MD, Erkan, D. "Treatment of the antiphospholipid syndrome". N Engl J Med. vol. 349. 2003. pp. 1177.

(A review of the treatments for CAPS.)

Bucciarelli, S, Espinosa, G, Cervera, R. "Mortality in the catastrophic antiphospholipid syndrome. causes of death and prognostic factgors in a series of 250 patients". Arthritis Rheum. 2006. pp. 54-2568.

(A review of the first 250 patients entered into the international CAPS registry, with treatment outcomes. This paper is being used as the primary reference for treatment of CAPS with therapeutic plasma exchange.)

Erkan, D, Asherson, RA, Espinosa, G. "Long-term outcome of catastrophic antiphospholipid syndrome survivors". Ann Rheum Dis. vol. 62. 2003. pp. 530.

(This paper describes the long term (>5 years) outcomes in 136 patients with CAP and the proportion who relapse.)
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