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2244 Part XII: Hemostasis and Thrombosis Chapter 131: The Antiphospholipid Syndrome 2245

A5 anticoagulant effect, reported as a reduction in the annexin A5 LMWH treatment versus aspirin therapy. In the LMWH/aspirin group
anticoagulant ratio. In contrast to the lupus “anticoagulant” effect, this 35/47 (77.8%) had a livebirth, and in the aspirin group 34/43 (79.1 per-
assay measures and reports a procoagulant effect for the antibodies. cent) had a livebirth (p = 0.7). 302
70
(Disclosure: One of the authors (J.H.R.) is inventor of this assay, U.S. The presence of positive aPL laboratory assays alone is not an indi-
Patents #6284475 and #7252959.) cation for treatment in pregnant women without a history of sponta-
neous pregnancy losses, other attributable pregnancy complications,
DIFFERENTIAL DIAGNOSIS thrombosis, or SLE. Therefore, the inclusion of aPL tests in routine pre-
natal testing panels should be discouraged.
Chapters 133 and 134 address the general subject of vascular thrombo- Although prednisone was reported to possibly improve the out-
sis and its differential diagnosis. When vascular occlusion occurs in the come of pregnancy in women with APS, those benefits are associated
303
setting of a known autoimmune disorder such as SLE, the possibility with significant toxicity. Glucocorticoids or intravenous IgG should
of a vasculitis, rather than a thrombotic condition, should be consid- be considered only for patients who are refractory to anticoagulant
ered. Patients with CAPS may, at first, appear to have other multisystem therapy, who have a severe immune thrombocytopenia or a significant
vasoocclusive disorders, such as thrombotic thrombocytopenic purpura contraindication to heparin therapy. Treatment with the combination of
or disseminated vasculitis, and may also manifest laboratory findings of prednisone and heparin is associated with an increased risk of osteope-
disseminated intravascular coagulation. nia and vertebral fractures. 304
The differential diagnosis of a prolonged aPTT includes hereditary
and acquired coagulation factor deficiencies, inhibitors to coagulation THERAPY, COURSE, AND PROGNOSIS
proteins (e.g., acquired hemophilia A; Chap. 128), and the presence,
or use, of anticoagulants. The diagnosis of LA is substantiated through There is general agreement that APS patients with recurrent spontane-
plasma mixing studies and specific factor assays. A positive immunoassay ous thrombosis require long-term, and perhaps lifelong, anticoagulant
for aPL—that is, aCL and/or anti-β GPI antibodies—helps confirm the therapy and APS patients with recurrent spontaneous pregnancy losses
2
diagnosis. require antithrombotic therapy for most of the gestational period. There
When an elevated level aPL antibody level is detected, the clinician are differences of opinion among experts regarding the approaches
must exclude the possibility of an infectious etiology for the antibodies; to treatment of patients with a single thrombotic event, patients with
these occur frequently in syphilis, Lyme disease, HIV-1, and hepatitis a history of thrombotic events in the distant past (>5 years), patients
C. Occasional patients may have artifactually elevated antibodies from with stroke, and patients with thrombotic events that were associated
299
increased polyclonal immunoglobulin levels. In such cases, diagno- with a provocative factor such as trauma, surgery, stasis, pregnancy, and
sis is aided by specific tests for suspected infection, quantitative mea- estrogens.
surement of serum immunoglobulins, and subtraction of background
controls using uncoated microtiter wells. Antipsychotic or other medi- THROMBOSIS
cations should be excluded as causative agents.
The accumulated evidence from randomized controlled trials indicates
that patients with APS and thrombosis should be treated with warfarin
PREGNANCY COMPLICATIONS for the long-term, and maintained at a therapeutic international nor-
A systematic review of treatments given to maintain pregnancy in malized ratio (INR) of 2.0 to 3.0. Patients with arterial thrombosis
305
women with prior miscarriages and APS concluded that combined may require a higher anticoagulant intensity as a retrospective study
unfractionated heparin and aspirin may reduce pregnancy loss by showed that a higher intensity (INR >3.0) was necessary for prevent-
54 percent compared to aspirin alone. Three trials of aspirin alone ing recurrences in this group of patients, but this issue is controver-
300
showed no significant reduction in pregnancy loss ; intravenous sial. Two other studies reported no benefit for high-intensity warfarin
300
306
immunoglobulin, whether in combination with or without unfrac- but the number of patients with arterial thrombosis was not high. 299,305
tionated heparin (UFH) and aspirin, was associated with an increased The issue of appropriate antithrombotic treatment of aPL-associated
risk of pregnancy loss or premature birth when compared to UFH or stroke is even more controversial. One major study concluded that
low-molecular-weight heparin (LMWH) combined with aspirin. there was no benefit for warfarin anticoagulation compared to aspirin
Taking together the available data, women with a history of three therapy. 307
or more spontaneous pregnancy losses and evidence of aPL antibod- For patients treated acutely with intravenous UFH, care must be
ies should be treated with a combination of low-dose aspirin (75 to 81 taken to determine whether the patient has a preexisting LA that can
mg/day) and prophylactic doses of UFH (i.e., 5000 U every 12 hours interfere with aPTT monitoring of heparin levels. This problem can be
subcutaneously). Treatment should be started as soon as pregnancy is circumvented by using an LA-insensitive aPTT reagent or be avoided by
documented and continued until delivery so as to reduce the rate of late treatment, where appropriate, with a LMWH.
complications. 183,301 In especially high-risk situations, induction of early An important practical consequence of the LA effect is that proth-
delivery may be necessary. Unfractionated heparin at the prophylactic rombin time and INR results can be artifactually elevated in some
dosage of 5000 U q12h subcutaneously should be started approximately patients with APS and LAs treated with warfarin anticoagulant ther-
4 to 6 hours after delivery, if significant bleeding has ceased, and con- apy. A multicenter study reported that all but one of the commercial
308
tinued at least until the patient is fully ambulatory. Many physicians thromboplastins in use at nine centers provided acceptable INR values
recommend continuing prophylactic therapy for 6 weeks after delivery for APS patients with LA. New thromboplastins should be checked
309
even if the patients have not experienced thrombosis. For patients who for their responsiveness to LA prior to their use in monitoring oral anti-
experienced thromboembolism, prophylaxis by heparin or oral antico- coagulant treatment in patients with APS. Chromogenic factor X (CFX)
agulant therapy is warranted for at least 6 weeks after delivery. assays can be used as an alternative to INR for APS patients, especially in
Although treatment with LMWH has become widely used for patients with a prolonged baseline prothrombin time prior to initiating
recurrent fetal loss as a replacement for prophylactic dose UFH, a warfarin therapy, those who are persistently positive for LA and those
prospective randomized controlled trial has questioned the benefit of patients who continue to have recurrent venous thromboembolism

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