| The difference between the coagulation disorders Hemophilia A and Hemophilia B lies in: | View Page |
| Which of the following tests could be used to distinguish whether an abnormal screening coagulation test result (PT or aPTT) is caused by a factor deficiency or an inhibitor?. | View Page |
| Which of the following coagulation factor(s) are found only in the extrinsic pathway. | View Page |
| Which coagulation pathway is initiated when collagen is exposed, and involves the substances HMWK, Fletcher Factor, and Hageman Factor? | View Page |
| Which of the following coagulation disorders can be attributed to a genetic platelet disorder, where giant platelets are commonly seen in the peripheral smear of an affected patient? | View Page |
| 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 is not a consequence associated with deficiencies in coagulation factors? | View Page |
| An Introduction to the Fundamentals of Coagulation The ability of the body to maintain a state of homeostasis, or physiological equilibrium, is absolutely essential for effective, efficient functionality of all body systems.
The mechanisms involved in blood coagulation, also known as hemostasis or blood clotting, serve to illustrate this concept.
Hemostasis is the cessation of free blood flow, external to the vascular system, when a vessel wall has been breached.
With the maintenance of homeostasis in mind, it is vital that the body be able to rapidly repair vascular damage, arresting blood flow in the process, while simultaneously maintaining blood in a fluid state within the vascular compartment.
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| 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 Vessel size as related to time required for clotting to occur, amount of products used (platelets and clotting factors), and size of the corresponding bleed. | 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 |
| 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 Overview of Vascular System Involvement in Primary Hemostasis:
Vasoconstriction
Reroute blood flow
Platelet aggregation
Contact activation of coagulation system (start of secondary hemostasis at this point) | View Page |
| Overview of Secondary Hemostasis Secondary hemostasis is the series of interrelated chemical processes which lead to the formation of durable fibrin strands, as well as being involved in their incorporation into the existing platelet plug, creating a fibrin clot. The fibrin strands themselves are manufactured through the interaction of various coagulation factors, via a process known as the coagulation cascade. After strand construction, these fibrin monomers are woven into the framework of the platelet plug, adding greater strength and stability. Once woven into the platelet plug, and further stabilized with covalent cross-linking, a fibrin clot (the end goal of secondary hemostasis) is achieved. The fibrin clot is more durable than the platelet plug, and is more of a long term fix, allowing time for continued vascular repair. | 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 Coagulation Cascade Consequences linked to deficiencies in coagulation factors;
Coagulation does not proceed at its usual pace, it is much slower than normal.
Activation of subsequent factors may be delayed or inhibited all together.
The time required for a clot to form is prolonged.
The breach fails to seal, and free bleeding continues.
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| The ultimate goal of secondary hemostasis is: | View Page |
| A Snapshot of the Entire Coagulation Cascade | View Page |
| Secondary Hemostasis – The Extrinsic Pathway The shortest, and least complex of the three pathways, the extrinsic pathway primarily focuses on the interaction of tissue factor with factor VII, leading to the activation of factor VII. Tissue factor, a substance expressed on the surface of cells such as fibroblasts and macrophages found outside the vasculature, initiates coagulation when plasma contained within the vessel walls leaks outside the broken vessel, and comes into contact with these cells. The nomenclature, extrinsic pathway, comes from the fact that tissue factor is external to the vasculature. | 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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| Which of the following statements is incorrect? | 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 |
| Collecting Blood Specimens for Coagulation Testing The specimen of choice for coagulation testing is plasma. Venous blood is drawn into a 3.2% buffered sodium citrate tube (blue top tube), yielding a whole blood sample with a 9:1 blood to anticoagulant ratio. Inadequate filling of the collection tube will decrease this ratio, and may affect test results. A blue top tube used for coagulation testing should be drawn before any other tubes containing additives. This includes tubes containing other anticoagulants and/or plastic serum tubes containing clot activators. A serum tube that does not contain an additive can be collected before the blue top tube. If a winged blood collection set is used in drawing a specimen for coagulation testing, a discard tube should be drawn first. The discard tube must be used to fill the blood collection tubing dead space to assure that the proper anticoagulant/blood ratio is maintained, but the discard tube does not need to be completely filled. The discard tube should be a nonadditive or a coagulation tube. If a blood specimen used for coagulation testing must be collected from an indwelling line that may contain heparin, the line should be flushed with 5 mL of saline, and the first 5 mL of blood or 6-times the line volume (dead space volume of the catheter) be drawn off and discarded before the coagulation tube is filled. | 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 - 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 |
| Which of the following statements is incorrect? | 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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| Fibrin/Fibrinogen Degradation Products and D-dimers The presence of D-dimers in plasma or whole blood indicates that fibrin has been formed and degraded (fibrinolysis). Plasmin can also degrade intact fibrinogen, generating fibrinogen degradation products that are detected in fibrin/fibrinogen degradation products (FDP) assays. D-dimers and FDP can become elevated whenever the coagulation and fibrinolytic systems are activated. The presence of D-dimer confirms that both thrombin and plasmin have been generated since it can only be produced as the result of the plasmin degradation of fibrin. This makes the test for D-dimers more specific for fibrinolysis than the FDP test that also detects the products of the direct proteolysis of fibrinogen (fibrinogenolysis).The D-dimer test can be useful in the diagnosis of deep venous thrombosis (DVT) or pulmonary embolism (PE), two forms of venous thromboembolism (VTE). When the test is being used for this purpose, it is important that D-dimer levels are accurately measured and accurately reported because of the serious nature of this clinical decision. If the test is positive in a patient suspected to have DVT or PE, clinicians proceed with further diagnostic tests. If the test is negative, depending on the clinical situation and the sensitivity of the D-dimer assay, DVT or PE is considered unlikely and further diagnostic tests for DVT or PE might not be pursued. D-dimer is a sensitive, but not specific, diagnostic test for disseminated intravascular coagulation, and an indicator of increased risk of future myocardial infarction in patients evaluated for chest pain. | View Page |
| Which of the following statements is incorrect? | View Page |
| 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 - Inherited Inherited disorders are those which are considered to be inborn, and have some familial linkage. Hemophilia A is a deficiency of coagulation factor VIII. It is the most commonly encountered hereditary based coagulation disorder. Found almost exclusively in males, its pattern of inheritance is sex-linked recessive. This disorder presents clinically with hemorrhagic events ranging in severity from mild to severe. Patients often present with spontaneous bleeding into their joints, a classic symptom of this affliction. The treatment of Hemophilia A often involves the administration of commercial factor VIII products. | View Page |
| Coagulation Disorders - Inherited Hemophilia B is a deficiency of coagulation factor IX. Found almost exclusively in males, its pattern of inheritance is sex-linked recessive. This disorder presents almost identically to Hemophilia A in terms of symptoms, and has a very similar pattern of inheritance. Be sure to keep in mind that while similar, Hemophilia A and B are caused by a deficiency in different coagulation factors. The treatment of Hemophilia B involves therapeutic administration of Factor IX concentrates. | View Page |
| Coagulation Disorders - Inherited Von Willebrands Disease is a platelet disorder. This disorder is characterized by a functional defect in Von Willebrands factor (vWF) itself. This disease often clinically manifests with a concurrent deficiency of factor VIII, but will present with a normal platelet count. As far as genetics and inheritance, both men and women are affected equally. Von Willebrands factor is essential for platelet binding, therefore, a defect in vWF causes impaired platelet adhesion and aggregation. The treatment of Von Willebrands Disease involves the administration cryoprecipitate, as it is rich in vWF. | View Page |
| Coagulation Disorders - Acquired A lack of Vitamin K can cause a loss of functionality in Vitamin K dependant coagulation factors, specifically, factors II, VII, IX and X.
Most often associated with a diet lacking in Vitamin K, it may also present in situations of broad spectrum antibiotic use, where normal flora in the gut have been eliminated.
As one might expect, treatment involves a diet rich in Vitamin K containing foods, and judicious use of broad spectrum antibiotics. | View Page |
| Coagulation Disorders - Acquired Disseminated Intravascular Coagulation (DIC) is best described as a disorder of consumption, because clotting factors are depleted from the blood. Basically, clotting occurs randomly throughout the body, as opposed to just in the localized areas where vascular damage has occurred, consuming clotting factors and other components such as platelets in the process. Symptoms may range from a mild bleed, to severe, profuse bleeding, primarily dependant upon the availability of clotting factors. As more and more coagulation factors and components are consumed, the disorder progresses and symptoms worsen. Most heavily impacted are the levels of factors I, V, and VIII as well as the number of available platelets. Clinically, DIC is detected via an elevated (positive) FDP, positive D-dimer test, a prolonged PT and APTT, plus the manifestation of hemorrhagic episodes. DIC is diagnosed as two primary types, acute and chronic. Acute DIC manifests in a few hours or a few days, has a high mortality rate, and is seen in infections, obstetric complications, liver disease, and tissue injury. Chronic DIC is a secondary condition to some other disease state. Once you treat the primary disease, this type of DIC will go away. Treatment is often factor replacement therapy through the use of fresh frozen plasma and/or cryoprecipitate. | View Page |
| Coagulation Disorders - Platelet Disorders Bernard-Soulier Syndrome is a genetic platelet disorder characterized by abnormal platelet function tests, unusually large platelets, and a moderate decrease in platelet count. Clinically, patients present with mucotaneous bleeding of varying severity, as well as having gingival bleeds, epistaxis, purpura, and gastrointestinal hemorrhaging. Treatment can range from the administration of iron supplements up to red cell replacement therapy if the episodic bleeding is severe enough to warrant it. | 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 |
| Anticoagulation Therapy - Heparin Therapy The use of heparin is prophylactic. It is used either to prevent thromboembolism (a condition in which a blood clot forms inside a vessel), or used to limit a previous thromboembolism. Heparin inhibits thrombin. The degree of inhibition is dosage dependant. Low doses of heparin inhibit initial thrombin formation in the coagulation cascade, and act to slow down overall thrombin generation. At higher doses, heparin can inhibit thrombin entirely, making blood coagulation impossible. Heparin is a potent anticoagulant. Accurate monitoring is essential. The activated partial thromboplastin time (APTT) and/or activated clotting time is used to monitor unfractionated heparin therapy. | View Page |
| Anticoagulation Therapy - Oral Anticoagulant Therapy The therapeutic use of oral anticoagulants is typically the long-term solution for the patient in terms of managing situations of thrombosis. Warfarin, a dicumarol derivative, is one of the most popular oral anticoagulants used today. While heparin is administered intravenously and acts to inhibit thrombin, warfarin is given orally, taken in pill form, and functions as a Vitamin K antagonist. In earlier discussions, it was mentioned that certain clotting factors are considered to be vitamin K dependant. They require vitamin K molecules for their action to occur. Vitamin K dependant factors include factor II, VII, IX, and X. Vitamin K dependant metabolic processes involved with these coagulation factors are inhibited by drugs such as warfarin. The chemical structure of warfarin and similar anticoagulants enables them to bind competitively with free vitamin K. The prothrombin time (PT/INR) is used to monitor oral anticoagulant therapy. | View Page |
| Case James Brown, a phlebotomist from the laboratory went to the second floor of Memorial Hospital to draw a STAT BMP (chem-8), CBC, and PT on a patient. The patient was in critical condition so the lab results were crucial for treatment. James quickened his pace in order to speed up the result time. He collected the specimens and took them back to the lab. However, the technologist in hematology and coagulation notified him that he would need to recollect the specimen because the CBC and PT were clotted. | View Page |
| Discussion When drawing blood into evacuated tubes, it is best to draw the tiger top and red top tubes first, so that tissue fluids and fragments that cause blood to clot are retained in a tube which will clot anyway. Such tissue fluids and fragments are most likely to be present in the first tube to be drawn. If tissue fluids and fragments are present in a light blue top tube used for coagulation tests, they will interfere with the test results. However, recent studies have shown that accurate coagulation results may be obtained from the first tube drawn. It is nevertheless recommended that tiger and red top tubes be drawn first when using the evacuated tube system.If blood had been drawn first into a syringe, the order in which the blood is expelled from the syringe into the tubes would be different. Since no anticoagulant is present in the syringe the blood must first be expelled into the light blue top tube, then the lavender top tube, and finally the tiger top tube. This is so that the blood is promptly mixed with the anticoagulants present within the light blue and lavender top tubes before clotting begins. Clots in a lavender top tube are likely to cause a falsely low platelet count.Relevant topics:Lavender top tubes, Light blue top tubes | View Page |
| Discussion The blood pressure cuff was correctly inflated to 40 mmHg. The site for the incision is indeed the inside of the forearm a few inches below the bend of the elbow, and the cut was correctly made parallel to the bend of the elbow. However, the phlebotomist did not allow the alcohol to dry, and then made the additional mistake of wiping the incision with alcohol. Alcohol will retard blood coagulation, resulting in a falsely elevated bleeding time. It is also important to ask the patient about medications taken within the past week. Certain medications, particularly aspirin, will result in an elevated bleeding time.Relevant topics:Bleeding time: introduction 1, Bleeding time: introduction 2, Bleeding time: performance, Bleeding time, Apply blood pressure cuff, Bleeding time: prepare the site | View Page |
| Light blue top tubes These tubes contain the anticoagulant sodium citrate.
They are used mostly for coagulation (clotting) studies.
They must be completely filled to assure proper ratio of anticoagulant to blood.They must be inverted immediately after filling to prevent clotting.
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| Clots Blood clots when the coagulation factor proteins within the plasma are activated.Blood starts to clot almost immediately after it is drawn unless it is exposed to an anticoagulant.Clots within the blood specimen, even if not visible to the naked eye, will yield inaccurate results. | View Page |
| Partial collection tubes Filling a light blue-topped tube to its recommended volume is especially critical; if it is filled incompletely, coagulation results will be incorrectly reported as abnormal.If a short draw is anticipated, a “partial collection” tube which contains less anticoagulant and requires less blood may be used.The light blue topped collection tube shown on the left requires reduced blood volume, and is filled only to the line.
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| Blood clots When a blood sample is left standing without anticoagulant, it forms a coagulum or blood clot.
The clot contains coagulation proteins, platelets, and entrapped red and white blood cells.
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| Plasma proteins Numerous types of proteins are dispersed in the plasma. These include:
Coagulation proteins (blood clotting factors), which, if activated, will form a blood clot , and
Serum proteins, which are left dispersed in liquid after the clot is formed. Serum proteins include:
Albumin, a marker of nutrition, and
Globulins, or antibodies. | View Page |
| Serum Serum is the fluid that is left over the coagulum after the specimen is centrifuged (spun down).
Serum contains all the same substances as plasma, except for the coagulation proteins, which are left behind in the blood clot.
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| Platelets Platelets are small cell fragments present in large numbers in blood.They work together with the blood coagulation proteins to form a blood clot. | View Page |