Original Article
Prolonged Activated Partial Thromboplastin Time: Difficulties in Discriminating Coexistent Factor VIII Inhibitor and Lupus Anticoagulant
Clinical and Applied Thrombosis/Hemostasis 2015, Vol. 21(2) 149-154 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1076029614541516 cat.sagepub.com
Paul R. J. Ames, MD, MSc, PhD1,2, Maria Graf, MD3, Jeremy Archer, BSc2, Nicola Scarpato, MD3, and Luigi Iannaccone, BSc4
Abstract To review the diagnostic difficulties of a prolonged activated partial thromboplastin time (aPTT) when 2 inhibitors with opposite clinical presentations coexist, we searched MEDLINE from January 1970 to November 2013 using acquired, factor VIII (FVIII), factor IX, hemophilia A and B, inhibitor, lupus anticoagulant (LA), antiphospholipid, anticardiolipin, anti-b2-glycoprotein I, antibodies, syndrome, bleeding, and thrombosis. We identified 13 articles for a total of 15 cases of possible coexistence of FVIII inhibitor and LA. The presenting clinical manifestation was thrombosis in 6 cases and bleeding in 9 cases. Activated partial thromboplastin time was the presenting laboratory abnormality in all cases, and first-line investigations suggested the coexistence of LA and acquired FVIII inhibitor. None of the articles addressed the diagnostic accuracy of the screening tests by performing ‘‘second line’’ assays. We reviewed the diagnostic pitfalls of the cases under study and provide some guidance for alternative tests when facing a prolonged aPTT that may have a double meaning. Keywords lupus anticoagulant, acquired hemophilia
Introduction
Materials and Methods
The differential diagnosis of a prolonged activated partial thromboplastin time (aPTT) is quite extensive and necessitates further investigations following an algorithm to identify factor deficiencies and inhibitors.1 However, once the laboratory differential diagnosis has narrowed down to the presence of inhibitors, their identification is of the utmost importance to avoid significant delays2 in the correct therapeutic approach3 that could be otherwise fatal.4 Things may be further complicated by the coexistence of different inhibitors such as an acquired factor VIII (FVIII) and a lupus anticoagulant (LA) that underscore completely opposite clinical scenarios. Both inhibitors prolong the aPTT and may affect each other in clotting assays hence their discrimination may be quite challenging5 regardless of whether the presenting clinical presentation is bleeding or thrombosis. To address this rare but important laboratory and clinical scenario, we performed a review of case reports and case series where an LA coexisted with acquired FVIII inhibitor, and we critically reviewed the laboratory methodology employed to differentiate the coexistent inhibitors and the management of the clinical phenotypes.
We performed a PubMed literature search from January 1970 to November 2013 using the following search terms: acquired, FVIII, factor IX (FIX), hemophilia A and B, inhibitor, LA, antiphospholipid, anticardiolipin, anti-b2-glycoprotein I, antibodies, and syndrome. The minimal inclusion criteria required that the title or the abstract described the coexistence of an LA with acquired FVIII inhibitor. This search yielded 379 articles; allowing for replication and after checking titles and abstracts for the coexistence of LA with acquired hemophilia 1
Haemostasis & Thrombosis Department, William Harvey Research Institute, Charterhouse Square, London, United Kingdom 2 Haemostasis & Thrombosis Department, St George’s Hospital, London, United Kingdom 3 Dipartimento di Medicina Molecolare e Biotecnologie Mediche - Universita` degli Studi di Napoli Federico II - VIa Pansini, Napoli, Italy 4 Chemical Pathology Department, A. Cardarelli Hospital, Naples, Italy Corresponding Author: Paul R. J. Ames, Haemostasis & Thrombosis Department, St George’s Hospital, Blackshaw Road, London SW17 0QT, United Kingdom. Email: [email protected]
Downloaded from cat.sagepub.com at Gazi University on February 2, 2015
150
Clinical and Applied Thrombosis/Hemostasis 21(2)
Table 1. Cases of Coexistent Lupus Anticoagulant and Acquired Factor VIII (Factor IX) Inhibitor: Test Patterns.a FVIII, IU Age/Sex
aPTTr
37/F 64/F 64/F
5.03b 2.26 1.86
38/F 62/F 29/F 60/F 59/M 30/M 68/M 60/F 92/F 70/M 63/F 30/F
LA
DRVVT þ PL DRVVT þ PL Staclot LA/PNP (known LA) 3.00 KCT þ inosithin 3.50 DRVVT þ PL Prolonged DRVVT þ PL 1.85c DRVVT (HP) 1.54 DRVVT þ PL 2.10 DRVVT þ PL 3.20 KCT þ inosithin 4.05 KCT þ inosithin 3.00 Staclot LA/PNP 3.03 DRVVT 52.6’’ KCT 3.00 Staclot LA/PNP
FVIII Inhibitor
aCL IgG/IgM aB2GPI Clotting Chromogenic Clotting (BU) ELISA Ref ND ND 33
ND ND ND
2
Prolonged Activated Partial Thromboplastin Time: Difficulties in Discriminating Coexistent Factor VIII Inhibitor and Lupus Anticoagulant
Clinical and Applied Thrombosis/Hemostasis 2015, Vol. 21(2) 149-154 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1076029614541516 cat.sagepub.com
Paul R. J. Ames, MD, MSc, PhD1,2, Maria Graf, MD3, Jeremy Archer, BSc2, Nicola Scarpato, MD3, and Luigi Iannaccone, BSc4
Abstract To review the diagnostic difficulties of a prolonged activated partial thromboplastin time (aPTT) when 2 inhibitors with opposite clinical presentations coexist, we searched MEDLINE from January 1970 to November 2013 using acquired, factor VIII (FVIII), factor IX, hemophilia A and B, inhibitor, lupus anticoagulant (LA), antiphospholipid, anticardiolipin, anti-b2-glycoprotein I, antibodies, syndrome, bleeding, and thrombosis. We identified 13 articles for a total of 15 cases of possible coexistence of FVIII inhibitor and LA. The presenting clinical manifestation was thrombosis in 6 cases and bleeding in 9 cases. Activated partial thromboplastin time was the presenting laboratory abnormality in all cases, and first-line investigations suggested the coexistence of LA and acquired FVIII inhibitor. None of the articles addressed the diagnostic accuracy of the screening tests by performing ‘‘second line’’ assays. We reviewed the diagnostic pitfalls of the cases under study and provide some guidance for alternative tests when facing a prolonged aPTT that may have a double meaning. Keywords lupus anticoagulant, acquired hemophilia
Introduction
Materials and Methods
The differential diagnosis of a prolonged activated partial thromboplastin time (aPTT) is quite extensive and necessitates further investigations following an algorithm to identify factor deficiencies and inhibitors.1 However, once the laboratory differential diagnosis has narrowed down to the presence of inhibitors, their identification is of the utmost importance to avoid significant delays2 in the correct therapeutic approach3 that could be otherwise fatal.4 Things may be further complicated by the coexistence of different inhibitors such as an acquired factor VIII (FVIII) and a lupus anticoagulant (LA) that underscore completely opposite clinical scenarios. Both inhibitors prolong the aPTT and may affect each other in clotting assays hence their discrimination may be quite challenging5 regardless of whether the presenting clinical presentation is bleeding or thrombosis. To address this rare but important laboratory and clinical scenario, we performed a review of case reports and case series where an LA coexisted with acquired FVIII inhibitor, and we critically reviewed the laboratory methodology employed to differentiate the coexistent inhibitors and the management of the clinical phenotypes.
We performed a PubMed literature search from January 1970 to November 2013 using the following search terms: acquired, FVIII, factor IX (FIX), hemophilia A and B, inhibitor, LA, antiphospholipid, anticardiolipin, anti-b2-glycoprotein I, antibodies, and syndrome. The minimal inclusion criteria required that the title or the abstract described the coexistence of an LA with acquired FVIII inhibitor. This search yielded 379 articles; allowing for replication and after checking titles and abstracts for the coexistence of LA with acquired hemophilia 1
Haemostasis & Thrombosis Department, William Harvey Research Institute, Charterhouse Square, London, United Kingdom 2 Haemostasis & Thrombosis Department, St George’s Hospital, London, United Kingdom 3 Dipartimento di Medicina Molecolare e Biotecnologie Mediche - Universita` degli Studi di Napoli Federico II - VIa Pansini, Napoli, Italy 4 Chemical Pathology Department, A. Cardarelli Hospital, Naples, Italy Corresponding Author: Paul R. J. Ames, Haemostasis & Thrombosis Department, St George’s Hospital, Blackshaw Road, London SW17 0QT, United Kingdom. Email: [email protected]
Downloaded from cat.sagepub.com at Gazi University on February 2, 2015
150
Clinical and Applied Thrombosis/Hemostasis 21(2)
Table 1. Cases of Coexistent Lupus Anticoagulant and Acquired Factor VIII (Factor IX) Inhibitor: Test Patterns.a FVIII, IU Age/Sex
aPTTr
37/F 64/F 64/F
5.03b 2.26 1.86
38/F 62/F 29/F 60/F 59/M 30/M 68/M 60/F 92/F 70/M 63/F 30/F
LA
DRVVT þ PL DRVVT þ PL Staclot LA/PNP (known LA) 3.00 KCT þ inosithin 3.50 DRVVT þ PL Prolonged DRVVT þ PL 1.85c DRVVT (HP) 1.54 DRVVT þ PL 2.10 DRVVT þ PL 3.20 KCT þ inosithin 4.05 KCT þ inosithin 3.00 Staclot LA/PNP 3.03 DRVVT 52.6’’ KCT 3.00 Staclot LA/PNP
FVIII Inhibitor
aCL IgG/IgM aB2GPI Clotting Chromogenic Clotting (BU) ELISA Ref ND ND 33
ND ND ND
2
