350
Letters to the Editor Blood Coagulation and Fibrinolysis 2015, 26:350–353
Prenatal diagnosis in a family with purfura fulminans Sharda Shanbhag, Navin Pai, Kanjaksha Ghosh and Shrimati Shetty National Institute of Immunohaematology (Indian Council of Medical Research), KEM Hospital Campus, Parel, Mumbai, India Correspondence to Dr Shrimati Shetty, National Institute of Immunohaematology (ICMR), KEM Hospital Campus, Parel, Mumbai 400012, India Tel: +91 22-24138518; fax: +91 22-24138521; e-mail: [email protected]
Prenatal diagnosis in the second trimester of pregnancy in case of haemophilia is offered on a routine basis at our centre. Detection of congenital protein C deficiency with purpura fulminans, a rarely diagnosed condition, can also be offered using molecular biology techniques. If the causative mutation is known, the diagnosis can aid early intervention, and thus assist prevention of deadly consequences of severe protein C deficiency and other complications in advanced pregnancy [1,2]. Severe protein C deficiency is a rare autosomal recessive disorder that presents in the neonatal period with purpura fulminans, a fatal condition characterised by cutaneous haemorrhage and gangrenous necrosis [3–5]. Such a case of a 3-day-old male child was referred to our laboratory for thrombophilia profile. This child born of consanguineous marriage between first-degree cousins had a history of two neonatal deaths of siblings. In spite of rigorous treatment and supplementation with fresh frozen plasma, the patient succumbed to the condition on the 27th day of life. However, further testing of the sample, though posttransfused, revealed protein C antigen and activity levels to be 3 and 5%, respectively, whereas those of the parents ranged between 36 and 42%. Following molecular analysis, it was found that the propositus showed a known homozygous deletion in exon 5 of the PROC: 3156delC. Parents were found to be heterozygous carriers for the mutation and thus were counselled about an option of reliable prenatal diagnosis in their subsequent pregnancy [6]. Hence, in the second trimester of pregnancy, with the consent of parents for antenatal diagnosis and subsequent procedures required for the same, amniotic fluid sampling was done at the Wadia Maternity Hospital using appropriate measures. PROC defects in the amniotic fluid DNA as well as the parents’ DNA were screened for by PCR amplification of exon 5 and direct sequencing using ABI 3130XL sequencer. After studying the sequences of the same, it was found that the fetus carried the same deletion mutation as in the index case. A diagnosis of affected fetus was made and the family was informed about the results and counselled
accordingly. The mother underwent termination of pregnancy in the next few days. In conclusion, we report prenatal diagnosis of protein C deficiency with purpura fulminans for the first time in India.
Acknowledgements Conflicts of interest
There are no conflicts of interest.
References 1
2 3 4 5
6
Salonvaara M, Kuismanen K, Mononen T, Riikonen P. Diagnosis and treatment of a new born with homozygous protein C deficiency. Acta Paediatr 2004; 93:137–139. Kirkinen P, Salonvaara M, Nikolajev K, Vanninen R, Heinonen K. Antepartum findings in fetal protein C deficiency. Prenat Diagn 2000; 20:746–749. Goldenberg NA, Manco-Johnson MJ. Protein C deficiency. Haemophilia 2008; 14:1214–1221. Aroor S, Varma C, Mundkur SC. Purpura fulminans in a child: a case report. J Clin Diagn Res 2012; 6:1812–1813. Price VE, Ledingham DL, Kru¨mpel A, Chan AK. Diagnosis and management of neonatal purpura fulminans. Semin Fetal Neonatal Med 2011; 16:318– 322. Pai N, Shetty S, Ghosh K, Protein C. (PROC) gene mutations in two Indian families with purpura fulminans. Ann Hematol 2010; 89:835–836. DOI:10.1097/MBC.0000000000000251
Plasminogen activator inhibitor type 1 deficiency revealed by severe bleeding after prostatectomy in a 76-year-old male Frederic Bauduera,b, Fanny Me´nardc and Aguirre Mimounc a
Department of Clinical Hematology, Centre Hospitalier de la Coˆte Basque, Bayonne, bLaboratory MRGM, EA 4576, Universite´ de Bordeaux, Bordeaux and c Laboratory of Hematology, Centre Hospitalier de la Coˆte Basque, Bayonne, France Correspondence to Frederic Bauduer, MD, PhD, Service d’He´matologie, CH de la Coˆte Basque, 13 Avenue J. Loeb, 64100 Bayonne, France Tel: +33 05 59 44 38 32; fax: +33 05 59 44 38 37; e-mail: [email protected]
A 76-year-old male originating from south-western France presented at the hematology consultation because of severe and prolonged hematuria after prostatectomy. His medical history did not include significant problems. Noticeably, he did not notice any spontaneous or provoked bleeding tendency. His previous operations including varicose vein stripping, hemorrhoidectomy, neurosurgery for narrowing of the lumbar vertebral canal, skin tumor excision, and several dental extractions had been uneventful. He declared that his mother had heavy menses (noticeably she died at 101 years) and his daughter had suffered from hemorrhagic shock after uterine myomectomy. He did not experience excessive bleeding during the time of the
0957-5235 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Letters to the Editor 351
surgical procedure, but repeated episodes of severe hematuria developed from day 2 postsurgery. The bleeding was significant inducing anemia (Hb: 8.2 g/dl) and requiring red blood cell transfusions. Hematuria resolved after administration of fresh frozen plasma. The usual preoperative coagulation tests were within the normal range regarding activated partial thromboplastin time: 37 s (35 sec), prothrombin time: 12.1 s (11.7–14), fibrinogen: 3.67 g/l, and platelet counts. Further investigations revealed no platelet function defects and von Willebrand disease was ruled out. The PFA-100 occlusion time and all coagulation factors (including factor XIII) were normal except factor XI at 44% (in relation with heterozygosity for the Ser 225 Phe mutation). Importantly, plasminogen activator inhibitor type 1 (PAI-1) deficiency was found using a colorimetric assay (0.7 and 0.6 U/ml on two different samples, normal >2 U/ml). The same double deficiency for factor XI and PAI-1 was also documented in two of his three children. PAI-1 is a downregulator of the fibrinolytic system. The corresponding gene is located on chromosome 7q21.3–22 and some defects within this gene have been described in association with PAI-1 deficiency (Online Mendelian Inheritance in Man # 613329, transmission: autosomal recessive). Clinical manifestations include mostly delayed bleeding tendency after injury or surgery because of premature clot lysis [1]. Menorrhagia is part of the clinical picture in the young female [2] (the patient’ mother was probably PAI-1-deficient). PAI-1 deficiency is not necessarily detected in the young; the first individual reported in the literature with this disorder was also 76 years old [3]. Complete deficiency seems associated with life-threatening hemorrhages and prolonged wound healing [4]. In our case, PAI-1 activity levels under 1 IU/ml associated with major postsurgical bleeding support the diagnosis of significant PAI-1 deficiency. The real prevalence of this disorder is not known, but almost 100 carriers have been identified in the Amish population [1]. PAI-1 is likely to play a role in the genesis of our two major current ‘killer’ diseases, atherosclerosis and cancer [5]. Considering this fact, the marked longevity of patient’ mother is intriguing. Here, one must underscore that PAI-1 deficiency induced bleeding only after prostate surgery, an organ associated with high fibrinolytic activity, and not after other procedures. Fibrinolysis inhibitors (aminocaproic acid or tranexamic acid) are efficient drugs for treating or preventing hemorrhages in PAI-1-deficient individuals [1–3]. Furthermore, the associated partial deficiency in factor XI is to be noted. Usually, it does not induce significant bleeding risk per se. However, in combination with PAI-1 deficiency, it could have further jeopardized the stability of the fibrin clot because of relative decreased thrombin-activatable fibrinolysis inhibitor production [6], which may be relevant in this context of surgery with fibrinolysis overstimulation. Such multiple inherited coagulation factor deficiencies seem to be more frequent in isolated human groups as our Basque population [7].
Acknowledgements Conflicts of interest
There are no conflicts of interest.
References 1 2
3
4
5 6 7
Mehta R, Shapiro AD. Plaminogen activator inhibitor type 1 deficiency. Haemophilia 2008; 14:1255–1260. Repine T, Osswald M. Menorrhagia due to a qualitative deficiency of plasminogen activator inhibitor-1: case report and literature review. Clin Appl Thromb Hemost 2004; 10:293–296. Schleef RR, Higgins DL, Pillemer F, Levitt LJ. Bleeding diathesis due to decreased functional activity of type 1 plasminogen activator inhibitor. J Clin Invest 1989; 83:1747–1752. Iwaki T, Tanaka A, Miyawaki Y, Suzuki A, Kobayashi T, Takamatsu J, et al. Lifethreatening hemorrhage and prolonged wound healing are remarkable phenotypes manifested by complete plasminogen activator inhibitor-1 deficiency in humans. J Thromb Haemost 2011; 9:1200–1206. Iwaki T, Urano T, Umemuka K. PAI-1, progress in understanding the clinical problem and its aetiology. Br J Haematol 2012; 157:291–298. Bouma BN, Meijers JC. Role of blood coagulation factor XI in downregulation of fibrinolysis. Curr Opin Hematol 2000; 7:266–272. Bauduer F, Ducout L, Degioanni A, Dutour O. Is there a ‘Basque’ profile regarding autosomal recessive deficiencies of coagulation factors? Haemophilia 2004; 10:276–279. DOI:10.1097/MBC.0000000000000254
Achilles’ heel of Aristotle Claudia Sto¨llbergera, Christian Wegnerb and Josef Finsterera a Krankenanstalt Rudolfstiftung, Juchgasse and bVienna Institute of Demography of the Austrian Academy of Sciences, Wien, Austria
Correspondence to Dr Claudia Sto¨llberger, Steingasse 31/18, A-1030 Wien, ¨ sterreich O Tel: +43 676 403 11 87; fax: +43 1 71165 2209; e-mail: [email protected]
ARISTOTLE was a trial, comparing apixaban with warfarin in 18 201 patients with atrial fibrillation. Apixaban was superior to warfarin in preventing stroke/embolism, caused less bleeding, and resulted in lower mortality [1]. On the contrary, the results of ARISTOTLE have to be interpreted with caution because of missing patients. Vital status at the end of the trial was missing in 380 patients. It remains unknown at which time they were lost. It is not reported how this problem was dissolved statistically. Missing vital status was because of withdrawal of consent in 199 patients (apixaban-group n ¼ 92, warfarin-group, n ¼ 107) and loss to follow-up in 69 patients (apixaban-group, n ¼ 35; warfarin-group, n ¼ 34) [1]. The results of the Eq. (380) (199 þ 69) shows that 112 patients are missing. It is unknown how many of these 112 patients were randomized to which treatment. No data about clinical characteristics of the missing patients are reported; thus, it cannot be assessed whether they were ‘sicker’ than the remaining patients. It is known from social sciences that those less satisfied with their health are more likely to become nonresponders to follow-up investigations [2,3]. Thus, it can be assumed that several missing patients might
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
352 Blood Coagulation and Fibrinolysis 2015, Vol 26 No 3
Table 1
Outcome events according to the published results and 2 simulation models Reported in Granger et al.a
Events N for efficacy outcomes Missing vital status due to withdrawal Missing vital status due to loss Missing vital status not reportedb Valid N for efficacy outcomes Primary outcome: stroke or systemic embolism Key secondary efficacy outcome: death from any cause N for bleeding outcomes and net clinical outcomes N minus missing cases in vital status Primary safety outcome: Major bleeding Intracranial Other location Stroke, systemic embolism, or major bleeding Stroke, systemic embolism, major bleeding or death from any cause
Apixaban
Warfarin
P
9120 92 35 56 8937 212 603
9081 107 34 56 8884 265 669
0.010 0.047
9,088 8905 327 52 275 521 1009
9,052 8855 462 122 340 666 1168
Letters to the Editor Blood Coagulation and Fibrinolysis 2015, 26:350–353
Prenatal diagnosis in a family with purfura fulminans Sharda Shanbhag, Navin Pai, Kanjaksha Ghosh and Shrimati Shetty National Institute of Immunohaematology (Indian Council of Medical Research), KEM Hospital Campus, Parel, Mumbai, India Correspondence to Dr Shrimati Shetty, National Institute of Immunohaematology (ICMR), KEM Hospital Campus, Parel, Mumbai 400012, India Tel: +91 22-24138518; fax: +91 22-24138521; e-mail: [email protected]
Prenatal diagnosis in the second trimester of pregnancy in case of haemophilia is offered on a routine basis at our centre. Detection of congenital protein C deficiency with purpura fulminans, a rarely diagnosed condition, can also be offered using molecular biology techniques. If the causative mutation is known, the diagnosis can aid early intervention, and thus assist prevention of deadly consequences of severe protein C deficiency and other complications in advanced pregnancy [1,2]. Severe protein C deficiency is a rare autosomal recessive disorder that presents in the neonatal period with purpura fulminans, a fatal condition characterised by cutaneous haemorrhage and gangrenous necrosis [3–5]. Such a case of a 3-day-old male child was referred to our laboratory for thrombophilia profile. This child born of consanguineous marriage between first-degree cousins had a history of two neonatal deaths of siblings. In spite of rigorous treatment and supplementation with fresh frozen plasma, the patient succumbed to the condition on the 27th day of life. However, further testing of the sample, though posttransfused, revealed protein C antigen and activity levels to be 3 and 5%, respectively, whereas those of the parents ranged between 36 and 42%. Following molecular analysis, it was found that the propositus showed a known homozygous deletion in exon 5 of the PROC: 3156delC. Parents were found to be heterozygous carriers for the mutation and thus were counselled about an option of reliable prenatal diagnosis in their subsequent pregnancy [6]. Hence, in the second trimester of pregnancy, with the consent of parents for antenatal diagnosis and subsequent procedures required for the same, amniotic fluid sampling was done at the Wadia Maternity Hospital using appropriate measures. PROC defects in the amniotic fluid DNA as well as the parents’ DNA were screened for by PCR amplification of exon 5 and direct sequencing using ABI 3130XL sequencer. After studying the sequences of the same, it was found that the fetus carried the same deletion mutation as in the index case. A diagnosis of affected fetus was made and the family was informed about the results and counselled
accordingly. The mother underwent termination of pregnancy in the next few days. In conclusion, we report prenatal diagnosis of protein C deficiency with purpura fulminans for the first time in India.
Acknowledgements Conflicts of interest
There are no conflicts of interest.
References 1
2 3 4 5
6
Salonvaara M, Kuismanen K, Mononen T, Riikonen P. Diagnosis and treatment of a new born with homozygous protein C deficiency. Acta Paediatr 2004; 93:137–139. Kirkinen P, Salonvaara M, Nikolajev K, Vanninen R, Heinonen K. Antepartum findings in fetal protein C deficiency. Prenat Diagn 2000; 20:746–749. Goldenberg NA, Manco-Johnson MJ. Protein C deficiency. Haemophilia 2008; 14:1214–1221. Aroor S, Varma C, Mundkur SC. Purpura fulminans in a child: a case report. J Clin Diagn Res 2012; 6:1812–1813. Price VE, Ledingham DL, Kru¨mpel A, Chan AK. Diagnosis and management of neonatal purpura fulminans. Semin Fetal Neonatal Med 2011; 16:318– 322. Pai N, Shetty S, Ghosh K, Protein C. (PROC) gene mutations in two Indian families with purpura fulminans. Ann Hematol 2010; 89:835–836. DOI:10.1097/MBC.0000000000000251
Plasminogen activator inhibitor type 1 deficiency revealed by severe bleeding after prostatectomy in a 76-year-old male Frederic Bauduera,b, Fanny Me´nardc and Aguirre Mimounc a
Department of Clinical Hematology, Centre Hospitalier de la Coˆte Basque, Bayonne, bLaboratory MRGM, EA 4576, Universite´ de Bordeaux, Bordeaux and c Laboratory of Hematology, Centre Hospitalier de la Coˆte Basque, Bayonne, France Correspondence to Frederic Bauduer, MD, PhD, Service d’He´matologie, CH de la Coˆte Basque, 13 Avenue J. Loeb, 64100 Bayonne, France Tel: +33 05 59 44 38 32; fax: +33 05 59 44 38 37; e-mail: [email protected]
A 76-year-old male originating from south-western France presented at the hematology consultation because of severe and prolonged hematuria after prostatectomy. His medical history did not include significant problems. Noticeably, he did not notice any spontaneous or provoked bleeding tendency. His previous operations including varicose vein stripping, hemorrhoidectomy, neurosurgery for narrowing of the lumbar vertebral canal, skin tumor excision, and several dental extractions had been uneventful. He declared that his mother had heavy menses (noticeably she died at 101 years) and his daughter had suffered from hemorrhagic shock after uterine myomectomy. He did not experience excessive bleeding during the time of the
0957-5235 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Letters to the Editor 351
surgical procedure, but repeated episodes of severe hematuria developed from day 2 postsurgery. The bleeding was significant inducing anemia (Hb: 8.2 g/dl) and requiring red blood cell transfusions. Hematuria resolved after administration of fresh frozen plasma. The usual preoperative coagulation tests were within the normal range regarding activated partial thromboplastin time: 37 s (35 sec), prothrombin time: 12.1 s (11.7–14), fibrinogen: 3.67 g/l, and platelet counts. Further investigations revealed no platelet function defects and von Willebrand disease was ruled out. The PFA-100 occlusion time and all coagulation factors (including factor XIII) were normal except factor XI at 44% (in relation with heterozygosity for the Ser 225 Phe mutation). Importantly, plasminogen activator inhibitor type 1 (PAI-1) deficiency was found using a colorimetric assay (0.7 and 0.6 U/ml on two different samples, normal >2 U/ml). The same double deficiency for factor XI and PAI-1 was also documented in two of his three children. PAI-1 is a downregulator of the fibrinolytic system. The corresponding gene is located on chromosome 7q21.3–22 and some defects within this gene have been described in association with PAI-1 deficiency (Online Mendelian Inheritance in Man # 613329, transmission: autosomal recessive). Clinical manifestations include mostly delayed bleeding tendency after injury or surgery because of premature clot lysis [1]. Menorrhagia is part of the clinical picture in the young female [2] (the patient’ mother was probably PAI-1-deficient). PAI-1 deficiency is not necessarily detected in the young; the first individual reported in the literature with this disorder was also 76 years old [3]. Complete deficiency seems associated with life-threatening hemorrhages and prolonged wound healing [4]. In our case, PAI-1 activity levels under 1 IU/ml associated with major postsurgical bleeding support the diagnosis of significant PAI-1 deficiency. The real prevalence of this disorder is not known, but almost 100 carriers have been identified in the Amish population [1]. PAI-1 is likely to play a role in the genesis of our two major current ‘killer’ diseases, atherosclerosis and cancer [5]. Considering this fact, the marked longevity of patient’ mother is intriguing. Here, one must underscore that PAI-1 deficiency induced bleeding only after prostate surgery, an organ associated with high fibrinolytic activity, and not after other procedures. Fibrinolysis inhibitors (aminocaproic acid or tranexamic acid) are efficient drugs for treating or preventing hemorrhages in PAI-1-deficient individuals [1–3]. Furthermore, the associated partial deficiency in factor XI is to be noted. Usually, it does not induce significant bleeding risk per se. However, in combination with PAI-1 deficiency, it could have further jeopardized the stability of the fibrin clot because of relative decreased thrombin-activatable fibrinolysis inhibitor production [6], which may be relevant in this context of surgery with fibrinolysis overstimulation. Such multiple inherited coagulation factor deficiencies seem to be more frequent in isolated human groups as our Basque population [7].
Acknowledgements Conflicts of interest
There are no conflicts of interest.
References 1 2
3
4
5 6 7
Mehta R, Shapiro AD. Plaminogen activator inhibitor type 1 deficiency. Haemophilia 2008; 14:1255–1260. Repine T, Osswald M. Menorrhagia due to a qualitative deficiency of plasminogen activator inhibitor-1: case report and literature review. Clin Appl Thromb Hemost 2004; 10:293–296. Schleef RR, Higgins DL, Pillemer F, Levitt LJ. Bleeding diathesis due to decreased functional activity of type 1 plasminogen activator inhibitor. J Clin Invest 1989; 83:1747–1752. Iwaki T, Tanaka A, Miyawaki Y, Suzuki A, Kobayashi T, Takamatsu J, et al. Lifethreatening hemorrhage and prolonged wound healing are remarkable phenotypes manifested by complete plasminogen activator inhibitor-1 deficiency in humans. J Thromb Haemost 2011; 9:1200–1206. Iwaki T, Urano T, Umemuka K. PAI-1, progress in understanding the clinical problem and its aetiology. Br J Haematol 2012; 157:291–298. Bouma BN, Meijers JC. Role of blood coagulation factor XI in downregulation of fibrinolysis. Curr Opin Hematol 2000; 7:266–272. Bauduer F, Ducout L, Degioanni A, Dutour O. Is there a ‘Basque’ profile regarding autosomal recessive deficiencies of coagulation factors? Haemophilia 2004; 10:276–279. DOI:10.1097/MBC.0000000000000254
Achilles’ heel of Aristotle Claudia Sto¨llbergera, Christian Wegnerb and Josef Finsterera a Krankenanstalt Rudolfstiftung, Juchgasse and bVienna Institute of Demography of the Austrian Academy of Sciences, Wien, Austria
Correspondence to Dr Claudia Sto¨llberger, Steingasse 31/18, A-1030 Wien, ¨ sterreich O Tel: +43 676 403 11 87; fax: +43 1 71165 2209; e-mail: [email protected]
ARISTOTLE was a trial, comparing apixaban with warfarin in 18 201 patients with atrial fibrillation. Apixaban was superior to warfarin in preventing stroke/embolism, caused less bleeding, and resulted in lower mortality [1]. On the contrary, the results of ARISTOTLE have to be interpreted with caution because of missing patients. Vital status at the end of the trial was missing in 380 patients. It remains unknown at which time they were lost. It is not reported how this problem was dissolved statistically. Missing vital status was because of withdrawal of consent in 199 patients (apixaban-group n ¼ 92, warfarin-group, n ¼ 107) and loss to follow-up in 69 patients (apixaban-group, n ¼ 35; warfarin-group, n ¼ 34) [1]. The results of the Eq. (380) (199 þ 69) shows that 112 patients are missing. It is unknown how many of these 112 patients were randomized to which treatment. No data about clinical characteristics of the missing patients are reported; thus, it cannot be assessed whether they were ‘sicker’ than the remaining patients. It is known from social sciences that those less satisfied with their health are more likely to become nonresponders to follow-up investigations [2,3]. Thus, it can be assumed that several missing patients might
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
352 Blood Coagulation and Fibrinolysis 2015, Vol 26 No 3
Table 1
Outcome events according to the published results and 2 simulation models Reported in Granger et al.a
Events N for efficacy outcomes Missing vital status due to withdrawal Missing vital status due to loss Missing vital status not reportedb Valid N for efficacy outcomes Primary outcome: stroke or systemic embolism Key secondary efficacy outcome: death from any cause N for bleeding outcomes and net clinical outcomes N minus missing cases in vital status Primary safety outcome: Major bleeding Intracranial Other location Stroke, systemic embolism, or major bleeding Stroke, systemic embolism, major bleeding or death from any cause
Apixaban
Warfarin
P
9120 92 35 56 8937 212 603
9081 107 34 56 8884 265 669
0.010 0.047
9,088 8905 327 52 275 521 1009
9,052 8855 462 122 340 666 1168
