A Case of Graves’ Thrombosis?

Pinto‐Sietsma SJ, Gerdes V, Bouwmans E, Hamulyak K, Kroon A, ten Cate H, A Case of Graves’ Thrombosis? Journal of Coagulation Disorders., October 2009; 1(1): 99-102


Sara‐Joan Pinto‐Sietsma ^1, Victor Gerdes ^2, Esther Bouwmans ^3, Karly Hamulyak ^4, A Abraham Kroon ¹ and Hugo ten Cate ¹

Affiliations: ¹ Division of Vascular Medicine, Department of Internal Medicine, Academic Hospital Maastricht and ² Department of Internal Medicine, Slotervaart Hospital, and Consultant in Vascular Medicine, Academic Medical Centre and ³ Department of Internal Medicine, VieCuri Medical Centre and ⁴ Division of Hematology, Department of Internal Medicine, Academic Hospital Maastricht

Correspondence: Sara‐Joan Pinto‐Sietsma, Division of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Centre, Meibergdreef 9, PO Box 22660, 1105 AZ, Amsterdam, The Netherlands

Pharmacoeconomic studies of bypassing agents in mild‐to‐moderate bleeding episodes in patients with hemophilia and inhibitors: a critical appraisal

De Paula Ev, Ozelo MC, Pharmacoeconomic studies of bypassing agents in mild‐to‐moderate bleeding episodes in patients with hemophilia and inhibitors: a critical appraisal. Journal of Coagulation Disorders., October 2009; 1(1): 93-98


Erich V De Paula and Margareth C Ozelo

Affiliation: Hemocentro da UNICAMP, Campinas, Brazil


ABSTRACT

The development of neutralizing antibodies against factor VIII and IX complicates the clinical management of patients with hemophilia, and adds significant costs to their treatment. For this reason, several formal economic analysis have been performed comparing treatment of mild and moderate bleeding episodes in these patients in an effort to determine whether one of the two available bypassing agents would be cost‐effective compared with the other. Here we review and discuss the available evidence about the economic aspects of the alternatives for on‐demand treatment of mild and moderate bleeding episodes for hemophilia patients with inhibitors.

Keywords: Bleeds, hemophilia, inhibitor, economic, recombinant activated factor VII (rFVIIa), activated prothrombin complex concentrate (aPCC)

Correspondence: Margareth Castro Ozelo, Rua Carlos Chagas, 480, Distrito Barão Geraldo, PO. Box 6198, 13084‐878 Campinas, São Paulo, Brazil

Central Venous Access Devices (CVAD) for Pediatric Patients with Hemophilia: A Review

Traffic of rFVIIa through Endothelial Cells and Redistribution into Subendothelium: Implications for a Prolonged Hemostatic Effect

Lopez‐Vilchez I, Tusell J, Hedner U, Altisent C, Escolar G, Galan AM, Traffic of rFVIIa through Endothelial Cells and Redistribution into Subendothelium: Implications for a Prolonged Hemostatic Effect. Journal of Coagulation Disorders., October 2009; 1(1): 1-6


I Lopez‐Vilchez ^1, J Tusell ^2, U Hedner ^3, C Altisent ^4, G Escolar ¹ and AM Galan ¹

Affiliations: ¹ Serv. Hemoterapia‐Hemostasia, Hospital Clinic, CDB, IDIBAPS, UB and ² Novo Nordisk Pharma SA and ³ Research and Development, Novo Nordisk A/S, Måløv, Denmark, and University of Lund and ⁴ Unitat d’Hemofilia, Hospital Universitari Vall d’Hebron


ABSTRACT

Background
Clinical evidence suggests that the hemostatic action of recombinant activated factor VII (rFVIIa) exceeds its predicted plasma life. Mechanisms involved in the long‐lasting effects of rFVIIa for prophylactic treatment of patients with hemophilia and inhibitors have not been fully elucidated.

Objectives
The traffic of rFVIIa through the endothelial cells (EC) and its redistribution into the subendothelial compartment was investigated. Its possible hemostatic action in experiments with flowing blood was also assessed.

Methods
Cultured EC and umbilical veins were exposed to rFVIIa (6 μg/mL) for up to 2 h. Immunocytochemical techniques were combined with confocal microscopy to localize rFVIIa into EC and to trace its possible redistribution into subendothelial compartments. Vessels exposed to rFVIIa were de‐endothelized and exposed to flowing blood to determine possible modifications in their hemostatic capacity.

Results
Immunocytochemical studies revealed a significantly enhanced presence of FVIIa dispersedly distributed in the cytoplasm of EC previously exposed to rFVIIa. rFVIIa relocated into nuclear and peripheral areas when prolonged incubations (24 h) were performed. Immunocytochemical studies revealed that rFVIIa localizes into the endothelium and subendothelium of incubated umbilical vessels. In perfusion studies, this rFVIIa redistributed into the subendothelium improved fibrin generation and enhanced platelet thrombus formation.

Conclusions
These results indicate that rFVIIa can be internalized and redistributed into endothelial and subendothelial compartments. This rFVIIa remains functional and promotes hemostatic activity when vessels are denuded. These findings may explain the prolonged prophylactic action of rFVIIa in some clinical conditions.

Keywords: Pharmacodynamics, endothelial cells, hemostatic action, recombinant activated factor VII traffic, prophylaxis

Correspondence: Irene López‐Vilchez, Servicio de Hemoterapia‐Hemostasia, Hospital Clinic, C/Villarroel 170, 08036 Barcelona, Spain

Immunotolerance Induction Treatments in Hemophilia

Safety of Radiosynovectomy in Hemophilic Synovitis: it is Time to Re‐evaluate!

Prophylaxis in Patients with Severe Hemophilia and Inhibitor

von Willebrand Factor Proteolysis by ADAMTS13

Cardiac Surgery and Percutaneous Coronary Interventions in Patients with Hemophilia B: an Overview of Published Reported Cases

Acquired von Willebrand Syndrome in Childhood and Adolescence

Will AM, Acquired von Willebrand Syndrome in Childhood and Adolescence. Journal of Coagulation Disorders., October 2009; 1(1): 55-64

Andrew M Will

Affiliation: Royal Manchester Children’s Hospital, Manchester, UK

Submission date: 2nd July 2009, Revision date: 29th August 2009, Acceptance date: 5th September 2009


ABSTRACT

Acquired von Willebrand syndrome (AVWS) is a rare condition usually seen in middle‐aged and elderly patients. This review summarizes the clinical features, etiology, pathophysiology, classification, and management of 113 children and adolescents with AVWS. There were nine underlying conditions associated with the occurrence of AVWS in younger patients: patients taking valproic acid, congenital heart disease, renal tumors, glycogen storage disease type 1a, hypothyroidism, systemic lupus erythematosus, E/beta0 thalassemia, acute lymphoblastic leukemia, and one case following an Epstein–Barr infection. Diagnostic criteria included recent onset bleeding or bruising in a patient with no previous personal history of bleeding or family history of a bleeding disorder with laboratory tests suggestive of von Willebrand disease (VWD) or the presence of abnormal von Willebrand multimers. The pathophysiology and management of acute bleeding was dependent on the primary underlying disease. Successful treatment of the underlying disease was almost always associated with sustained correction of the AVWS.

Keywords: acquired von Willebrand syndrome, children, adolescents, valproate, congenital heart disease, Wilms, hypothyroidism, systemic lupus erythematosus

Correspondence: Ward 84, Royal Manchester Children’s Hospital, Oxford Road, Manchester M13 9WL, UK

Rituximab in the Treatment of Postpartum Acquired Hemophilia A

Mazzucconi MG, Biondo F, Santoro C, Rituximab in the Treatment of Postpartum Acquired Hemophilia A. Journal of Coagulation Disorders., October 2009; 1(1): 47-54

Maria Gabriella Mazzucconi, Francesca Biondo and Cristina Santoro

Affiliation: Haematology Institute, Dipartimento di Biotecnologie cellulari ed Ematologia, ‘‘Sapienza’’ University of Rome, Italy

Submission date: 10th July 2009, Revision date: 2nd September 2009, Acceptance date: 14th September 2009


ABSTRACT

Acquired hemophilia A is a rare disorder caused by the development of autoantibodies against coagulation factor VIII: it is often characterized by severe bleeding tendency. Its incidence is 0.2–1 per million persons per year. It may be associated with malignancies, autoimmune disorders, or pregnancy but, in about 50% of cases, no cause can be identified. Postpartum acquired hemophilia A represents 7–21% of all cases, with an incidence of about 1/350 000 deliveries. The aim of the management of acquired hemophilia A and, in particular of postpartum acquired hemophilia A, is the control of bleeding, if present, and the eradication of the inhibitor. The latter can be obtained with immunosuppressive drugs. However, cyclophosphamide and other alkylating agents should not be used in young women with postpartum inhibitor because of the risk of infertility. Complete remission rate obtained with these agents is about 80% or more but, in some cases, persistence of the inhibitor despite treatment or relapse after response represent an actual risk of recurrent bleedings. Therefore, alternative therapeutic approaches are advisable. Rituximab has been used in acquired hemophilia A since 2001 either as first‐line therapy or in resistant/relapsed patients. Its efficacy is very high (about 90% eradication rate); it is safe and well tolerated, especially in young people. For these reasons, Rituximab can play a role in the therapeutic approach to postpartum acquired hemophilia A. Few cases have been treated up to now, but the results are very promising. Inhibitor eradication was obtained in all cases. No relevant side‐effects were noted, nor did infections occur. Cytotoxic immunosuppressive drugs can compromise fertility in young female patients, whereas Rituximab can be a valid and safe alternative treatment.

Keywords: acquired hemophilia A, inhibitor to factor VIII, immunosuppressive therapy, postpartum factor VIII inhibitor, Rituximab

Correspondence: Maria Gabriella Mazzucconi , Associate Professor, Dipartimento di Biotecnologie cellulari ed Ematologia, “Sapienza” University of Rome, via Benevento n. 6, 00161, Roma, Italy

Renal Hemophilic Pseudotumors

Gürkan E, Renal Hemophilic Pseudotumors. Journal of Coagulation Disorders., October 2009; 1(1): 17-20

Emel Gürkan

Affiliation: Department of Haematology, C¸ ukurova University Medical School, Adana, Turkey

Submission date: 1st July 2009, Revision date: 2nd August 2009, Acceptance date: 10th August 2009


ABSTRACT

Severe hemophilic patients are prone to develop long‐term sequelae such as pseudotumor formation caused by repeated and unresolved hematomas leading to subsequent encapsulated mass lesion. Among these, renal hemophilic pseudotumors are seen as a rather rare event. Once developed, this serious condition should be approached carefully, first by maintaining adequate hemostasis with appropriate factor replacement therapy and, later on, complete surgical excision should be targeted. Without surgical intervention, complete resolution is generally not possible. Other treatment modalities such as radiotherapy may be helpful in addition to surgery preoperatively in order to reduce bleeding complications. However, experience of this approach is limited to those pseudotumors of other sites such as bone and pelvic pseudotumors. Rarely, a true pseudotumor may mimic a malignancy; therefore, accurate assessment by radiological means is required. Considering the difficulties in management, it is of great importance to constitute early substitutive treatment for the prevention of pseudotumors.

Keywords: renal pseudotumor, hemophilia, management

Correspondence: Emel Gürkan, Çukurova University Faculty of Medicine, Department of Hematology, 01330 Adana, Turkey

Gastrointestinal Angiodysplasia and Acquired von Willebrand Syndrome: A Review of an Enigmatic Association

Saxena R, Sharma P, Gastrointestinal Angiodysplasia and Acquired von Willebrand Syndrome: A Review of an Enigmatic Association. Journal of Coagulation Disorders., October 2009; 1(1): 11-16

Renu Saxena and Prashant Sharma

Affiliation: Department of Hematology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India

Submission date: 15th June 2009, Revision date: 29th June 2009, Acceptance date: 14th August 2009


ABSTRACT

von Willebrand disease (VWD), the commonest inherited bleeding disorder, is characterized by reduced levels and/or abnormal function of von Willebrand factor (VWF). It may rarely be acquired (von Willebrand syndrome, VWS) in association with a variety of underlying conditions including myeloid, lymphoid and nonhematologic malignancies, autoimmune disorders, specific pharmaceutical agents, valvular heart defects and endocrine abnormalities.
Gastrointestinal bleeding due to intestinal angiodysplasia is a well‐documented complication of VWD as well as the acquired VWS, predominantly seen in elderly patients. Its high prevalence in disease subtypes associated with reduced or absent high molecular weight (HMW) VWF multimers suggests that the specific loss of these molecules is the primary pathologic event in abnormal hemostasis under high shear stress blood flow conditions. This link, first postulated specifically by Warkentin and colleagues, has now been borne out by both laboratory and epidemiological studies.

VWF HMW multimer deficiency also provides a plausible link between senile aortic stenosis and gastrointestinal bleeding in Heyde syndrome. Enhanced proteolysis of HMW multimers by the shear‐dependent VWF cleaving metalloproteinases as well as avid platelet binding of uncoiled HMW multimers results in accelerated clearance from circulation. The resultant deficiency mimicking VWD type 2A frequently resolves after surgical correction of the cardiac defect.

The diagnosis and management of occult gastrointestinal bleeding from angiodysplasia in VWD or VWS are often challenging as is differentiating the acquired from the inherited forms of the disorder. Multiple therapeutic approaches have been tried with varying degrees of success.

Keywords: acquired von Willebrand disease, angiodysplasia, aortic stenosis, Heyde syndrome, high molecular weight multimers, high shear stress, occult gastrointestinal bleeding

Correspondence: DrRenu Saxena, Professor and Head, Department of Hematology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India

An Overview of Blastocystis hominis Infection and Published Experience in Hemophilic Population

Aguilar C, Lucía JF, An Overview of Blastocystis hominis Infection and Published Experience in Hemophilic Population. Journal of Coagulation Disorders., October 2009; 1(1): 43-46

Carlos Aguilar ¹ and F José Lucía ²

Affiliations: ¹Department of Haematology, Hospital General Santa Ba´rbara, Soria, Spain and ²Department of Haematology, Hospital Universitario Miguel Servet, Zaragoza, Spain

Submission date: 10th June 2009, Revision date: 16th July 2009, Acceptance date: 16th August 2009


ABSTRACT

Blastocystis hominis is a parasite with worldwide spread that infects from 10–15% to 30–50% of asymptomatic individuals in developed and developing countries respectively. Nine subtypes of the parasite have been reported, and the diagnosis usually involves microscopic observation of vacuolar or cystic forms of the parasite in stools. Controversy regarding the commensal or pathogenic nature of the infection has remained for decades, but recent epidemiological and microbiological studies support an emerging pathogenic potential for the parasite. Clinical manifestations of the disease include non‐specific gastrointestinal symptoms (namely diarrhea, abdominal pain, nausea), which are usually self‐limited. Specific treatment, most often with metronidazol or cotrimoxazol, is able to achieve more rapid resolution of symptoms and clearance of the infection. Bleeding has not been shown to be a common manifestation or complication of blastocystosis. Only two cases of enterocolitis caused by Blastocystis hominis infection have been reported in hemophiliacs, and only one of them presented with lower gastrointestinal bleeding, which rapidly resolved after treatment of the infection with metronidazol and a short course of recombinant factor VIII. There seem to be no specific features of Blastocystis hominis infection in hemophiliacs and, where bleeding occurs, it is unlikely to be severe and can probably be readily stopped with isolated doses of factor VIII/IX or DDAVP. Investigations to rule out other infectious or non‐infectious causes of intestinal bleeding should be carried out in such cases.

Keywords: hemophilia, gastrointestinal bleeding, Blastocystis hominis

Correspondence: DrCarlos Aguilar, Department of Haematology, Hospital General Santa Bárbara, Paseo Santa Bárbara s/n, 42.002 Soria, Spain

Dental and Periodontal Health in Children with Hemophilia

Alpkılıç Baskirt E, Albayrak H, Ak G, Pınar Erdem A, Sepet E, Zulfikar B, Dental and Periodontal Health in Children with Hemophilia. Journal of Coagulation Disorders., October 2009; 1(1) 7-10

E Alpkılıç Baskirt ^1, H Albayrak ^2, G Ak ^1, A Pınar Erdem ^2, E Sepet ² and B Zulfikar ³

Affiliations: Departments of Oral Medicine and Oral Surgery ¹ and Pedodontics ^{2,3 ,} Faculty of Dentistry, Istanbul University and  Department of Paediatric Haematology‐Oncology, Cerrahpasa Medical Faculty, Istanbul University

Submission Date: 9th June 2009, Revision Date: 14th July 2009, Acceptance Date: 30th July 2009


ABSTRACT

Aim
The aim of this study was to determine the dental and periodontal health of children with hemophilia A in different aspects.

Methods
The gingival index, plaque index, and dmf(t)‐dmf(s), DMF(T)‐DMF(S) scores of 36 children (aged between 6 and 12 years) with hemophilia A and 39 healthy children were analyzed. Type of hemophilia, dietary habits, and frequency of tooth brushing, educational and economic level of the parents, and parents’ dental habits were determined by a questionnaire.

Results
All the analyses were carried out by means of commercial statistical software. Statistical analyses were performed by chi‐square, Kruskal–Wallis and independent t tests. The difference in plaque index scores between the study and control groups (P = 0.077) was not statistically significant. Gingival index scores of the children with hemophilia were statistically higher than the control group (t = 3.10; P = 0.003). No difference was found in dmf(t)‐dmf(s) scores, but DMF(T)‐DMF(S) scores of the study group were statistically higher than the control group (P = 0.001; P = 0.012). The frequency of tooth brushing was defined statistically different between the two groups (P = 0.044). The frequency of sugar consumption by the children with hemophilia was found to be statistically higher than that of the control group (P = 0.006). Although the maternal educational levels of the two groups were similar (P = 0.130), paternal education levels and the economic levels of the study group were statistically lower than those of the control group (P = 0.002).

Conclusion
We conclude that children with hemophilia A have significantly higher GI and DMF(T)‐DMF(S) scores compared with matched, healthy control subjects. Expanded preventive measures, educational, and recall programs should be organized for these “special needs” patients.

Keywords: hemophilia, dental, periodontal, children, DMF

Correspondence: Esra Alpkilic Baskirt, Halıcılar Avenue, Oksuzler Street, No: 18/6 Fatih, Istanbul, Turkey