Coagulation Biology and Disease
Blood provides oxygen to billions of tissues and cells in the human body. Hemostasis is the primary stage of wound healing which involves coagulation. Platelets are the crucial mediators that are activated upon tissue injury that encourage primary hemostasis via adhesion, activation, and aggregation. They play a significant role in stimulating the coagulation factors and other mediators to achieve hemostasis. Coagulation is a dynamic process that prevents excessive bleeding when a blood vessel is injured, blood changing from a liquid to a gel. The Cascade of events that prevents excessive bleeding is referred to as the coagulation pathway. Hemostasis is divided into two primary and secondary stages. Aggregation of platelets forming a plug is the primary stage of hemostasis. The secondary stage comprises of the two paths- intrinsic and extrinsic. Both of these pathways consist of certain factors that circulate in the bloodstream and finally meet up at a point to form the common pathway. This in turn activates fibrinogen into fibrin. Platelets further bind together through fibrin mesh which is responsible to stabilize the platelet plug. Coagulation disorders are disruptions that affect the blood’s clotting activities resulting in either hemorrhage or thrombosis. Some of the most common coagulation disorders are-
- Haemophilia
- Von Willebrand disease
- Clotting factor deficiencies
- Hypercoagulable states
- Deep venous thrombosis
These clotting disorders develop due to several conditions and can be either acquired or hereditary. They can be diagnosed with blood tests and imaging. Symptoms may include extreme fatigue, joint pain, headache, bruising, swelling, vision problems, and prolonged bleeding. The major causes of coagulation disorders are-
- Vitamin K deficiency
- Liver disease
- Disseminated intravascular coagulation (DIC)
- Development of circulating anticoagulants
- Factor V Leiden
- Antithrombin III (ATIII) deficiency
- Protein C or protein S deficiency
- Prothrombin (PT) gene mutation
- Antiphospholipid antibody syndrome
Some treatment options can help to relieve symptoms such as iron supplementation, blood transfusion, replacement therapy, desmopressin, heparin, and warfarin. Currently, there is no cure for coagulation disorders approved by FDA, however, gene therapy has proved to be a significant benefit for treating X-linked genetic disorders. The goal is to provide clinical and biochemical improvement in animal models by replacing a particular gene that is either deficient or dysfunctional as a result of a germline mutation. Gene therapy has proved to be cost-effective and highly efficient for a continuous source of clotting factor from a single treatment. Strategies such as zinc finger nucleases, transcription activator-like endonucleases, guiding RNA molecules to target the site for revision, and sequence correction by Cas9 endonuclease are being considered for clinical application as a treatment for coagulation factor deficiency. Several critical hurdles are associated with gene therapy including large-scale production of gene therapy vectors and immune obstacles to successful gene transfer. Thus, the outcome of gene therapy will require evaluation in randomized clinical trials and formal monitoring.
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