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Familial Occurrence of Primary Antiphospholipid Syndrome
Thrombosis Research 95 (1999) 127–129
BRIEF COMMUNICATION
Familial Occurrence of Primary Antiphospholipid Syndrome A. Cantalapiedra, A.G. Avello, J.L. Navarro and J.M. Cesar S. Hematologı´a. Hospital Ramo´n y Cajal, Madrid, Spain. (Received 2 July 1998 by J. Aznar; revised/accepted 30 December 1998)
Key Words: Familial antiphospholipid syndrome; Lupus anticoagulant
T
he term antiphospholipid syndrome (APS) describes the association of antiphospholipid antibodies, including lupus anticoagulant (LA) antibodies and anticardiolipin antibodies (ACA) and the presence of vascular thrombosis, fetal loss recurrence, or thrombocytopenia [1]. Although APS can be associated to systemic lupus erythematosus (SLE) or other autoimmune diseases, a primary form of this syndrome is currently accepted [2]. The familial occurrence of APS is an uncommon condition that has been associated with findings of autoimmune disease [3–7] and specific HLA haplotypes [8,9] but rarely as a primary APS [10]. We describe two family members (father and daughter) suffering episodes of venous thrombosis and thrombocytopenia associated with the presence of ACA and LA in absence of autoimmune disease. In case 1, a 30-year-old woman had a spontaneous thrombosis affecting the right subclavian vein. There was no history of SLE or symptoms of autoimmune disease. Both activated partial thromboAbbreviations: APS, antiphospholipid syndrome; LA, lupus anticoagulant; ACA, anticardiolipin antibodies; SLE, systemic lupus erythematosus; aPTT, activated partial thromboplastin time; dRVV, diluted Russell viper venom; ESR, erythrocyte sedimentation rate. Corresponding author: J.M. Cesar, Department Hematology, Hospital Ramo´n y Cajal, Ctera Colmenar km 9,1, 28034 Madrid, Spain. Fax: 134 (91) 330 80 53; E-mail: ,[email protected]..
plastin time (aPTT) and diluted Russell viper venom (dRVV) were prolonged. LA was found positive according to the criteria of the scientific subcommittee for LA [11]. ACAs were also positive (Table 1). Over the next 10 years, she had four episodes of ecchymoses due to severe thrombocytopenia, which improved with prednisone (Table 2). In case 2, her father, an asymptomatic 62-yearold man, suffered an episode of central retinal vein thrombosis. He was found positive for LA. ACAs were also positive (Table 1).
1. Materials and Methods 1.1. Coagulation Tests Venous blood was collected in silicone-coated tubes containing 3.8% trisodium citrate in proportion 9:1. Platelet-poor plasma was obtained by centrifugation at 25003g for 15 minutes. aPTT and prothrombin time (PT) were performed using reactives from Ortho Diagnostic Systems (Raritan, NJ, USA). The tissue thromboplastin inhibition test was performed as described by Schleider et al. [12] and the dRVV as described Thiagarajan et al. [13], by using a reactive from American Diagnostic (Greenwich, UK). Platelet neutralization test was conducted according to Triplett et al. [14]. ACA were measured by an ELISA supplied by Chromogenix (Mo¨lndal, Sweden). Antiplatelet antibodies were measured according to von dem Borne et al. [15] (indirect test).
0049-3848/99 $–see front matter 1999 Elsevier Science Ltd. All rights reserved. PII S0049-3848(99)00010-9
128
A. Cantalapiedra et al./Thrombosis Research 95 (1999) 127–129
Table 1. Laboratory studies in both patients
aPTT (seconds) aPTT (patient plasma1normal plasma) aPTT (patient plasma1normal platelets) dRVV (ratio) dRVV (patient plasma1normal plasma) dRVV (patient plasma1normal platelets) Tissue tromboplastin inhibition (ratio) Platelet counts 3 109/L Prothrombin time (seconds) ACA (GPL/mL) Fluoresc treponemal antibody-absorption Anti b2GPI (SGU)
2. Results Serological tests of both patients are summarized in Table 1. In both cases, positive LAs were demonstrated by aPTT and dRVV. Moreover, ACAs were also positive. These antiphospholipid antibodies persist for 10 and 2 years for case 1 and case 2, respectively. Other assays including, erythrocyte sedimentation rate (ESR), antinuclear antibodies, and anti-DNA antibodies were always negative. The antiplatelet antibodies were negative. This assay was always performed before to the administration of prednisone in the four episodes of thrombocytopenia. This therapy did not improve the results of the coagulation tests.
3. Discussion This work describes two patients with evidence of primary APS. Both daughter and father have been observed for 10 and 2 years, respectively, and they never developed clinical or analytical data of autoimmune disease. Familial LA has been associated with lupus-like disorders [3–7]. Some of these pa-
Table 2. Episodes of thrombocytopenia in case 1 Date
Basal
Outcome/days
1987 1992 1994 1997
7 8 35 5
170/7 186/12 96/5 130/7
Platelet count (3109/L).
Therapy Prednisone Prednisone Prednisone Prednisone
1 1 1 1
mg/kp/day mg/kp/day mg/kp/day mg/kp/day
Daughter
Father
Control
86 62 45 1.4 1.5 1.2 1.5 185 11.6 25 negative 19.6
166 100 52 1.9 2.0 1.2 1.5 83 11.5 23 — 89.1
33 — 42 ,1.2 ,1.2 ,1.3 150–300 11.5 ,23 — ,20
tients carried the HLA haplotypes DR4 [9], DR5 [9], or DR7 [8] and suffer SLE or other autoimmune diseases. However, familial occurrence of primary APS seems to be a rare condition. Gaeta and Brancaccio report an adolescent with myocardial infarction (Italian) [10]. ACL antibodies (GPL) were positive in the propositus, although they became negative in the second month. His sister was shown to have a positive LA, associated to thrombocytopenia and recurrent miscarriages [9]. The cases described in our work have a positive LA that affects the aPTT and dRVVT as well as positive ACA. Positive ACA causing APS are due to antiB2glycoprotein-1 antibodies [15]. It has been suggested that these antibodies also could be responsible for the abnormal dRVV and are frequently associated to thrombosis episodes [16], the complication suffered by both patients. Moreover, case 1 suffered to date four episodes of thrombocytopenia. Three of them were severe and coursed with moderate bleeding. Prednisone was always effective but did not modify the abnormal coagulation tests.
References 1. Harris EN, Asherson RA, Gharavi AE, Morgan SH, Derue G, Hugues GRV. Thrombocytopenia in SLE and related autoimmune disorders: Association with anticardiolipin antibody. Br J Haematol 1985;59:227–30. 2. Alarco´n-Segovia D, Sa´nchez Guerrero J. Primary antiphospholipid syndrome . J Rheumatol 1989;16:482–8.
A. Cantalapiedra et al./Thrombosis Research 95 (1999) 127–129
3. Exner T, Barber S, Kronenberg H, Rickard KA. Familial association of the lupus anticoagulant. Br J Haematol 1980;45:89–96. 4. Mackie JJ, Colaco CB, Machin SJ. Familial lupus anticoagulant. Br J Haematol 1987;67: 359–63. 5. Ford PM, Brunet D, Lillicrap DP, Ford SE. Premature stroke in a family with lupus anticoagulant and antiphospholipid antibodies. Stroke 1990;21:66–71. 6. Dagenais P, Urowitz MB, Gladman DD, Norman CS. A family study of the antiphospholipid syndrome associated with other autoimmune diseases. J Rheumatol 1992;19:1393–6. 7. May K, West SG, Moulds J, Kotzin BL. Different manifestations of the antiphospholipid antibody syndrome in a family with systemic lupus erithematosus. Arthritis Rheum 1993; 36:528–33. 8. Savi M, Ferraccioli GF, Neri TM, Zanelli P, Dall’Aglio PP, Tincani A, Balestrieri G, Carella G, Cattaneo R. HLA-DR antigens and anticardiolipin antibodies in northern Italian systemic lupus erithematosus patients. Arthritis Rheum 1988; 31:1568–70. 9. Arnett FC, Olsen ML, Anderson KL, Reveille JD. Molecular analysis of major histocompatibility complex alleles associated with the lupus anticoagulant. J Clin Invest 1991;87:1490–5. 10. Gaeta G, Brancaccio V. Sindrome da anticorpi antifosfolipidi primaria a carattere familiare
11.
12.
13.
14.
15.
16.
129
con infarto del miocardio in adolescente. G Ital Cardiol 1995;25:1025–30. Brandt JT, Triplett DA, Alving B, Scharrer I. Criteria for the diagnosis of lupus anticoagulant: an update. Thromb Haemost 1995;74: 1185–90. Schleider MA, Nachman RL, Jaffe EA, Coleman M. A clinical study of Lupus anticoagulant. Blood 1976;48:499–509. Thiagarajan P, Pengo V, Shapiro SS. The use of the diluted Russell viper venom time for the diagnosis of lupus anticoagulants. Blood 1986;68:689–74. Tripplett DA, Brandt JT, Kaczor D, Schaeffer MS. 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. Von dem Borne AEG, Helmerhorst FM, van Leeuwen EF, Pegels HG, von Riesz E, Engelfriet CP. Autoinmune thrombocytopenia: Detection of platelet antibodies with the suspension immunofluorescence test. Br J Haematol 1980;45:319–27. Mc Neil HP, Simpson RJ, Chesterman CN, Krilis SA. Antiphospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: b2-Glycoprotein I (apolipoprotein H). Proc Natl Acad Sci USA 1990;87:4120–4.
BRIEF COMMUNICATION
Familial Occurrence of Primary Antiphospholipid Syndrome A. Cantalapiedra, A.G. Avello, J.L. Navarro and J.M. Cesar S. Hematologı´a. Hospital Ramo´n y Cajal, Madrid, Spain. (Received 2 July 1998 by J. Aznar; revised/accepted 30 December 1998)
Key Words: Familial antiphospholipid syndrome; Lupus anticoagulant
T
he term antiphospholipid syndrome (APS) describes the association of antiphospholipid antibodies, including lupus anticoagulant (LA) antibodies and anticardiolipin antibodies (ACA) and the presence of vascular thrombosis, fetal loss recurrence, or thrombocytopenia [1]. Although APS can be associated to systemic lupus erythematosus (SLE) or other autoimmune diseases, a primary form of this syndrome is currently accepted [2]. The familial occurrence of APS is an uncommon condition that has been associated with findings of autoimmune disease [3–7] and specific HLA haplotypes [8,9] but rarely as a primary APS [10]. We describe two family members (father and daughter) suffering episodes of venous thrombosis and thrombocytopenia associated with the presence of ACA and LA in absence of autoimmune disease. In case 1, a 30-year-old woman had a spontaneous thrombosis affecting the right subclavian vein. There was no history of SLE or symptoms of autoimmune disease. Both activated partial thromboAbbreviations: APS, antiphospholipid syndrome; LA, lupus anticoagulant; ACA, anticardiolipin antibodies; SLE, systemic lupus erythematosus; aPTT, activated partial thromboplastin time; dRVV, diluted Russell viper venom; ESR, erythrocyte sedimentation rate. Corresponding author: J.M. Cesar, Department Hematology, Hospital Ramo´n y Cajal, Ctera Colmenar km 9,1, 28034 Madrid, Spain. Fax: 134 (91) 330 80 53; E-mail: ,[email protected]..
plastin time (aPTT) and diluted Russell viper venom (dRVV) were prolonged. LA was found positive according to the criteria of the scientific subcommittee for LA [11]. ACAs were also positive (Table 1). Over the next 10 years, she had four episodes of ecchymoses due to severe thrombocytopenia, which improved with prednisone (Table 2). In case 2, her father, an asymptomatic 62-yearold man, suffered an episode of central retinal vein thrombosis. He was found positive for LA. ACAs were also positive (Table 1).
1. Materials and Methods 1.1. Coagulation Tests Venous blood was collected in silicone-coated tubes containing 3.8% trisodium citrate in proportion 9:1. Platelet-poor plasma was obtained by centrifugation at 25003g for 15 minutes. aPTT and prothrombin time (PT) were performed using reactives from Ortho Diagnostic Systems (Raritan, NJ, USA). The tissue thromboplastin inhibition test was performed as described by Schleider et al. [12] and the dRVV as described Thiagarajan et al. [13], by using a reactive from American Diagnostic (Greenwich, UK). Platelet neutralization test was conducted according to Triplett et al. [14]. ACA were measured by an ELISA supplied by Chromogenix (Mo¨lndal, Sweden). Antiplatelet antibodies were measured according to von dem Borne et al. [15] (indirect test).
0049-3848/99 $–see front matter 1999 Elsevier Science Ltd. All rights reserved. PII S0049-3848(99)00010-9
128
A. Cantalapiedra et al./Thrombosis Research 95 (1999) 127–129
Table 1. Laboratory studies in both patients
aPTT (seconds) aPTT (patient plasma1normal plasma) aPTT (patient plasma1normal platelets) dRVV (ratio) dRVV (patient plasma1normal plasma) dRVV (patient plasma1normal platelets) Tissue tromboplastin inhibition (ratio) Platelet counts 3 109/L Prothrombin time (seconds) ACA (GPL/mL) Fluoresc treponemal antibody-absorption Anti b2GPI (SGU)
2. Results Serological tests of both patients are summarized in Table 1. In both cases, positive LAs were demonstrated by aPTT and dRVV. Moreover, ACAs were also positive. These antiphospholipid antibodies persist for 10 and 2 years for case 1 and case 2, respectively. Other assays including, erythrocyte sedimentation rate (ESR), antinuclear antibodies, and anti-DNA antibodies were always negative. The antiplatelet antibodies were negative. This assay was always performed before to the administration of prednisone in the four episodes of thrombocytopenia. This therapy did not improve the results of the coagulation tests.
3. Discussion This work describes two patients with evidence of primary APS. Both daughter and father have been observed for 10 and 2 years, respectively, and they never developed clinical or analytical data of autoimmune disease. Familial LA has been associated with lupus-like disorders [3–7]. Some of these pa-
Table 2. Episodes of thrombocytopenia in case 1 Date
Basal
Outcome/days
1987 1992 1994 1997
7 8 35 5
170/7 186/12 96/5 130/7
Platelet count (3109/L).
Therapy Prednisone Prednisone Prednisone Prednisone
1 1 1 1
mg/kp/day mg/kp/day mg/kp/day mg/kp/day
Daughter
Father
Control
86 62 45 1.4 1.5 1.2 1.5 185 11.6 25 negative 19.6
166 100 52 1.9 2.0 1.2 1.5 83 11.5 23 — 89.1
33 — 42 ,1.2 ,1.2 ,1.3 150–300 11.5 ,23 — ,20
tients carried the HLA haplotypes DR4 [9], DR5 [9], or DR7 [8] and suffer SLE or other autoimmune diseases. However, familial occurrence of primary APS seems to be a rare condition. Gaeta and Brancaccio report an adolescent with myocardial infarction (Italian) [10]. ACL antibodies (GPL) were positive in the propositus, although they became negative in the second month. His sister was shown to have a positive LA, associated to thrombocytopenia and recurrent miscarriages [9]. The cases described in our work have a positive LA that affects the aPTT and dRVVT as well as positive ACA. Positive ACA causing APS are due to antiB2glycoprotein-1 antibodies [15]. It has been suggested that these antibodies also could be responsible for the abnormal dRVV and are frequently associated to thrombosis episodes [16], the complication suffered by both patients. Moreover, case 1 suffered to date four episodes of thrombocytopenia. Three of them were severe and coursed with moderate bleeding. Prednisone was always effective but did not modify the abnormal coagulation tests.
References 1. Harris EN, Asherson RA, Gharavi AE, Morgan SH, Derue G, Hugues GRV. Thrombocytopenia in SLE and related autoimmune disorders: Association with anticardiolipin antibody. Br J Haematol 1985;59:227–30. 2. Alarco´n-Segovia D, Sa´nchez Guerrero J. Primary antiphospholipid syndrome . J Rheumatol 1989;16:482–8.
A. Cantalapiedra et al./Thrombosis Research 95 (1999) 127–129
3. Exner T, Barber S, Kronenberg H, Rickard KA. Familial association of the lupus anticoagulant. Br J Haematol 1980;45:89–96. 4. Mackie JJ, Colaco CB, Machin SJ. Familial lupus anticoagulant. Br J Haematol 1987;67: 359–63. 5. Ford PM, Brunet D, Lillicrap DP, Ford SE. Premature stroke in a family with lupus anticoagulant and antiphospholipid antibodies. Stroke 1990;21:66–71. 6. Dagenais P, Urowitz MB, Gladman DD, Norman CS. A family study of the antiphospholipid syndrome associated with other autoimmune diseases. J Rheumatol 1992;19:1393–6. 7. May K, West SG, Moulds J, Kotzin BL. Different manifestations of the antiphospholipid antibody syndrome in a family with systemic lupus erithematosus. Arthritis Rheum 1993; 36:528–33. 8. Savi M, Ferraccioli GF, Neri TM, Zanelli P, Dall’Aglio PP, Tincani A, Balestrieri G, Carella G, Cattaneo R. HLA-DR antigens and anticardiolipin antibodies in northern Italian systemic lupus erithematosus patients. Arthritis Rheum 1988; 31:1568–70. 9. Arnett FC, Olsen ML, Anderson KL, Reveille JD. Molecular analysis of major histocompatibility complex alleles associated with the lupus anticoagulant. J Clin Invest 1991;87:1490–5. 10. Gaeta G, Brancaccio V. Sindrome da anticorpi antifosfolipidi primaria a carattere familiare
11.
12.
13.
14.
15.
16.
129
con infarto del miocardio in adolescente. G Ital Cardiol 1995;25:1025–30. Brandt JT, Triplett DA, Alving B, Scharrer I. Criteria for the diagnosis of lupus anticoagulant: an update. Thromb Haemost 1995;74: 1185–90. Schleider MA, Nachman RL, Jaffe EA, Coleman M. A clinical study of Lupus anticoagulant. Blood 1976;48:499–509. Thiagarajan P, Pengo V, Shapiro SS. The use of the diluted Russell viper venom time for the diagnosis of lupus anticoagulants. Blood 1986;68:689–74. Tripplett DA, Brandt JT, Kaczor D, Schaeffer MS. 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. Von dem Borne AEG, Helmerhorst FM, van Leeuwen EF, Pegels HG, von Riesz E, Engelfriet CP. Autoinmune thrombocytopenia: Detection of platelet antibodies with the suspension immunofluorescence test. Br J Haematol 1980;45:319–27. Mc Neil HP, Simpson RJ, Chesterman CN, Krilis SA. Antiphospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: b2-Glycoprotein I (apolipoprotein H). Proc Natl Acad Sci USA 1990;87:4120–4.