Thrombosis Research 133 (2014) 301–302
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Letter to the Editors-in-Chief Complete prekallikrein deficiency masquerading as a lupus anticoagulant
Dear Editors, A 24 year old Afro-Caribbean woman presented to her local hospital in August 2011 with acute neurological involvement, including left hemiparesis, left hemianopia and right-sided headache. She was transferred to St Thomas’ Hospital and systemic lupus erythematosus was diagnosed based on arthritis, vasculitic rash and positive serology for anti-nuclear antibodies (HEp-2 with diffuse nuclear pattern), anti-dsDNA, anti-Ro, anti-La and anti-ribonucleoprotein antibodies. She was found to have proteinuria with urinary protein creatinine ratio of 400 mg protein/mmol creatinine (reference interval (RI) 0-15) and granular casts in the urine. A renal biopsy confirmed combined Class IV - S (A/C) and Class V Lupus Nephritis. Activity Index - 15/24; Chronicity Index - 2/12. Her manifestations improved on prednisolone 40 mg/day, mycophenolate mofetil 2 g/day and hydroxychloroquine 400 mg/day. There was no previous history of thrombosis or pregnancy morbidity. Although not anticoagulated she had a markedly elevated activated partial thromboplastin time (APTT) of 140.5 s at presentation which was further investigated upon referral on fresh blood samples. Blood was collected into Vacuette® tubes (Greiner Bio-One Ltd, Stonehouse, UK) containing a one tenth volume of 0.105 M tri-sodium citrate and double centrifuged to obtain platelet poor plasma (PPP) [1,2]. The PPP for lupus anticoagulant (LA) testing was stored at –80 ° C until use. Coagulation screening on fresh plasma, comprising prothrombin time, APTT, thrombin time and fibrinogen, was performed on a Sysmex CA1500 (Sysmex UK Ltd, Milton Keynes, UK) using Siemens/Dade® Innovin®, Actin FS®, Thromboclotin® and Thrombin-Reagent® (Siemens Healthcare, Marburg, Germany) respectively. LA assays were performed on the CA1500 using Life Diagnostics LA Screen and LA Confirm (Life Therapeutics, Clarkston, USA) for dilute Russell’s viper venom time (dRVVT), and APTT using PTT-LA (Diagnostica Stago UK, Theale, UK) in the screen and addition of Bio/Data LA Confirmation Reagent™ (Alpha Laboratories, Eastleigh, UK) for the confirmatory test. Screen and confirm clotting times were converted to normalised ratios via NPP clotting times [1,2]. All elevated screens received the confirmatory test plus a screen and confirmatory test on 1:1 mixing studies with a commercial normal pooled plasma (NPP), CRYOcheck™ Normal Reference Plasma (Alpha Laboratories) [1–3]. A screen ratio above the locally derived RI with ≥10% correction by the confirm ratio was considered consistent with the presence of a LA [1,2]. The coagulation screen was normal except for a slightly elevated thrombin time ratio of 1.28 (RI 0.80-1.23). The dRVVT screen was 1.20 (RI 0.86-1.19) and corrected by 34.4% via a confirm of 0.84 (RI 0.831.13). The mixing test dRVVT screen was 1.19 (RI 0.90-1.10) and corrected by 25.2% via a confirm of 0.89 (RI 0.94-1.13). The PTT-LA screening test clotting time was prolonged to beyond the standard analyser 0049-3848/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.thromres.2013.11.014
acquisition time, which in view of the normal APTT with LAunresponsive Actin FS® and absence of haemorrhagic symptoms, was considered likely due to the LA reacting more potently in PTT-LA than dRVVT [4]. There was insufficient plasma to investigate further. IgG and IgM anticardiolipin antibody (aCL) levels were normal. The patient was not then referred for coagulation testing until January 2013 at a routine outpatient appointment. The laboratory was now using Sysmex CS2100i analysers for clotting screens and CS2000i models for LA testing. Reagents were identical although LA assay ratios were derived from RI mean clotting times not NPP values [5]. The clotting screen was normal except for an elevated fibrinogen of 5.2 g/L (RI 1.7-3.9). dRVVT, Taipan snake venom time (TSVT) [6] and IgG and IgM anti-β2glycoprotein I antibodies were normal. The PTT-LA screen was now measurable yet markedly elevated and evidenced 23.9% correction by the confirm. Remarkably for what appeared to be such a potent antibody, mixing tests were negative, and a repeat sample was requested to investigate further. Full results for this and subsequent samples from June 2013 are given in Table 1. IgG and IgM aCL levels were re-tested on both samples from June 2013 and remained normal. C-reactive protein (CRP) levels were b 5 mg/L (RI 0-4) on every occasion, excluding its interference in the clotting assays [7]. The markedly elevated PTT-LA screens with N 10% confirmatory test correction accompanied by normal coagulation screening would normally suggest the presence of a LA. However, whilst LAs can be diluted to undetectable levels in 1:1 mixing tests [1,2,4] the persistently negative results were inconsistent with such a potent antibody, which could also reasonably be expected to manifest even with the Actin FS® reagent. Additional testing was undertaken on the final sample. PTT-LA analysis on a semi-automated mechanical clot-detection coagulometer, a KC10 (Amelung, Lemgo, Germany), generated similarly abnormal results and thus did not exclude sample incompatibility with photo-optical clot detection of the automated analysers. An APTT on the KC10 with a LA-responsive routine reagent, TriniCLOT aPTT HS (Diagnostica Stago UK) gave a ratio of 3.0 (RI 0.8-1.2) that corrected to normal in a 1:1 mixing with NPP, suggesting a factor deficiency. Performing automated PTT-LA screen mixing test on a greater ratio of patient to control plasma (4:1) generated a normal ratio and was highly suggestive of a factor deficiency, and emphasised that presence of such a potent inhibitor was unlikely. Not all LAs generate confirmatory test results within reference ranges as some possess a degree of resistance to the overwhelming effect of the higher phospholipid concentration [1,8], but a modified PTT-LA confirm with a further increase in phospholipid concentration [9] failed to reduce the result. As Actin FS® employs ellagic acid as contact-activator, which is insensitive to prekallikrein (PK) deficiency [10], whilst the other two APTT reagents employ PK-sensitive silica activator, one-stage clotting assays for high molecular weight kininogen (HMWK) and PK were performed on a CS2100i with the TriniCLOT aPTT HS reagent and short incubation time of three minutes. HMWK was 84.8 U/dL (RI 50-150) but PK was undetectable. In view of the now persistently normal dRVVT and inability of the apparent APTT-reactive LA to inhibit even a small amount of NPP, the only clear coagulation abnormality was PK
302
Letter to the Editors-in-Chief
Table 1 Serial coagulation screen and lupus anticoagulant testing. Date
02.01.2013 05.06.2013 20.06.2013
INR
(0.8–1.2) 1.0 0.9 0.9
APTT ratio
dRVVT ratio
TSVT ratio
Undiluted test plasma PTT-LA screen ratio
PTT-LA confirm ratio
(0.8–1.2) 1.1 1.1 1.0
(0.85-1.17) 0.96 0.92 0.92
(0.87-1.14) 1.02 ND ND
(0.80–1.20) 4.51 4.84 4.75
(0.82-1.18) 3.43 4.01 3.16
% correction of screen by confirm
1:1 mix (test:NPP) PTT-LA screen ratio
PTT-LA confirm ratio
(b10%) 23.9 17.1 33.5
(0.86-1.10) 0.99 0.96 0.96
(0.88-1.12) 0.93 0.98 0.94
Modified PTT-LA confirm ratio
4:1 mix (test:NPP) PTT-LA screen ratio
(0.80-1.20) ND ND 3.16
(0.80-1.20) ND ND 0.95
INR, international normalised ratio; APTT, activated partial thromboplastin time; dRVVT, dilute Russell’s viper venom time; TSVT, Taipan snake venom time; PTT-LA, Stago partial thromboplastin time-lupus anticoagulant reagent; NPP, normal pooled plasma; ND, not done. Reference ranges are given in parentheses.
deficiency. Prolongation of ellagic acid-activated APTT has been described in homozygous PK deficiency [11] yet PK does not significantly influence FXII activation by ellagic acid [12] and the normal Actin FS® APTT, previously reported in homozygous PK deficiency [13], was unremarkable. Phospholipid composition variation contributes to inconsistent sensitivity to factor deficiencies between APTT reagents [14] and can specifically affect the contact pathway [15]. Unal et al reported a homozygous PK deficient patient with grossly discrepant results between two silica-activated APTTs [16]. Despite the probable presence of a LA, the discrepancy was considered too marked to be explained by a LA alone, and the lower result was obtained with the LA-responsive reagent. The PTT-LA screen contains dilute rabbit brain phospholipid whereas the confirm employs concentrated, phosphatidyl-enhanced platelet phospholipid. We conclude that our patient had a LA at presentation but subsequent analyses apparently positive for LA by PTT-LA were due to variation in responsiveness to complete prekallikrein deficiency arising from the differing phospholipid composition of the screen and confirm assays. Conflict of Interests Statement The authors have no financial or personal conflicts of interest. Acknowledgements The authors wish to acknowledge Payalben Patel, Richard Polgrean, Valerie Barton, Dervilla Gorman and Aidan Culhane for performing some of the specialist diagnostic assays. References [1] Pengo V, Tripodi A, Reber G, Rand JH, Ortel TL, Galli M, De Groot PG. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. Update of the guidelines for lupus anticoagulant detection. J Thromb Haemost, 7; 2009 1737–40. [2] Keeling D, Mackie I, Moore GW, Greer IA, Greaves M. and British Committee for Standards in Haematology. Guidelines on the investigation and management of antiphospholipid syndrome. Br J Haematol 2012;157:47–58. [3] Exner T. Diagnostic methodologies for circulating anticoagulants. Thromb Haemost 1995;74:338–44. [4] Arnout J. Antiphospholipid syndrome: diagnostic aspects of lupus anticoagulants. Thromb Haemost 2000;86:83–91. [5] Moore GW, Brown KL, Bromidge ES, Drew AJ, Ledford-Kraemer MR. Lupus anticoagulant detection: out of control? Int J Lab Haematol 2013;35:128–36. [6] Moore GW, Bromidge ES, Polgrean RF, Archer RA, Squires I. Taipan snake venom time coupled with ecarin time testing enhances lupus anticoagulant detection in nonanticoagulated patients. J Thromb Haemost 2013;11(Suppl. 2) [abstract #PB3.62–6].
[7] Schouwers SM, Delanghe JR, Devreese KM. Lupus anticoagulant (LAC) testing in patients with inflammatory status: does C-reactive protein interfere with LAC test results? Thromb Res 2010;125:102–4. [8] Favaloro EJ, Bonar R, Marsden K. Lupus anticoagulant testing – sometimes mixing is required: potential for false negatives without mixing studies. Blood Coagul Fibrinolysis 2013;24:673–6. [9] Stevenson KJ, Sneddon JM. The role of lipids in the detection of lupus anticoagulant by the dilute Russell Viper venom test: are platelets or reagents containing hexagonal HII phases necessary? Br J Haematol 1994;86:583–9. [10] Abildgaard CF, Harrison J. Fletcher factor deficiency: family study and detection. Blood 1974;43:641–4. [11] Hathaway WE, Assmus SL, Montgomery RR, Dubansky AS. Activated partial thromboplastin time and minor coagulopathies. Am J Clin Pathol 1979;71:22–5. [12] España F, Ratnoff OD. The role of prekallikrein and high-molecular-weight kininogen in the contact activation of Hageman factor (factor XII) by sulfatides and other agents. J Lab Clin Med 1983;102:487–99. [13] François D, Trigui N, Leterreux G, Flaujac C, Horellou MH, Mazaux L, Vignon D, Conard J, de Mazancourt P. Severe prekallikrein deficiencies due to homozygous C529Y mutations. Blood Coagul Fibrinolysis 2007;18:283–6. [14] Stevenson KJ, Easton AC, Curry A, Thomson JM, Poller L. The reliability of activated partial thromboplastin time methods and the relationship to lipid composition and ultrastructure. Thromb Haemost 1986;55:250–8. [15] Schousboe I. The inositol-phospholipid-accelerated activation of prekallikrein by activated factor XII at physiological ionic strength requires zinc ions and high-Mr kininogen. Eur J Biochem 1990;193:495–9. [16] Unal S, Jariwala PD, Mahoney DH, Teruya J. A challenging diagnosis of homozygous prekallikrein deficiency during the preoperative evaluation of an infant with intractable seizures: A literature review of surgical management in this disorder. LabMedicine 2010;41:271–4.
Gary W. Moore Diagnostic Haemostasis and Thrombosis Laboratories, GSTS Pathology, St. Thomas’ Hospital, London, UK Corresponding author at: Department of Haemostasis and Thrombosis, GSTS Pathology, 4th floor North Wing, St. Thomas’ Hospital, Westminster Bridge Road, London SE1 7EH, UK. Tel.: +44 20 7188 0814; fax: +44 20 7188 2726. E-mail address: [email protected]. Shirish R. Sangle Lupus Research Unit, The Rayne Institute, St Thomas' Hospital, London, UK Robert A. Archer James C. Maloney Athif Rahman Diagnostic Haemostasis and Thrombosis Laboratories, GSTS Pathology, St. Thomas’ Hospital, London, UK David P. D’Cruz Lupus Research Unit, The Rayne Institute, St Thomas' Hospital, London, UK 10 September 2013
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Letter to the Editors-in-Chief Complete prekallikrein deficiency masquerading as a lupus anticoagulant
Dear Editors, A 24 year old Afro-Caribbean woman presented to her local hospital in August 2011 with acute neurological involvement, including left hemiparesis, left hemianopia and right-sided headache. She was transferred to St Thomas’ Hospital and systemic lupus erythematosus was diagnosed based on arthritis, vasculitic rash and positive serology for anti-nuclear antibodies (HEp-2 with diffuse nuclear pattern), anti-dsDNA, anti-Ro, anti-La and anti-ribonucleoprotein antibodies. She was found to have proteinuria with urinary protein creatinine ratio of 400 mg protein/mmol creatinine (reference interval (RI) 0-15) and granular casts in the urine. A renal biopsy confirmed combined Class IV - S (A/C) and Class V Lupus Nephritis. Activity Index - 15/24; Chronicity Index - 2/12. Her manifestations improved on prednisolone 40 mg/day, mycophenolate mofetil 2 g/day and hydroxychloroquine 400 mg/day. There was no previous history of thrombosis or pregnancy morbidity. Although not anticoagulated she had a markedly elevated activated partial thromboplastin time (APTT) of 140.5 s at presentation which was further investigated upon referral on fresh blood samples. Blood was collected into Vacuette® tubes (Greiner Bio-One Ltd, Stonehouse, UK) containing a one tenth volume of 0.105 M tri-sodium citrate and double centrifuged to obtain platelet poor plasma (PPP) [1,2]. The PPP for lupus anticoagulant (LA) testing was stored at –80 ° C until use. Coagulation screening on fresh plasma, comprising prothrombin time, APTT, thrombin time and fibrinogen, was performed on a Sysmex CA1500 (Sysmex UK Ltd, Milton Keynes, UK) using Siemens/Dade® Innovin®, Actin FS®, Thromboclotin® and Thrombin-Reagent® (Siemens Healthcare, Marburg, Germany) respectively. LA assays were performed on the CA1500 using Life Diagnostics LA Screen and LA Confirm (Life Therapeutics, Clarkston, USA) for dilute Russell’s viper venom time (dRVVT), and APTT using PTT-LA (Diagnostica Stago UK, Theale, UK) in the screen and addition of Bio/Data LA Confirmation Reagent™ (Alpha Laboratories, Eastleigh, UK) for the confirmatory test. Screen and confirm clotting times were converted to normalised ratios via NPP clotting times [1,2]. All elevated screens received the confirmatory test plus a screen and confirmatory test on 1:1 mixing studies with a commercial normal pooled plasma (NPP), CRYOcheck™ Normal Reference Plasma (Alpha Laboratories) [1–3]. A screen ratio above the locally derived RI with ≥10% correction by the confirm ratio was considered consistent with the presence of a LA [1,2]. The coagulation screen was normal except for a slightly elevated thrombin time ratio of 1.28 (RI 0.80-1.23). The dRVVT screen was 1.20 (RI 0.86-1.19) and corrected by 34.4% via a confirm of 0.84 (RI 0.831.13). The mixing test dRVVT screen was 1.19 (RI 0.90-1.10) and corrected by 25.2% via a confirm of 0.89 (RI 0.94-1.13). The PTT-LA screening test clotting time was prolonged to beyond the standard analyser 0049-3848/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.thromres.2013.11.014
acquisition time, which in view of the normal APTT with LAunresponsive Actin FS® and absence of haemorrhagic symptoms, was considered likely due to the LA reacting more potently in PTT-LA than dRVVT [4]. There was insufficient plasma to investigate further. IgG and IgM anticardiolipin antibody (aCL) levels were normal. The patient was not then referred for coagulation testing until January 2013 at a routine outpatient appointment. The laboratory was now using Sysmex CS2100i analysers for clotting screens and CS2000i models for LA testing. Reagents were identical although LA assay ratios were derived from RI mean clotting times not NPP values [5]. The clotting screen was normal except for an elevated fibrinogen of 5.2 g/L (RI 1.7-3.9). dRVVT, Taipan snake venom time (TSVT) [6] and IgG and IgM anti-β2glycoprotein I antibodies were normal. The PTT-LA screen was now measurable yet markedly elevated and evidenced 23.9% correction by the confirm. Remarkably for what appeared to be such a potent antibody, mixing tests were negative, and a repeat sample was requested to investigate further. Full results for this and subsequent samples from June 2013 are given in Table 1. IgG and IgM aCL levels were re-tested on both samples from June 2013 and remained normal. C-reactive protein (CRP) levels were b 5 mg/L (RI 0-4) on every occasion, excluding its interference in the clotting assays [7]. The markedly elevated PTT-LA screens with N 10% confirmatory test correction accompanied by normal coagulation screening would normally suggest the presence of a LA. However, whilst LAs can be diluted to undetectable levels in 1:1 mixing tests [1,2,4] the persistently negative results were inconsistent with such a potent antibody, which could also reasonably be expected to manifest even with the Actin FS® reagent. Additional testing was undertaken on the final sample. PTT-LA analysis on a semi-automated mechanical clot-detection coagulometer, a KC10 (Amelung, Lemgo, Germany), generated similarly abnormal results and thus did not exclude sample incompatibility with photo-optical clot detection of the automated analysers. An APTT on the KC10 with a LA-responsive routine reagent, TriniCLOT aPTT HS (Diagnostica Stago UK) gave a ratio of 3.0 (RI 0.8-1.2) that corrected to normal in a 1:1 mixing with NPP, suggesting a factor deficiency. Performing automated PTT-LA screen mixing test on a greater ratio of patient to control plasma (4:1) generated a normal ratio and was highly suggestive of a factor deficiency, and emphasised that presence of such a potent inhibitor was unlikely. Not all LAs generate confirmatory test results within reference ranges as some possess a degree of resistance to the overwhelming effect of the higher phospholipid concentration [1,8], but a modified PTT-LA confirm with a further increase in phospholipid concentration [9] failed to reduce the result. As Actin FS® employs ellagic acid as contact-activator, which is insensitive to prekallikrein (PK) deficiency [10], whilst the other two APTT reagents employ PK-sensitive silica activator, one-stage clotting assays for high molecular weight kininogen (HMWK) and PK were performed on a CS2100i with the TriniCLOT aPTT HS reagent and short incubation time of three minutes. HMWK was 84.8 U/dL (RI 50-150) but PK was undetectable. In view of the now persistently normal dRVVT and inability of the apparent APTT-reactive LA to inhibit even a small amount of NPP, the only clear coagulation abnormality was PK
302
Letter to the Editors-in-Chief
Table 1 Serial coagulation screen and lupus anticoagulant testing. Date
02.01.2013 05.06.2013 20.06.2013
INR
(0.8–1.2) 1.0 0.9 0.9
APTT ratio
dRVVT ratio
TSVT ratio
Undiluted test plasma PTT-LA screen ratio
PTT-LA confirm ratio
(0.8–1.2) 1.1 1.1 1.0
(0.85-1.17) 0.96 0.92 0.92
(0.87-1.14) 1.02 ND ND
(0.80–1.20) 4.51 4.84 4.75
(0.82-1.18) 3.43 4.01 3.16
% correction of screen by confirm
1:1 mix (test:NPP) PTT-LA screen ratio
PTT-LA confirm ratio
(b10%) 23.9 17.1 33.5
(0.86-1.10) 0.99 0.96 0.96
(0.88-1.12) 0.93 0.98 0.94
Modified PTT-LA confirm ratio
4:1 mix (test:NPP) PTT-LA screen ratio
(0.80-1.20) ND ND 3.16
(0.80-1.20) ND ND 0.95
INR, international normalised ratio; APTT, activated partial thromboplastin time; dRVVT, dilute Russell’s viper venom time; TSVT, Taipan snake venom time; PTT-LA, Stago partial thromboplastin time-lupus anticoagulant reagent; NPP, normal pooled plasma; ND, not done. Reference ranges are given in parentheses.
deficiency. Prolongation of ellagic acid-activated APTT has been described in homozygous PK deficiency [11] yet PK does not significantly influence FXII activation by ellagic acid [12] and the normal Actin FS® APTT, previously reported in homozygous PK deficiency [13], was unremarkable. Phospholipid composition variation contributes to inconsistent sensitivity to factor deficiencies between APTT reagents [14] and can specifically affect the contact pathway [15]. Unal et al reported a homozygous PK deficient patient with grossly discrepant results between two silica-activated APTTs [16]. Despite the probable presence of a LA, the discrepancy was considered too marked to be explained by a LA alone, and the lower result was obtained with the LA-responsive reagent. The PTT-LA screen contains dilute rabbit brain phospholipid whereas the confirm employs concentrated, phosphatidyl-enhanced platelet phospholipid. We conclude that our patient had a LA at presentation but subsequent analyses apparently positive for LA by PTT-LA were due to variation in responsiveness to complete prekallikrein deficiency arising from the differing phospholipid composition of the screen and confirm assays. Conflict of Interests Statement The authors have no financial or personal conflicts of interest. Acknowledgements The authors wish to acknowledge Payalben Patel, Richard Polgrean, Valerie Barton, Dervilla Gorman and Aidan Culhane for performing some of the specialist diagnostic assays. References [1] Pengo V, Tripodi A, Reber G, Rand JH, Ortel TL, Galli M, De Groot PG. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. Update of the guidelines for lupus anticoagulant detection. J Thromb Haemost, 7; 2009 1737–40. [2] Keeling D, Mackie I, Moore GW, Greer IA, Greaves M. and British Committee for Standards in Haematology. Guidelines on the investigation and management of antiphospholipid syndrome. Br J Haematol 2012;157:47–58. [3] Exner T. Diagnostic methodologies for circulating anticoagulants. Thromb Haemost 1995;74:338–44. [4] Arnout J. Antiphospholipid syndrome: diagnostic aspects of lupus anticoagulants. Thromb Haemost 2000;86:83–91. [5] Moore GW, Brown KL, Bromidge ES, Drew AJ, Ledford-Kraemer MR. Lupus anticoagulant detection: out of control? Int J Lab Haematol 2013;35:128–36. [6] Moore GW, Bromidge ES, Polgrean RF, Archer RA, Squires I. Taipan snake venom time coupled with ecarin time testing enhances lupus anticoagulant detection in nonanticoagulated patients. J Thromb Haemost 2013;11(Suppl. 2) [abstract #PB3.62–6].
[7] Schouwers SM, Delanghe JR, Devreese KM. Lupus anticoagulant (LAC) testing in patients with inflammatory status: does C-reactive protein interfere with LAC test results? Thromb Res 2010;125:102–4. [8] Favaloro EJ, Bonar R, Marsden K. Lupus anticoagulant testing – sometimes mixing is required: potential for false negatives without mixing studies. Blood Coagul Fibrinolysis 2013;24:673–6. [9] Stevenson KJ, Sneddon JM. The role of lipids in the detection of lupus anticoagulant by the dilute Russell Viper venom test: are platelets or reagents containing hexagonal HII phases necessary? Br J Haematol 1994;86:583–9. [10] Abildgaard CF, Harrison J. Fletcher factor deficiency: family study and detection. Blood 1974;43:641–4. [11] Hathaway WE, Assmus SL, Montgomery RR, Dubansky AS. Activated partial thromboplastin time and minor coagulopathies. Am J Clin Pathol 1979;71:22–5. [12] España F, Ratnoff OD. The role of prekallikrein and high-molecular-weight kininogen in the contact activation of Hageman factor (factor XII) by sulfatides and other agents. J Lab Clin Med 1983;102:487–99. [13] François D, Trigui N, Leterreux G, Flaujac C, Horellou MH, Mazaux L, Vignon D, Conard J, de Mazancourt P. Severe prekallikrein deficiencies due to homozygous C529Y mutations. Blood Coagul Fibrinolysis 2007;18:283–6. [14] Stevenson KJ, Easton AC, Curry A, Thomson JM, Poller L. The reliability of activated partial thromboplastin time methods and the relationship to lipid composition and ultrastructure. Thromb Haemost 1986;55:250–8. [15] Schousboe I. The inositol-phospholipid-accelerated activation of prekallikrein by activated factor XII at physiological ionic strength requires zinc ions and high-Mr kininogen. Eur J Biochem 1990;193:495–9. [16] Unal S, Jariwala PD, Mahoney DH, Teruya J. A challenging diagnosis of homozygous prekallikrein deficiency during the preoperative evaluation of an infant with intractable seizures: A literature review of surgical management in this disorder. LabMedicine 2010;41:271–4.
Gary W. Moore Diagnostic Haemostasis and Thrombosis Laboratories, GSTS Pathology, St. Thomas’ Hospital, London, UK Corresponding author at: Department of Haemostasis and Thrombosis, GSTS Pathology, 4th floor North Wing, St. Thomas’ Hospital, Westminster Bridge Road, London SE1 7EH, UK. Tel.: +44 20 7188 0814; fax: +44 20 7188 2726. E-mail address: [email protected]. Shirish R. Sangle Lupus Research Unit, The Rayne Institute, St Thomas' Hospital, London, UK Robert A. Archer James C. Maloney Athif Rahman Diagnostic Haemostasis and Thrombosis Laboratories, GSTS Pathology, St. Thomas’ Hospital, London, UK David P. D’Cruz Lupus Research Unit, The Rayne Institute, St Thomas' Hospital, London, UK 10 September 2013
