Patient Is Clotting: What Do You Mean, the aPTT Is Prolonged?

Dennis Williams, MD; Duncan C. MacIvor, MD

Disclosures

February 21, 2013

In This Article

Diagnosis and Discussion

The most likely cause of the isolated prolonged aPTT in this patient is LA. In this patient with LA and a history of thrombosis, thrombocytopenia, and lupus, the most likely diagnosis is antiphospholipid syndrome (APS).

Overview of Antiphospholipid Syndrome

APS is one of the most common acquired risk factors for thrombosis. This disease causes both venous and arterial thrombosis in many organ systems and is a major cause of late first- and second-trimester pregnancy loss.[4] It is characterized by antiphospholipid antibodies (aPL-Abs) that are actually directed against proteins that bind anionic phospholipids. Several phospholipid binding proteins have been identified, including beta2-glycoprotein I (beta2-GPI), prothrombin, protein S, thrombomodulin, and others.[5]

The prevalence of aPL-Abs in the general population varies with studies and may range from 2% to 15%.[5] The risk for thrombosis may be as high as 3% per year.[5,6] In most cases, these antibodies are transient, but if they are persistent, the risk of developing APS symptoms may reach 30%. The prevalence of aPL-Abs increases with a diagnosis of systemic lupus erythematosus (30%-40%), thrombosis (30%), or recurrent fetal loss (5%-60%).[4,7]

An aPL-Ab that binds to protein-phospholipid complexes causes thrombosis by means of mechanisms that are incompletely understood but may include inhibition of natural anticoagulation (proteins C and S), endothelial cell activation, and platelet activation.[1] Mechanisms leading to fetal loss are also unclear but may include complement activation and interference with adequate placentation through thrombosis.[8,9]

Clinical manifestations. Clinical manifestations of APS are diverse, including those that are part of the APS classification criteria (arterial and venous thrombosis, pregnancy morbidity) and those that are not (livedo reticularis, thrombocytopenia). The prevalence of various clinical manifestations was reported in a large, multicenter, international cohort study enrolling 1000 patients with either primary or secondary APS. The most frequent manifestation was deep vein thrombosis (32%), followed by thrombocytopenia (22%), livedo reticularis (20%), stroke (13%), superficial thrombophlebitis (9%), pulmonary embolism (9%), fetal loss (8%), transient ischemic attack (7%), and hemolytic anemia (7%).[10]

Approximately 1% of patients with APS present with catastrophic APS (CAPS).[10] CAPS is characterized by rapidly progressive multiorgan thrombosis of small vessels occurring over days to weeks with a mortality rate of approximately 50% despite treatment.[11] Approximately 46% of patients develop CAPS as their first manifestation of APS. The most common organ systems involved are cardiorespiratory, central nervous system, and renal.[12]

Diagnostic Criteria

The diagnosis of APS can be made by using classification criteria that were first proposed in Sapporo, Japan, in 1998[13] and revised in Sydney, Australia, in 2005.[14] The consensus statement contains both clinical and laboratory criteria and the diagnosis is confirmed with one of each.

Clinical criteria. Clinical criteria include vascular thrombosis as defined by 1 or more clinical episodes of arterial, venous, or small-vessel thrombosis and/or pregnancy morbidity:

  • Vascular thrombosis: must be confirmed by objective validated criteria including unequivocal imaging or histopathologic studies

  • Pregnancy morbidity: 1 or more unexplained deaths of a morphologically normal fetus at 10 or more weeks of gestation

  • One or more premature births of a morphologically normal neonate before 34 weeks of gestation due to eclampsia, severe preeclampsia, or placental insufficiency

  • Three or more unexplained consecutive pregnancy losses before 10 weeks of gestation with no evidence of maternal/paternal chromosomal or maternal hormonal/anatomic causes

Laboratory criteria. Diagnose presence of aPL-Abs on 2 or more occasions at least 12 weeks apart and within 5 years of clinical presentation; demonstrated by 1 or more of the following tests:

  • LA measured according to the guidelines of the International Society on Thrombosis and Haemostasis;

  • Anticardiolipin antibodies (aCL-Abs), IgM and/or IgG, measured by standardized enzyme-linked immunosorbent assay [ELISA] in medium or high titer [> 40 GPL or MPL units, or > 99th percentile]); and

  • Anti-beta2-GPI antibody, IgM and/or IgG, measured by standard ELISA with a titer > 99th percentile

Criteria for CAPS. Preliminary diagnostic criteria for CAPS were proposed in 2003[4] and include:

  • Evidence of involvement of 3 or more organs/systems/and or tissues;

  • Simultaneous development of these manifestations in multiple systems within a week of each other;

  • Confirmation by histopathology in at least 1 system; and

  • Laboratory confirmation of the presence of aPL-Abs.

If all 4 criteria are satisfied, CAPS can be definitively diagnosed.[15]

Antibody testing. Laboratory testing to detect aPL-Abs is based on either direct identification of the antibody through ELISA or indirect detection of the antibody through prolongation of phospholipid dependent coagulation tests (testing for LA). The LA actually represents an aPL-Ab that happens to interfere with the test through its binding to phospholipids; it does not describe the specificity of the antibody itself. In addition, not all aPL-Abs interfere with phospholipid-dependent coagulation tests, and therefore not all aPL-Abs have LA activity. Testing for aCL-Abs by ELISA is likewise not specific for any particular aPL-Ab. Positivity simply reflects the presence of an antibody specific for a protein bound to cardiolipin. The only widely used test for the actual aPL-Ab specificity is the ELISA for anti-beta2-GPI antibody. Others are available but not widely used.

Although specificity of the antibody may not be known (unless anti-beta2-GPI is positive), the clinical significance of the antibody can be estimated by its test characteristics. Several studies suggest that patients who test positive for LA may have a greater increased risk for thrombosis than patients testing positive for aCL, especially those with beta2-GPI specificity.[16,17] Additionally, studies show that aPL-Abs specifically directed against beta2-GPI are an independent risk factor for thrombosis and pregnancy complications and confer a greater risk compared with aCL-Abs. However, alone, neither seems to be as strong a risk factor as LA.[1,17] Immunoglobulin isotype and titer may also influence risk.[18] Finally, multiple positive tests for aPL-Abs are more strongly associated with thrombosis than are single positive tests.[17] Transiently present aPL-Abs due to infections may be clinically insignificant.

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