LETTERS TO THE EDITORS
References 1 Maheshwari R, Kelley SP, Langkamer VG, Loveday E. Spontaneous recurrent haemarthrosis following unicompartmental knee arthroplasty and its successful treatment by coil embolisation. Knee 2004; 11: 413–5. 2 Karataglis D, Marlow D, Learmonth DJ. Atraumatic haemarthrosis following total knee replacement treated with selective embolisation. Acta Orthop Belg 2006; 72: 375–7. 3 Sandoval E, Ortega FJ, Garcia-Rayo MR, Resines C. Popliteal pseudoaneurysm after total knee arthroplasty secondary to intraoperative arterial injury with a surgical pin: review of the literature. J Arthroplasty 2008; 23: 1239. e7-11.
4 Saksena J, Platts AD, Dowd GSE. Recurrent haemarthrosis following total knee replacement. Knee 2009; 17: 7–14. 5 Tat-Sing Law M, McClure DN. Therapeutic embolization in the treatment of recurrent haemarthrosis following knee arthroplasty. ANZ J Surg 2010; 80: 247–9. 6 Scoles PV, King D. Traumatic aneurysm of the descending geniculate artery: a complication of suction drainage in synovectomy for hemophilic arthropathy. Clin Orthop Relat Res 1980; 150: 245–6. 7 Kickuth R, Anderson S, Peter-Salonen K, L€ammle B, Eggli S, Triller J. Hemophilia A pseudoaneurysm in a patient with high responding inhibitors complicating total knee arthroplasty: embolization: a costreducing alternative to medical therapy.
e89
Cardiovasc Intervent Radiol 2006; 29: 1132–5. 8 Rodriguez-Merchan EC. Total knee replacement in haemophilic arthropathy. J Bone Joint Surg Br 2007; 89: 186–8. 9 Park JJ, Slover JD, Stuchin SA. Recurrent hemarthrosis in a hemophilic patient after revision total knee arthroplasty. Orthopedics 2010; 33: 771. 10 Saarela MS, Tiitola M, Lappalainen K et al. Pseudoaneurysm in association with a knee endoprothesis operation in an inhibitor-positive haemophilia A patient – treatment with local thrombin. Haemophilia 2010; 16: 686–8.
Polymorphism of thrombin-activatable fibrinolysis inhibitor and risk of intracranial haemorrhage in factor XIII deficiency M. NADERI,* A. DORGALALEH,† S. ALIZADEH,† Z. KASHANI KHATIB,† S. TABIBIAN,† A . K A Z E M I , † H . D A R G A H I † and T . B A M E D I * *Ali Ebn-e Abitaleb Hospital Research Center for Adolescents Health, Zahedan University of Medical Sciences, Zahedan; and †Department of Hematology, Allied Medical School, Tehran University of Medical Sciences, Tehran, Iran
Factor XIII (FXIII) deficiency is an extremely rare autosomal recessive bleeding disorder with estimated prevalence of at around 1/2 000 000 in the general population. Presumptive diagnosis of FXIII deficiency was made by clot solubility test in 5 M urea or 1% monochloroacetic acid. In patients with abnormal screening clot solubility test, the disease can be confirmed by more specific tests such as quantitative FXIII activity assay, antigen (FXIII Ag) assay or more precisely using molecular analysis. All patients with severe FXIII deficiency (C) was selected for confirmation of the disorder because our study population was also selected from this area [8,9]. Then three reported mutations including FXIII Val34Leu, FXIII Tyr204Phe and FXIII Pro564Leu and a common polymorphism of TAFI, Thr325Ile were performed by polymerase chain reaction amplification of genomic DNA followed by restriction enzyme digestion (PCRRFLP). This study revealed that the prevalence of intracranial haemorrhage in our large population is 16.5% and intraparenchymal is the most common site of ICH (91.4%) and subdural haemorrhage and epidural haemorrhage was observed in two patients (5.9%) (Table 1). Temporal and occipital were common anatomical regions of Intraparenchymal haemorrhage (each 26.4%) and temporo-occipital was the other common region (11.7%). We also found that therapeutic response with FFP, cryoprecipitate and Fibrogammin P was excellent and Haemophilia (2014), 20, e79--e112
all patients except one did not experience recurrent intracranial haemorrhage. Our molecular analysis revealed that C.559T>C nucleotide exchange in exon 4 which leads to tryptophan to arginine substitution in FXIII A subunit is a causative mutation in our patients and all study patients were homozygous for this mutation [8,9]. Molecular studies of Tyr204Phe, Pro564Leu and Val34Leu polymorphisms revealed that no one in case or control groups was positive for these mutations. We also found that TAFI Thr325Ile polymorphism is much higher in FXIII-deficient patients with ICH in comparison with the case group. A significant correlation was present between TAFI Thr325Ile polymorphism in homozygous form and occurrence of spontaneous intracranial haemorrhage (OR 18.9, 95% CI 3.8–95.1). There was also a significant difference between case and control group about homozygous TAFI Thr325Ile polymorphism (P < 0.001). There was no correlation between TAFI Thr325Ile polymorphism in heterozygous manner and intracranial haemorrhage (OR 1.1, 95% CI 0.6–4.6) and it is amazing that in contrast to homozygous form of polymorphism, heterozygosity was higher in patients with negative history of intracranial haemorrhage and this difference was statistically significant (P < 0.006). It is also important to state that our patient with history of ICH and poor response to replacement therapy with FFP, cryoprecipitate and Fibrogammin P was homozygous for TAFI Thr325Ile polymorphism. Thr325Ile is a common polymorphism of TAFI that its robust association with stroke was proven [6,7]. However, in case–control study of Serhat Tokgoz no association was found between cerebral venous thrombosis and several mutations of TAFI include 1040C/T (Thr325Ile polymorphism [10]. Besides the role of TAFI in ischaemic stroke, several other reasons led us to assess the role of a common polymorphism of TAFI, Thr325Ile on occurrence of ICH in patients with severe FXIII deficiency. These reasons include, Thr325Ile polymorphism is decreased circulating level and also associated with 60% decreased of antifibrinolytic effect of TAFI that seems to be a risk factor for bleeding. TAFI has also a significant role in regulation of blood pressure and also elevated level of TAFI-enhanced atherosclerosis progression. In fact in this case–control study, due to the large number of patients with factor deficiency in our haemophilia centre we were able to assess the effect of TAFI Thr325Ile polymorphism on occurrence of ICH in an extremely rare bleeding disorder. Study of patients revealed that umbilical cord bleeding was the most common clinical presentation (84.2%) in all study population. Haematomas and ecchymosis were other common clinical presentations among our © 2013 John Wiley & Sons Ltd
LETTERS TO THE EDITORS
e91
Table 1. Characteristics of 34 factor XIII (FXIII)-deficient patients with intracranial haemorrhage.
Gender
Thr325Ile
Age of ICH
Male Female Male Female Female Female Male Male Male Female Male Male Female Male Male Male Male Male Female Male Male Female Female Female Female Male Male Male Female Male Male Male Male Female
Homo Homo Homo Homo Homo Homo Homo Homo Homo Homo Homo Homo Homo Homo Homo Homo Homo Homo Homo Homo Homo Homo Homo Hetero Hetero Hetero Hetero Hetero Hetero Hetero Hetero Hetero NM NM
2.1 4.2 3.2 3.5 4.6 1.6 1.8 2.9 2.7 3.4 2.8 2.8 3.9 3.4 3.8 2.5 2.6 2.4 3.3 2.4 4.8 4.5 3.9 3.9 2.9 5.5 4.5 3.8 3.6 4.8 4.5 5.6 4.8 5.5
Site of ICH Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Epidural haemorrhage Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Subdural haemorrhage
Diagnosis CT CT CT CT CT CT MRI CT CT CT CT CT CT CT CT MRI MRI CT CT CT CT CT CT CT CT CT CT CT CT CT CT CT CT CT
Treatment FFP + Cryo FFP + Cryo Cryo + Fibro. Cryo + Fibro. Cryo + Fibro. Cryo + Fibro. FFP + Cryo + FFP + Cryo FFP + Cryo FFP + Cryo FFP + Cryo FFP + Cryo FFP + Cryo FFP + Cryo + FFP + Cryo FFP + Cryo FFP + Cryo + FFP + Cryo + FFP + Cryo FFP + Cryo FFP + Cryo FFP + Cryo FFP + Cryo FFP + Cryo Cryo + Fibro. FFP + Cryo FFP + Cryo FFP + Cryo FFP + Cryo FFP + Cryo + FFP + Cryo FFP + Cryo FFP + Cryo Cryo + Fibro.
P P P P Fibro. P
Fibro. P
Fibro. P Fibro. P
P
Fibro. P
P
Surgery No Yes No Yes No Yes No Yes No Yes Yes Yes No No Yes No No Yes No Yes No Yes Yes No No Yes No Yes Yes Yes Yes No No No
R.T Good Good Good Good Good Good Bad Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good
No. of ICH
N.C
1 1 1 2 1 1 3 1 1 1 2 1 1 1 1 1 1 1 2 2 1 1 1 1 2 1 1 1 1 1 1 1 1 1
Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes No Yes
Dead family members with FXIII deficiency
Cause of death in family
+
CNSB
– – + + – – + – + – + – – – + – – – + – + – – + – – – + – + – –
– – UN CNSB – – CNSB – CNSB – CNSB – – – UN –
CNSB – CNSB – – CNSB – – – CNSB – CNSB – –
Homo, homozygous; Hetero, heterozygous; NM, non-mutant; N.C, neurological complication; CNSB, central nervous system bleeding; UC, umbilical cord bleeding; FFP, fresh frozen plasma; Cryo, cryoprecipitate; Fibro., fibrogammin; R.T, response to treatment; ICH, intracranial haemorrhage.
patients that were observed in 82.8% of patients. Gum bleeding, prolonged menorrhagia, and epistaxis were observed in 17.1, 12.7 and 11.4% respectively. These clinical presentations were not significantly different between the two groups of patients (P > 0.05). In patients with ICH, 35.3% had a positive history of death in family that in 29.4% cause of death was CNS bleeding. The mean age of death in these individuals was 1.5 2 years that was due to lack of physician referral and timely diagnosis of disease, these children died because of traumatic or non-traumatic cerebral haemorrhage. Although this is a claim it seems that these mortalities were due to FXIII deficiency. Presence of one or more children with CNS bleeding due to FXIII deficiency is a reason for our claim. Moreover in the case group, after ICH, neurological complications were those observed in all patients except intwo, including behavioural disorders (social dysfunction) (59.4%), developmental disorders (25%), aphasia (9.4%) and haemiplegia (6.2%). © 2013 John Wiley & Sons Ltd
Therefore, we want to find a secondary genetic factor to predict the risk an ICH in our patients. We want to evaluate all of our patients for this potential factor. With use of this predict factor, all suspected patients to CNS bleeding underwent intensive medical care. As 94% of patients with intracranial haemorrhage and 77% of all patients had this mutation in heterozygous or homozygous manners the screening for this mutation after diagnosis of FXIII deficiency seems to be necessary. The use of this mutation in homozygous manner as a predictive indicator for occurrence of intracranial haemorrhage in FXIII-deficient patients can be useful and decrease the rate of morbidity and mortality in these patients. It seems that determination of plasma levels of TAFI and its association with ICH in FXIII give more valuable data. Assessment the association of TAFI Thr325Ile polymorphism with occurrence of ICH in FXIII deficiency with other genotypes can reveal the effect of this axillary factor in other populations. Haemophilia (2014), 20, e79--e112
e92
LETTERS TO THE EDITORS
Acknowledgements
Disclosures
This study with project number of 91-3-31-19076 was approved and supported by Tehran University of Medical Sciences. All authors of this manuscript thank the vice chancellor of Tehran University of Medical Sciences.
The authors stated that they had no interests which might be perceived as posing a conflict or bias.
References 1 Hsieh L, Nugent D. Factor XIII deficiency. Haemophilia 2008; 14: 1190–200. 2 Naderi M, Eshghi P, Saneei Moghaddam E et al. Safety of human blood products in rare bleeding disorders in southeast of Iran. Haemophilia 2013; 19: e90–2. 3 Bajzar L. Thrombin activatable fibrinolysis inhibitor and an antifibrinolytic pathway. Arterioscler Thromb Vasc Biol 2000; 20: 2511–8. 4 Karimi M, Bereczky Z, Cohan N, Muszbek L (eds). Factor XIII deficiency. Semin Thromb Haemost; 2009; 35: 426–38.
5 Reiner AP, Schwartz SM, Frank MB et al. Polymorphisms of coagulation factor XIII subunit A and risk of nonfatal haemorrhagic stroke in young white women. Stroke 2001; 32: 2580–7. 6 Mosnier LO, Bouma BN. Regulation of fibrinolysis by thrombin activatable fibrinolysis inhibitor, an unstable carboxypeptidase B that unites the pathways of coagulation and fibrinolysis. Arterioscler Thromb Vasc Biol 2006; 26: 2445–53. 7 Willemse JL, Hendriks DF. A role for procarboxypepidase U (TAFI) in thrombosis. Front Biosci 2007; 12: 1973–87.
8 Trinh CH, Sh ElSayed W, Eshghi P et al. Molecular analysis of sixteen unrelated factor XIIIA deficient families from south-east of Iran. Br J Haematol 2008; 140: 581–4. 9 Tamaddon GH, Kazemi A, Rastegar G, Alla F, Hejazi S. Molecular basis of inherited factor XIII-A deficiency among patients from Sistan-Baluchestan. Zahedan Journal of Research in Medical Sciences. 2010; 11: 19–24. 10 Tokgoz S, Zamani A, Durakbasi-Dursun H et al. TAFI gene polymorphisms in patients with cerebral venous thrombosis. Acta Neurol Belg 2013; 113: 291–7.
A rare case of acquired haemophilia in a patient with chronic myelomonocytic leukaemia successfully treated with decitabine D . S H A H , * R . K U M A R † and S . G A I K A Z I A N † *Department of Internal Medicine; and †Department of Hematology Oncology, Oakland University William Beaumont School of Medicine, Royal Oak, MI, USA
Acquired haemophilia is a rare and fatal disorder; heightened awareness of this disease is required in cases of unexplained bleeding. Haematological malignancy is a potential aetiology of acquired haemophilia, and treating this underlying condition may result in a favourable outcome. We report a rare case of acquired haemophilia in a chronic myelomonocytic leukaemia (CMML) patient who responded dramatically after the initiation of decitabine. This is the first reported association between the hypomethylating agent decitabine and acquired haemophilia. A 58-year-old man presented to our hospital after he developed diffuse ecchymosis and spontaneous left Correspondence: Darshil Shah, Department of Internal Medicine, Oakland University William Beaumont School of Medicine, Beaumont Health System, 3601 W 13 Mile Road, Royal Oak, MI 48073, USA. Tel.: +1 248 551 5000; fax; +1 248 898 4680; e-mail: [email protected] Accepted after revision 7 October 2013 DOI: 10.1111/hae.12301 Haemophilia (2014), 20, e79--e112
iliopsoas haematoma. He was diagnosed with CMML-1 on a bone marrow examination 6 months prior. Bone marrow biopsy at that time demonstrated hypercellular marrow (60 70%) with marked monocytic (15%) hyperplasia. Myeloid blasts were within the normal range (2%), and the cytogenetics were normal. The patient was also diagnosed with rheumatoid arthritis during this time, had elevated cyclic citrullinated peptide levels (above 250), and was on chronic steroid therapy. His activated prothrombin time (aPTT) upon presentation was markedly prolonged (96.3 s; normal, 25–32 s), whereas the prothrombin time was normal (11.2 s). A mixing study failed to correct the aPTT prolongation. A quantitative assay of factor VIII (FVIII) inhibitors detected an inhibitor level of >200 BU. FVIII activity was
References 1 Maheshwari R, Kelley SP, Langkamer VG, Loveday E. Spontaneous recurrent haemarthrosis following unicompartmental knee arthroplasty and its successful treatment by coil embolisation. Knee 2004; 11: 413–5. 2 Karataglis D, Marlow D, Learmonth DJ. Atraumatic haemarthrosis following total knee replacement treated with selective embolisation. Acta Orthop Belg 2006; 72: 375–7. 3 Sandoval E, Ortega FJ, Garcia-Rayo MR, Resines C. Popliteal pseudoaneurysm after total knee arthroplasty secondary to intraoperative arterial injury with a surgical pin: review of the literature. J Arthroplasty 2008; 23: 1239. e7-11.
4 Saksena J, Platts AD, Dowd GSE. Recurrent haemarthrosis following total knee replacement. Knee 2009; 17: 7–14. 5 Tat-Sing Law M, McClure DN. Therapeutic embolization in the treatment of recurrent haemarthrosis following knee arthroplasty. ANZ J Surg 2010; 80: 247–9. 6 Scoles PV, King D. Traumatic aneurysm of the descending geniculate artery: a complication of suction drainage in synovectomy for hemophilic arthropathy. Clin Orthop Relat Res 1980; 150: 245–6. 7 Kickuth R, Anderson S, Peter-Salonen K, L€ammle B, Eggli S, Triller J. Hemophilia A pseudoaneurysm in a patient with high responding inhibitors complicating total knee arthroplasty: embolization: a costreducing alternative to medical therapy.
e89
Cardiovasc Intervent Radiol 2006; 29: 1132–5. 8 Rodriguez-Merchan EC. Total knee replacement in haemophilic arthropathy. J Bone Joint Surg Br 2007; 89: 186–8. 9 Park JJ, Slover JD, Stuchin SA. Recurrent hemarthrosis in a hemophilic patient after revision total knee arthroplasty. Orthopedics 2010; 33: 771. 10 Saarela MS, Tiitola M, Lappalainen K et al. Pseudoaneurysm in association with a knee endoprothesis operation in an inhibitor-positive haemophilia A patient – treatment with local thrombin. Haemophilia 2010; 16: 686–8.
Polymorphism of thrombin-activatable fibrinolysis inhibitor and risk of intracranial haemorrhage in factor XIII deficiency M. NADERI,* A. DORGALALEH,† S. ALIZADEH,† Z. KASHANI KHATIB,† S. TABIBIAN,† A . K A Z E M I , † H . D A R G A H I † and T . B A M E D I * *Ali Ebn-e Abitaleb Hospital Research Center for Adolescents Health, Zahedan University of Medical Sciences, Zahedan; and †Department of Hematology, Allied Medical School, Tehran University of Medical Sciences, Tehran, Iran
Factor XIII (FXIII) deficiency is an extremely rare autosomal recessive bleeding disorder with estimated prevalence of at around 1/2 000 000 in the general population. Presumptive diagnosis of FXIII deficiency was made by clot solubility test in 5 M urea or 1% monochloroacetic acid. In patients with abnormal screening clot solubility test, the disease can be confirmed by more specific tests such as quantitative FXIII activity assay, antigen (FXIII Ag) assay or more precisely using molecular analysis. All patients with severe FXIII deficiency (C) was selected for confirmation of the disorder because our study population was also selected from this area [8,9]. Then three reported mutations including FXIII Val34Leu, FXIII Tyr204Phe and FXIII Pro564Leu and a common polymorphism of TAFI, Thr325Ile were performed by polymerase chain reaction amplification of genomic DNA followed by restriction enzyme digestion (PCRRFLP). This study revealed that the prevalence of intracranial haemorrhage in our large population is 16.5% and intraparenchymal is the most common site of ICH (91.4%) and subdural haemorrhage and epidural haemorrhage was observed in two patients (5.9%) (Table 1). Temporal and occipital were common anatomical regions of Intraparenchymal haemorrhage (each 26.4%) and temporo-occipital was the other common region (11.7%). We also found that therapeutic response with FFP, cryoprecipitate and Fibrogammin P was excellent and Haemophilia (2014), 20, e79--e112
all patients except one did not experience recurrent intracranial haemorrhage. Our molecular analysis revealed that C.559T>C nucleotide exchange in exon 4 which leads to tryptophan to arginine substitution in FXIII A subunit is a causative mutation in our patients and all study patients were homozygous for this mutation [8,9]. Molecular studies of Tyr204Phe, Pro564Leu and Val34Leu polymorphisms revealed that no one in case or control groups was positive for these mutations. We also found that TAFI Thr325Ile polymorphism is much higher in FXIII-deficient patients with ICH in comparison with the case group. A significant correlation was present between TAFI Thr325Ile polymorphism in homozygous form and occurrence of spontaneous intracranial haemorrhage (OR 18.9, 95% CI 3.8–95.1). There was also a significant difference between case and control group about homozygous TAFI Thr325Ile polymorphism (P < 0.001). There was no correlation between TAFI Thr325Ile polymorphism in heterozygous manner and intracranial haemorrhage (OR 1.1, 95% CI 0.6–4.6) and it is amazing that in contrast to homozygous form of polymorphism, heterozygosity was higher in patients with negative history of intracranial haemorrhage and this difference was statistically significant (P < 0.006). It is also important to state that our patient with history of ICH and poor response to replacement therapy with FFP, cryoprecipitate and Fibrogammin P was homozygous for TAFI Thr325Ile polymorphism. Thr325Ile is a common polymorphism of TAFI that its robust association with stroke was proven [6,7]. However, in case–control study of Serhat Tokgoz no association was found between cerebral venous thrombosis and several mutations of TAFI include 1040C/T (Thr325Ile polymorphism [10]. Besides the role of TAFI in ischaemic stroke, several other reasons led us to assess the role of a common polymorphism of TAFI, Thr325Ile on occurrence of ICH in patients with severe FXIII deficiency. These reasons include, Thr325Ile polymorphism is decreased circulating level and also associated with 60% decreased of antifibrinolytic effect of TAFI that seems to be a risk factor for bleeding. TAFI has also a significant role in regulation of blood pressure and also elevated level of TAFI-enhanced atherosclerosis progression. In fact in this case–control study, due to the large number of patients with factor deficiency in our haemophilia centre we were able to assess the effect of TAFI Thr325Ile polymorphism on occurrence of ICH in an extremely rare bleeding disorder. Study of patients revealed that umbilical cord bleeding was the most common clinical presentation (84.2%) in all study population. Haematomas and ecchymosis were other common clinical presentations among our © 2013 John Wiley & Sons Ltd
LETTERS TO THE EDITORS
e91
Table 1. Characteristics of 34 factor XIII (FXIII)-deficient patients with intracranial haemorrhage.
Gender
Thr325Ile
Age of ICH
Male Female Male Female Female Female Male Male Male Female Male Male Female Male Male Male Male Male Female Male Male Female Female Female Female Male Male Male Female Male Male Male Male Female
Homo Homo Homo Homo Homo Homo Homo Homo Homo Homo Homo Homo Homo Homo Homo Homo Homo Homo Homo Homo Homo Homo Homo Hetero Hetero Hetero Hetero Hetero Hetero Hetero Hetero Hetero NM NM
2.1 4.2 3.2 3.5 4.6 1.6 1.8 2.9 2.7 3.4 2.8 2.8 3.9 3.4 3.8 2.5 2.6 2.4 3.3 2.4 4.8 4.5 3.9 3.9 2.9 5.5 4.5 3.8 3.6 4.8 4.5 5.6 4.8 5.5
Site of ICH Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Epidural haemorrhage Intraparenchymal Intraparenchymal Intraparenchymal Intraparenchymal Subdural haemorrhage
Diagnosis CT CT CT CT CT CT MRI CT CT CT CT CT CT CT CT MRI MRI CT CT CT CT CT CT CT CT CT CT CT CT CT CT CT CT CT
Treatment FFP + Cryo FFP + Cryo Cryo + Fibro. Cryo + Fibro. Cryo + Fibro. Cryo + Fibro. FFP + Cryo + FFP + Cryo FFP + Cryo FFP + Cryo FFP + Cryo FFP + Cryo FFP + Cryo FFP + Cryo + FFP + Cryo FFP + Cryo FFP + Cryo + FFP + Cryo + FFP + Cryo FFP + Cryo FFP + Cryo FFP + Cryo FFP + Cryo FFP + Cryo Cryo + Fibro. FFP + Cryo FFP + Cryo FFP + Cryo FFP + Cryo FFP + Cryo + FFP + Cryo FFP + Cryo FFP + Cryo Cryo + Fibro.
P P P P Fibro. P
Fibro. P
Fibro. P Fibro. P
P
Fibro. P
P
Surgery No Yes No Yes No Yes No Yes No Yes Yes Yes No No Yes No No Yes No Yes No Yes Yes No No Yes No Yes Yes Yes Yes No No No
R.T Good Good Good Good Good Good Bad Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good
No. of ICH
N.C
1 1 1 2 1 1 3 1 1 1 2 1 1 1 1 1 1 1 2 2 1 1 1 1 2 1 1 1 1 1 1 1 1 1
Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes No Yes
Dead family members with FXIII deficiency
Cause of death in family
+
CNSB
– – + + – – + – + – + – – – + – – – + – + – – + – – – + – + – –
– – UN CNSB – – CNSB – CNSB – CNSB – – – UN –
CNSB – CNSB – – CNSB – – – CNSB – CNSB – –
Homo, homozygous; Hetero, heterozygous; NM, non-mutant; N.C, neurological complication; CNSB, central nervous system bleeding; UC, umbilical cord bleeding; FFP, fresh frozen plasma; Cryo, cryoprecipitate; Fibro., fibrogammin; R.T, response to treatment; ICH, intracranial haemorrhage.
patients that were observed in 82.8% of patients. Gum bleeding, prolonged menorrhagia, and epistaxis were observed in 17.1, 12.7 and 11.4% respectively. These clinical presentations were not significantly different between the two groups of patients (P > 0.05). In patients with ICH, 35.3% had a positive history of death in family that in 29.4% cause of death was CNS bleeding. The mean age of death in these individuals was 1.5 2 years that was due to lack of physician referral and timely diagnosis of disease, these children died because of traumatic or non-traumatic cerebral haemorrhage. Although this is a claim it seems that these mortalities were due to FXIII deficiency. Presence of one or more children with CNS bleeding due to FXIII deficiency is a reason for our claim. Moreover in the case group, after ICH, neurological complications were those observed in all patients except intwo, including behavioural disorders (social dysfunction) (59.4%), developmental disorders (25%), aphasia (9.4%) and haemiplegia (6.2%). © 2013 John Wiley & Sons Ltd
Therefore, we want to find a secondary genetic factor to predict the risk an ICH in our patients. We want to evaluate all of our patients for this potential factor. With use of this predict factor, all suspected patients to CNS bleeding underwent intensive medical care. As 94% of patients with intracranial haemorrhage and 77% of all patients had this mutation in heterozygous or homozygous manners the screening for this mutation after diagnosis of FXIII deficiency seems to be necessary. The use of this mutation in homozygous manner as a predictive indicator for occurrence of intracranial haemorrhage in FXIII-deficient patients can be useful and decrease the rate of morbidity and mortality in these patients. It seems that determination of plasma levels of TAFI and its association with ICH in FXIII give more valuable data. Assessment the association of TAFI Thr325Ile polymorphism with occurrence of ICH in FXIII deficiency with other genotypes can reveal the effect of this axillary factor in other populations. Haemophilia (2014), 20, e79--e112
e92
LETTERS TO THE EDITORS
Acknowledgements
Disclosures
This study with project number of 91-3-31-19076 was approved and supported by Tehran University of Medical Sciences. All authors of this manuscript thank the vice chancellor of Tehran University of Medical Sciences.
The authors stated that they had no interests which might be perceived as posing a conflict or bias.
References 1 Hsieh L, Nugent D. Factor XIII deficiency. Haemophilia 2008; 14: 1190–200. 2 Naderi M, Eshghi P, Saneei Moghaddam E et al. Safety of human blood products in rare bleeding disorders in southeast of Iran. Haemophilia 2013; 19: e90–2. 3 Bajzar L. Thrombin activatable fibrinolysis inhibitor and an antifibrinolytic pathway. Arterioscler Thromb Vasc Biol 2000; 20: 2511–8. 4 Karimi M, Bereczky Z, Cohan N, Muszbek L (eds). Factor XIII deficiency. Semin Thromb Haemost; 2009; 35: 426–38.
5 Reiner AP, Schwartz SM, Frank MB et al. Polymorphisms of coagulation factor XIII subunit A and risk of nonfatal haemorrhagic stroke in young white women. Stroke 2001; 32: 2580–7. 6 Mosnier LO, Bouma BN. Regulation of fibrinolysis by thrombin activatable fibrinolysis inhibitor, an unstable carboxypeptidase B that unites the pathways of coagulation and fibrinolysis. Arterioscler Thromb Vasc Biol 2006; 26: 2445–53. 7 Willemse JL, Hendriks DF. A role for procarboxypepidase U (TAFI) in thrombosis. Front Biosci 2007; 12: 1973–87.
8 Trinh CH, Sh ElSayed W, Eshghi P et al. Molecular analysis of sixteen unrelated factor XIIIA deficient families from south-east of Iran. Br J Haematol 2008; 140: 581–4. 9 Tamaddon GH, Kazemi A, Rastegar G, Alla F, Hejazi S. Molecular basis of inherited factor XIII-A deficiency among patients from Sistan-Baluchestan. Zahedan Journal of Research in Medical Sciences. 2010; 11: 19–24. 10 Tokgoz S, Zamani A, Durakbasi-Dursun H et al. TAFI gene polymorphisms in patients with cerebral venous thrombosis. Acta Neurol Belg 2013; 113: 291–7.
A rare case of acquired haemophilia in a patient with chronic myelomonocytic leukaemia successfully treated with decitabine D . S H A H , * R . K U M A R † and S . G A I K A Z I A N † *Department of Internal Medicine; and †Department of Hematology Oncology, Oakland University William Beaumont School of Medicine, Royal Oak, MI, USA
Acquired haemophilia is a rare and fatal disorder; heightened awareness of this disease is required in cases of unexplained bleeding. Haematological malignancy is a potential aetiology of acquired haemophilia, and treating this underlying condition may result in a favourable outcome. We report a rare case of acquired haemophilia in a chronic myelomonocytic leukaemia (CMML) patient who responded dramatically after the initiation of decitabine. This is the first reported association between the hypomethylating agent decitabine and acquired haemophilia. A 58-year-old man presented to our hospital after he developed diffuse ecchymosis and spontaneous left Correspondence: Darshil Shah, Department of Internal Medicine, Oakland University William Beaumont School of Medicine, Beaumont Health System, 3601 W 13 Mile Road, Royal Oak, MI 48073, USA. Tel.: +1 248 551 5000; fax; +1 248 898 4680; e-mail: [email protected] Accepted after revision 7 October 2013 DOI: 10.1111/hae.12301 Haemophilia (2014), 20, e79--e112
iliopsoas haematoma. He was diagnosed with CMML-1 on a bone marrow examination 6 months prior. Bone marrow biopsy at that time demonstrated hypercellular marrow (60 70%) with marked monocytic (15%) hyperplasia. Myeloid blasts were within the normal range (2%), and the cytogenetics were normal. The patient was also diagnosed with rheumatoid arthritis during this time, had elevated cyclic citrullinated peptide levels (above 250), and was on chronic steroid therapy. His activated prothrombin time (aPTT) upon presentation was markedly prolonged (96.3 s; normal, 25–32 s), whereas the prothrombin time was normal (11.2 s). A mixing study failed to correct the aPTT prolongation. A quantitative assay of factor VIII (FVIII) inhibitors detected an inhibitor level of >200 BU. FVIII activity was
