Antiphospholipid syndrome: review.

Abstract: Antiphospholipid syndrome spans many medical disciplines. Classic criteria include the presence of anticardiolipin antibody or lupus anticoagulant with typical complications of thrombosis or pregnancy loss. Other common associated manifestations include livedo reticularis, thrombocytopenia, valvular heart disease, and nephropathy with renal insufficiency, hypertension, and proteinuria. Treatment of serious complications with anticoagulation is standard; generally warfarin for thrombosis and aspirin/heparin for pregnancy prophylaxis. Detailed recommendations regarding precise intensity and duration of anticoagulation are still a subject of debate.

Key Words: acquired thrombophilia, anticardiolipin antibody, antiphospholipid syndrome, lupus anticoagulant, recurrent pregnancy loss, thrombosis

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Introduction

Clinically, the antiphospholipid syndrome (APS) spans many medical disciplines. As the syndrome becomes more thoroughly described, research has moved from case reports of empiric treatments toward randomized and controlled trials. The current challenge for practitioners is to critically interpret these trials and translate sometimes contradictory results into effective patient care.

Presentations of APS may be varied, although classic criteria include only arterial or venous thrombosis and specific obstetric complications. Presence of antiphospholipid antibody (aPL) alone, in the absence of typical clinical complications, does not indicate a diagnosis of APS; long-term asymptomatic aPL-positive patients exist. When diagnosed in patients with underlying autoimmune disease (usually systemic lupus erythematosus, or SLE), APS is termed secondary APS; in otherwise healthy persons it is termed primary APS. Catastrophic antiphospholipid syndrome (CAPS) represents the severe end of the spectrum with multiple organ thromboses in a rapid period of time.

Current criteria for APS exist for purposes of classification and to facilitate studies of treatment and etiology, rather than for diagnosis of individuals in clinical practice. An international consensus statement on classification criteria for APS proposed two criteria: the presence of persistently moderate to high titer immunoglobulin G (IgG) or immunoglobulin M (IgM) anticardiolipin antibody (aCL) or lupus anticoagulant (LA) and the clinical complications of vascular thrombosis or pregnancy morbidity (1) (Table 1). In contrast, physicians caring for aPL-positive patients recognize other associated complications that include livedo reticularis, valvular heart disease, or thrombocytopenia, at times in the absence of more typical vascular or pregnancy events (Table 2).

Spectrum of Antiphospholipid Antibodies

The earliest recognized aPL was the biologic false-positive serologic test for syphilis (BFP-STS). Although the BFP-STS does not fulfill laboratory criteria for APS, it often prompts evaluation for other aPLs. Moderate to high titer IgG and IgM aCL, and LA, are much more closely associated with typical complications, as is the recently recognized anti-[beta]2 glycoprotein I antibody. While there is no consensus among APS experts as to what constitutes, medium-to-high titer, a cut-off of 40 U is often used.

Clinical significance of aPLs other than aCL and LA is uncertain when they appear in the absence of standard tests. Tests for IgG, IgM, and immunoglobulin A isotypes of antibodies to phosphatidylserine, phosphatidylethanolamine, and other phospholipids are sometimes performed. The resulting panel of 20 or more tests commonly results in at least one positive test result, and such reports need to be interpreted with caution. (2)

The serum protein [beta]2-glycoprotein I, or [beta]2GPI, (which demonstrates in vitro anticoagulant properties) is a requirement for binding of autoimmune aCL to cardiolipin coated plates in the standard enzyme-linked immunosorbent assay (ELISA). [beta]2GPI bound to phospholipid produces an epitope against which most autoimmune aCL are directed. (3) Anti-[beta]2GPI antibodies are found in the sera of many but not all patients with aCL.

Laboratory Testing

In the functional LA coagulation assay, aPL prolong phospholipid-dependent coagulation steps in vitro by competing with coagulation factors for binding to phospholipid. The most sensitive and commonly performed assay is the dilute Russell viper venom time (dRVVT). Diagnosis requires failure to correct the prolonged coagulation time by mixing studies, correction by addition of excess phospholipid, and exclusion of other coagulopathies. In the more sensitive but less specific aCL assay, aCL are detected by an ELISA that utilizes cardiolipin as the antigen, in the presence of [beta]2GPI. (1) Anti-[beta]2GPI antibodies, detected by ELISA on [beta]2GPI coated plates, have been suggested to be more specific than aCL in predicting complications. Although increasingly used clinically, the anti-[beta]2GPI test requires further standardization and validation. (4)

Sapporo criteria require two aPL tests 6 weeks apart to rule out transient infection-induced aCL antibodies. Elevated aCL have been identified in 32% of acute phase sera from patients with common infections (including mycoplasma and adenovirus); titers decreased or became negative in convalescent sera. (5) Infection-induced aPL are not generally associated with complications, and may be detected in chronic infections such as syphilis, HIV, and hepatitis C. They most often bind phospholipid directly in the ELISA test in a [beta]2GPI-independent manner. APL can also be induced by certain drugs (including chlorpromazine, procainamide, and others) or by lymphoproliferative disorders. Such aPL are often IgM in isotype and reversible once the drug is discontinued; they are not commonly associated with thrombosis. (6)

Etiology and Pathogenesis

Autoimmune aPL represent a family of autoantibodies directed at phospholipid-binding plasma proteins, rather than at phospholipid itself. [beta]2GPI represents the most important of a number of potentially relevant phospholipid-binding proteins, including prothrombin, proteins C and S, and Annexin V. Multiple mechanisms are likely. (7) By binding to phospholipid-binding proteins, aPL may interfere with maintenance of coagulation homeostasis. APL also activate endothelial cells, (8) induce increased tissue factor expression on monocytes, (9) and interact with placental Annexin V. (10) Complement activation may be an additional mechanism in fetal loss. (11)

The origin of aPL is hypothesized to be an incidental exposure to environmental (primarily infectious) agents inducing aPL in susceptible individuals via a molecular mimicry mechanism. Gharavi et al have shown that a viral peptide mimicking the [beta]2GPI-phospholipid binding domain induces anti-[beta]2GPI antibodies in a murine model that are associated with typical clinical complications. (12,13) Familial occurrence of aPL has been reported, and suggested genetic associations include HLA-DR4, DR7, DRw53 and C4 null allele. (14)

Epidemiology of aPL

ACL antibodies are seen in the general population. Prevalence is 2 to 4%, and they are usually low in titer and more common in the elderly. In contrast, about one-third of SLE patients are aCL positive. LA prevalence is < 1% in the general population, and about 15% in SLE patients. The strength of the association between aPL and thrombosis varies, depending on both the aPL(s) tested and the populations studied. Titer and isotype are important: IgG aCL is more strongly associated with clinical events than is IgM aCL, and the risk of thrombosis increases with higher titers. Immunoglobulin A aCL and low titers of IgG and IgM aCL are less frequently associated with complications. (15)

APL account for a significant proportion of thromboses in the general population: approximately 50% of stroke patients younger than age 50, (16) and up to 20% of idiopathic deep vein thrombosis (DVT) patients, (17) are aPL positive. ACL are predictive of DVT and pulmonary embolism (PE) in the general population. In a nested case-control subset of the Physicians Health Study, a positive aCL test at study onset was associated with subsequent development of DVT and PE. (18)

Risk of thrombosis in lupus patients is significant; there is a 50% chance of thrombosis over 20 years for LA-positive SLE patients, (19) and a 52% chance of developing any APS complication over 10 years for aPL-positive lupus patients. (20) Women with pregnancy events alone have a high likelihood of developing thrombosis in later years. Erkan et al have shown a thrombosis rate of 60% by 10 years after delivery. (21)

The presence of additional prothrombotic risk factors in aPL-positive individuals likely influences thrombosis risk. In the currently accepted "second-hit" hypothesis, a second trigger event--such as cigarette smoking, oral contraceptives, surgical procedures, prolonged immobilization, or a genetic prothrombotic state may increase the likelihood of an aPL-positive patient developing a vascular event.

Clinical Manifestations

Arterial Occlusion

Stroke and transient ischemic attack (TIA) are the most common presentation of arterial thrombosis and make up 23% of initial presenting events in APS. Recurrent stroke may lead to multi-infarct dementia. Large vessels may be affected, including the aorta with aortic occlusion. Involvement of peripheral vessels is variable and may include mesenteric arteries, leading to bowel ischemia, or peripheral arteries, leading to digital or extremity gangrene. Ophthalmic vessel occlusion may lead to amaurosis fugax or visual loss. (22)

Venous Occlusion

DVT, often accompanied by PE, is the most common manifestation of APS overall. (22) Pulmonary hypertension may develop due to recurrent PEs or small vessel thrombosis. Unusual venous distributions may include ophthalmic veins, renal or splenic veins, hepatic veins (leading to Budd-Chiari syndrome), portal or mesenteric veins, and the sagittal sinus. Adrenal vein thrombosis leading to adrenal insufficiency may be difficult to diagnose but is the initial symptom of the syndrome in 36% of patients who develop this complication. (23)

Hematologic Manifestations

Hematologic manifestations include thrombocytopenia, Coombs positive hemolytic anemia. Evans syndrome and microangiopathy. (22) While common, thrombocytopenia is not currently a clinical criterion for APS. It correlates strongly with the presence of aPL in SLE patients. Platelet counts less than 100 X [10.sup.9]/L are present in 90% of SLE patients with both lupus anticoagulant and a high titer aCL. (24) Thrombotic microangiopathic hemolytic anemia in association with aPL is increasingly recognized. In a recent literature review, authors identified 46 cases; for more than half of these patients, it was the presenting manifestation of the syndrome. (25)

Cutaneous Manifestations

Livedo reticularis, a lattice-like pattern of superficial skin veins, is the most common cutaneous manifestation of APS. Livedo reticularis in young patients with a history of vascular or pregnancy events should raise the possibility of aPL, although livedo is not specific for APS and may be a normal variant. In the presence of aPL, however, livedo is strongly associated with arterial, but not venous, events. Other skin findings include superficial cutaneous necrosis, pyodermalike ulcerations, subungual splinter hemorrhages, and anetoderma. (26)

Nonthrombotic Neurologic Manifestations

Although ischemic stroke and/or TIA make up >50% of neurologic complications in APS, (22) other less common and at times controversial neurologic manifestations are reported, including chorea, transverse myelitis, multiple sclerosis-like syndrome, and seizures. Migraines, a nonspecific symptom, are common. Chorea has been associated with both oral contraceptive use and pregnancy in APS patients. (27) Seizure disorders may result from an ischemic and/or a depolarization mechanism. (28) The association of transverse myelitis and a multiple sclerosis-like syndrome with aPL are controversial but reported. (29) Cognitive dysfunction independent of cerebrovascular disease appears increased in patients with APS, and SLE patients with a positive LA have an elevated risk of cognitive dysfunction. (30)

Renal Manifestations

Thrombosis may develop at any location within the renal vasculature, including the renal artery, intrarenal arterioles, glomerular capillaries, and renal veins. Isolated hypertension may reflect renal artery stenosis without total occlusion. Focal cortical ischemia with infarction may occur. Usual manifestations of APS-related glomerular dysfunction include decreased creatinine clearance, hypertension, and proteinuria in the absence of active sediment. (31) Renal biopsy differentiates between lupus glomerulonephritis and aPL nephropathy in SLE patients with aPL. Characteristic changes on renal biopsy are those of thrombotic microangiopathy, with thrombi, cortical atrophy, and glomerular membrane duplication. (32) APS nephropathy may result in end stage renal disease, and aPL may complicate renal transplantation. There is an increased prevalence of vascular access thrombosis in LA-positive hemodialysis patients (33) and an increased risk of transplant failure in aPL-positive patients. (34)

Cardiac Manifestations

Valvular heart disease is the most common form of aPL-related cardiac involvement. Prevalence is estimated at 32 to 82% of aPL patients, with higher estimates based on studies utilizing transesophageal echos. (35)

Manifestations of valvular disease may be seen in both primary and secondary APS patients. Specific findings range from valvular thickening to nodular excrescences (LibmanSacks), mitral and aortic regurgitation, and severe distortion and dysfunction. Stenosis is relatively uncommon. Histologic examination of involved valves shows deposits of IgG aCL, complement, and fibrin; inflammation is not prominent. (36) Valve replacement surgery in these patients has significant morbidity and mortality. (37)

Although uncommon, case reports describe intracardiac thrombus mimicking myxoma with embolic manifestations. Prospective studies support aPL as a risk factor for coronary artery disease and myocardial infarction, especially in young and middle-aged individuals. (38-40) Patients with aPL have an increased risk of coronary artery bypass graft occlusion; (41) an association of aPL with increased risk of atherosclerosis has also been suggested. (42)

Avascular Necrosis

Avascular necrosis (AVN) may be increased in aPL-positive patients independent of corticosteroid use: 73% of SLE patients with AVN in one report were aPL-positive. (43) In a recent large series, asymptomatic AVN on MRI was identified in 20% of primary APS patients. (44)

Obstetric Complications

Obstetric manifestations of APS are not restricted to fetal loss. Current APS criteria include loss and/or early delivery due to pre-eclampsia, intrauterine growth restriction (IUGR), or fetal distress. (1) Fetal loss ([greater than or equal to] 10 weeks of gestation) is more strongly associated with aPL than are earlier pregnancy losses. Pre-embryonic and embryonic loss (< 10 weeks of gestation) do occur in aPL-positive patients. However, since early pregnancy losses are common in the general population, the diagnosis of APS should be made only with three or more consecutive losses in the absence of other identifiable etiologies. Overall, approximately half of aPL-associated pregnancy losses occur in the first trimester. (45) The two greatest risk factors for fetal loss are high titer IgG aCL and a history of previous fetal loss. These patients have up to 80% risk of current pregnancy loss. (46)

In addition to pregnancy losses, associated maternal obstetric complications include pre-eclampsia/eclampsia and HELLP syndrome (hemolytic anemia, elevated liver enzymes, and low platelet counts). Arterial or venous thrombosis and other aPL-related complications such as severe thrombocytopenia may also occur. (45)

Neonatal complications include prematurity (estimated at 30-60% and more common in SLE patients), intrauterine growth restriction, and rarely fetal or neonatal thrombosis. (47) Preterm delivery is the strongest risk factor for adverse neonatal outcome. (48)

Prevalence of aCL in the general OB population is not increased, and screening of healthy pregnant women is not indicated. (49) While both aCL and LA predict fetal loss, concordance is incomplete, so both must be tested if APS is suspected. Other aPLs are not as helpful in predicting risk. Antibodies directed against other phospholipids, such as antiphosphatidylserine or antiphosphatidylethanolamine, do not generally identify additional patients. (2) It is not clear if anti-[beta]2GPI antibodies add significant predictive value to aCL and LA in identifying patients at risk for fetal loss, (50) although occasional patients may present with these antibodies alone.

Exclusion of confounding conditions is important in aPL-positive patients with pregnancy morbidities. Gynecologic conditions may include uterine abnormalities, hormonal imbalance (eg, luteal phase defect), maternal and paternal karyotype abnormalities, or fetal genetic abnormalities. In addition, presence of a heritable procoagulant state, such as factor V Leiden, may mimic APS. (51)

Catastrophic APS

CAPS is a rare, life-threatening complication of aPL, which presents as acute multiorgan failure with predominant small vessel occlusion. Multiple thromboses of small and medium size vessels may occur despite adequate anticoagulation. About 250 patients worldwide have been reported, and mortality is estimated at 50% despite therapy. Intra-abdominal vessels are most commonly affected; other common manifestations include renal dysfunction with hypertension, pulmonary involvement, thrombocytopenia, cutaneous necrosis, and cerebral complications. Disseminated intravascular coagulation occurs in 20% of patients. Potential triggers have been identified in 55% of reported cases with infection being the most common. (52) Preliminary classification criteria for CAPS include involvement of greater than 3 organs, development of manifestations in < 1 week, histopathology showing small vessel occlusion, and laboratory confirmation of aPL. (53) Retrospective evaluation of long-term outcome for CAPS survivors has found that 66% remained symptom free (on anticoagulation) over an average follow up of 67 months; 26% percent developed further APS-related events. (54)

Therapy for APS

Therapy of the antiphospholipid syndrome generally involves anticoagulation for thrombosis (Table 3) or pregnancy prophylaxis (Table 4). Treatment is less well defined for the associated nonthrombotic complications, atypical complications, and for asymptomatic patients.

Asymptomatic aPL-positive Patients

No prospective data exist to support prophylactic anticoagulant therapy in asymptomatic aPL-positive patients, although randomized studies are in progress. (55) Current recommendations from a recent consensus statement favor low-dose aspirin (eg, 81 mg/d) in asymptomatic patients until prospective data are available. (56) Avoidance of reversible thrombotic risk factors (eg, smoking or oral contraceptives), and prophylaxis during high-risk periods such as surgery or immobilization are important considerations.

History of Obstetric Complications Without Thrombosis

A subset of aPL patients present with aPL and obstetric complications alone; these patients have not been routinely treated with prophylaxis after the immediate postpartum period. A retrospective study of subsequent thrombosis in 65 patients with prior pregnancy events, however, has shown such patients to have a 59% rate of thrombosis over 10 years of follow up; patients who continued on low-dose aspirin, however, had a rate of 10%. (21) Based on these data, the current recommendation is low-dose aspirin postpartum indefinitely.

Arterial or Venous Thrombosis

Retrospective studies suggested that long-term, high intensity (international normalized ratio [INR] 3-4) warfarin was most effective in preventing recurrent thromboembolic events, (57) but the necessity of high-intensity anticoagulation has become controversial. A recent prospective randomized controlled trial of two intensities of warfarin therapy in 114 aPL-positive patients with previous thrombosis followed for a mean of 2.7 years concluded that moderate (INR 2-3) and high (INR 3-4) intensity anticoagulation were similarly effective. (58) However, several criticisms limit interpretation of these results. The study excluded those patients who had already developed recurrent thrombosis on warfarin therapy. Four of six patients with clot in the high INR group had an INR < 2.0 at the time of thrombosis, and the high intensity group was subtherapeutic 43% of the time. Finally, 80% of patients had venous and not arterial thrombosis. Overall, less intense anticoagulation may be acceptable for APS patients with venous events but not necessarily arterial events.

Another recent trial, the Antiphospholipid Antibody and Stroke Study (APASS), (59) found no difference in recurrence rate of stroke in aPL-positive patients randomized to aspirin versus warfarin. A prospective cohort study within the Warfarin versus Aspirin Recurrent Stroke Study, APASS evaluated 1,770 stroke patients randomized to aspirin 325 mg or warfarin (INR 2.2) for presence of aPL. Outcome measures included two-year rate of death (any cause), ischemic stroke, TIA, myocardial infarction, DVT, PE, and other thromboembolic events. A total of 720/1,770 stroke patients were aPL-positive (41%). APL status was not associated with an increased risk of recurrent thrombo-occlusive events. Event rates were 22.2% (aPL-positive) versus 21.8% (aPL-negative). While the study showed no difference in the recurrence rate between the two therapies, a major concern was the relatively high rate of positive aPL tests, which were evaluated once and included many of low titer.

Nonthrombotic Manifestations

Few studies address the treatment of the nonthrombotic manifestations of APS. Most of these complications (eg, cardiac valve involvement or cognitive dysfunction) are generally managed with low-dose aspirin. It is not clear that anticoagulation with warfarin impacts progression of these manifestations. Thrombocytopenia with platelet counts greater than 100 X [10.sup.9]L due to APS does not generally require treatment. Corticosteroids and/or IV immunoglobulin (IVIG) are initial therapies for platelet counts less than 50 X [10.sup.9]L. Danazol occasionally stabilizes platelet counts, and splenectomy has been effective in corticosteroid-resistant cases.

Obstetric Complications

Earliest treatment for recurrent pregnancy loss associated with aPL was a combination of high dose prednisone and low-dose aspirin, with successful outcome in 75% of treated pregnancies. High maternal and fetal morbidity resulted, however, including gestational diabetes, hypertension, and premature rupture of membranes. A randomized controlled study of prednisone and aspirin as compared with heparin and aspirin showed low-dose subcutaneous heparin with low-dose aspirin to be equally efficacious with less morbidity, (60) and this regimen has become standard therapy for aPL pregnancy prophylaxis in patients with prior complications. Pregnancy success rates are about 75% (versus 40% for treatment with low-dose aspirin alone), (61,62) low-dose heparin is as effective as a higher dose for fetal prophylaxis. (63) Although early studies used unfractionated heparin, most patients are now treated with low molecular weight heparin (LMWH) due to ease of administration and lower risk of side effects. Empiric secondline therapy for aspirin/heparin failure is most often addition of IVIG, based on successful case reports, (64) although a small placebo-controlled study showed no benefit. (65)

Therapeutic dose heparin in combination with low-dose aspirin is the standard therapy for patients with a history of both obstetric complications and prior thrombosis. Low-dose aspirin alone is usually given to asymptomatic medium-to-high titer aPL-positive patients during pregnancy.

The relationship of aPL to infertility has been controversial. Although prevalence of aPL antibodies is increased in patients undergoing in vitro fertilization (IVF), a recent prospective study found that aspirin and heparin treatment of IVF patients with positive aPL antibodies and history of failed IVF cycles does not improve IVF cycle outcome. (66)

Catastrophic APS

Anticoagulation, corticosteroids, and plasma exchange or IVIG appear to impact survival rate for patients with CAPS. Since many patients have an identifiable trigger such as infection, treatment of any underlying condition is also essential. In addition to heparin, corticosteroid, and IVIG with plasmapheresis, other reported therapies include cyclophosphamide, thrombin inhibitors, fibrinolytics, and prostacyclin. (52)

Other Therapies

LMWH may occasionally be used long-term for patients with thrombosis for whom warfarin is ineffective, but major concerns include expense, risk of osteoporosis, and difficulty in monitoring. Although not supported by prospective data, anti-platelet agents are increasingly used, especially in patients with recurrent TIAs despite aspirin therapy. (67) Hydroxychloroquine has a known anti-platelet effect and is sometimes prescribed for asymptomatic APS patients: it is associated with a reduced risk of thrombosis in aPL-positive SLE patients. (68)

Novel therapies are on the horizon: LJP 1,082, a tetravalent conjugate of recombinant domain 1 of [beta]2GPI, is a proposed B-cell toleragen currently in clinical trials. (69) In the future, emerging anticoagulants, complement inhibitors, interleukin-3, or statins may assume new roles for patients with APS. (70,71)

Controversies in Treatment

Despite the current focus on developing evidence-based treatment, decisions regarding therapy for APS patients must still often be based on clinical experience and anecdotal reports. Certain treatment recommendations, however, are unequivocal. Low-dose aspirin and heparin therapy is indicated for pregnancy prophylaxis in women with previous obstetric complications, and greatly improves pregnancy outcome. Although clearly some form of anticoagulation is indicated in patients with thrombotic events, the precise therapy, intensity of anticoagulation, and duration of treatment are in question. Given recent data, it is reasonable to treat venous events with moderate-intensity warfarin therapy (INR 2.0-3.0). Since the APASS study included a large number of older, low-titer patients, it seems premature to abandon treatment of APS patients with stroke (or other arterial thrombosis) with high intensity warfarin. It is not known whether anticoagulant therapy with warfarin benefits valvular heart disease, cognitive dysfunction, renal disease, or MS-like syndromes. Most practitioners currently treat asymptomatic moderate- to high-titer individuals with low-dose aspirin. (56)

Duration of warfarin therapy may not be lifelong for all patients. Some patients are stable for years with loss of detectable antibody, and it is not known if they may safely discontinue therapy. Patients who have a complication in the setting of a potentially reversible risk factor, such as oral contraceptives or pregnancy, may not require indefinite anticoagulation. The presence of congenital risk factors (Factor V Leiden, prothrombin 20 210 mutation, MTHFR mutation, and protein C, S, or antithrombin III deficiencies) can aid in directing treatment and recommendations: presence of an additional risk factor might support more aggressive therapy. Serious perioperative complications can occur in APS patients despite prophylaxis. Purely elective surgery should be avoided, and vigorous antithrombotic measures used for any APS patient undergoing a surgical procedure. Warfarin is generally changed to low-molecular-weight heparin and occasionally even IV heparin perioperatively to minimize time of periods without anticoagulation. (72)

Great spirits have always encountered violent opposition from mediocre
minds.
--Albert Einstein

Table 1. Classification criteria for antiphospholipid syndrome (Sapporo
criteria) (a,b)

Laboratory criteria
  Anticardiolipin ab   Medium or high titer IgG and/or IgM isotype
                       Positive on two or more occasions (6 weeks apart)
                       [beta]2GPI-dependent ELISA
  -or-
  Lupus anticoagulant  Prolonged phospholipid-dependent coagulation test
                         (aPTT, dRVVT, KCT)
                       Failure to correct on mixing with normal
                         platelet-poor plasma
                       Correction with adding excess phospholipid
                       Exclusion of other coagulopathies
                       Positive on two or more occasions (6 weeks apart)
Clinical Criteria:
  Vascular thrombosis  One or more episodes of arterial, venous, or
                         small vessel thrombosis in any tissue or organ,
                         confirmed by imaging, Doppler studies or
                         histopathology (thrombosis without significant
                         inflammation in the vessel wall)
  -or-
  Pregnancy morbidity  One or more fetal deaths > 10th week gestation
                         with normal fetal morphology (ultrasound or
                         exam)
                       -or-
                       One or more premature births of a morphologically
                         normal neonate < 34th week gestation because of
                         severe preeclampsia or severe placental
                         insufficiency
                       or-
                       Three or more unexplained consecutive spontaneous
                         abortions < 10th week gestation with anatomic,
                         hormonal and chromosomal (maternal/paternal)
                         abnormalities excluded

(a) IgG, immunoglobulin G; IgM, immunoglobulin M; [beta]2GPI,
[beta]2-glycoprotein I; ELISA, enzyme-linked immunosorbent assay; aPTT,
activated partial thromboplastin time; dRVVT, dilute Russell viper venom
time; KCT, Kaolin clotting time.
(b) Diagnosis requires one laboratory and one clinical criterion. (1)

Table 2. Clinical manifestations of antiphospholipid syndrome (a)


Arterial thrombosis       Cerebral vascular accident; extremity
                            gangrene; mesenteric infarction; aortic
                            occlusion
Venous thrombosis         Deep venous thrombosis; pulmonary emboli;
                            mesenteric, hepatic, or renal vein
                            thrombosis; adrenal insufficiency
Obstetric complications   Fetal loss, recurrent pre-embryonic/embryonic
                            losses; pre-eclampsia; intrauterine growth
                            retardation
Hematologic               Thrombocytopenia; hemolytic anemia; Evans
                            syndrome; thrombotic microangiopathic
                            hemolytic anemia
Cutaneous                 Livedo reticularis; cutaneous necrosis;
                            pyoderma-like ulcerations; digital gangrene
Neurologic complications  Seizures; chorea; transverse myelitis;
  (non-stroke)              multiple sclerosis-like syndrome
Renal complications       Nephropathy with glomerular thrombosis;
                            cortical necrosis; renal infarction
Cardiac complications     Mitral and/or aortic insufficiency;
                            intracardiac thrombosis, coronary artery
                            thrombosis
Avascular necrosis
Catastrophic APS          With multisystem failure

(a) APS, antiphospholipid syndrome.

Table 3. Management of non-obstetric APS complications (a)

(+) aPL and complication                  Treatment

Asymptomatic                              No treatment (low titer aPL)
                                            or Ld aspirin (moderate to
                                            high titer aPL)
History pregnancy complications only      Ld aspirin
Venous thrombosis                         Warfarin (INR: 2.0-3.0)
Arterial thrombosis                       Warfarin (INR: 3.0-3.5)
Recurrent thrombosis                      Warfarin (INR: 3.0-4.0) and Ld
                                            aspirin
Thrombocytopenia > 50,000 X [10.sup.9]L   No treatment
Thrombocytopenia                          Corticosteroid, intravenous
  [less than or equal to] 50,000 X          immunoglobulin
  [10.sup.9]L
Catastrophic APS                          Anticoagulation,
                                            corticosteroid, and
                                            intravenous immunoglobulin
                                            or plasmapheresis

(a) aPL, antiphospholipid antibody; APS, antiphospholipid syndrome; Ld
aspirin, low-dose aspirin (81-100 mg/day); INR, international normalized
ratio.

Table 4. Management of obstetric APS complications (a,b,c)

(+) aPL pregnant patient                Treatment

Low aCL, no previous loss               None or Ld aspirin
(+) Moderate-high aCL/LA, 0-2 early     Ld aspirin
  losses
(+) aPL and HTN, abnormal renal         Ld aspirin
  function
(+) aPL and > 3 early or > 1 late loss  Ld aspirin and prophylactic
                                          heparin (d)
(+) aPL and pre-eclampsia/IUGR/         Ld aspirin and prophylactic
  placental infarction/other              heparin
  prothrombotic risk factor/special
  circumstances (e.g. AMA and IVF)
(+) aPL and previous thrombosis         Ld aspirin and therapeutic
                                          heparin (e) (not warfarin)
                                          while trying to conceive and
                                          throughout pregnancy

(a) aPL, antiphospholipid antibody; Ld aspirin, low-dose aspirin (81-100
mg/day); LA, lupus anticoagulant; HTN, hypertension; early,
pre-embryonic/embryonic) loss <10 weeks gestation; late, fetal loss > 10
weeks gestation; IUGR, intrauterine growth restriction; AMA, advanced
maternal age; IVF, in vitro fertilization.
(b) All aPL pregnancies require third trimester fetal monitoring with
non-stress tests and/or ultrasounds.
(c) Postpartum anticoagulation for minimum six weeks.
(d) Prophylactic heparin (usual dose) is 5000 units unfractionated
heparin subcutaneously BID (or equivalent low-molecular-weight heparin).
(e) Therapeutic heparin (usual dose) is unfractionated heparin
subcutaneously BID, with mid-interval PTT 60-80 sec (or equivalent
low-molecular-weight heparin).

Accepted March 24, 2005.

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RELATED ARTICLE: Key Points

* Antiphospholipid syndrome (APS) is characterized by the presence of anticardiolipin antibody or lupus anticoagulant together with, typical clinical manifestations of thrombosis or pregnancy loss and morbidity.

* The spectrum of manifestations associated with APS is broad and includes, in addition to thrombosis and pregnancy morbidity, thrombocytopenia, livedo reticularis, cardiac valvular disease, and an acute syndrome of multiorgan thrombosis termed "catastrophic antiphospholipid syndrome."

* Treatment of APS is still evolving but generally involves anticoagulation with warfarin for thrombosis and prophylactic therapy with aspirin and heparin during pregnancy in patients with previous obstetric complications.

Lisa R. Sammaritano, MD

From Weill Medical College of Cornell University, Hospital of Special Surgery, New York, NY.

Dr. Sammaritano has no disclosures to declare.

Reprint requests to Lisa R. Sammaritano, MD, Associate Professor of Clinical Medicine, Weill Medical College of Cornell University, Hospital for Special Surgery, 535 East 70th Street, Room 777, New York, NY 10021. Email: [e-mail]