Disorders of Primary Hemostasis

• Thrombin functions as a 1. procoagulant 2. tissue repair helper and 3. anti-coagulant
• Thrombin helps in tissue repair by inducing chemotaxis of neutrophils and monocytes
• Thrombin functions as an anti-coagulant by helping activate plasminogen into plasmin, which breaks down fibrin clots. It also forms a complex with thrombomodulin (a protein on blood vessel endothelial cells) that deactivates thrombin
• Deactivation of thrombin helps stop the coagulation cascade by deactivating other factors like V
• Procoagulation and anti-coagulation mechanisms happen at the same time, but the dissolution of the clot is just slower
• Thrombin acts as a procoagulant by 1. activating fibrinogen , 2. activating factors XI, VIII, and V as a feedback loop, 3. activates XIII which stabilizes clot, and 4. promotes secretion of serotonin (vasoconstriction)
• The MAIN substrate of thrombin is fibrinogen
• Thrombin-mediated tissue repair occurs through 1. increased vascular permeability, 2. increased adhesion of WBC to endothelial cells and 3. release of PDGF
• Thrombin mediates PDGF release, which stands for platelet derived growth factor. PDGF stimulates the proliferation of fiberoblasts (which can become collagen), smooth muscle cells, and endothelial cells. Wound healing!
• The fibrinolytic system breaks down fibrin clots and is activates at the same time coagulation is.
• Fibrin lysis is the gradual cleavage of fibrin by enzymes which are then removed by macrophages
• FIBRINOLYTIC SYSTEM: Tissue plasminogen activator (TPA) is released by damaged endothelial cells and activates plasminogen to plasmin (which breaks down fibrin)
• Disorders of primary hemostasis result from defects in the formation of a good platelet plug
• The effects from a disorder in primary hemostasis could be severe like hemorrhage or milder like longer bleeding time
• Quantitative primary hemostasis disorders are more common and are 1. Thrombocytopenia (decrease in platelets) and 2. Thrombocytosis (increase)
• Thrombocytopenia is worse than thrombocytosis (since clot is still localized and can be broken down like normal)
• A decrease in megakaryocytes in bone marrow can cause thrombocytopenia
• Thrombocytopenia can be caused by 1. deficient platelet production, 2. abnormal distribution of platelets, and 3. increased destruction of platelets
• All disorders of primary hemostasis are caused by platelet issues
• 1. deficient platelet production can be spontaneous due to anemia and pancytopenia, or caused through bone marrow damage like from chemo or radiation
• 2. About 1/3 of platelets are stored in the spleen for rapid release, and splenomegaly can cause abnormal distribution of platelets (decreased circulation, altered function, etc)
• 3. Increased destruction of platelets is immune-mediated and due to idiopathic (unknown) or secondary cause.
• Immune thrombocytopenic purpura (ITP) is an autoimmune disease and is a diagnosis of exclusion; symptom is very easy bruising
• ITP stands for immune thrombocytopenia purpura and is mostly genetic but can be secondary. Patients will have little red splotches on body that look like dark freckles
• In qualitative disorders of platelets, congenital forms are rare but can include 1. Platelet surface membrane defects (GPIB, GPIIbIIIa) 2. Platelet release or secretion defects, 3. Platelet coagulant activity defects, and 4. Abnormal platelet protein interactions
• A defect in GPIB would affect adhesion of plateltes to endothelium and a defect in GPIIbIIIa would affect attachment of fibrinogen (and no fibrin strands would form at injury site)
• Bc the mouth is very vascularized and bleeding-prone, dentists may be the 1st to realize a platelet disorder is present
• Glanzmann's thrombasthenia is a rare inherited disorder that causes the blood to clot too slowly due to defective or absence of GPIIbIIIa on platelets
• Defects in platelet coagulation activity is caused by von Willebrand disease, which is an inherited deficientcy of vWF
• vWF is found in endothelial cells and platelet graules
• vWF is the glue between platelets and exposed collagen and is a carrier protein for factor VIII.
• There are 3 types of vWF disease
• Type 1 of von Willebrand disease is an autosomal dominant disorder that makes up 70% of all cases. It results in a decrease of vWF (quantitative) and results in mild bleeding
• Type 2 von Willebrand disease affects the structure of vWF (qualitative), makes up most of other cases of disease, and results in mild bleeding
• Type 3 von Willebrand disease is the rarest type, and is an autosomal recessive disorder. It results in no vWF (quantitative) and severe bleeding.
• Purpura are red splotches caused by internal bleeding and can be caused by a variety of things
• Primary purpura results from skin fragility
• Purpura is associated with vascular disorders
• Secondary purpura results from other disease processes like malaria and have no genetic causes. could be from vessel damage, infectious disease, endotoxins, etc..