LabCE: Fundamentals of Hemostasis
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, a process known as platelet adhesion.
The difference between the coagulation disorders Hemophilia A and Hemophilia B lies in
The deficient factor and the products used in treatment.
The ultimate goal of secondary hemostasis is: The formation of a platelet plug. The production of coagulation factors. The formation of a fibrin clot. Dissolution of the fibrin clot.
The formation of a fibrin clot.
Prothrombin Time (PT)
The prothrombin time (PT) 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 these two pathways. PT results are used in conjunction with other diagnostic tests, as well as the clinical picture of the patient, to determine any hemostatic abnormalities that may be present. In addition to being an integral part of the coagulation disorder assessment process, the PT is also used to determine the therapeutic effectiveness of oral anticoagulants by monitoring drugs such as warfarin. PT 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; this value can be converted to the International Normalized Ratio (INR).
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 and becomes dislodged) or to limit a previous thromboembolism. Other key points about heparin include: - Heparin inhibits thrombin. The degree of inhibition is dosage-dependent. - Low doses of heparin inhibit initial thrombin formation in the coagulation cascade and 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.
Primary hemostasis consists of two key parts
The vascular system Platelets (thrombocytes)
A lack of Vitamin K can cause
a loss of functionality in Vitamin K-dependent 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.
The formation of a platelet plug is the goal of
primary hemostasis
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. the entire vascular response typically lasts less than one minute
Anticoagulant therapy is employed in a number of clinical situations. Some of these clinical situations include
- After an episode of thrombosis, such as deep venous thrombosis (DVT) in the veins of the legs, to prevent reoccurrence. - Prophylactically after some surgeries, especially those involving vascular repair such as coronary bypass surgery, to prevent clots from blocking newly formed vasculature. - In heart valve and chamber disorders, there is an increased risk of thrombosis. Although there are new anticoagulant therapies, this fundamentals course will discuss the most common forms of anticoagulants, heparin and warfarin.
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 patient A 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. Currently, the bleeding time test is no longer recommended and should not be used to assess platelet function. NOTE: Aspirin and other drugs may falsely prolong platelet function. Patients must be asked about aspirin use and be aspirin free for 7-10 days prior to testing for valid results.
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.
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 complement 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 aid 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.
Which of the following is not a variable in the effectiveness of hemostasis?
All of the above are variables in the effectiveness of hemostasis.
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?
Bernard-Soulier Syndrome
Which of the following statements regarding coagulation disorders is incorrect? Please select the single best answer Hemophilia A and B, as well as von Willebrands Disease, are considered to be inherited disorders. Damage to the liver can cause hemostatic dysfunction as it is the primary site for clotting factor production. Clotting factors are not vitamin K-dependent, therefore, a deficiency in this vitamin would not affect function. DIC is considered a disorder of consumption because clotting factors are depleted from the blood.
Clotting factors are not vitamin K-dependent, therefore, a deficiency in this vitamin would not affect function.
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. The time required for a clot to form is prolonged. The breach fails to seal, and free bleeding continues.
Basic 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. 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.
A current, recommended treatment for von Willebrand's Disease (VWD) is?
Deamino-D-arginine vasopressin
The Intrinsic Pathway
Exposure to contact substances, such as collagen, can activate the intrinsic pathway. The exposed collagen is the location where a complex between High Molecular Weight Kininogen (HMWK), Prekallikrein (also known as Fletcher Factor, which activates to Kallikrein), and factor XII (Hageman Factor) forms. Together, this biochemical complex, adhered to the collagen-binding site, catalyzes the conversion of factor XII to its activated form, XIIa, thereby triggering the intrinsic pathway. Here is where the "cascade" or "waterfall" nomenclature becomes evident as each activated factor triggers the conversion and activation of subsequent factors. Factor XIIa, activated previously, catalyzes the conversion of factor XI into XIa, while in the presence of HMWK. Note: This reaction can occur without HMWK but will be much slower. Next, activated factor XI (XIa) catalyzes the conversion of factor IX into IXa, in the presence of ionized Calcium. Then activated factor IX (IXa), along with ionized calcium, platelet factor, and factor VIII, activates factor X, which activates the next factor, prothrombin into thrombin in the common pathway.
Factor Assays
Factor Assays can be used to determine the cause of an unexpected, prolonged PT or APTT. They are 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 involves performing a PT and APTT, except that plasma known to be deficient in a specific factor type is combined with the patient's 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.
Which of the following coagulation factor(s) is(are) found only in the extrinsic pathway?
Factor VII
All of the following processes occur during primary hemostasis except: Please select the single best answer Physical decrease in the size of damaged vessel. Fibrin strands are added to the newly formed clot. Blood flow is rerouted around the damaged vessel. Platelets adhere to exposed collagen at the site of the breach.
Fibrin strands are added to the newly formed clot.
The term that describes the process by which fibrin strands are broken down, then removed from an established clot is:
Fibrinolysis
The Extrinsic Pathway
Focuses on interaction of tissue factor (sometimes referred to as factor III) 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 name extrinsic pathway comes from the fact that tissue factor is external to the vasculature. 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 considered 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. This pathway is sometimes referred to as the Tissue Factor Pathway.
Prothrombin group
II, VII, IX, X Vitamin K dependent
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.
Indicators of a potential liver problem include: - A decrease in the vitamin K-dependent factors, starting with factor VII, followed by reductions in factor II and X levels. - Factor V levels are decreased in both acute and chronic liver disease, while factor IX levels are typically slightly reduced until the advanced stages of liver disease. - An increase in factor VIII. There is an increased production of factor VIII by the sinusoidal endothelial cells when the liver is damaged. - 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 the administration of fresh frozen plasma.
Which coagulation pathway is initiated when collagen is exposed and involves the substances HMWK, Fletcher Factor, and Hageman Factor?
Intrinsic Pathway
Platelets have three primary functions:
Maintenance of Vascular Integrity - Platelets contain chemicals within their granules vital to the normal growth and maintenance of the vascular system. Platelet Plug Formation - Platelets are the fundamental components of the physical barrier that initially fills the breach in the compromised vessel. Stabilization of the Platelet Plug - Inherent platelet stickiness acts as a strong bond between the platelet and the exposed subendothelium and between platelets themselves. Fibrin strands will weave in amongst the bound platelets that make up the platelet plug, further compressing and solidifying the structure and creating a fibrin clot.
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?
Mixing Studies
Mixing Studies
Mixing studies can be 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 patient's plasma is mixed with an equal volume of pooled normal plasma, and then a PT and APTT are performed off the mixture. Testing is performed on the "mix" with and without an incubation period. The incubated sample is important to detect the presence of time/temperature-dependent inhibitors. If the addition of the pooled plasma brings the resultant values into the normal range, then the pooled plasma contained factors in which the patient's sample was deficient, and the patient has a factor deficiency. If the results are not "corrected" or brought back into the normal range after the addition of pooled normal plasma, then an inhibitor may be present. If correction has occurred, the next step in the diagnostic sequence of events is to perform a factor assay to determine which specific factor is lacking.
platelet aggregation
Once platelets begin to adhere to exposed surfaces, chemical signals activate changes in the shape of the platelets from discoid to a spiny sphere, which promotes platelets to adhere to one another, not just 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.
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 endothelial cell lining, exposing the subendothelium and collagen and releasing chemical signals that trigger subsequent hemostatic mechanisms.
Characteristics of the Platelet
Platelets are produced in the bone marrow by highly specialized cells called megakaryocytes. About 70-80% of a person's total platelet count is circulating in the vasculature at any given time. The other 20-30% are pooled in the spleen. The average lifespan of a platelet is 9-12 days. Platelets play a significant role in primary hemostasis, as they are the "bricks," or building blocks of the developing platelet plug, the forerunner to the end-stage fibrin clot. Platelets have inherent adhesive properties, which are essential for adherence to the site of vascular damage and binding to one another in aggregation activities. Platelets must be present in sufficient number and be functionally active for optimal clotting to occur. Platelet functionality tends to be more crucial than the number of platelets available, however, as patients with lower platelet counts can still clot relatively effectively as compared to those patients with intrinsic platelet defects.
Overview of Secondary Hemostasis
Secondary hemostasis is the series of interrelated chemical processes that lead to the formation of durable fibrin strands and their incorporation into the existing platelet plug, creating a fibrin clot. The fibrin strands 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.
Which of the following statements is incorrect? Fibrinolysis is the term used to describe the process by which fibrin is removed from a clot, leading to its dissolution. The specimen of choice for coagulation testing is plasma collected using 3.2% sodium citrate as an anticoagulant. The APTT test is used to monitor warfarin therapy. INR is a way to report PT results.
The APTT test is used to monitor warfarin therapy.
Which of the following statements is incorrect? Please select the single best answer Platelet assays are superior to bleeding time tests for assessing platelet function. If patient coagulation studies are "corrected" by mixing studies, that patient has a factor deficiency. The fibrinogen assay is a quantitative measure of factor I. The D-dimer test can detect products of fibrinogenolysis but not fibrinolysis.
The D-dimer test can detect products of fibrinogenolysis but not fibrinolysis.
Prothrombin Time (PT), continued
The International Normalized Ratio (INR) component of the laboratory result is a calculated value 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.
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. In addition to being an integral part of the coagulation disorder assessment process, the APTT is used to determine the therapeutic effectiveness of heparin administration. 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 that may be present. 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.
The Common Pathway
The common pathway is sometimes referred to as the final common pathway or thrombin pathway. It starts with the activation of factor X by way of the intrinsic pathway, the extrinsic pathway, or both. Factor X is also referred to as either Stuart-Prower Factor or Thrombokinase. It is produced in the liver and is vitamin K dependent. Activated factor X (Xa), in the presence of factor V (necessary cofactor), ionized calcium, and platelet factor act to convert prothrombin (precursor) to its active form, thrombin, by cleaving the prothrombin molecule. After its conversion from prothrombin, thrombin catalyzes the conversion of fibrinogen into a fibrin monomer. Additionally, thrombin triggers the conversion of factor XIII into factor XIIIa, forming covalent bonds that crosslink and stabilize the fibrin monomers. Finally, thrombin feeds back into the intrinsic and common pathways, accelerating the action of factors XI, V, and VIII. As large quantities of thrombin accumulate, it begins to have a down-regulating function by inhibiting several coagulation factors and thus slowing down the cascade.
All of the following are activities associated with platelets except: Please select the single best answer Stabilization of the platelet plug. Formation of the platelet plug. Adhesion of platelets to exposed collagen as well as to one another. The degradation of fibrin strands during fibrinolytic processes. Maintenance of the vasculature.
The degradation of fibrin strands during fibrinolytic processes.
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. 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 <100 mg/dL are often associated with free bleeding or impaired hemostatic function.
Fibrin Formation via the Coagulation Cascade
The formation of fibrin involves three interconnected biochemical pathways: intrinsic, extrinsic, and common. These pathways allow for the interaction of coagulation factors via a finely tuned sequence of chemical processes, where the factors 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, however, often lead to impaired vascular repair and depressed hemostatic activity.
From what you have learned thus far, which of the following would not impact the effectiveness of hemostatic processes? The availability of coagulation factors. The functional effectiveness of available platelets. The presence and subsequent activation of neutrophils. The degree to which the vasculature has been damaged and the size of the corresponding bleed.
The presence and subsequent activation of neutrophils.
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 when 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 D-dimer test more specific for fibrinolysis than the FDP test, which 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.
In summary, we have covered the events which comprise primary hemostasis.
The process begins with damage to a vessel wall, as blood flows outside the vasculature. The body responds with vasoconstriction, decreasing blood flow to the affected area. Platelets begin sticking to the damaged vessel walls. As the platelets stick, they release chemicals that signal other platelets to respond. As other platelets arrive, they begin sticking to one another, clumping together, forming a plug to fill in the breach. This plug, while strong, is a temporary fix and must be reinforced with fibrin strands to effectively fill the breach during the vessel repair process.
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 (light 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 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 ensure 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.
Oral Anticoagulant Therapy
The therapeutic use of oral anticoagulants is typically the long-term solution for the patient in managing situations of thrombosis. Warfarin, a dicumarol derivative, is one of the most popular oral anticoagulants used today. While heparin is administered intravenously or subcutaneously and inhibits 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 vitamin K-dependent. They require vitamin K molecules for their action to occur. The Vitamin K-dependent factors include II, VII, IX, and X. Vitamin K-dependent 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.
Which of the following statements is incorrect? The tissue factor/factor VII complex is part of the intrinsic pathway. The PT is a test used to assess the extrinsic pathway, while the APTT assesses the functionality of the intrinsic pathway. TFPI is an inhibitor that helps to control coagulation pathway activity. The coagulation cascade demonstrates a "waterfall" effect, as each factor is activated by the activation of a preceding factor.
The tissue factor/factor VII complex is part of the intrinsic pathway.
The Fibrinolytic System
There is a very close relationship between the formation of fibrin and its eventual degradation, or lysis. A fibrin clot serves as a temporary seal intended to prevent continued blood loss from the damaged vessel while repair activities are performed. The breakdown of the clot begins almost as soon as the clot is formed! The process by which fibrin is broken down and removed from the clot, ultimately leading to the complete dissolution of the clot, is called fibrinolysis. Fibrin strands woven into the clot structure are cleaved into soluble fibrin fragments and then removed by macrophages. The action of fibrinolysis also serves to restore blood flow into the area that had been sealed off, helping to promote further healing. Fibrinolysis is mediated by a proteolytic enzyme called plasmin. Plasminogen is the inactive precursor form of plasmin that is found in plasma. Plasmin takes on fibrinolytic properties after activation, digesting both fibrin and fibrinogen. Inhibitors act to control the process, serving as a check and balance system for fibrinolytic activities.
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. Regarding coagulation, disease status and genetics can adversely affect the functionality of many hemostatic processes. Impaired hemostatic mechanisms, be it acquired in cases of disease or inherited, 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 several inherited or acquired disease states. The following pages are intended to introduce some of the more commonly encountered coagulation disorders.
Which of the following is not true in terms of platelet characteristics?
Usually are found circulating in their inactive, spiny form or morphology.
Overview of Vascular System Involvement in Primary Hemostasis:
Vasoconstriction Rerouting of the blood flow Platelet aggregation Contact activation of coagulation system (start of secondary hemostasis)
The activation of factor X signals the beginning of the
common pathway
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.
Hemophilia A
is a deficiency of coagulation factor VIII. It is important to note that Hemophilia A can also be acquired versus inherited in cases where patients produce auto-antibodies against factor VIII. Following are other key points regarding hemophilia A: It is the most commonly encountered hereditary coagulation disorder. Found more commonly 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.
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 mucocutaneous bleeding of varying severity, as well as having gingival bleeds, epistaxis, purpura, and gastrointestinal hemorrhaging. Treatment can range from the administration of iron supplements to red cell replacement therapy if the episodic bleeding is severe enough to warrant it.
Von Willebrands Disease
is a platelet disorder characterized by a functional defect in the von Willebrands factor (vWF). Because Factor VIII binds to VWF for transport in the blood, people with vWF deficiencies can also have decreased quantities of functional Factor VIII. Although vWF problems affect platelet function, these patients usually have normal platelet counts. 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 for persons with von Willebrands Disease who are bleeding involves the administration of the modified antidiuretic hormone, deamino-D-arginine vasopressin (DDAVP). DDAVP can temporarily raise levels of vWF and factor VIII. Cryoprecipitate was formerly the method of treatment but has since been replaced with DDAVP.
Disseminated Intravascular Coagulation (DIC)
is best described as a disorder of consumption because clotting factors are depleted from the blood. The following are characteristics of DIC: 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 dependent 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. Low fibrinogen (factor I) levels are also useful in detecting DIC.
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 warfarin.
The activated partial thromboplastin time (APTT) is used to
monitor the intrinsic pathway and the effectiveness of heparin therapy.
Platelet aggregation is essential
to platelet plug formation because the platelets are now able to span the center of the breach, where there was obviously no exposed collagen to bind to before, as well as clumping behind one another to bolster or strengthen the barrier. The formation of the platelet plug signals the end of primary hemostasis and serves to initiate upcoming processes associated with secondary hemostasis.
Platelet adhesion occurs when which factor binds receptors on the platelet surface with receptors on exposed subendothelial tissue?
von Willebrands factor