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Research Projects Funded in 2005

Haemostatic Changes during Pregnancy in Healthy Women and Women with Inherited Bleeding Disorders Presenting with Menorrhagia

Dr. Christine Demers
1st year funding
Centre Hospitalier Universitaire Affilié de Québec

Inherited bleeding disorders are associated with a wide spectrum of clinical symptoms depending on the type and the severity of the disease. During pregnancy, the risk of bleeding is generally low in affected women, because the levels of many of the coagulation factors naturally rise over the course of a pregnancy. However, the risk of bleeding can be significant at delivery and after the pregnancy (during the post-partum period), because these levels once again fall to the baseline. In fact, it has been demonstrated that the risk of postpartum hemorrhage is increased to 10 to 25% in women with bleeding disorders compared to less than 1% in the general population. Management is difficult, in part, because there is a lack of information concerning variation of the coagulation factors during pregnancy both in normal women and in women with bleeding disorders.

In this study we are planning to recruit 2 groups of women: 20 normal and 25 with an inherited bleeding disorder. The first objective of this study is to evaluate how the levels of coagulation factors vary over the course of pregnancy in both groups, and also to determine the rate with which these coagulation factors return to the baseline after delivery. Coagulation factors will be measured 3 times during pregnancy, at delivery and 4 times in the 4 weeks postpartum. We will try to co-ordinate this blood testing, whenever possible, with the regular testing of pregnancy

Post-partum bleeding is very difficult to assess and at the present time there is no way of objectively measuring it. However, there is a graphical chart that has been extensively evaluated in women with heavy periods. The second objective of the study is to evaluate if a modified version of the chart is a useful tool to measure post partum bleeding. All women will complete the pictorial chart during the 4 weeks postpartum.

With this study, we hope that a better understanding of coagulation during and after pregnancy will result in a better management of pregnancy for women affected with an inherited bleeding disorders.

Investigation of Clotting Factor Activity Heterogeneity in Severe Hemophilia A

Dr. Man-Chiu Poon and Gary D. Sinclair
1st year funding
University of Calgary
Calgary, Alberta

Persons with severe hemophilia (clotting factor activity below 1%) tend to bleed frequently and spontaneously into joints, leading to disabling arthritis. The current standard of treatment is regular, preventative factor concentrate infusion. This p6rimary prophylaxis started at an early age improves quality of life but the treatment is intensive; representing a burden to those with hemophilia and their families. It is also expensive. Often, a device is implanted to facilitate infusion and this may be complicated by infection and thrombosis.

Among severely affected individuals, approximately 10-15% have milder than expected bleeding symptoms. It is important to identify these persons so that their treatment can be customized, avoiding unnecessary infusion. We believe that some severe persons have factor VIII in their blood, but below the 1% detectable by routine laboratory methods. Furthermore, in the ongoing Canadian Prophylaxis trial (Dr. Victor Blanchette), some severely affected need only once or twice weekly FVIII infusion – the FVIII levels would be below 1% for a period before the next infusion and yet appear protective.

The focus of this research is to develop a sensitive assay to accurately measure circulating factor VIII levels between 0 and 1%, based on measurement of the activity of the enzyme, thrombin, that develops in proportion to the level of FVIII activity present. Three aspects of hemophilia treatment will then be investigated with participation from clinics across Canada. First, we will measure FVIII activity on 200 severe hemophilia A persons at a time when they have not been treated for 5 days or more (or at diagnosis) to determine if their “baseline” FVIII levels have a bearing on when they had their first spontaneous joint bleeding. We will take into account whether the affected individuals have inherited other mutations thought to promote clotting despite very low FVIII activity. Secondly, for patients in the Canadian Dose Escalation Prophylaxis study (Dr. Blanchette), we will measure the plasma FVIII level prior to their next FVIII injection. This may help discover the minimal FVIII level that will protect against bleeding and hence determine the frequency of FVIII infusions. Lastly, we will investigate (with Dr. Carcao) if the baseline FVIII level of severe hemophilia A persons can be related to how much FVIII is recovered after an injection, and how quickly the recovered FVIII disappears.

In conclusion, this study will assess the minimum level of FVIII below 1% that is still protective to help customize treatment for individuals with severe hemophilia.

The Role of Vitamin C in Bleeding Disorders

Dr. Alex Levin
2nd year funding
The Hospital for Sick Children
Toronto, Ontario

Vitamin C plays a critical role in preventing bleeding by keeping blood vessel walls sturdy. There are currently no normal values for children. Establishing normal ranges is important to serve as a basis for future research trying to understand why some children bleed more than others especially if they have other bleeding tendencies. Perhaps low vitamin C levels play a role. Prior attempts to measure vitamin C levels have been unreliable due to testing methods which were affected by diet, time of day and other factors. We will measure vitamin C levels from a type of blood cell called lymphocytes. Lymphocyte levels of vitamin C are more accurate and less subject to daily fluctuation. We have developed a High Performance Liquid Chromatography (HPLC) method for measuring lymphocyte vitamin C levels. Pilot testing using 50 samples showed that the test works very well. We will get specimens of blood from patients who are already getting a blood count test for other reasons. No extra blood or needle sticks need to be taken. Patients will be identified from Departments and Divisions at The Hospital for Sick Children who have patients who are likely not to suffer from conditions that influence vitamin C levels and who do not have a bleeding disorder. Parents will answer a brief questionnaire designed to identify dietary habits which might be affecting vitamin C levels.

After establishing normal age and gender related values for vitamin C (ascorbic acid) in healthy children, we will apply to begin researching the possible role of unrecognized vitamin C deficiency in bleeding disorders and eye (retina) haemorrhage. We will measure vitamin C levels in children with bleeding disorders such as haemophilia, von Willebrand disease, and idiopathic thrombocytopaenic purpura, comparing those children who have prominent bleeding problems to those who do not. Likewise, we will examine vitamin C levels in victims of Shaken Baby syndrome and accidental head injury with and without retinal hemorrhages. Lastly we will examine the effects of routine childhood immunization on vitamin C lymphocyte levels.