| We know that hemostatic events are triggered by a break in the inert epithelial lining of the vasculature, but what specific product(s) act as initiators? | View Page |
| Which of the following laboratory tests of hemostatic function is a screening test used to assess the functionality of both the intrinsic and common pathways? | View Page |
| An Introduction to the Fundamentals of Coagulation Blood flow is arrested by way of a complex series of interrelated physiological and biochemical processes. There are a wide variety of factors that influence the effectiveness of hemostatic processes including the following: Type of, and degree of, vessel damage Ability of vasoconstriction to occur Availability of platelets & their functionality Availability of clotting factors & their functionality Absence of inhibitors & anticoagulants | View Page |
| An Introduction to the Fundamentals of Coagulation The ability to control bleeding hinges primarily on the availability of both platelets and coagulation factors, as well as their adequate functionality.
It is important to note, however, that there are limits in the size, or the degree of damage that can be controlled and repaired without outside (medical) intervention.
As one may expect, and the prior chart illustrates, damage to a larger vessel yields a more substantial bleed, and in turn consumes a greater quantity of coagulation components.
These variables can radically alter the effectiveness of hemostatic control mechanisms.
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| An Introduction to the Fundamentals of Coagulation As we will discover later in the course, there are other variables which impact the effectiveness of hemostatic mechanisms as well, such as acquired disease states, and inborn metabolic pathway defects.
For now, however, our focus will be on the mechanisms, processes, and components which work together to achieve coagulation, or the cessation of blood flow from a damaged vessel.
Note: The terms coagulation and hemostasis are used interchangeably throughout this course.
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| From what you have learned thus far, which of the following would not impact the effectiveness of hemostatic processes? | View Page |
| Introduction to Hemostatic Mechanisms | View Page |
| Introduction to Primary Hemostasis Primary hemostasis is considered the starting point for the hemostatic response mounted by the body, subsequent to vascular damage. Its activation serves as a trigger for ensuing hemostatic processes, as the mechanisms are all interrelated. Primary hemostasis consists of two key parts: The vascular system Platelets (thrombocytes) | View Page |
| Primary Hemostasis – The Vascular System Our blood circulates freely through undamaged, intact vessels. The design of the vasculature, or blood vessels, is such that the walls of the vessels are chemically inert to both coagulation factors and platelets under normal conditions. Damage to a vessel breaks that inert epithelial lining, exposing the subendothelium and collagen, and releasing chemical signals that trigger subsequent hemostatic mechanisms. | View Page |
| Primary Hemostasis – The Vascular System The first specific, recognizable hemostatic mechanism is a process known as vasoconstriction, which is initiated by chemical signals stemming from a breach of the vasculature. Vasoconstriction, or vascular constriction, immediately reduces the quantity of blood flowing through the damaged area. Its action is the physical decrease in the size of the vessel, and the redirection of blood flow around, and away from, the damaged area. Vasoconstriction is akin to putting a clamp on a pliable piece of plastic tubing. A short process in terms of the overall time elapsed, the entire vascular response typically lasts less than one minute! Though fleeting, vasoconstriction is an exceedingly important hemostatic mechanism as it prepares the damaged vessel for subsequent repair activities. | View Page |
| Primary Hemostasis – The Vascular System & Platelet Involvement As discussed earlier, a break in the vessel endothelium leads to exposure of collagen and the vessel's subendothelial surface. Ruptured endothelial cells leak ADP and Serotonin, which are the chemical triggers that induce platelet adhesion, the next step in the sequence of hemostatic events. Circulating platelets are drawn to the area by those liberated chemical signals, and begin to physically attach themselves to the rough, damaged surfaces of the breach. As platelets continue to arrive and bind to the exposed collagen and basement membrane, a rudimentary barrier begins to form, as the platelets themselves serve to fill in the breached vessel wall. Platelets possess an inherent “sticky” property which enables them to adhere to one another, and not just to the damaged vessel endothelium. The process by which platelets bind to one another is referred to as platelet aggregation, and is vital because it allows for a platelet plug to be formed. The platelet plug is the structure responsible for plugging the hole in the vessel wall. | View Page |
| Primary Hemostasis – Platelet Kinetics Kinetic Processes Specific to Platelets. Adhesion – When platelets adhere to exposed collagen, they take on a characteristic “spiny” shape. Their inherent stickiness, and the aforementioned spiny shape serve to compliment each other during this process. Von Willebrands Factor (vWF) is absorbed by surface receptors on both the platelet and exposed subendothelial tissue, thereby linking the platelets to the tissue. Release – This process occurs prior to aggregation. Platelets dump the contents of their granules (ADP, Serotonin, & Calcium), which aids the upcoming aggregation process by acting as a chemical signal. Aggregation – Platelets physically bind to each other, not just to the exposed subendothelial walls and collagen of the breached vessel. Platelet aggregation requires sufficient chemical signal stimulation. Stabilization (technically part of secondary hemostasis as fibrin is a product of secondary hemostasis)– This process strengthens the platelet plug with the addition of interwoven fibrin strands, ultimately producing a fibrin clot. The durable fibrin clot is the ultimate goal of hemostatic processes. | View Page |
| Secondary Hemostasis – Fibrin Formation via the Coagulation Cascade The formation of fibrin involves three interconnected biochemical pathways; the intrinsic, extrinsic, and common pathways. These pathways allow for the interaction of coagulation factors via a finely tuned sequence of chemical processes, where the factors themselves control the activity of the pathway. Most coagulation factors are stimulated and activated by the preceding factor , hence the term, "coagulation cascade." Since factor activation requires the activation of a preceding factor, a deficiency in the functionality or availability of any factor would seriously impact the effectiveness of the coagulation process. Factor deficiencies do occur, however, and often lead to impaired vascular repair and depressed hemostatic activity. | View Page |
| Secondary Hemostasis – The Extrinsic Pathway It should be noted that this pathway is sometimes referred to as the Tissue Factor Pathway.
Once a vessel has been breached, tissue factor is exposed to circulating factor VII, and the two substances bind to form a complex.
The newly formed tissue factor/factor VII complex is thought to be the primary physiological stimulus for blood coagulation.
In other words, more hemostatic activities are initiated by the extrinsic pathway than the intrinsic.
This complex leads to the activation of factor VII (factor VIIa) which is now ready to catalyze the conversion of factor X to factor Xa as part of the common pathway.
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| Secondary Hemostasis – The Extrinsic Pathway Functional control of the extrinsic pathway is mediated by Tissue Factor Pathway Inhibitor (TFPI) which binds to and inhibits factor X. Remember, for hemostatic processes to continue, factor VIIa must be able to promote the chemical conversion of factor X into factor Xa. TFPI effectively blocks this action, thereby controlling the initiation of the common pathway. The Prothrombin time (PT) is used to monitor the extrinsic pathway, and the activity of oral anticoagulants such as Coumarin. | View Page |
| Laboratory Tests of Hemostatic Function Coagulation tests provide information that is used in diagnosing coagulation disorders, evaluating hemostatic function prior to surgery, and monitoring the effectiveness of anticoagulant therapy. | View Page |
| Laboratory Tests of Hemostatic Function Specimen rejection criteria established by your laboratory should be followed at all times, as improperly collected or processed coagulation specimens could adversely affect patient results. Generally speaking, hemolyzed specimens should not be used in coagulation testing because ADP liberated from lysed red blood cells can interfere with a number of coagulation tests, especially those involving platelet assessment. Grossly lipemic specimens may cause erroneous results or a clot may not be detected if a photo-optical coagulation system is used. An alternative method that is not affected by lipemia, such as an electromechanical method, may be required One way to avoid a grossly lipemic specimen is to ask the patient to fast prior to specimen collection. | View Page |
| Laboratory Tests of Hemostatic Function – Prothrombin Time The prothrombin time is a screening test that helps to assess the functionality of both the extrinsic and common pathways. The effectiveness and presence of factors I, II, V, VII, and X are assayed in this diagnostic test, as they are all found in the aforementioned pathways. The results of the prothrombin time are used in conjunction with other diagnostic tests, as well as the clinical picture of the patient, to determine any hemostatic abnormalities which may be present. In addition to being an integral part of the coagulation disorder assessment process, the PT is also used to determine therapeutic effectiveness of oral anticoagulants, by monitoring drugs such as Warfarin, Coumarin, and Dicoumarol. Prothrombin time test results are reported as the number of seconds needed for a clot to form in the patient specimen using the laboratory's instrument/reagent system, and as the International Normalized Ratio (INR). | View Page |
| Laboratory Tests of Hemostatic Function – Prothrombin Time The INR component of the laboratory result is a calculated value that is used by the clinician to monitor anticoagulant therapy and adjust dosage as dictated by clinical status. An INR of 2.0 - 3.0 is often desired as the therapeutic range. The following formula is used by the clinical laboratory to derive an INR value. The INR must be adjusted for every new lot of PT reagent. INR= (PT of patient/PT of geometric mean of the normal population)ISI The International Sensitivity Index, or ISI value, is provided by the reagent manufacturer as the relative sensitivity of the reagent itself. The INR is used to standardize PT results, and in turn, anticoagulant therapy, across laboratory instrumentation, methodologies, and locale. Be sure to frequently check that ISI values match those of the lot currently in use as erroneous results may otherwise occur . | View Page |
| Laboratory Tests of Hemostatic Function - APTT The activated partial thromboplastin time (APTT) is a screening test that helps to assess the functionality of both the intrinsic and common pathways. The effectiveness and presence of all the coagulation factors are assayed by this diagnostic test with the exception of factors VII and XIII. The results of the activated partial thromboplastin time are used in conjunction with other diagnostic tests, as well as the clinical picture of the patient, to determine hemostatic abnormalities which may be present. In addition to being an integral part of the coagulation disorder assessment process, the APTT is used to determine therapeutic effectiveness of heparin administration. Activated partial thromboplastin time results are presented to the clinician in seconds- the actual time elapsed until a clot was detected using the laboratory's instrument/reagent system. | View Page |
| Tests of Hemostatic Function – Fibrinogen Assay The fibrinogen assay performed in the clinical laboratory is a quantitative measure of factor I.
This assay is used to determine whether there is enough fibrinogen present to allow for normal clotting.
It is performed in cases of an unexpected, prolonged bleeding event, or an unexpected abnormal PT and/or APTT.
Additionally, it is also used to aid in the diagnosis of disseminated intravascular coagulation (DIC).
A normal reference range is typically around 200-400 mg/dl.
That range is significant because fibrinogen levels
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| Tests of Hemostatic Function - Platelet Function Assay A platelet function assay (PFA) is a screening test for the evaluation of platelets/primary hemostasis. Common clinical applications include the following: Preoperative evaluation of platelet function Determining the presence of drug-induced platelet dysfunction Determining platelet functionality in high-risk pregnancy Evaluation of patients with suspected inherited or acquired platelet disorders such as von Willebrand disease Evaluation of a bleeding patientA PFA instrument is able to differentiate between drug-induced platelet defects and other platelet defects. PFA tests are superior to the bleeding time test. The bleeding time is often not reproducible and, in spite of attempts at standardization, remains prone to variations in test results between persons performing the test. It is also relatively insensitive to platelet function. The bleeding time cannot be used to identify patients who may have recently ingested aspirin or non-steroidal anti-inflammatory drugs or patients who may have a platelet defect attributable to these drugs. The bleeding time is used to assess platelet function, but may be affected by platelet quantity. NOTE: Aspirin, and some other drugs, may falsely prolong bleeding times. Patients must be asked about aspirin use, and be aspirin free for 7-10 days prior to testing, for valid results. | View Page |
| Tests of Hemostatic Function - Mixing Studies Performed after an unexpected, prolonged PT or APTT is encountered to determine if the problem stems from a factor deficiency or the presence of an inhibitor. To perform the test, the patients’ plasma is mixed with an equal volume of pooled normal plasma, and then a PT and APTT are performed off the mixture. If the addition of the pooled plasma brings the resultant values into normal range, then the pooled plasma contained factors the patient's sample was deficient in, and the patient has a factor deficiency. If the results are not “corrected” or brought back into normal range after the addition of pooled normal plasma, then an inhibitor may be present. The next step in the diagnostic sequence of events, if correction has occurred, is to perform a factor assay, to determine which specific factor is lacking. | View Page |
| Tests of Hemostatic Function - Factor Assays Used to determine the cause of an unexpected, prolonged PT or APTT.
This test is performed after mixing studies have been run, because factor assays are able to identify specific factor deficiencies or inhibitors.
Think of mixing studies as being the screening test, while factor assays are confirmatory tests for specific factor deficiencies.
The test itself is involves performing a PT and APTT, except that plasma known to be deficient in a specific factor type is combined with the patients plasma, comparing the resultant time to a standard curve.
The percent of activity, and amount of correction with normal plasma determines the specific factor deficiencies.
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| Coagulation Disorders This course began with a discussion on homeostasis, the body’s desire to maintain a status of physiological equilibrium. Our inborn system of chemical checks and balances, activators and inhibitors, can be disrupted by numerous factors, two of the more common being acquired disease states and disorders passed on to offspring via inheritance. In regard to coagulation, both disease status and genetics can adversely affect the functionality of many hemostatic processes. Impaired hemostatic mechanisms, be it acquired in cases of disease or inherent, may result in situations of either hemorrhage or thrombosis. A situation of hemorrhage, or bleeding external to the vasculature, most often stems from physical vessel trauma, but may also arise from a wide variety of disease states. Thrombosis does not require physical trauma, and is the activation of hemostatic processes at an inappropriate time in an inappropriate place, and may arise from a number of inherited or acquired disease states. The following pages are intended to serve as an introduction to some of the more commonly encountered coagulation disorders. | View Page |
| Coagulation Disorders and Liver Disease The liver is the site of production for the vast majority of our clotting factors. Therefore, impaired liver function could adversely affect these hemostatic proteins. Some early indicators of a potential liver problem include: An increase in factor VIII. It is not produced in the liver and will be present in elevated numbers as the body attempts to compensate. The PT is sensitive to liver function, so an unexpected, prolonged PT should be evaluated. A lack of fibrinogen is often indicative of severe liver disease. It is difficult to treat liver disease, so therapy typically centers around replacing the missing factors by way of administration of fresh frozen plasma. | View Page |
| Which of the following statements regarding coagulation disorders is incorrect? | View Page |