Sonja Alesci

Comorbidities and bleeding pattern in elderly haemophilia A patients

Summary.  The increasing numbers of comorbidities related to higher age and their treatment constitute a challenge in the treatment of haemophiliacs. Comparing prevalences of morbidities in the elderly haemophilia A population (n = 29) and the general elderly population of Germany reveals some differences. HCV infections are more frequent in the elderly haemophilia population (69% vs. 0.6%). Prevalence of cancer was five times higher than in the age matched general population (28% vs. 5.2%). Cardiac diseases seem to be less frequent although the prevalences of cardiovascular risk factors like hypertension, diabetes, and body mass index (BMI) >25 do not differ in comparison to the general population. A reduction of bleeding symptoms or dosage of FVIII could not be observed. There is a tendency of increasing bleeding symptoms with increasing age of the patients due to more frequent spontaneous joint bleedings, malignancies or treatment with phenprocoumon or ASA. In consequence, FVIII dosage had to be increased in eight patients (28%). Our patient population at the age >60 years is very small and no statistical evidence can be shown, therefore appropriate treatment of elderly haemophiliacs needs further evaluation in multicentre studies with sufficient patient numbers.

Engineered factor IX variants bypass FVIII and correct hemophilia A phenotype in mice

The complex of the serine protease factor IX (FIX) and its cofactor, factor VIII (FVIII), is crucial for propagation of the intrinsic coagulation cascade. Absence of either factor leads to hemophilia, a disabling disorder marked by excessive hemorrhage after minor trauma. FVIII is the more commonly affected protein, either by X-chromosomal gene mutations or in autoimmune-mediated acquired hemophilia. Whereas substitution of FVIII is the mainstay of hemophilia A therapy, treatment of patients with inhibitory Abs remains challenging. In the present study, we report the development of FIX variants that can propagate the intrinsic coagulation cascade in the absence of FVIII. FIX variants were expressed in FVIII-knockout (FVIII-KO) mice using a nonviral gene-transfer system. Expression of the variants shortened clotting times, reduced blood loss after tail-clip assay, and reinstalled clot formation, as tested by in vivo imaging of laser-induced vessel injury. In addition, we confirmed the therapeutic efficacy of FIX variants in mice with inhibitory Abs against FVIII. Further, mice tolerant to wild-type human FIX did not develop immune responses against the protein variants. Our results therefore indicate the feasibility of using variants of FIX to bypass FVIII as a novel treatment approach in hemophilia with and without neutralizing FVIII Abs.

Association between phenotype and genotype in carriers of haemophilia A

Summary.  Female carriers of haemophilia might suffer from increased bleeding tendency therefore the assessment of the bleeding risk is very important for improving care. This single‐centre study documents the occurrence of bleedings in 46 carriers of haemophilia A including bleeding after tooth extraction (77%), easy bruising (67%), postsurgical bleeding (61%), menorrhagia (50%) or prolonged postpartum bleeding (43%). The F8 gene mutation of all 46 carriers (median age: 36.5 years, 15–80 years; mean FVIII:C activity: 59 ± 24.45%; normal range: 64–167%) was determined, and family history of haemophilia was recorded. For analysis, the bleeding tendency of the carriers was differentiated by severity into three groups. There was no statistically significant difference of FVIII:C between these groups. However, a correlation was found between the severity of bleeding tendency and the type of F8 gene mutation (P < 0.05) as well as the severity of haemophilia in affected male relatives (P < 0.0005). Results show that even carriers with a FVIII:C activity as high as 50–60% are at increased risk of bleeding. Incidence and intensity of bleeding symptoms of haemophilia A carriers are high and correlated with the phenotype of the male haemophilic relative and the underlying F8 gene mutation.

Age-dependent increase of FVIII:C in mild haemophilia A

Summary.  Variability of FVIII:C levels in healthy individuals and age‐dependent increase are a known phenomenon. In haemophilia, increasing FVIII:C levels with age have not been described yet. In our study, we evaluated this issue retrospectively in a cohort older than 45 years of 29 patients with mild haemophilia and 14 patients with moderate or severe haemophilia at last visit at the haemophilia centre Frankfurt. The median duration of observation evaluated in this study was 17 years (range 5–28). Results show a significant correlation of increasing FVIII:C levels with age in mild haemophilia (P = 0.000041) and a non‐significant tendency to a higher increase in higher age (P = 0.085652). The median difference of FVIII:C level between the first and last measurement was 8% of normal plasma concentration (range −3% to +35%). Median FVIII:C level increase of patients younger than 62 years was 7.5% (range −3 to 22), median increase in older patients was 12% (range 0–35). This tendency could not be correlated to decreased number of bleedings, but FVIII substitution dosage should be adapted to changing plasma levels at higher age to prevent overdosing or thrombotic risks. Possible causes and contributing factors for increasing FVIII:C levels are discussed. Statistical significance remains to be confirmed in larger prospective studies also including younger patients.

Comprehensive Treatment of Periodontitis in Patients With von Willebrand Disease

BACKGROUND Hemophilia A and B and von Willebrand disease (VWD) belong to the most frequent congenital coagulation disorders and are a significant problem in patients who require periodontal therapy or tooth extraction. These patients need specialist management because even minor invasive procedures can precipitate a prolonged bleeding episode. However, although dental care presents major challenges in these patients, only a few studies are available. METHODS In this case series, the comprehensive periodontal treatment of four patients with hemorrhagic disorders (VWD type I and mild hemophilia B) is described. There was a close collaboration between the periodontist and the hematologist: all patients were scheduled for premedication with desmopressin and other pharmaceuticals at the hematologists office. After one session of scaling and root planing was performed in all patients, local agents such as tranexamic acid were used. In the course of periodontal therapy, access-flap surgery was performed in one of the four patients. RESULTS Before treatment, the rates of probing depths (PDs) of 4 to 6 mm (20% to 57%) or ≥ 7 mm (2% to 20%) were high. Three months after treatment, the rates of PDs of 4 to 6 mm (5% to 42%) or ≥ 7 mm (0% to 2%) decreased significantly in all patients. Attachment gains were also observed. A secondary hemorrhage did not occur in any of the patients, and wound healing proceeded without any complications. CONCLUSION Effective periodontal treatment can be provided to patients with hemorrhagic disorders with the combined efforts of the periodontist and hematologist.

Is gingival bleeding a symptom of patients with type 1 von Willebrand disease? A case–control study

BACKGROUND Von Willebrand disease (VWD) is the most common inherent bleeding disorder resulting in prolonged bleeding time. Gingival bleeding is a frequently reported symptom of VWD. However, gingival bleeding is also known as a leading symptom of plaque-induced gingivitis and untreated periodontal disease. Gingival bleeding in VWD patients (VWD) may be triggered by gingival inflammation and not a genuine symptom. Thus, this study evaluated whether type 1 VWD determines an increased susceptibility to gingival bleeding in response to the oral biofilm. METHODS Fifty cases and 40 controls were examined haematologically (VWF antigen, VWF Ristocetin cofactor, factor VIII activity) and periodontally [Gingival Bleeding Index (GBI), bleeding on probing (BOP), Plaque Control Record (PCR), periodontal inflamed surface area (PISA), vertical probing attachment level]. RESULTS GBI was significantly higher in controls (12.2%) than in VWD (10%). The study failed to find a significant difference regarding BOP between VWD (17%) and controls (17.2%). Multiple regressions identified PCR and PISA to be associated with GBI and BOP. VWD was negatively associated with GBI. Smoking and number of remaining teeth was negatively associated with BOP. CONCLUSION VWD is not associated with a more pronounced inflammatory response to the oral biofilm in terms of GBI and BOP.

Platelet inhibition and bleeding complications in patients with haemophilia/von Willebrand's disease and coronary artery disease

Since the introduction of clotting factor concentrates in the 1960s, life expectancy of patients with haemophilia in developed countries has increased to almost the background population [1]. Consequently, the ageing haemophilic population is confronted with age-related co-morbidities [2]. Several studies of cause-specific mortality have found lower rates of death from ischaemic heart disease in the haemophilic population compared with the general male population [3]. With the described increased life expectancy more patients with haemophilia and von Willebrand’s disease are suffering from coronary heart disease [3]. So far no standard treatment guidelines do exist because prospective studies are missing. It is important to assess the risk of bleeding in the haemophilia/ VWD population requiring platelet inhibition. This enables physicians to improve care for these patients. Hypertension, dyslipidemia, smoking and diabetes explained 57.7% of estimated risk of coronary artery disease (CAD) death of patients 50 years of age and older with at least one CAD risk factor who attended different clinics involved in primary prevention across Europe in the EURIKA study. To characterize CAD in the haemophilia /VWD patient population must be one goal for the specialists because therapy might be very challenging. The aim of this investigation was to describe the antithrombotic treatment used in patients with von Willebrand’s disease or haemophilia with CAD. In addition to this we will characterize bleeding complications and long-term treatment in these patients. Eligible von Willebrand’s (VWD) and haemophilic patients who attended our haemophilia centre were identified through lists. Demographics, clinical symptoms, treatment, information on outcome were collected from medical records. The minimum observational period was two years. The study had been approved by the local medical ethical committee. All patients had to be aged over 18. The inclusion criteria were patients with haemophilia A or B or VWD and CAD, proved by coronary angiography. Regarding VWD, only patients with bleeding tendency and decreased VWF: Rco < 40% were included. Carriers were not included; even patients with acquired inhibitors of FVIII were excluded. We described the coronary risk factors and co-morbidities. Bleeding complications in patients who require antiplatelet therapy were covered and changes in patterns of substitution and therapy regime were examined. The following symptoms were recorded: easy bruising, epistaxis, gum bleeding, easy bruising, menorrhagia, postpartal bleeding or bleeding after surgical procedures. Baseline characteristics were summarized in case of normally distributed data by medians and standard deviation (SD). Data were analysed using BIAS Statistical Software version 2 (Bremen, Germany). Forty pts of 480 screened patients in total were included in the register; 27 men and 13 women. Mean age was 70 years (SD 11.8 years). Thirty-two patients had VWD 1, one pt VWD type 3, two pts had acquired VWD and five patients had mild haemophilia A. All pts were treated with on-demand substitution. Due to CAD, all pts needed long-term treatment with antiplatelet or anticoagulation therapy. All coronary risk factors were found in this patient. First, arterial hypertension (n = 40), further hyperlipoproteinemia (n = 21). Nicotine abuse was rare (n = 2). Adipositas (median BMI 25.2 SD 4.1) was not common. Records of family history were not possible to obtain. Besides CAD, pts suffered even from other atherosclerotic diseases. One patient with haemophilia A had a peripheral arterial occlusive disease. This patient received warfarin (because of a concomitant deep vein thrombosis). Furthermore, one pt had a cerebral microangiopathy (VWD 1), another major apoplexy (VWD 1). One pt sustained an embolic occlusion of the radial artery (acquired VWD) and two an arterial eye occlusion (VWD 1). All of them received antiplatelet therapy with ASS 100 mg and/ or clopidogrel (Table 1). Twenty-two pts were treated by antiplatelet therapy in the course; of which 14 pts were treated with aspirin-monotherapy. Four pts received a dual platelet inhibition with ASS and clopidogrel: three pts suffered a myocardial infarction and needed stenting; one patient needed stenting without myocardial infarction. Four pts were treated with clopidogrel monotherapy. One pt sustained an embolic occlusion of the radial artery and an arterial eye occlusion. Two patients had peripheral arterial occlusive disease. Two pts received LMWH preceded once since surgery and once in M. Hodgkin and thrombocytopenia. Three pts (VWD 1), received warfarin due to severe heart insufficiency after bypass-surgery, one with haemophilia A due to a concomitant deep vein thrombosis. Only one major bleeding (upper gastrointestinal bleeding) was observed in the aspirin treated group. No major bleeding was observed in the clopidogrel treated group or in the pts with dual antiplatelet therapy. Even in the group treated with LMWH and warfarin no bleeding or thromboembolic complications occurred. Especially re-stenosis did not occur. A prophylactic treatment with a FVIII/VW-Factor concentrate was not performed. The minimum observational period was 2 years; data were recorded from 1990 until 2010. In the present study we investigated different bleeding complications in pts with VWD and haemophilia. Special interest was contributed to the long-term antiplatelet or anticoagulation treatment due to prevalence of CAD. Patients with bleeding disorders can be treated with antiplatelet therapy or anticoagulation, but still bleeding complications occur. In our cohort, only one patient had a major bleeding, but haematoma is quite common and obviously waged to stop the therapy. Correspondence: S. Alesci, Goethe University Hospital, Medical Clinic III, Theodor-Stern-Kai 7Haemophilia Centre, 65760, Frankfurt, Hessen, Germany. Tel.: +49 (0)69 6301 5051; fax: +49 (0)69 6301 6738; e-mail: Rosa.Alesci@kgu.de

Successful treatment of an injury bleeding on a patient suffering from mild von Willebrand’s disease and predisposition to allergic diseases, with recombinant factor VIIA

1 Giannelli F. Factor IX. Baillieres Clin Haematol 1989; 2: 821–48. 2 Yoshitake S, Schach BG, Foster DC, Davie EW, Kurachi K. Nucleotide sequence of the gene for human factor IX (antihemophilic factor B). Biochemistry 1985; 24: 3736–50. 3 World Federation of Hemophilia Report on the Annual Global Survery 2007. http:// www.wfh.org 4 Giuseppe C, Paola N, Fabiana B et al. Denaturing HPLC Procedure for factor IX Gene Scanning, Clinical Chemistry 2003; 5: 815–8. 5 Giuseppe T, Donata B, Roberta S et al. The Italian haemophilia B mutation database, a tool for genetic counselling, carrier detection and prenatal diagnosis. Blood Transfus 2007; 5: 158–63.