BL.2.2: Hemostasis Flashcards
What is hemostasis?
Hemostasis is the process whereby an injury to a blood vessel triggers a series of enzymatic reactions resulting in the formation of platelet and fibrin plugs at the site of the injury which then stems the loss of blood.
Identify the elements that compose the hemostatic system. Understand the basic paradigm for coagulation factor activation.
Components of Hemostasis1. Coagulation factors2. Platelets3. Endothelium–vessel wall.Basic paradigm: Clotting factors circulate in inactivated form until needed. The procoagulant proteins circulate in excess concentration in the plasma in an inactive form or zymogen. Only a small percentage of the pro-enzymes need to be activated by proteolytic cleavage to form the clot.
Describe the blood clotting pathway.
General idea: Endothelial wall becomes damaged, exposing collagen, tissue factor, and von Willebrand factor. Platelets bind to the site of injury and change configuration, exposing certain proteins that attract fibrinogen and vWF (thus binding more platelets). They also release granules containing thromboxane (leading to vasoconstriction of damaged vessel), vWF and ADP (to bind and activate other platelets), various clotting factors, etc. When a platelet integrin A2bB3 is activated, it binds vWF, fibronectin, and fibrinogen to accumulate with other platelets. Fibrinogen gets converted to fibrin and forms a network that is the clot.
List which components of the system are vitamin K dependent factors.
Vitamin K-dependent factors: Factors II, VII, IX, and X.
Distinguish the extrinsic and intrinsic pathways.
Extrinsic: tissue factor + VIIa -> Xa.Intrinsic: XIIa -> XIa -> IXa + VIII -> Xa.Common: Xa -> IIa -> Ia + XIII -> clot.
Describe the screening tests to measure PT.
The protime (PT) measures the procoagulant activity of the factors VII, X, V, II and fibrinogen. This is the extrinsic pathway and the lower part of the coagulation cascade. The protime normal range is generally between 9 and 12 seconds, however this value is based on the potency of the material (thromboplastin) that is used to start the reaction in the laboratory. Therefore, the results are also reported as compared to an international normalized ratio (INR). An INR of 1.0 would be a normal value. The protime can be long because of a deficiency of any of the above mentioned factors, but the most common situation results from a deficiency of the vitamin K dependent factors, VII, X, and II either because of a lack of vitamin K or inadequate liver function. The drug, Warfarin, because of its affect in inhibiting the vitamin K dependent reactions, also results in a prolonged protime. The protime is used to monitor Warfarin therapy.
Describe the screening tests to describe aPTT.
The activated partial thromboplastin time (PTT) measures the procoagulant activity of the entire pathway. However, it is most sensitive to deficiencies of the higher numbered factors, especially XI, VIII and IX. It is not affected by deficiencies of Factor VII. The PTT can be prolonged also by anticoagulant drugs such as heparin or acquired anticoagulants such as fibrin split products. The normal range in most laboratories is usually 25-32 seconds. The PTT is used to monitor heparin therapy. Patients with hemophilia will have a prolonged PTT. Useful to detect Factor VIII, IX, XI, XII deficiencies
Explain the function of platelets in hemostasis. Describe the process of platelet aggregation.
Platelets adhere to the site of vessel injury where collagen is exposed. A plasma protein, von Willebrand factor (and endothelial protein) and a platelet membrane protein (glycoprotein 6), are involved with the adherence. The platelets become activated by the generation of thrombin at the site of the injury and as the platelets are stimulated receptors for fibrinogen are exposed. These activated platelets change shape and release ADP, vasoactive amines and form thromboxane A2. Thromboxane contracts smooth muscle and causes vasoconstriction of the vessel at the site of the injury which also helps stop the leakage of blood. The platelet has receptors for some of the coagulation proteins and forms a surface for the coagulation cascade with the end result in increasing the production of thrombin.
Explain how thrombin acts as the central regulation point for coagulation. Describe normal homeostasis in the coagulation system.
The goal of the series of reactions known as the coagulation cascade is to produce thrombin (Factor IIa). The thrombin converts fibrinogen, a soluble protein, to fibrin which makes a fibrous network in the clot. Thrombin also promotes platelet aggregation so that at the same time fibrin is being formed a firm mass of aggregated platelets and fibrin together make a plug that seals the injury in the vessel. Thrombin is also important in activating the cofactors in the coagulation cascade (Factors V and VIII), as well as activating the factors responsible for lysing the clot (fibrinolytic factors) and activates protein C which helps prevent uncontrolled thrombosis.
Explain the contribution and influence of endothelial cells on coagulation.
An in-tact endothelium inhibits coagulation, prevents platelet aggregation, promotes clot breakdown, and provides a barrier to the reactive elements in the vessel wall.An injured endothelium exposes collagen, tissue factor or negatively charged surfaces which bind platelets and initiate the clotting cascade.
Describe the regulatory mechanisms of coagulation, i.e., protein C pathway, antithrombin, fibrinolytic pathway.
The activation of the clotting cascade and of platelets is inhibited by an intact vascular endothelium and by continuous blood flow which washes away platelets and any activated factors.In addition, there are a number of natural anticoagulant proteins. Anti-thrombin III is a protein that binds with high affinity to heparin and to thrombin and inactivates it. It also inactivates Factors 2,9,10,11,12.Thrombin can activate another regulatory protein called protein C, which cleaves Factors Va and VIIIa, which are the cofactors of coagulation Fibrin is degraded by an enzyme called plasmin.The pro-enzyme plasminogen is activated by tissue plasminogen activator (TPA). Fibrin split or degradation products and D-dimer are formed. Fibrinolysis is inhibited by plasminogen activator inhibitors (PAIs) and alpha 2-antiplasmin.
List some of the major congenital or acquired disease states causing bleeding and/or clotting.
Congenital: Hemophilia A & B- X linked disorders, Factor VIII and Factor IX deficiency, respectively. Factor XI deficiency, Factor VII deficiency, von Willebrand disease are other congenital disordersAcquired: Liver disease, Vitamin K deficiency, warfarin or rat poison ingestion
What is aPTT?What is it testing?
Activated Partial Thromboplastin Time (aPTT or PTT): A surface activating agent (proclotting), calcium, and platelet phospholipid are added to citrated (anticoagulant) plasma– measure how many seconds until a clot forms.Generally about 30 seconds is normal.Mainly measures intrinsic/common pathway; thus measures activity of the entire clotting cascade, except Factor VII (VII is extrinsic pathway).Sensitive to inhibition by heparin and fibrin split products (which are also anticoagulants).
What is TT?What is it testing?
Thrombin time: Add thrombin to plasma.Measures common pathways conversion of fibrinogen to fibrin.Sensitive to inhibitory effects of fibrin split products and heparin.
What is PFA?What is it testing?
Platelet function analyzer: can determine an in vitro bleeding time with agonists. Faster.