Bleeding and Clotting
Blood is essential for life. As a result, bleeding is inevitable when we have an injury and clotting is necessary to stop bleeding when it happens. The system that our bodies have developed to stop bleeding relies upon many parts. When bleeding starts, a blood vessel in our body is broken and spills the blood. The injured blood vessel first comes into contact with platelets in our blood to start the clotting process. The platelets are activated when the first contact with the injured blood vessel occurs and caused to release their contents. This brings more platelets to the injured blood vessel and starts a process of protein activations known as the clotting cascade. The proteins of the clotting cascade, known as Factors. Activation of one factor leads to the activation of the next factor, like a chain of dominoes, until fibrinogen is activated into fibrin. The fibrin acts like glue to hold together the blood and platelets that form the clot that stops bleeding. Once the blood vessel is healed, our body will dissolve the un-needed clot through a system known as thrombolysis in the weeks or months afterwards.
Problems with any of the parts of clotting can lead to disorders of bleeding or excess clotting. Everyone will bleed from time to time, so it may be difficult to tell if someone has a disorder. Some bleeding disorder are discovered because there is a family history of a disorder such as Hemophilia or von Willebrand’s Disease or there are other family members who are known to bruise or bleed easily, sometimes known as “free bleeders.” Other times, there is no family history and the bleeding just seems excessive. The symptoms of excessive bleeding might include easy and frequent bruises which may occur with very minor injuries, frequently occurring nosebleeds, constant bleeding from the gums when you brush your teeth, the need for a blood transfusion due to bleeding, prolonged bleeding after surgery, and excessively heavy, frequent or prolonged menstrual periods. Patients with a bleeding disorder may be treated by giving medicines that might help increase the levels of the factors or promote a clot to form, a transfusion with platelets or another blood product, or the replacement of a missing factor with a specific factor product.
Disorders of excessive clotting leads to clots forming at unexpected times. A clot that forms in a blood vessel that is uninjured will cause the blood flow to be blocked. This leads to pain and swelling when it occurs in the blood vessel of the legs, where it happens most often and is known at a DVT or Deep Vein Thrombosis. A new clot like this can break up and shower clots to other areas of the body like the lungs or brain where it can be life-threatening. The disorders of excessive clotting may sometimes be inherited from parents and other family members, but there are also risk factors that can provoke a clot to form. These risk factors including birth control pills, smoking, obesity, dehydration, and excessive sitting. Controlling these risk factors can help to decrease a person’s risk of developing a blood clot. Blood clots are most frequently treated with medications known as “blood thinners,” which slow down the ability of our bodies to form clots. Life-threatening clots are sometimes treated with surgical removal or medicines which can help to dissolve clots.
A person who has a bleeding or clotting disorder requires highly specialized care in treatment centers that have specialized expertise. A federal network of treatment centers may be accessed throughout the United States to deliver this expert care. Treatment centers, such as ours, are able to offer physicians who are experts with bleeding disorders, a dedicated nurse coordinator, physical therapist, social worker, and dentistry. These core services are part of an annual comprehensive visit at the center. In addition, services such as pharmacy, orthopedics, genetics, and gynecology may be accessed through these centers. Other services that treatment centers have available also include camps, educational outreach, patient support, specialty pharmacy or homecare support and research. Our center also provides coordinated care with Dr. Anita Rajasekhar and the other physicians of the Adult Hematology service to provide for a smooth transition as pediatric patients grow into adulthood and to provide them with lifelong comprehensive care.
Dr. Herzog’s research program seeks to develop gene therapy for hemophilia and to establish prophylactic immune tolerance protocols Severe hemophilia is characterized by frequent spontaneous bleeding. His work in canine hemophilia has shown that gene transfer can permanently correct this defect, and clinical trials have been ongoing to translate these successes to a therapy for humans. Using interdisciplinary approaches, the lab is also pursuing several alternative strategies to induce tolerance to therapeutic proteins such as hepatic gene transfer, mucosal tolerance, and immune modulation. Important mechanistic aspects of these studies include organ-specific immunity, innate immunity, and immune regulation/regulatory T cells. We are using small and large models of hemophilia to advance basic science toward clinical application.
Dr. Markusic’s lab is using novel adeno-associate virus (AAV) vectors for gene therapy to treat hemophilia. They wish to model and identify strategies to minimize immune responses against human factor IX protein and AAV following gene transfer. The lab also wishes to translate effective strategies in hemophilia models that induce tolerance and reverse pre-existing immunity to coagulator factor to treat autoimmune disease.
For over three decades, Dr. Srivastava’s research has been focused on two parvoviruses, the non-pathogenic adeno-associated virus (AAV) and a common human pathogen, the parvovirus B19, and the development of recombinant parvovirus vectors for human gene therapy. His laboratory has made seminal contributions to the field of parvoviruses, which include: identification of cellular co-receptors for AAV as well as parvovirus B19; elucidation of various steps involved in parvovirus trafficking in the cell and nuclear transport; identification of cellular proteins involved in the regulation of AAV DNA replication and encapsidation; development of recombinant AAV and parvovirus B19 vectors; transgenic and knockout mouse models to study parvovirus-induced pathogenicity, and the use of parvovirus vectors for gene transfer and gene therapy. The current emphasis is on developing recombinant parvovirus vectors for gene therapy for genetic diseases such as beta-thalassemia and sickle cell disease, and malignant disorders such as hepatoblastoma and hepatocellular carcinoma.
Dr. Hoffman’s research is particularly interested in the mechanisms surrounding the generation of antigen-specific regulatory T-cells (Tregs), and the role they have in tolerance induction following gene transfer. Our major focus is aimed at exploiting the unique molecular and cellular mechanisms of liver-directed AAV gene therapy in order to re-establish immunological self-tolerance to a protein through the induction and expansion of antigen-specific regulatory T-cells. Through an innovative strategy, our group seeks to develop a clinically relevant therapy that will abrogate the progression of autoimmune neurological diseases such as Multiple Sclerosis.