Catastrophic Antiphospholipid Syndrome

Transcription

1 ARTHRITIS & RHEUMATISM Vol. 48, No. 12, December 2003, pp DOI /art , American College of Rheumatology REVIEW Catastrophic Antiphospholipid Syndrome Where Do We Stand? Doruk Erkan, 1 Ricard Cervera, 2 and Ronald A. Asherson 3 Introduction Antiphospholipid syndrome (APS) is a distinct autoimmune disorder characterized by vascular thromboses and/or pregnancy morbidity in the presence of antiphospholipid antibodies (apl; most commonly anticardiolipin antibodies [acl]), lupus anticoagulant (LAC) positivity, and/or anti 2 -glycoprotein I (anti- 2 GPI) antibodies (1). Fewer than 1% of APS patients present with a life-threatening condition due to multiple organ thromboses and failure, which is defined as catastrophic APS (CAPS) (2). CAPS differs from classic APS in several ways. In classic APS, single venous or arterial medium-to-large blood vessel occlusions usually dominate the clinical picture, and recurrences are rare with adequate anticoagulation. In CAPS, however, severe multiple organ dysfunction characterized by rapid, diffuse small vessel ischemia and thromboses predominantly affecting the parenchymal organs dominates the clinical picture. It remains unknown why some patients develop CAPS rather than classic APS; however, the role of trigger factors has been well demonstrated in CAPS patients. Some of these trigger factors (e.g., surgery or oral contraceptive use) are also evident in patients with classic APS; however, the proposed double- or triplehit hypothesis may be applicable to CAPS patients. Furthermore, CAPS is fatal in approximately half of all patients despite treatment (3,4). 1 Doruk Erkan, MD: Hospital for Special Surgery, Weill Medical College of Cornell University, New York, New York; 2 Ricard Cervera, MD, PhD: Institut Clínic d Infeccions i Immunologia, Hospital Clinic, Barcelona, Catalonia, Spain; 3 Ronald A. Asherson, MD: University of Cape Town School of Medicine, Cape Town, South Africa. Address correspondence and reprint requests to Doruk Erkan, MD, Assistant Attending Physician, Hospital for Special Surgery, 535 East 70th Street, New York, NY derkan@pol.net. Submitted for publication March 31, 2003; accepted in revised form August 20, Following the initial description of CAPS in 1992 (2), the first comprehensive literature review of 50 CAPS patients was published in 1998 (3). Three years later, a second literature review described an additional 80 CAPS patients (4). In a recent review article, the clinical manifestations and differential diagnosis of CAPS as well as diagnostic tests for CAPS and treatment of CAPS patients were discussed in detail (5). Since CAPS is being increasingly recognized by physicians, the purpose of this article is to review the recent developments in CAPS with a special emphasis on the treatment options. We hope that this article will assist physicians in the early diagnosis and treatment of this debilitating syndrome, which we hope will eventually improve the disastrous outcome of the majority of CAPS patients. Difficulties in the management of CAPS patients The management of CAPS patients is challenging for the following reasons: 1) multiple thrombotic events occur simultaneously or in an evolving manner; 2) the presentation often differs from that of vascular thrombosis (Table 1) and can be difficult to distinguish from those of disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets syndrome), or systemic vasculitis; and 3) the optimal treatment regimen is unknown. CAPS is a rare condition, which makes the syndrome difficult to study. Prospective, large-scale controlled studies do not exist, and our knowledge of CAPS, including treatment strategies, is based on reviews of published case reports (3,4). Furthermore, until recently, a standardized diagnostic and therapeutic approach to CAPS patients did not exist. The lack of standardization resulted in classification of lifethreatening APS events as CAPS by some, but not by all 3320

2 CATASTROPHIC APS 3321 Table 1. Conditions associated with catastrophic antiphospholipid syndrome Malignant hypertension Acute respiratory distress syndrome Disseminated intravascular coagulation Microangiopathic hemolytic anemia Schistocytes Thrombocytopenia (6). Thus, a nonstandardized diagnosis system may have resulted in over- or underdiagnosis of CAPS and may have had a negative impact on outcomes International Taormina Consensus Statement on Classification and Treatment of CAPS Preliminary CAPS classification criteria (Table 2) and treatment guidelines (Figure 1) have been proposed and accepted in Taormina, Sicily during the 10th International Congress on apl (7). This consensus statement has major importance because CAPS patients with debatable diagnoses or less severe disease ( probable CAPS) will now be classified separately from definite CAPS patients. Although these criteria and guidelines are accepted for classification purposes, they will also provide us with a more consistent diagnostic and therapeutic paradigm and will assist in future multicenter studies. Analysis of the treatment of 130 reported CAPS patients The clinical characteristics and outcomes of 130 reported CAPS patients have been reviewed in two different series (3,4). Based on these series, 63 of 130 CAPS patients (48%) died at the time of the reported event. Older age and higher number of involved organs were associated with mortality (Table 3) (7). Splenic (P 0.001), cardiac (P 0.007), and intestinal (P 0.04) involvement were significantly associated with death, while involvement of other organs (such as the peripheral vascular system, brain, lungs, kidneys, skin, adrenal glands, and liver) did not differ between survivors and nonsurvivors. With respect to laboratory tests, thrombocytopenia was associated with death (P 0.014), but hemolysis, DIC, and the presence of schistocytes were not. Interestingly, in this series, there were no differences regarding the number of medications used by each patient when survivors were compared with nonsurvivors (Table 3). However, each patient received an average of more than two treatments. When each treatment was analyzed individually, only anticoagulation had a significant effect on mortality. Since there were only a few patients in the series who had received anticoagulation alone, it is difficult to recommend anticoagulation as the sole therapy, because most received this in conjunction with other treatments. The highest survival rate was achieved with the combination of anticoagulation, corticosteroids, and plasmapheresis or intravenous immunoglobulin (IVIG) (70%) (7). Furthermore, the addition of cyclophosphamide to the regimen did not change the outcome. International CAPS registry The European Forum on Antiphospholipid Antibodies has recently created an international registry of CAPS patients. This registry contains clinical, laboratory, and therapeutic data on all reported cases of CAPS as well as on many additional patients whose data have Table 2. Preliminary criteria for the classification of CAPS* 1. Evidence of involvement of 3 organs, systems, and/or tissues 2. Development of manifestations simultaneously or in 1 week 3. Confirmation by histopathology of small vessel occlusion in at least 1 organ/tissue 4. Laboratory confirmation of the presence of apl (LAC and/or acl and/or anti- 2 GPI antibodies) Definite CAPS All 4 criteria Probable CAPS All 4 criteria, except for involvement of only 2 organs, systems, and/or tissues All 4 criteria, except for the absence of laboratory confirmation of the presence of apl at least 6 weeks after a first positive result (due to the early death of a patient never tested for apl before onset of CAPS) 1, 2, and 4 1, 3, and 4, plus the development of a third event in 1 week but 1 month, despite anticoagulation treatment * Proposed and accepted during the 10th International Congress on Antiphospholipid Antibodies (apl), September 2002 in Taormina, Sicily. CAPS catastrophic antiphospholipid syndrome; LAC lupus anticoagulant; acl anticardiolipin antibodies; anti- 2 GPI anti 2 -glycoprotein I. Adapted, with permission, from ref. 7. Usually clinical evidence of vessel occlusions, confirmed by imaging techniques when appropriate. Renal involvement is defined by a 50% rise in serum creatinine, severe systemic hypertension ( 180/100 mm Hg), and/or proteinuria ( 500 mg/24 hours). For histopathologic confirmation, significant evidence of thrombosis must be present, although vasculitis may coexist occasionally. If the patient had not been previously diagnosed as having APS, the laboratory confirmation requires detection of the presence of apl on 2 occasions at least 6 weeks apart (not necessarily at the time of the event), according to the proposed preliminary criteria for the classification of definite APS (1).

3 3322 ERKAN ET AL Figure 1. Treatment algorithm for catastrophic antiphospholipid syndrome (APS). Shown are treatment guidelines that were proposed and accepted during the 10th International Congress on Antiphospholipid Antibodies, September 2002 in Taormina, Sicily. IVIG intravenous immunoglobulin; SLE systemic lupus erythematosus. Adapted, with permission, from ref. 7. been fully registered. This registry can be freely consulted through the Internet ( MIMMUN/FORUM/CAPS.HTM), and it is expected that the periodic analysis of these data will allow us to increase our knowledge of this condition. Treatment strategies for CAPS If CAPS is suspected, aggressive treatment is required without delay. General measures (described below) should be applied in addition to first-line thera- Table 3. Analysis of 130 reported patients with catastrophic antiphospholipid syndrome (CAPS) Clinical characteristic Deceased (n 63)* Recovered (n 67)* P Age at CAPS event, mean years Organs involved, mean SD Medications used, mean SD * At the time of CAPS.

4 CATASTROPHIC APS 3323 Table 4. Treatment options for catastrophic antiphospholipid syndrome* First line Second line Third line Experimental Anticoagulation IVIG Fibrinolytics Anticytokines Corticosteroids Plasma exchange with Cyclophosphamide Other or without FFP Prostacyclin Ancrod Defibrotide * IVIG intravenous immunoglobulin; FFP fresh frozen plasma. pies (anticoagulation and corticosteroids). Second-line therapies are necessary in the absence of a clinical response or in the presence of ongoing thrombosis despite first-line treatment. In the case of a deteriorating clinical situation, one of the third-line treatments (with which experience is very limited and/or the effects on outcome are unknown) should be considered (Table 4). General measures Early diagnosis and aggressive treatment are crucial in the management of CAPS patients. The presentation of CAPS patients may evolve gradually, and some of the clinical manifestations (such as renal, gastrointestinal, or bone marrow involvement) may not be as evident as others. Thus, a high index of clinical suspicion and careful investigation are required. As soon as the diagnosis of definite or probable CAPS is suspected, anticoagulation and corticosteroids should be commenced (first-line treatment). Furthermore, intensive care therapy, hemodialysis for renal failure, mechanical ventilation for pulmonary failure, or inotropic drugs for cardiogenic shock also play an important role in the management of CAPS patients. Treatment or elimination of possible precipitating factors (e.g., infections, tissue necrosis, drugs [mostly oral contraceptives], or surgical procedures) is also extremely important. Antibiotics should be started as soon as possible if infection is suspected. In the case of necrotic tissues or organs, debridement or amputation should be performed without delay, and these procedures may significantly improve the outcome (8). Severe hypertension due to renal artery/vein thrombosis or thrombotic microangiopathy is common in CAPS patients, necessitating aggressive antihypertensive therapy. Surgical or interventional measures may be needed. Patients may present with hypotension in cases of adrenal involvement/hemorrhage. Surgical procedures (even minor ones) in asymptomatic (no history of vascular or pregnancy event) apl-positive, APS, and CAPS patients deserve special attention. During the perioperative period, these patients are at high risk for vascular thrombosis and, rarely, for CAPS. In a recent study, we found that of 15 CAPS survivors who developed further thrombotic events, 6 (40%) experienced thromboses during the perioperative period (9). For thrombosis prophylaxis, the most effective pharmacologic methods should be combined with physical methods such as intermittent venous compression, and patients should be closely observed for the signs and symptoms of thrombotic events. Strategies that may guide physicians in their perioperative management of APS patients are summarized in Table 5 (10). Table 5. Recommendations to prevent CAPS (in apl-positive patients) and for the perioperative medical management of APS and CAPS patients* Preoperative assessment Surgical and interventional procedures should be the last option in the management of APS patients Platelet count /liter due to APS requires no specific therapy; thrombocytopenia does not protect against thrombosis Perioperative considerations Minimize intravascular manipulation for access and monitoring Set pneumatic blood pressure cuffs to inflate infrequently to minimize stasis in the distal vascular bed Avoid tourniquets Maintain high suspicion that any deviation from a normal course may reflect arterial or venous thrombosis Perioperative anticoagulation Keep periods without anticoagulation to an absolute minimum Employ pharmacologic and physical antithrombosis interventions vigorously and start immediately before the operation, continuing until the patient is fully ambulating Be aware that APS patients can develop recurrent thrombosis despite appropriate prophylaxis Be aware that current conventional doses of antithrombotic agents can result in underanticoagulation ; APS patients may benefit from an aggressive approach with higher-than-standard doses * See Table 2 for definitions. Adapted, with permission, from ref. 10.

5 3324 ERKAN ET AL Medical management Anticoagulation (usually intravenous heparin followed by a warfarin derivative), corticosteroids, plasmapheresis, and IVIG are the most commonly prescribed medications/treatments for CAPS patients. Other reported management options for CAPS patients include fibrinolytics, prostacyclin, defibrotide, danazol, cyclophosphamide, and azathioprine. In selected cases, thrombectomy or embolectomy can be performed. A treatment algorithm based on the Taormina Consensus Statement is shown in Figure 1 (7). Anticoagulation (unfractionated or low molecular weight heparin). Heparin accelerates the activity of antithrombin 1,000-fold, which results in inhibition of thrombin, factor Xa, and other activated clotting factors (11). Thus, heparin inhibits clot formation and lyses existing clots. Furthermore, in vitro, heparin inhibits the binding of apl to their target and absorbs apl, although these effects are not clear in vivo (12). Intravenous heparin is usually administered for 7 10 days followed by life-long administration of warfarin, aiming for an international normalized ratio (INR) of 3. For those patients with positive LAC and elevated baseline activated partial thromboplastin time, monitoring anti factor Xa activity can assure adequate anticoagulation. CAPS is usually refractory to anticoagulation alone, which mandates the use of additional agents. Heparin-induced thrombocytopenia may further complicate the clinical picture due to bleeding complications or thrombosis. New thrombotic events have been reported in heparin-treated patients in association with thrombocytopenia, resulting from irreversible aggregation of platelets induced by heparin, the so-called white-clot syndrome (13,14). This occurs due to the presence of antibody that binds to platelet factor IV and heparin (15). Corticosteroids. Corticosteroids inhibit the excessive cytokine response via suppression of the humoral and cell-mediated immune responses. Corticosteroid treatment is indicated in CAPS in order to treat manifestations of systemic inflammatory response syndrome (SIRS) and not the underlying thrombotic storm (16). SIRS is characterized by diffuse inflammation of the vascular endothelium, and the major mediators of SIRS are tumor necrosis factor (TNF ) and interleukin-1 (IL-1) (17). Some of the major clinical manifestations of CAPS resulting from multiple small vessel occlusive disease and consequent tissue necrosis (i.e., adult respiratory distress syndrome [ARDS], decreased cardiac function, and cerebral dysfunction) may be directly attributable to SIRS (17), and these effects require high-dose corticosteroid therapy. Most commonly, intravenous pulse methylprednisone (1,000 mg/day) is administered for 3 5 days followed by high doses of methylprednisone (1 2 mg/kg/ day). The dosage should be tapered according to the therapeutic response. It is important to note that corticosteroids alone do not prevent further thrombotic events. IVIG. IVIG blocks antibody binding to macrophage receptors, increases T suppressor cells, possibly decreases antibody synthesis, and increases the catabolism of circulating IgG (18). The dose is usually 0.4 gm/day per kilogram of body weight for 4 5 days. IVIG has been used in the treatment of idiopathic thrombocytopenic purpura, and it is specifically helpful in the presence of thrombocytopenia. IVIG is contraindicated in patients with IgA deficiency, since IVIG can result in severe anaphylactic reactions in these patients. Furthermore, IVIG infusion may exacerbate renal dysfunction in patients with existing renal involvement, particularly in those older than age 65, receiving known nephrotoxic drugs, with volume depletion, and with sepsis. Especially in these patients, IVIG should be administered at the minimum concentration and rate of infusion. Low sucrose containing products are preferred. Headache is common after IVIG infusions, and severe persistent headaches due to aseptic meningitis have been reported. IVIG increases blood viscosity; however, there has been no direct association between IVIG infusion and thrombosis. Plasma exchange with or without fresh frozen plasma (FFP). Although the exact mechanism is unclear, plasma exchange can remove pathologic IgG acl and anti- 2 GPI as well as cytokines, TNF, and complement. Furthermore, FFP contains natural anticoagulants, especially antithrombin III and protein C. The most often used procedure is the removal of 2 3 liters of plasma for a minimum of 3 5 days. Plasma exchange is the treatment of choice for TTP, which has characteristics and presentation somewhat similar to those of CAPS. A recent article which reviewed the literature from 1983 through December 2002 reported the analysis of the clinical and laboratory features of 46 patients with thrombotic microangiopathic hemolytic anemia (TMHA) associated with apl (19). Twenty-eight patients (61%) had primary APS, and TMHA was the first clinical manifestation of APS in 26 patients (57%). By order of decreasing frequency, the clinical presentations were as follows: hemolytic uremic syndrome (26%), CAPS (23%), acute renal failure

6 CATASTROPHIC APS 3325 (15%), malignant hypertension (13%), TTP (13%), and HELLP syndrome (4%). Steroids were the most frequent treatment (69% of episodes), followed by plasma exchange (62%), anticoagulant or antithrombotic agents (48%), immunosuppressive agents (31%), and immunoglobulins (12%). Recovery occurred in only 34% of episodes treated with steroids and in 70% of episodes treated with plasma exchange. Investigators in the study concluded that plasma exchange is indicated as a first line of treatment for all patients with TMHA associated with apl (19). One report has suggested that anti- 2 GPI levels can be used as a marker of CAPS activity and response to plasma exchange (20). Furthermore, the same report indicated that patients with IgA isotypes of acl may not benefit from plasma exchange (20). Although investigators in several studies reported that plasma exchange improves outcomes in APS patients (20,21) and is specifically indicated if schistocytes are present, it is important to note that most of the reported CAPS patients had received plasmapheresis together with FFP. Thus, it is difficult to know whether plasma exchange or FFP alone would be beneficial. Fibrinolytics (streptokinase, urokinase, tissue plasminogen activator). Fibrinolytics cause lysis of thrombi. These agents should be considered in case of nonsatisfactory response to first- and second-line agents. They are not commonly used due to increased risk of bleeding complications. Cyclophosphamide. Cyclophosphamide is an alkylating agent which interferes with nucleic acids and proteins. The initial dose is usually gm/m 2 of body surface area intravenously. Although no benefit was found in the series of 130 CAPS patients (3,4), cyclophosphamide could theoretically be used to prevent apl rebound after plasma exchange and/or in the presence of systemic lupus erythematosus flares. Prostacyclin. Prostacyclin results in vasodilation of all vascular structures and inhibition of platelet aggregation. The dose is 5 ng/kg/minute for 7 days according to one case report (22). However, since there are also reports suggesting that prostacyclin therapy can induce a rebound thrombosis (23,24), prostacyclin infusions should be used with caution. Ancrod. Ancrod is a purified fraction of Malayan pit viper venom that results in defibrination and correction of prostacyclin-stimulating factor and plasminogen activator deficiencies. Ancrod was used in only one CAPS patient (25). Defibrotide. Defibrotide is an alkali metal salt of single-stranded DNA. It is an adenosine receptor agonist with affinity to adenosine receptors A1 and A2, an effect that appears to have antithrombotic function. Defibrotide has multiple vascular endothelial cell modulatory actions, including 1) up-regulation of endogenous prostaglandin E 2 (PGE 2 ) and PGI 2 ; 2) downregulation of prothrombotic leukotriene B 4 ; 3) reconstitution of platelets own deaggregatory actions via stimulation of vascular prostacyclin; 4) stimulation of fibrinolysis, primarily by the down-regulation of plasminogen activator inhibitor 1 (PAI-1) and secondarily by increasing endogenous tissue plasminogen activator activity; and 5) down-regulation of endothelin 1 (ET-1) (26). The dose and duration of defibrotide are mg/kg/day for a minimum of 3 weeks. Defibrotide may also be given orally at double the intravenous dose. There is only one case report of defibrotide use in CAPS; however, it may have an important role in the management of CAPS as a polypharmacologic agent in the future (26). Anticytokine treatment. There have been no reports of the use of anticytokine therapy (etanercept, infliximab, or anakinra) for CAPS patients. Although we cannot recommend the use of these agents in CAPS based on our current knowledge, they nevertheless may represent a new therapeutic option. In support of this is the recent report of a study in which the cytokine levels of a patient with CAPS were evaluated. The study demonstrated that vascular endothelial cell injury might play a major role in the pathogenesis of CAPS (26). In the study, a CAPS patient who had not responded to combination therapy with heparin, warfarin, aspirin, and dipyridamole was treated with defibrotide within the context of an investigational phase II protocol. Based on this protocol, a pattern of results for the following panel of assays was identified as being representative of vascular endothelial cell injury in multiorgan dysfunction syndromes (including CAPS): PAI-1, platelet count, arachidonic acid induced platelet aggregation (AAagg), ET-1, TNF, IL-1, IL-2, IL-6, and von Willebrand antigen. Prior to initiation of defibrotide, TNF, PAI-1, and ET-1 levels were elevated, while the AA-agg level and platelet count were decreased. After 25 days of defibrotide treatment, the complete spectrum of vascular endothelial cell injury markers normalized. It is important to note that down-regulation of cytokines by defibrotide continues only until normal levels are reached, unlike the effects of anti-tnf antibodies, the continuous administration of which leads to subnormal levels. Thus, anti-tnf therapy should be used very carefully in patients with multiorgan failure.

7 3326 ERKAN ET AL Furthermore, it has been recently reported that patients treated with TNF antagonists have statistically significant increases in both IgM and IgG acl. Even though the development of acl was not associated with an increased number of thromboembolic events in this study, this risk cannot be excluded until proven otherwise (27). We therefore suggest that levels of the above markers be tested in CAPS patients (if possible) in order to better understand the role of anticytokine therapy in this condition. Although no studies regarding the action of various anti-tnf agents in this disease have yet been undertaken, in an emergency situation such as CAPS, intravenous infusions of infliximab rather than the other anti-tnf agents may be preferable, and these infusions could be repeated after hours, particularly in patients with complications of SIRS (e.g., ARDS). Other treatment strategies. Other novel anticoagulation strategies have been developed with new drugs, many of which are still in clinical trials; not surprisingly, none of these new strategies has yet been formally tested in APS or CAPS patients. Hirudin is the most potent naturally occurring specific inhibitor of thrombin. At present, most clinical benefits of hirudin have been demonstrated in the management of patients with heparin-induced thrombocytopenia, and hirudin has been licensed for this indication (28). However, hirudin is a logical choice for clinical trials in CAPS treatment failures. Bivalirudin (shorter half-life than hirudin) and argatroban are two other thrombin inhibitors. Again, even though there is no reported experience in APS patients with these agents, they may be used in cases resistant to standard treatment. Antiplatelet agents such as dipyridamole, ticlopidine, or clopidogrel may have a more important role to play in the management of APS or CAPS patients in the future, but these compounds have not yet been formally studied. Long-term management and prognosis of CAPS Recent studies suggest that low-intensity warfarin might be effective in preventing thromboembolism in APS patients (29). Thus, some authorities prefer to advocate an INR of for those with first venous thrombosis, reserving high-intensity anticoagulation (INR of ) for those with recurrent events. In CAPS patients, we recommend high-intensity anticoagulation, even though this has not been supported prospectively. An INR of 4.0 provides no additional therapeutic benefit in most patients and is associated with a higher risk of bleeding. Aspirin or statins (hydroxymethylglutarylcoenzyme A reductase inhibitors) can be considered as an additional long-term treatment in CAPS patients because of the severe and widespread thromboses that have occurred. Aspirin inhibits prostaglandin and thromboxane A 2 synthesis by blocking the enzyme cyclooxygenase. It has been hypothesized that inhibition of platelet aggregation can decrease exposure of negatively charged phospholipids, which eventually decreases antibody binding (30). Statins are used widely for the treatment of hypercholesterolemia. These agents can inhibit the endothelial activation mediated by anti- 2 GPI antibodies (31). Whether statins are effective in CAPS is unknown; however, they can be considered as an addition to anticoagulation when patients continue to have clots despite optimal therapy. CAPS recurrence is unusual, and patients generally have a stable course with continued anticoagulation. We recently demonstrated that 66% of patients who survived an initial CAPS event remained symptom free with anticoagulation during an average followup of 67.2 months. Twenty-six percent of the survivors developed further APS-related events, but none developed further CAPS (9). Conclusion Although rare, CAPS is still a challenge for physicians. Currently, it is not possible to predict which patients will develop CAPS; however, genetic studies of CAPS patients (including genetic differences in HLA, protein C, and protein S profiles) and of how they differ from those with classic APS are now being planned. The clinical manifestations of CAPS are based not only on the effects of multiorgan thromboses, but also on the presumed major cytokine response to necrotic tissue which results in further vascular occlusive events not seen in patients with classic APS. Both thrombosis and cytokine response have to be treated early and effectively, and the search for new agents will be predicated on the unraveling of the pathogenesis of the condition itself. ACKNOWLEDGMENT The authors wish to thank Margaret G. Peterson, PhD, for her assistance with statistical analysis. REFERENCES 1. Wilson WA, Gharavi AE, Koike T, Lockshin MD, Branch DW, Piette J-C, et al. International consensus statement on preliminary

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