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CHAPTER 131 during their pregnancies and the postpartum period. CAPS patients have a

THE ANTIPHOSPHOLIPID high mortality and, in addition to anticoagulants, often require plasmaphere-
sis and immunosuppressive agents. Patients without clinical manifestations of
SYNDROME APS or a history of SLE should generally not undergo diagnostic screening for
aPL antibodies and, if tested and found to be positive, should not be commit-
ted to antithrombotic therapy solely on the basis of laboratory abnormalities.

Jacob H. Rand and Lucia Wolgast

DEFINITION AND HISTORY
SUMMARY The antiphospholipid (aPL) antibody syndrome (APS) is a disorder in
which vascular thrombosis or pregnancy complications attributable to
The antiphospholipid (aPL) syndrome (APS) is an acquired thrombophilic placental insufficiency occur in patients with laboratory evidence for
disorder in which patients have vascular thrombosis and/or pregnancy com- antibodies directed against proteins that bind to phospholipids. The
plications attributable to placental insufficiency, accompanied by laboratory syndrome was first proposed to be a distinct entity, “the anticardiolipin
evidence for the presence of antiphospholipid antibodies in blood. The dis- (aCL) syndrome,” in 1985 and soon was renamed APS. While precise
1
2
order is referred to as primary APS when it occurs in the absence of systemic data are not available, the syndrome is thought to affect approximately
3,4
lupus erythematosus (SLE), and secondary APS in its presence. Any portion of 10 percent of patients with venous thrombosis, and approximately
the circulatory tree can be affected, although the most frequently affected 20 percent of women with three unexplained fetal losses before
vessels are the deep veins of the lower extremities. Abnormalities that have 12 weeks of gestation, or at least one intrauterine fetal death after 12 weeks
5
been reported in association with the syndrome include virtually all other of gestation.
The term “aPL antibodies” can refer to (1) antibodies that rec-
autoimmune disorders, immune thrombocytopenia, acquired platelet func- ognize protein-phospholipid complexes as in cofactor-dependent
tion abnormalities, hypoprothrombinemia, acquired inhibitors of coagulation aCL assays, (2) antibodies that recognize the proteins directly as in
factors, livedo reticularis, heart valve abnormalities, atherosclerosis, pulmo- anti-β glycoprotein I assays (anti-β GPI), (3) an abnormal coagulation
2
2
nary hypertension, and migraine. Rare patients have a catastrophic form of test in several assays that report inhibition of phospholipid-dependent
APS (CAPS) in which there is disseminated thrombosis in large- and small- coagulation reactions, collectively as termed lupus anticoagulant (LA)
vessel thrombi, often after a triggering event such as infection or surgery, and tests, and (4) antibodies that recognize phospholipid directly as in
often with multiorgan ischemia and infarction. syphilis and are not associated with the APS disease entity.
6–8
APS is a misnomer, the main antigenic targets for thrombogenic aPL anti- A brief review of the history of APS helps explain the confusing
bodies are epitopes on phospholipid-binding proteins, the most important terminology (Table 131–1); the reader is referred to references 6 to 8
of which appears to be β -glycoprotein I (β GPI). The syndrome is identified for more detailed accounts. In retrospect, the first assay for aPL auto-
2
2
by persistent abnormalities of laboratory tests for antibodies against these antibodies was Moore and Mohr’s report of the “biologic false-positive”
9
serologic tests for syphilis (BFP syphilis test) in 1952 ; this abnormality
phospholipid–protein cofactor complexes, detected by immunoassays and by came to be associated with systemic lupus erythematosus (SLE). The
10
coagulation assays (also known as “lupus anticoagulant assays”) that, paradox- contemporaneous introduction, of the activated partial thromboplas-
ically, report the inhibition of phospholipid-dependent coagulation reactions. tin time (aPTT), which used cephalin, a phospholipid extract of ani-
Long-term warfarin anticoagulant therapy is the usual treatment for throm- mal brains, as the “partial thromboplastin” (distinct from the “complete
bosis in patients with APS, although there is some controversy about whether thromboplastin,” tissue factor, and phospholipid), led to the recogni-
11
treatment of patients with APS stroke might be better treated with aspirin. tion of a unique type of anticoagulant in patients with SLE, that was
12
Patients with recurrent spontaneous pregnancy losses and APS generally are frequently associated with BFP syphilis tests. Because the of its initial
13
treated with aspirin and heparin for prophylaxis against deep vein thrombosis association with SLE this phenomenon was misnamed LA. It became
recognized that the LA was purely an in vitro phenomenon that was
not limited to SLE and that was not associated with bleeding complica-
tions unless another hemostatic defect was present. Furthermore, the
6
LA came to be associated with recurrent pregnancy losses 14,15 and with
16
Acronyms and Abbreviations: aCL, anticardiolipin; APC, activated protein C; aPL, thrombotic and embolic manifestations. The development, in 1983, of
antiphospholipid; APS, antiphospholipid syndrome; aPTT, activated partial throm- the aCL antibody assay, that measured antibodies against the anionic
boplastin time; ARDS, acute respiratory distress syndrome; ASIA, autoimmune/ phospholipid, cardiolipin (diphosphatidylglycerol), the primary antigen
autoinflammatory syndrome induced by adjuvants; AVWS, acquired von Willebrand in the syphilis test reagent, was the advance that led to the identifi-
17
syndrome; BFP syphilis test, biologic false-positive serologic test for syphilis; β GPI, cation of a new syndrome. Within a few years, it became recognized
2
β -glycoprotein I; CAPS, catastrophic APS; CMV, cytomegalovirus; dRVVT, dilute Rus- that aPL antibodies did not bind phospholipids directly but instead were
2
sell viper venom time; ELISA, enzyme-linked immunosorbent assay; HCQ, hydroxy- directed against proteins that bound to the phospholipid, primarily
chloroquine; Ig, immunoglobulin; IL, interleukin; LA, lupus anticoagulant; LDL, β GPI (see “Pathogenesis” below). This information became important
2
low-density lipoprotein; LMWH, low-molecular-weight heparin; MAPK, mitogen- in helping to unravel the mechanisms for APS and in advancing diag-
activated protein kinase; NOACs, new oral anticoagulants; RVV, Russell viper venom; nostic testing toward the goal of distinguishing between the syndrome
SCR, short consensus repeat; SLE, systemic lupus erythematosus; TLR, toll-like recep- and incidental false-positive tests. Table 131–2 describes the current
tor; TM, thrombomodulin; t-PA, tissue-type plasminogen activator; UFH, unfraction- consensus investigational criteria for diagnosing APS. 18
ated heparin; VWF, von Willebrand factor. Most patients with elevated aPL antibodies do not have the syn-
drome; elevated aPL antibody levels can occur in patients with several

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