Page 2357 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 141 The Antiphospholipid Syndrome 2099

Hematologic Abnormalities heparin (LMWH). The prothrombin time and INR results can be
artifactually elevated in some patients with APS and LA. A multi-
Thrombocytopenia occurs in a large fraction of patients with APS, center study reported that all but one of the commercial thrombo-
but is rarely significant enough to cause bleeding complications or to plastins in use in nine centers provided acceptable INR values for
affect anticoagulant therapy. Most cases appear to be immune medi- APS patients with LA. Chromogenic factor X (CFX) assays can be
ated and are likely to reflect mild chronic immune thrombocytopenia used as an alternative to the INR to monitor warfarin in APS patients
(ITP). In a prospective cohort study, the 5-year thrombosis-free with a prolonged baseline PT, those who are persistently positive for
survival of aPL antibody–positive and aPL antibody–negative ITP LA and those patients with recurrent VTE. Therapeutic CFX values
patients was 39% and 98%, respectively, indicating that thrombocy- range from 20% to 40%; thus a CFX of 40% would approximate an
topenia itself is not protective against thrombosis in these patients. INR of 2.0, and a CFX of 20% would approximate an INR of 3.0.
This has been further substantiated by a recent systematic review and LMWH is generally recommended for treatment in the acute
meta-analysis that reported that an increased risk of thrombosis in setting. For those patients who require treatment with intravenous
patients with primary immune thrombocytopenia who also tested UFH (e.g., high risk patients for whom the short half-life of UFH
positive for antiphospholipid antibodies, particularly for LA for may be advantageous for bridging purposes), the physician must first
which the pooled OR for the risk of thrombosis was 6.11 (95% CI, determine that the baseline aPTT used for monitoring and adjusting
3.40–10.99). heparin dosage is not prolonged by a LA. If this is a problem, the
LA by themselves are not associated with abnormal hemostasis. heparin concentration may be estimated with one of the LA-insensitive
Therefore when patients with APS exhibit a bleeding tendency a aPTT reagents or measured directly with a specific heparin assay.
concurrent coagulopathy must be considered. In patients with normal Fibrinolytic therapy has been used in patients with primary APS
platelet counts, the differential diagnosis should include hypopro- who present with extensive thrombosis of the common femoral and
thombinemia, acquired thrombocytopathy, acquired factor VIII iliac veins extending to the lower vena cava, acute ischemic stroke,
inhibitor, and acquired von Willebrand syndrome. and acute myocardial infarction.
Although the direct-acting oral anticoagulants (DOACs) are as
TREATMENT OF PATIENTS WITH ANTIPHOSPHOLIPID effective as warfarin for VTE treatment, they have not been exten-
sively evaluated in APS patients. In two recent case studies, DOACs
SYNDROME failed to prevent thrombosis in APS patients. Of 6 APS patients
studied, 5 suffered recurrent venous thromboembolism and 1 suf-
There is general agreement that patients with recurrent or spontaneous fered a recurrent TIA after transitioning to DOACs. At least two
thrombosis require long-term anticoagulant therapy and that patients prospective randomized trials comparing warfarin with rivaroxaban
with recurrent spontaneous pregnancy losses require antithrombotic are currently in progress (ClinicalTrials.gov Identifier: NCT02116036
therapy for most of the gestational period and for the puerperium. NCT02157272), but until the results are available, DOACs should
There are unsettled differences of opinion regarding the approach to be used with caution in APS patients.
treatment of patients with single thrombotic events, or a history of
previous thrombotic events in the remote past (i.e., >5 years), or
patients with provoked thrombotic events after risk factors such as Stroke
surgery, pregnancy, or estrogens. The recent categorization of patients
into high, medium, and low risk groups based on multipositivity on There is controversy about the appropriate antithrombotic treatment
laboratory results may help guide management (see Table 141.4). of aPL antibody–associated stroke. Currently most hematologists and
rheumatologists view APS stroke as no different from other arterial
thrombotic manifestations of APS and treat with warfarin, with some
Thrombosis debate as to whether to use an INR target of 2.0–3.0 or a higher
intensity. Conversely many neurologists view APS stroke as no dif-
The accumulated evidence from randomized controlled trials indi- ferent from other arterial strokes and accept the APASS study conclu-
cates that regardless of single or multiple positivity for aPL antibodies, sion that treating with aspirin alone is as effective as warfarin but
patients with APS and thrombosis should be treated with long-term associated with a lower risk of bleeding (the daily dose in that study
warfarin with the dose adjusted to achieve an INR of 2.0–3.0. was 325 mg; however, most guidelines recommend 81 mg/day).
Although patients with unprovoked venous thromboembolism Guidelines issued in 2006 from the American Heart Association/
should probably be treated for the long term, duration of therapy for American Stroke Association stated that for patients with cryptogenic
provoked events is debatable. ischemic stroke or TIA associated with aPL antibodies, antiplatelet
Although there is a general consensus on this therapeutic range therapy is reasonable and for patients who meet the criteria for APS
for venous thrombosis, there is controversy as to whether patients with venous and arterial occlusive disease in multiple organs, miscar-
with arterial thrombosis may warrant a higher intensity of anticoagu- riages, and livedo reticularis, warfarin with a target INR of 2.0–3.0
lation because a retrospective study of a variety of patients with APS is reasonable.
showed that an INR >3.0 was required to prevent recurrence in this
group of patients. Although two major prospective, randomized,
controlled trials reported no benefit, and even some downside for Pregnancy Complications
high-intensity warfarin, there has been debate on whether these two
studies had sufficient numbers of patients with arterial thrombotic The current approach to treating pregnant women with APS and
events to allow those findings to be generalized beyond venous recurrent pregnancy losses or the other aPL antibody–associated
thromboembolism. Some investigators have recommended that complications of pregnancy includes daily low-dose aspirin
patients with myocardial infarction and triple positivity be treated (75–81 mg/day) and either UFH or LMWH. Although clinical
with higher-intensity warfarin of INR 3.0–4.0 or lower-intensity studies have shown efficacy with UFH, most clinicians treat with
warfarin of INR 2.0–3.0 plus low-dose aspirin. In addition, the LMWH because it has a better pharmacokinetic profile (it can be
triple-positive myocardial infarction patients who undergo percuta- given once daily subcutaneously rather than twice daily) and lower
neous coronary interventions and stent implantations should be risk of heparin-induced thrombocytopenia and osteopenia. Heparin
treated with triple antithrombotic regimens that include warfarin is then withheld when labor begins or 24 hours prior to a cesarean
(INR 2.0–3.0), low-dose aspirin, and clopidogrel. section. Anticoagulation with either LMWH or warfarin (although
Clinicians should be aware that the LA may impact monitoring most patients and physicians prefer LMWH for convenience, despite
of anticoagulation with both warfarin and unfractionated heparin the need for injection) is then resumed for 6 weeks because
(UFH) but has no impact on treatment with low-molecular-weight of the increased risk of VTE in this time period. This latter