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Transient lupus anticoagulants associated with hemorrhage rather than thrombosis: The hemorrhagic lupus anticoagulant syndrome
998
Becton and Stine
The Journal of Pediatrics June 1997
Transient lupus anticoagulants associated with hemorrhage rather than thrombosis: The hemorrhagic lupus anticoagulant syndrome D a v i d L. B e c t o n , MD, a n d Kimo C. Stine, MD From the Depaffment of Pediatrics, Section of Hematology/Oncology, Comprehensive Hemophilia Center, University of Medical Sciences and Arkansas Children's Hospital, Little Rock
Lupus anticoagulants (LAs) represent a diverse group of antibodies directed against phospholipids. Patients with LAs may be free of symptoms but can have thrombotic complications including stroke, placental infarction, and fetal loss. Rarely hemorrhagic symptoms have been reported. We describe six previously healthy children who were first seen with clinical bleeding and prolonged activated partial thromboplastin time. Laboratory evaluation revealed positive results on mixing studies and evidence of phospholipid dependence of the anticoagulant, suggesting LAs. Four of six patients had anticardiolipin antibodies, and all four who were tested had reduced factor II activity levels. In all patients, bleeding symptoms resolved spontaneously within 3 months, and laboratory findings returned to normal within 6 months. The hemorrhagic LA syndrome should be considered in previously healthy children with new-onset bleeding and prolonged activated partial thromboplastin time. This clinical entity probably represents a pathogenic mechanism distinct from thrombotic LA syndromes. (J Pediatr 1997; 130:998-1000) The so-called lupus anticoagulants represent a diverse group of antibodies directed against phospholipids. LAs may be found in patients with systemic lupus erythematosis and other autoimmune disorders, or in otherwise healthy persons, and are typically associated with thrombotic complications, t-5 However, there have been case reports of apparent LAs with transient hemorrhagic symptoms in children, often after a viral infection and sometimes associated with low levels of factor II activity. 6-t° We now describe six previously healthy children with clinical bleeding and prolonged activated partial thromboplastin time, who had laboratory evidence of LAs and reduced factor II levels. METHODS Prothrombin time and aPTT testing was performed by using standard reagents and an automated system. Mixing studies were performed with a 50:50 mix of patient and pooled normal human plasma, and measurements were made immediately and at i and 2 hours. Platelet neutralization was performed by using the method of Triplett et al.ll A Russell Submitted for publication Aug. 18, 1996; accepted Nov. 18, 1996. Reprint requests: David L. Becton, MD, 800 Marshall St., Little Rock, AR 72202. Copyright © 1997 by Mosby-Year Book, Inc. 0022-3476/97/$5.00 + 0 9/22/79373
aPTr LA PT RVVT SLE
Activatedpartial thromboplastin time Lupus anticoagulant Prothrombintime Russellviper venom test Systemiclupus erythematosus
viper venom test was performed by using Russell viper venom and the method of Thiagaraj an et al. 12Anticardiolipin antibodies (IgG and IgM) were measured by an enzymefinked immunosorbent assay method. Factor II levels were measured by using factor-deficient plasma in a PT method. Patients. All patients were otherwise healthy, with no history or family history of bleeding disorders. None had a history of SLE or other collagen vascular disease, and results of laboratory evaluation of collagen vascular disease were negative in all patients. Clinical and laboratory features are summarized in Tables I and II. All bleeding symptoms resolved within 4 months without therapy. RESULTS All six patients had prolonged aPTT (range, 37.45 to 81.25; mean, 61.25), which led to further hemostatic evaluation. Complete blood cell counts, including platelet counts, were normal in each patient. All male subjects had factor VIII and IX activities measured, and all patients had
The Journal of Pediatrics Volume 130, Number 6
Becton and Stine
999
Table I. Clinical features of patients with lupus anticoagulant Patient No.
Age (yr)
Gender
Hx viral illnesses
Clinical presentation
Follow-up (mo)
1 2 3 4 5 6
8.2 2.1 5.0 10.0 10.0 4.2
F M F M M M
N Y Y Y N Y
Epistaxis, bruising Bruising, epistaxis Epistaxis Elbow bleed Epistaxis Hematemesis, hernatomas
60 60 55 48 38 10
Hx, History.
Table II. Laboratory features at diagnosis and follow-up associated with lupus anticoagulant Patient
PT*
aPTT*,'J"
Mixing
PNWf
RVVT§
ACA*,#
Factor il*,¶
Time of follow-up sample (mo)
1 2 3 4 5 6
17/11.5 23/13.0 16.5/12.0 16.0/12.5 13.5/12.0 27.5/11.5
80.7/29.8 81.2/31.1 53.4/29.1 50.6/26.4 37.4/31.1 66.0/29.9
+ + + + + +
+ + + + + +
24 26.5 34 26.5 37.4 46.0
+/+/ND +/+/-/ND +/-
17/58 12/ND ND/ND 12/112 ND/ND 7/77
4 3 6 6 2 2
PNP, Plateletneutralizationprocedure;ACA, anticardiotipinantibodies;ND, Not done. *Initialand fo~low-upsamples, "taPTT:normalrange, 21 to 32 seconds. -~PNP:normalvalue,undetectable. §RWT: normalvalue, 24 to 33 seconds. #ACA: normalvalue,undetectable. ~[FactorII coagulationactivity:normalvalue, 50% to i00%.
measurement of von Willebrand antigen and ristocetin cofactor. Results of all hemophilia and von Willebrand testing were normal. Mixing studies with 1:1 dilution of patient and pooled normal human plasma were performed. All patients failed to correct their aPTTs, indicating the presence of a circulating anticoagulant rather than a factor deficiency. At that point, tests to co~ffirm the presence of LAs were performed, including the platelet neutralization procedure, Russell viper venom time, and anticardiolipin antibody. Findings of at least two of these tests were abnormal in each patient except patient 4, who had a normal RVVT and borderline levels of anticardiolipin antibody. In four patients, acute levels of factor II activity were obtained, and all were reduced significantly (range, 7% to 17%; mean, 13%). Follow-up laboratory evaluation, performed from 2 to 6 months after presentation, revealed normalization of all measured hemostatic testing in every patient, which correlated with complete clinical resolution. DISCUSSION We described six previously healthy children in whom bleeding symptoms were associated with a transient LA-like inhibitor. Although most patients had relatively minor
bleeding such as epistaxis or bruising, three had more severe symptoms, with large hematomas, hematemesis, or hemarthrosis. All patients had prolonged aPTTs, and positive results on mixing studies and platelet neutralization procedures; four of six had evidence of anticardiolipin antibodies; and all four tested had hypoprothrombinemia. Bleeding symptoms resolved within 3 months in all patients, and all previously abnormal coagulation parameters returned to normal. No therapy was required. Prolonged follow-up (range, 10 to 60 months; mean, 45.1 months) to date has been associated with no recurrent bleeding episodes and no evidence of collagen vascular disease. No patient had thrombosis. LAs are autoantibodies directed against negatively charged phospholipids or phospholipid-binding proteins, including those associated with clotting proteins such as prothrombin.l-5 They interfere with at least one phospholipid-dependent in vitro coagulation test, such as the agYr, RVVT, or dilute PT. 13 The diagnosis of LAs can be difficult and depends on heightened clinical suspicion and a carefully coordinated laboratory evaluation. There are three recognized components of the laboratory confirmation of LAs: (1) the use of sensitive screening reagents; (2) mixing studies to confirm the presence of a circulating anticoagulant; and (3) proof that the anticoagulant is phospholipid dependent. 14
1000
Becton and Stine
Patients with LAs may be symptom free but often have a tendency toward thrombosis, including deep-vein thrombosis, placental infarction, and stroke, a-5 LA-induced thrombosis may be related to complement activation triggered by the binding of the antibody to phospholipid, followed by platelet aggregation, endothelial damage, or both. The risk of thrombosis is usually long term and may be related to the status of the underlying disease. Hemorrhage in patients with LAs is much less common and has been associated with hypoprothrombinemia or low platelet counts. Previous case reports described individual pediatric patients with clinical and laboratory features similar to those which we observed in our six patients: (1) sudden onset of bleeding in a previously healthy child, (2) recent history of viral infection, (3) laboratory findings compatible with the diagnosis of LAs, (4) hypoprothrombinemia, (5) no evidence of collagen vascular disease or thrombosis, and (6) spontaneous resolution within 3 months, usually without therapy. 61° Recurrence of LAs or bleeding symptoms has not been reported in other case reports, and our six patients have been followed up for 10 to 60 months (mean, 45.3 months) without recurrent bleeding and with no clinical or laboratory evidence of collagen vascular disease. Although the laboratory findings (prolonged PT, aPTT, and RVVT; positive results on mixing studies and platelet neutralization procedures, and even anticardiolipin antibodies) of the hemorrhagic LA syndrome exhibited by our patients are almost identical to the "thrombotic" syndrome observed among patients with SLE and related disorders, these are clearly distinct clinical disorders. The understanding of LAs and anticardiolipin antibodies, as with the entire field of hemostasis and thrombosis, is evolving rapidly. Continued biochemical and molecular investigations will undoubtedly elicit specific distinctions between the hemorrhagic and thrombotic types of LA, leading to more appropriate nomenclature. In the interim, the presence of a lupuslike anticoagulant should be suspected in children with new-onset bleeding symptoms. The incidence of this syndrome is uncertain; our patients were seen during a 4-year period in an academic pediatric hematology program and represented the most common confirmed diagnosis in patients with prolonged aPTT other than hemophilia (A or B) or von Willebrand disease. After the detection of a prolonged aPTF in a child, mixing studies should be considered, and if results are positive, a complete LA profile should be obtained, including a prothrombin activity level. Patients
The Journal of Pediatrics June 1997
with confirmed hemorrhagic LA syndrome will usually spontaneously resolve without therapy, but corticosteroids have been used in some patients. 9 Prothrombin complex plasma products could be considered in patients with documented hypoprothrombinemia and significant bleeding, although the response to such infusions should be monitored clinically if ongoing antibody activity is suspected. REFERENCES
1. Ginsberg JS, Wells PS, Brill-Edwards P, Donovan D, Moffatt K, Johnston M, et al. Antiphosphnlipid antibodies and venous thromboembolism. Blood 1995;86:3685-91. 2. Morgan M, Downs K, Chesterman CN, Biggs JC. Clinical analysis of 125 patients with the lupus anticoagulant. Aust N Z J Med 1993;23(2):151-6. 3. Exner T. Diagnostic methodologies for circulating anticoagulants. Thromb Haemost 1995;74:338-44. 4. Nuss R, Hays T, Manco-Johnson M. Childhood thrombosis. Pediatrics 1995;96:291-4. 5. Manco-Johnson MJ, Nuss R. Lupus anticoagulant in children with thrombosis. Am J Hematol 1995;48:240-3. 6. Bemstein M, Salusinsky-Sternbach M, Bellefleur M, Esseltine D. Thrombotic and hemorrhagic complications in children with lupus anticoagulants. Am J Dis Child 1984;138: 1132-5. 7. Humphries JE, Acker MN, Pinkston JE, Ruddy S. Transient lupus anticoagulant associated with prothrombin deficiency: unusual cause of bleeding in a 5-year-old girl. Am J Pediatr Hematol Oncol 1994;16:372-6. 8. Jaeger U, Kapiotis S, Pabinger I, Puchhammer E, Kyrle PA, Lechner K. Transient lupus anticoagulant associated with hypoprothrombinemia and factor XII deficiency following adenovirus infection. Ann Hematol 1993;67:95-9. 9. Bemini JC, Buchanan GR, Ashcraft J. Hypoprothrombinemia and severe hemorrhage associated with a lupus anticoagulant. J Pediatr 1993;123:937-9. 10. Lee MT, Nardi MA, Hadzi-Nesie J, Karpatkin M. Transient hemorrhagi c diathesis associated with inhibitor of prothrombin with lupus anticoagulant in a 1~-year-old girl: report of a case and review of the literature. Am J Hematol 1996;51:307-14. l 1. Triplett D, Brandt J, Kaczor D, Schaeffer J. Laboratory diagnosis of lupus inhibitors: a comparison of the tissue thromboplastin inhibition procedure with a new platelet neutralization procedure. Am J Clin Pathol 1983;79:678-82. 12. Thiagarajan P, Pengo V, Shapiro SS. The use of dilute Russell viper venom time for the diagnosis of lupus anticoagulant. Blood 1986;68:869-74. 13. Triplett D. Evaluation of the minimally prolonged aPTT: Passovoy factor or lupus anticoagulant. Am J Pediatr Hematol Oncol 1996;18:247-8. 14. Brandt JT, Triplett D, Alving B, Scharrer I. Criteria for the diagnosis of lupus anticoagulants: an update. Thromb Haemost 1995;74:1185-90.
Becton and Stine
The Journal of Pediatrics June 1997
Transient lupus anticoagulants associated with hemorrhage rather than thrombosis: The hemorrhagic lupus anticoagulant syndrome D a v i d L. B e c t o n , MD, a n d Kimo C. Stine, MD From the Depaffment of Pediatrics, Section of Hematology/Oncology, Comprehensive Hemophilia Center, University of Medical Sciences and Arkansas Children's Hospital, Little Rock
Lupus anticoagulants (LAs) represent a diverse group of antibodies directed against phospholipids. Patients with LAs may be free of symptoms but can have thrombotic complications including stroke, placental infarction, and fetal loss. Rarely hemorrhagic symptoms have been reported. We describe six previously healthy children who were first seen with clinical bleeding and prolonged activated partial thromboplastin time. Laboratory evaluation revealed positive results on mixing studies and evidence of phospholipid dependence of the anticoagulant, suggesting LAs. Four of six patients had anticardiolipin antibodies, and all four who were tested had reduced factor II activity levels. In all patients, bleeding symptoms resolved spontaneously within 3 months, and laboratory findings returned to normal within 6 months. The hemorrhagic LA syndrome should be considered in previously healthy children with new-onset bleeding and prolonged activated partial thromboplastin time. This clinical entity probably represents a pathogenic mechanism distinct from thrombotic LA syndromes. (J Pediatr 1997; 130:998-1000) The so-called lupus anticoagulants represent a diverse group of antibodies directed against phospholipids. LAs may be found in patients with systemic lupus erythematosis and other autoimmune disorders, or in otherwise healthy persons, and are typically associated with thrombotic complications, t-5 However, there have been case reports of apparent LAs with transient hemorrhagic symptoms in children, often after a viral infection and sometimes associated with low levels of factor II activity. 6-t° We now describe six previously healthy children with clinical bleeding and prolonged activated partial thromboplastin time, who had laboratory evidence of LAs and reduced factor II levels. METHODS Prothrombin time and aPTT testing was performed by using standard reagents and an automated system. Mixing studies were performed with a 50:50 mix of patient and pooled normal human plasma, and measurements were made immediately and at i and 2 hours. Platelet neutralization was performed by using the method of Triplett et al.ll A Russell Submitted for publication Aug. 18, 1996; accepted Nov. 18, 1996. Reprint requests: David L. Becton, MD, 800 Marshall St., Little Rock, AR 72202. Copyright © 1997 by Mosby-Year Book, Inc. 0022-3476/97/$5.00 + 0 9/22/79373
aPTr LA PT RVVT SLE
Activatedpartial thromboplastin time Lupus anticoagulant Prothrombintime Russellviper venom test Systemiclupus erythematosus
viper venom test was performed by using Russell viper venom and the method of Thiagaraj an et al. 12Anticardiolipin antibodies (IgG and IgM) were measured by an enzymefinked immunosorbent assay method. Factor II levels were measured by using factor-deficient plasma in a PT method. Patients. All patients were otherwise healthy, with no history or family history of bleeding disorders. None had a history of SLE or other collagen vascular disease, and results of laboratory evaluation of collagen vascular disease were negative in all patients. Clinical and laboratory features are summarized in Tables I and II. All bleeding symptoms resolved within 4 months without therapy. RESULTS All six patients had prolonged aPTT (range, 37.45 to 81.25; mean, 61.25), which led to further hemostatic evaluation. Complete blood cell counts, including platelet counts, were normal in each patient. All male subjects had factor VIII and IX activities measured, and all patients had
The Journal of Pediatrics Volume 130, Number 6
Becton and Stine
999
Table I. Clinical features of patients with lupus anticoagulant Patient No.
Age (yr)
Gender
Hx viral illnesses
Clinical presentation
Follow-up (mo)
1 2 3 4 5 6
8.2 2.1 5.0 10.0 10.0 4.2
F M F M M M
N Y Y Y N Y
Epistaxis, bruising Bruising, epistaxis Epistaxis Elbow bleed Epistaxis Hematemesis, hernatomas
60 60 55 48 38 10
Hx, History.
Table II. Laboratory features at diagnosis and follow-up associated with lupus anticoagulant Patient
PT*
aPTT*,'J"
Mixing
PNWf
RVVT§
ACA*,#
Factor il*,¶
Time of follow-up sample (mo)
1 2 3 4 5 6
17/11.5 23/13.0 16.5/12.0 16.0/12.5 13.5/12.0 27.5/11.5
80.7/29.8 81.2/31.1 53.4/29.1 50.6/26.4 37.4/31.1 66.0/29.9
+ + + + + +
+ + + + + +
24 26.5 34 26.5 37.4 46.0
+/+/ND +/+/-/ND +/-
17/58 12/ND ND/ND 12/112 ND/ND 7/77
4 3 6 6 2 2
PNP, Plateletneutralizationprocedure;ACA, anticardiotipinantibodies;ND, Not done. *Initialand fo~low-upsamples, "taPTT:normalrange, 21 to 32 seconds. -~PNP:normalvalue,undetectable. §RWT: normalvalue, 24 to 33 seconds. #ACA: normalvalue,undetectable. ~[FactorII coagulationactivity:normalvalue, 50% to i00%.
measurement of von Willebrand antigen and ristocetin cofactor. Results of all hemophilia and von Willebrand testing were normal. Mixing studies with 1:1 dilution of patient and pooled normal human plasma were performed. All patients failed to correct their aPTTs, indicating the presence of a circulating anticoagulant rather than a factor deficiency. At that point, tests to co~ffirm the presence of LAs were performed, including the platelet neutralization procedure, Russell viper venom time, and anticardiolipin antibody. Findings of at least two of these tests were abnormal in each patient except patient 4, who had a normal RVVT and borderline levels of anticardiolipin antibody. In four patients, acute levels of factor II activity were obtained, and all were reduced significantly (range, 7% to 17%; mean, 13%). Follow-up laboratory evaluation, performed from 2 to 6 months after presentation, revealed normalization of all measured hemostatic testing in every patient, which correlated with complete clinical resolution. DISCUSSION We described six previously healthy children in whom bleeding symptoms were associated with a transient LA-like inhibitor. Although most patients had relatively minor
bleeding such as epistaxis or bruising, three had more severe symptoms, with large hematomas, hematemesis, or hemarthrosis. All patients had prolonged aPTTs, and positive results on mixing studies and platelet neutralization procedures; four of six had evidence of anticardiolipin antibodies; and all four tested had hypoprothrombinemia. Bleeding symptoms resolved within 3 months in all patients, and all previously abnormal coagulation parameters returned to normal. No therapy was required. Prolonged follow-up (range, 10 to 60 months; mean, 45.1 months) to date has been associated with no recurrent bleeding episodes and no evidence of collagen vascular disease. No patient had thrombosis. LAs are autoantibodies directed against negatively charged phospholipids or phospholipid-binding proteins, including those associated with clotting proteins such as prothrombin.l-5 They interfere with at least one phospholipid-dependent in vitro coagulation test, such as the agYr, RVVT, or dilute PT. 13 The diagnosis of LAs can be difficult and depends on heightened clinical suspicion and a carefully coordinated laboratory evaluation. There are three recognized components of the laboratory confirmation of LAs: (1) the use of sensitive screening reagents; (2) mixing studies to confirm the presence of a circulating anticoagulant; and (3) proof that the anticoagulant is phospholipid dependent. 14
1000
Becton and Stine
Patients with LAs may be symptom free but often have a tendency toward thrombosis, including deep-vein thrombosis, placental infarction, and stroke, a-5 LA-induced thrombosis may be related to complement activation triggered by the binding of the antibody to phospholipid, followed by platelet aggregation, endothelial damage, or both. The risk of thrombosis is usually long term and may be related to the status of the underlying disease. Hemorrhage in patients with LAs is much less common and has been associated with hypoprothrombinemia or low platelet counts. Previous case reports described individual pediatric patients with clinical and laboratory features similar to those which we observed in our six patients: (1) sudden onset of bleeding in a previously healthy child, (2) recent history of viral infection, (3) laboratory findings compatible with the diagnosis of LAs, (4) hypoprothrombinemia, (5) no evidence of collagen vascular disease or thrombosis, and (6) spontaneous resolution within 3 months, usually without therapy. 61° Recurrence of LAs or bleeding symptoms has not been reported in other case reports, and our six patients have been followed up for 10 to 60 months (mean, 45.3 months) without recurrent bleeding and with no clinical or laboratory evidence of collagen vascular disease. Although the laboratory findings (prolonged PT, aPTT, and RVVT; positive results on mixing studies and platelet neutralization procedures, and even anticardiolipin antibodies) of the hemorrhagic LA syndrome exhibited by our patients are almost identical to the "thrombotic" syndrome observed among patients with SLE and related disorders, these are clearly distinct clinical disorders. The understanding of LAs and anticardiolipin antibodies, as with the entire field of hemostasis and thrombosis, is evolving rapidly. Continued biochemical and molecular investigations will undoubtedly elicit specific distinctions between the hemorrhagic and thrombotic types of LA, leading to more appropriate nomenclature. In the interim, the presence of a lupuslike anticoagulant should be suspected in children with new-onset bleeding symptoms. The incidence of this syndrome is uncertain; our patients were seen during a 4-year period in an academic pediatric hematology program and represented the most common confirmed diagnosis in patients with prolonged aPTT other than hemophilia (A or B) or von Willebrand disease. After the detection of a prolonged aPTF in a child, mixing studies should be considered, and if results are positive, a complete LA profile should be obtained, including a prothrombin activity level. Patients
The Journal of Pediatrics June 1997
with confirmed hemorrhagic LA syndrome will usually spontaneously resolve without therapy, but corticosteroids have been used in some patients. 9 Prothrombin complex plasma products could be considered in patients with documented hypoprothrombinemia and significant bleeding, although the response to such infusions should be monitored clinically if ongoing antibody activity is suspected. REFERENCES
1. Ginsberg JS, Wells PS, Brill-Edwards P, Donovan D, Moffatt K, Johnston M, et al. Antiphosphnlipid antibodies and venous thromboembolism. Blood 1995;86:3685-91. 2. Morgan M, Downs K, Chesterman CN, Biggs JC. Clinical analysis of 125 patients with the lupus anticoagulant. Aust N Z J Med 1993;23(2):151-6. 3. Exner T. Diagnostic methodologies for circulating anticoagulants. Thromb Haemost 1995;74:338-44. 4. Nuss R, Hays T, Manco-Johnson M. Childhood thrombosis. Pediatrics 1995;96:291-4. 5. Manco-Johnson MJ, Nuss R. Lupus anticoagulant in children with thrombosis. Am J Hematol 1995;48:240-3. 6. Bemstein M, Salusinsky-Sternbach M, Bellefleur M, Esseltine D. Thrombotic and hemorrhagic complications in children with lupus anticoagulants. Am J Dis Child 1984;138: 1132-5. 7. Humphries JE, Acker MN, Pinkston JE, Ruddy S. Transient lupus anticoagulant associated with prothrombin deficiency: unusual cause of bleeding in a 5-year-old girl. Am J Pediatr Hematol Oncol 1994;16:372-6. 8. Jaeger U, Kapiotis S, Pabinger I, Puchhammer E, Kyrle PA, Lechner K. Transient lupus anticoagulant associated with hypoprothrombinemia and factor XII deficiency following adenovirus infection. Ann Hematol 1993;67:95-9. 9. Bemini JC, Buchanan GR, Ashcraft J. Hypoprothrombinemia and severe hemorrhage associated with a lupus anticoagulant. J Pediatr 1993;123:937-9. 10. Lee MT, Nardi MA, Hadzi-Nesie J, Karpatkin M. Transient hemorrhagi c diathesis associated with inhibitor of prothrombin with lupus anticoagulant in a 1~-year-old girl: report of a case and review of the literature. Am J Hematol 1996;51:307-14. l 1. Triplett D, Brandt J, Kaczor D, Schaeffer J. Laboratory diagnosis of lupus inhibitors: a comparison of the tissue thromboplastin inhibition procedure with a new platelet neutralization procedure. Am J Clin Pathol 1983;79:678-82. 12. Thiagarajan P, Pengo V, Shapiro SS. The use of dilute Russell viper venom time for the diagnosis of lupus anticoagulant. Blood 1986;68:869-74. 13. Triplett D. Evaluation of the minimally prolonged aPTT: Passovoy factor or lupus anticoagulant. Am J Pediatr Hematol Oncol 1996;18:247-8. 14. Brandt JT, Triplett D, Alving B, Scharrer I. Criteria for the diagnosis of lupus anticoagulants: an update. Thromb Haemost 1995;74:1185-90.