Quest 6: Coagulation and Hemostasis
Functionally, what do fibrin split by-products (FDPs) do in the course of the thrombin time test? Replace fibrinogen as substrate Bind calcium Dilute substrate Interfere with fibrin monomer polymerization All of the above.
Block polymerization. Thrombin time inhibitors could either be fibrin split products (which interfere with fibrin monomer polymerization) or antithrombins (e.g., heparin). Fibrinolysins can also produce abnormality both by destroying fibrin or fibrinogen and by providing fibrin split products.
A clotting disorder called Von Willebrand disease (VWD) occurs with equal frequency among men and women of the general population. As such, clinicians see this condition from time-to-time. However, women are more likely to experience symptoms of VWD because of the increased bleeding it causes during their menstrual periods, during pregnancy, and after childbirth. M/A: The source or function of von Willebrand factor (or disease if lacking) involves which of the following constructs? two main sources (platelets and endothelium) important for clot formation and stability is a protective, carrier protein for Factor VIII platelet adhesion patients with blood type AB are at greatest risk for vWF-related disease. mutations are exceedinly rare and seldom encountered in primary care settings, such as gynecology or family practice.
2 main sources important for clotting factor VIII carrier protein platelet adhesion Patients with blood group clear von Willebrand factor (vWF) faster. vWF is a large multimeric glycoprotein that mediates the attachment of platelets to damaged endothelium and also serves as the carrier protein for coagulation factor VIII (FVIII), protecting it from proteolytic degradation. Quantitative or qualitative defects in VWF result in von Willebrand disease (vWD), a common inherited bleeding disorder. It is produced by megakaryocytes and stored as granules in platelets, and the endothelium makes vWF too, but the platelet source is most important for important for clot formation and stability . von Willebrand disease (VWD) is the most common autosomal inherited bleeding disorder, with an estimated prevalence of 1 in 1000 individuals. VWD is classified into quantitative and qualitative forms. Diagnosis of VWD is complex and requires (1) a personal history of bleeding symptoms, (2) family history of bleeding or VWD, and (3) confirmatory laboratory testing. Mutations identified within VWFpp in VWD patients are associated with altered VWF structure and function. The assay of plasma VWFpp has clinical utility in assessing acute and chronic vascular perturbation associated with diseases such as thrombotic thrombocytopenic purpura, sepsis, and diabetes among others. The prevalance approximates 0.1%, but may be higher because half the population does not experience menses and goes undected until trauma occurs. Most patients are mildly to moderately affected and present with features of heterozygous classic vWd (type I). It is a very interesting disease.
This scarey QUEST query brefly introduces states of hypercoagulability or thrombophilia, which will be covered in a different venue, but deserves honorable mention herein. A normal and healthy response to bleeding for maintaining hemostasis involves the formation of a stable clot, and the physiological process is called coagulation. Hypercoagulability describes the pathologic state of exaggerated coagulation or coagulation in the absence of bleeding. Abnormal blot clotting (increased tendency of blood to thrombose) is a serious and too often FATAL problem that can be either acquired or inherited. Arterial thrombosis, such as in myocardial infarction and stroke, is different from venous thromboses, such as deep venous thrombosis (DVT) and pulmonary embolism (PE). Thromboembolism describes the migration of a local thrombus to distant areas leading to luminal obstruction. However, actual thrombosis occurs due to the interplay of both genetic and environmental factors and follows the multiple hit hypothesis and explains the inter-individual differences observed in patients with inherited mutations. M/A: After performing CBC, platelets count, D-dimer, PT and PTT testing, the typical clinical screening work-up for thrombophilia typically includes assays for which of the following assays? antithrombin III deficiency PCR for factor V Leiden mutation protein c and s deficiency prothrombin G2021A mutation anticardiolipin [aCL] elevated homocysteine level antiphosphatidylserine and apolipoprotein H (β2-glycoprotein 1) Taste test of homemade cookies.
ALL If you have heard of lupus, Vitamin B-12 or folate deficiency, recurrent spontaneous abortion, post-partum-dismise, DVT/PE, MI and Budd-Chiari Syndrome (liver attack thrombosis), then you are asked to become familiar with these tests. Lupus: antiphosphatidylserine and apolipoprotein H (β2-glycoprotein 1) Vitamin B-12 or folate deficiency: elevated homocysteine related clots. Recurrent spontaneous abortion and with thrombotic events in mother dimise shortly after birth: Anticardiolipin [aCL]. DVT/PE : prothrombin G2021A mutation and antithrombin III deficiency (hereditary) (both RARE) Solid organ clots (i.e., liver): protein c and s deficiency of "natural antcoagulant." Blood clots during pregnancy or estrogen replacement or OCs: PCR for factor V Leiden mutation DVT/PE : PCR for factor V Leiden mutation Myocardial infarction: Studies have shown a modest increase in the risk of coronary artery disease in patients with FVL. It has been observed that the FVL mutation is associated with an increased risk of stroke especially in women, smokers, and younger individuals. Taste testing of homemade cookies falls to a different venue, but was added to be certain that the other 7 responses were reviewed in earnest.
T/F: Activated factor XII with calcium ions and two cofactors (phospholipid from tissue thromboplastin and activated factor V) directly converts prothrombin to thrombin.
F F: Factor X is the lynchpin, not 12. If you answered true, then you were guessing. If so, you might want to go back and study the pathways again. Activated factor X with calcium and two cofactors (phospholipid from tissue thromboplastin and activated factor V (Va)) converts prothrombin to thrombin. Thrombin, in turn, converts fibrinogen to fibrin that cross-links to catch platelets. Factors VII/iX activates Factors Xa/Va referred to as the Factor V Complex or Prothrombin Activator; this, in turn, initiates the conversion of prothrombin to activate the common pathway.
T/F Factor VIII protein is one of the so-called negative "acute reaction" proteins or reactants.
F FALSE Factor VIII protein is one of the so-called POSITIVE "acute reaction" proteins whose synthesis is INCREASED in response to acute illness or stress such as COVID-19 infection and severe disease when abberant thrombosis is a grave problem.
A a previously healthy, 34 year-old patient, of mixed ethnicity, is bleeding (gums and bruising easily and excessive bleeding with dental prophylaxis, and menses seem to be heavier than of years past), but the reason why is not obvious and both the PT and aPTT tests are prolonged. She also complains of joint stiffness, especially in the morining. You suspect an acquired condition given the benign past medication history as an Air Force test pilot and was astronaut candidate. G1P1AB0 She takes no medications except for occasional ibuprofen. She takes a balanced diet, a daily vitamin with iron and exercises moderately. You suspect a new coagulation defect and think about the cascade. T/F: Like erythropoetin, prothrombin (Factor II) is a protein that is synthesized in the kidney and kidney is the major source of most coagulation factors.
F FALSE, but the bleeding problem has nothing to do with prothrombin. Perhaps there may be concurrent liver disease or new onset antibodies to phospholipids. What ever the problem, it seems that it is acquired. Prothrombin is made chiefly by cells in the liver. The protein circulates in the bloodstream in an inactive form until an injury occurs that damages blood vessels. In response to injury, prothrombin is converted to its active form, thrombin. Fibrinogen is a glycoprotein that is synthesized in the liver and the liver is a major source of many coagulation factors. Conversion of fibrinogen to fibrin under the influence of thrombin is the final major step in coagulation. Some disorders may be associated with antibodies to a variety of clotting factors. In systemic lupus erythematosus, for example, antiphospholipid antibodies and antibodies directed against factors II (prothrombin), VIII, IX, XI, XII, and XIII have been described. The diagnois of lupus should be considered since symptoms and diagnosis occur most often between the ages of 15 and 44 (and she is 34 years-old). In the United States, lupus is more common in people of color than in the Caucasian population.
T/F Continuous IV heparin would be expected to significantly prolong the PT test result.
F FALSE: Although both Coumadin (warfarin) and heparin inhibit the coagulation cascade (and thus the formation of fibrin), they have different mechanisms of action and activities. Levels ordinarily associated with continuous IV heparin usually do not significantly prolong the PT test outcome . A partial thromboplastin time (PTT) is best. Partial thromboplastin time (PTT) measures the overall speed at which blood clots by means of two consecutive series of biochemical reactions known as the intrinsic pathway and common pathway of coagulation. PTT measures the following coagulation factors: I (fibrinogen), II (prothrombin), V (proaccelerin), VIII (anti-hemophilic factor), X (Stuart-Prower factor), XI (plasma thromboplastin antecedent), and XII (Hageman factor). Heparin works in a totally different fashion. It works by binding to antithrombin III (ATIII), which as you will recall is a natural anticoagulant that acts on a bunch of different factors on both sides of the cascade, but seems to have more of an effect on the intrinsic arm than it does on the extrinsic arm of coagulation. Heparin binds to ATIII, causing a conformational change that activates ATIII and potentiates its action. BTW: Partial thromboplastin time (PTT) and activated partial thromboplastin time (aPTT) are used to test for the same functions; however, in aPTT, an activator is added that speeds up the clotting time and results in a narrower reference range. It's a lab modification to save tech time. Also, the aPTT is considered a more sensitive version of the PTT and is used to monitor the patient's response to heparin therapy. The reference range of the aPTT is 30-40 seconds.
T/F: Exposed plasma and membrane phospholipids have little bearing on circulating prothrombin.
F FALSE: Circulating prothrombin can bind to exposed plasma and membrane phospholipids to lead to clot formation. Antiphospholipid syndrome (APS) is a disorder of the immune system that causes an increased risk of recurrent venous or arterial thrombosis and/or fetal loss. Characteristic lab abnormalities in APS include persistently elevated levels of antibodies directed against membrane anionic phospholipids (ie, anticardiolipin [aCL] antibody, antiphosphatidylserine) or their associated plasma proteins, predominantly beta-2 glycoprotein I (apolipoprotein H); or evidence of a circulating anticoagulant.
T/F Factor V Leiden mutation decreases the chance of clumps of dangerous blood (clots) developing (thin blood). Women with the disorder risk developing hemorrhage during pregnancy
F FALSE: Factor V Leiden increases the chance of clumps of blood (clots) developing, which can be life-threatening. Women with the disorder risk developing blood clots during pregnancy or when taking the hormone estrogen. Without Factor V, Factor X has reigns too slowly proceed to the common pathway and conversely Factor V Leiden is resistant to degradation by activated Protein C, so it can cause excessive clotting. FYI, only if you care to know more: Factor V Leiden is the most common genetic predisposition to blood clots. Blood coagulation factor Va serves an indispensable role in hemostasis as cofactor for the serine protease factor Xa. In the presence of an anionic phospholipid membrane and calcium ions, factors Va and Xa assemble into the prothrombinase complex. Following formation of the ternary complex with the macromolecular zymogen substrate prothrombin, the latter is rapidly converted into thrombin, the KEY regulatory enzyme of coagulation. Activated protein C (APC), with its cofactor protein S, inactivates factors Va and VIIIa to provide a major natural anticoagulant system. APC cleaves factor Va to inhibit coagulation. The molecular basis of FVLeiden is a missense mutation in the factor V (FV) gene at G1691A, resulting in R506 being changed to glutamine (R506Q) 8-10. This change slows the inactivation of factor Va by APC, that is, factor V "resists" being degraded by APC, thereby creating a genetic risk factor that in association with environmental risk factors causes an increased risk for venous thrombosis.
Consider the term idiopathic. T/F: Platelet antibodies are rarely demonstrated in patients with chronic idiopathic thrombocytopenia purpura because antiplatelet autoantibodies have not been associated.
F FALSE: Platelet antibodies have been demonstrated in 80%-90% of patients with chronic ITP. Considering the term idiopathic is probably a misnomer here.
Bleeding disorders are not uncommon with liver disease. T/F: Damaged hepatocytes release von Willebrand's Factor to promote blood clotting and platelet adhesion.
F FALSE: von Willebrand factor is associated with subendothelial connective tissue; serves as a bridge between platelet glycoprotein GPIb/IX and collagen. Platelet phase - Damaged endothelial cells lining the blood vessel release von Willebrand's Factor, NOT HEPATOCYTES. In case you forgot already, vWF substance makes the surfaces of the endothelial cells "sticky". This condition may, by itself, be enough to close small blood vessels. In larger blood vessels, platelets begin to stick to the surfaces of endothelial cells. This effect is called platelet adhesion and is considered a physiological response and not a disease..
After low-dose aspirin therapy is stopped, it takes about a day for sufficient production of new (non-affected) platelets to reduce an elevated bleeding time to normal.
F False, longer. Certain drugs interfere with platelet function and produce a prolonged bleeding time. After a single small dose of aspirin, prolongation of the bleeding time over baseline is present by 2 hours or less, with maximum effect at about 24 hours. It takes 2-3 days (range 1-8d) for sufficient production of new platelets to reduce an elevated bleeding time to normal.
T/F: The major end-product in the clotting cascade is fibrinogen.
F False: Fibrinogen must be acted upon by thrombin (common pathway) to form fibrin. The ultimate goal in the clotting cascade is to enzymatically convert fibrinogen to fibrin (the mesh of the clot). This process must be carefully regulated to avoid bleeding and inappropriate clotting. Factor XIII crosslink the fibrin mesh to strenghten it.
T/F: Most clotting factors circulate in the 'active form' and are instantly ready for use (participation in the clotting cascade) should bleeding ensue.
F False: Most clotting factors are zymogens. A blood clot consists of plugs of platelets enmeshed in a network of insoluble fibrin molecules. Platelet aggregation and fibrin formation both require the proteolytic enzyme thrombin. Clotting also requires calcium ions [Ca2+]), which is why blood banks use a chelating agent to bind the calcium in donated blood so the blood will not clot in the bag. Sodium citrate is the buffer in blue-topped collection tubes and temporarily binds Ca++ cations until assays are performed. About a dozen other protein clotting factors, for which most of these circulate in the blood as inactive precursors, are activated by proteolytic cleavage. Acting sequentially, in turn, are proteases for other factors downstream in the system.
Hemophilia A & B are the result of clotting factor deficiencies. Hematology consults take a long time to obtain, especially in rural Texas and the diagnosis of hemophilia may be suspected. Some clotting factors are labile. T/F: To quickly diagnose factor IX deficiency in a suspected patient, one could add two-day old sera *(from some other known normal human being of the same blood type) to the patient's blood sample to correct the aPPT result. (A case of what do you know and when did you know it)
F The half-life of factor IX is approximately 18 to 24 hours and the half-life of factor VIII is 8 to 12 hours. This means that the amount of factor VIII working in the body drops by half 8 to 12 hours after aging so a significant residual amount of Factor IX should be present in the Normal-age reagent" to correct for a Factor IX deficiency. Conversely, an insignificant amount of Factor VIII should be present in the Normal-age reagent" to correct for a Factor VIII deficiency (5-6 half lives = nearly 0). FactorName V Proaccelerin (Labile factor) VII Proconvertin (Stable factor) VIII Antihaemophilic factor A, Antihaemophilic globulin IX Antihaemophilic factor B, Plasma thromboplastin component, Christmas factor
MC: The 'ROYAL' hemorrhagic disease known as hemophilia 'B' is usually associated with which of the following? Factor XI (deficiency) Factor IX (deficiency) Factor VIIIC (deficiency) Factor VI (deficiency) Factor XII (deficiency) Factor VII (deficiency)
Factor IX The hemorrhagic disease, known as hemophilia 'A', is usually associated with factor VIIIC deficiency, but a similar disease, hemophilia 'B,' may result from factor IX deficiency (and a similar, but milder, disease from Factor XI (deficiency) also exists. Factor IX deficiency is called hemophilia B. About 90% of clinical hemophilia cases are due to hemophilia A and about 9% to hemophilia B. Both are on the intrinsic side of the clotting cascade. Hemophilia B, also known as Christmas disease, is the second most common type of hemophilia. The hallmark clinical presentation of hemophilia B is joint involvement (hemarthroses), which typically presents in severe disease. The joints will become swollen, inflamed, painful, warm, with a limited range of movement. Recurrent hemarthrosis eventually causes erosion of joint cartilage and Charcot joints of hemophilic arthropathy. The most commonly affected joints are knees, elbows, ankles, shoulders, wrist, and hips. Hemophilia B is an inherited disease and it mostly affects males, but carrier females may show some signs of bleeding. It also has an X-linked recessive inherited mode of inheritance, but some acquired form has also been reported due to the development of autoantibodies toward factor IX. Hemophilia B is clinically less severe than hemophilia A. The disease manifestations can be categorized according to the degree of factor IX deficiency in the blood. In mild hemophilia, bleeding will present only after significant trauma or surgery, spontaneous bleeding is uncommon, and typically the diagnosis is made incidentally. In moderate hemophilia, bleeding usually presents after trauma, injury, dental work, or surgery. Recurrent joint bleeding may be present in up to 25% of cases, and the diagnosis usually gets delayed until late childhood or adulthood. The disease was named after Stephen Christmas, who was the first person diagnosed with the condition in 1952. The disorder was ubiquitous in the royal families of Spain, Germany, and Russia. One of the most famous families with this condition was that of Queen Victoria of England; thus, it is known as the "Royal disease." Patients with severe hemophilia are at risk of developing occult organ bleeding such as in the liver, spleen, bladder, kidneys, and spinal cord. Intracranial hemorrhage represents the most immediately life-threatening manifestation that could present as headache, vomiting, meningism, and lethargy; however, it could be silent and detected through routine imaging. It occurs in 1-4% of cases with the potential for chronic neurological disability. Extracranial bleeds such as subgaleal bleed and cephalohematoma can also be the initial presentation after delivery.
Which of the following does the warfarin (Coumadin) effect most profoundly? Factor VI Factor VII Factor VIII Factor XIII Factor I
Factor VII Factor VII is synthesized in the liver and is dependent on vit K for its activity. The half-life of factor VII is only 4-6 hrs, the shortest lived of the vit K-dependent coag factors. The coumarin vit K & antagonists produce rapid and profound depressive effect on f VII than on any of the other vitamin K—dependent factors. F VII is present in plasma and in serum and is stable in both. In factor VII deficiency the PT is abnormal; the APTT and bleeding time are normal or nearly so. Clotting factor IV is a calcium ion that plays an important role in all 3 pathways and VI simply does not exist (yet).
T/F: Abnormalities of blood coagulation take two main forms: failure to clot normally and failure to prevent excessive clotting.
T Empirically TRUE: Normal is the delicate balance between free-flow and clots. Anomalies may be congenital (genetic) or acquired. Hemostasis is the focus of this exercise and assocaited lecture. Hypercoagulable disease states will be discussed elsewhere and in due time (probably during hematology and OB/GYN lectures).
Factor VIII (FVIII) and von Willebrand factor (VWF) are two distinct glycoproteins that circulate in plasma as a tightly bound complex (FVIII/VWF). T/F: with hemophilia 'A', there are low levels or a complete lack of factor VIII but normal levels of VWF.
T Hemophilia encompasses a group of inherited disorders that alter blood coagulation. Hemophilia A, occurs in one out of 5000 males and accounts for 80% of hemophilia cases. Hemophilia A occurs in more than 400000 males worldwide, many of whom remain undiagnosed in the developing world. Classical hemophilia, also known as hemophilia A, is a hereditary hemorrhagic disorder resulting from a congenital deficit of factor VIII that manifests as protracted and excessive bleeding either spontaneously or secondary to trauma. An X-linked, recessive hemorrhagic trait or gene induces Hemophilia A. Hemophilia A's X-linked trait manifests as a congenital absence or decrease in plasma clotting Factor VIII, a pro-coagulation cofactor and robust initiator of thrombin that is essential for the generation of adequate amounts of fibrin to form a platelet-fibrin plug at sites of endothelial disruption. Female Hemophilia A gene carriers will transmit the gene to 50% of their male offspring, who will inherit the disorder. Female hemophilia gene carriers do not manifest symptoms of Hemophilia A but may have lower than usual quantities of Factor VIII. Male Hemophilia A patients do not transmit hemophilia to male offspring, but their female offspring will carry the hemophilia gene When the vascular endothelium sustains an injury, the hemostatic process initiates the coagulation cascade to restore vascular integrity and prevent further bleeding. Platelet activation occurs at the site of vascular rupture initiating promulgation of clotting factors and fibrin formation, resulting in a platelet-fibrin plug to inhibit further bleeding. Factor VIII, the deficit of which causes hemophilia A, provides essential enhancement of thrombin generation and promulgation of fibrin formation to inhibit further bleeding. Factor VIII adheres to von Willebrand factor to protect it from proteolytic degradation. Bleeding in hemophilia results from defective fibrin stabilization secondary to inadequate fibrin generation, which results in a failure of secondary hemostasis. Insufficient thrombin in the coagulation cascade results in a deficiency of fibrin. With hemophilia 'A', there are low levels or a complete lack of factor VIII but normal levels of VWF.
T/F: Thrombin (II) and Factor X are among the most affected clotting factors by antithrobombin (AT) and therefore heparin therapy idirectly affects Thrombin (II) and Factor X activity. .
T Heparin enhances antithrombin inhibition of factor Xa by approximately 1,000-fold. This is a very imporant concept and likely to appear on the PANCE is some fashion or another. Thrombin (II) and Factor X are most affected by AT and heparin i! The inhibitor also inactivates kallikrein and plasmin, also involved in blood coagulation. Antithrombin (AT) is a small protein molecule that inactivates several enzymes of the coagulation system. AT is one of the major naturally occurring inhibitors of coagulation and, as a gene product, acquired or hereditary deficiencies of this protein can result in excessive thrombin generation. Antithrombin is a glycoprotein produced by the liver and consists of 432 amino acids. It has an affinity to inhibit the activatiion of intrinsic and common pathway factors, including XIa, IXa, Xa and II1 (THROMBIN). PTT tests the function of all clotting factors except factor VII (tissue factor) and factor XIII (fibrin stabilizing factor).
T/F: The final common coagulation pathway consists of activated factor X plus activated factor V and PF-3 to convert factor II (prothrombin) to thrombin, and that in turn, leads to conversion of fibrinogen to fibrin.
T Indeed, activated factor X, in conjunction with Factor V, calcium, and platelets, phospholipids, are needed to convert factor II (prothrombin) to thrombin. Then, thrombin facilitates fibrinogen conversion. You should be able to draw out the core elements of the CC on demand and do it reflexively (leaving out the minutia). Factor V, or proaccelerin, is a protein made in the liver that helps convert prothrombin into thrombin. If there is not enough factor V or if it doesn't work correctly, blood may not clot effectively, and excessive bleeding ensures. In contrast, Factor V Leiden (mutant) causes excessive clotting becasue turnover is slowed and it hangs around too long.
Thromboplastin or thrombokinase is a mixture of both phospholipids and tissue factor found in plasma aiding blood coagulation through catalyzing the conversion of prothrombin to thrombin. T/F: The partial thromboplastin reagent is only a phospholipid platelet substitute without platelets and kallikrens..
T Platelets and kallikrens are not part of full or parthial thromboplastin reagents. The partial thromboplastin reagent is only a phospholipid platelet substitute without any of the other components of thromboplastin; phospholipid is the best answer! . Activated partial thromboplastin time (APTT) is also an "incomplete" thromboplastin reagent plus calcium is added to patient plasma, and the time necessary to form a fibrin clot is measured. When you see APTT think intrinsic pathway, mimicing platelet function and heparin effects.
T/F: It would NOT be wrong to state that the intrinsic coagulation system is, in part, platelet contact driven.
T Platelets play a really BIG role in the intrinsic coagulation system. Activated platelets secrete polyphosphates chains that serve to directly activate factor XII and ultimately initiate fibrin formation by the intrinsic pathway. Hemostasis stops bleeding at the site of vascular injury and maintains the integrity of blood vessels through the formation of clots. This regulated process consists of complex interactions between endothelial cells, platelets, von Willebrand factor and coagulation factors. Hemostasis is initiated by a damaged vessel wall, followed with a rapid adhesion, activation and aggregation of platelets to the exposed subendothelial matrix (collagens). At the same time, coagulation factors aggregate on the procoagulant surface of activated platelets to consolidate the platelet plug by forming a mesh of cross-linked fibrin. Platelets and coagulation mutually influence each other and there are strong indications that, thanks to the interplay between platelets and coagulation, Hemostasis is far more effective than the two processes separately. Clinically this is relevant because impaired interaction between platelets and coagulation may result in bleeding complications, while excessive platelet-coagulation interaction induces a high thrombotic risk.
T/F: Platelet or INTRINSIC system factor defects that occur before the prothrombin-to-thrombin stage (common pathway) do not affect the PT test because a complete thromboplastin reagent (TF & PL) activates the extrinsic coagulation system and therefore bypasses the intrinsic system that does not require TF.
T TRUE Platelet or intrinsic system factor defects before the prothrombin to thrombin stage do not affect the PT because a complete thromboplastin reagent activates the extrinsic coagulation system and bypasses the intrinsic system. Thromboplastin reagent contains phospholipids as well as tissue factor, both of which are needed in the activation of the extrinsic pathway, whereas partial thromboplastin does not contain tissue factor. Tissue factor is not needed to activate the intrinsic pathway. Tissue factor, also called platelet tissue factor, factor III, or CD142, is a protein encoded by the F3 gene, present in subendothelial tissue and leukocytes. Its role in the clotting process is the initiation of thrombin formation from the zymogen prothrombin.
The clotting activation sequence may begin with substances typically present within the blood and tissues interact. T/F: When blood clotting is initiated when contact is made between blood and exposed negatively charged surfaces, the cascade called the intrinsic system coagulation pathway is initated.
T TRUE, though the intrinsic cascade (which correlates best with inflammatory physiological circumstances as compared to the extrinsic cascade), is initiated when contact is made between blood and exposed negatively charged surfaces. The intrinsic system can be assessed by adding phospholipids and calcium (partial thromboplastin (PTT)) to a blood sample and marking the time until coagulation of the blood occurs. Two laboratory tests are used commonly to evaluate coagulation disorders: Prothrombin Time (PT) which measures the integrity of the extrinsic system as well as factors common to both systems and Partial Thromboplastin Time (PTT), which measures the integrity of the intrinsic system and the common components. If the PT test is normal and the PPT is abnormal, then the problem is likely at the level of the intrinsic pathway. If the PTT test is normal and the PT is abnormal, then the problem is likely at the level of the extrinsic pathway. If BOTH the PTT and PT tests are abnormal, then the problem is likely at the level of the common pathway.
You find yourself working in ER of Mt. Saint Elitist and a patient's wound (Princess Idunknowa) just seems to keeps-on bleeding. She is of Eastern Eurpean and Bristish descent and daughter of the Duke of Arendelle and consanguinity is a possibility. She is not on aspirin or blood thinners (xibans, heparin or coumadin) and no history of or findings consistent with liver diease. So you wisely think of possible heriditary coagulopathies after find an abnormal aPTT value and normal platelet count. T/F: In von Willebrand's disease, the entire factor VIII/vWfcomplex is decreased.
T TRUE. In von Willebrand's disease the vWf antigen is decreased, and platelets display decreased adhesiveness (manifested by decreased retention in glass bead columns) and also decreased platelet agglutination under the stimulus of the antibiotic ristocetin. In addition, the vWf is thought to stabilize factor VIII levels, so that a decrease in vWf leads to a decrease in factor VIII levels, both in the quantity of factor VIII as well as its activity. Thus, the entire factor VWf is thought to stabilize factor VIII levels, so that a decrease in vWf leads to a decrease in factor VIII levels, both in the quantity of factor VIII as well as its activity. In von Willebrand's disease the vWf antigen is decreased, and platelets display decreased adhesiveness and also decreased platelet agglutination under the stimulus of the antibiotic ristocetin. Thus, the entire factor VIII/vWfcomplex is decreased. Von Willebrand factor promotes the platelet adhesion phase of hemostasis by binding with a receptor on the platelet surface membrane (glycoprotein Ib/IX), thus connecting the platelets to the vessel wall. VWF is also required to maintain normal plasma factor VIII levels. In the perioperative period, patients are usually treated with VWF and factor FVIII (FVIII)‐containing concentrates to provide an immediate haemostatic response to prevent excessive bleeding during both elective and emergency surgery. With the introduction of recombinant VWF (rVWF), there is a need for guidance on the use of the various VWF products in the perioperative period for all types of patients and surgeries.
T/F: The APTT is also affected by warfarin (Coumadin).
T TRUE. Warfarin affects the production of factors dependent up vitamin K and that includes factors II, IX and X for which the aPTT is sensitive (intrinsic and common clotting pathways). The PT is best for coumadin because Factor VII turnover is rapid and unique to the Extrinsic pathway, so the PT serves as the "canary in the coal mine" for monitoing all viotamin K dependent factors; all the while knowing that to a lesser extent the APTT is also affected by warfarin (coumadin). When both the PT and aPTT are prolonged, a defect could include the common clotting pathway, and a deficiency of factors I, II, V, or X should then be considered, but context matter. A normal PT with an abnormal aPTT means that the defect lies within the intrinsic pathway, and a deficiency of factor VIII, IX, X, or XIII is suggested. When the PT is in the warfarin therapeutic range while on heparin and the APTT is also prolonged, the aPTT may be above therapeutic range for heparin.
T/F: The primary goal of the extrinsic clotting system is to use the ACTION extrinsic factor complex (factor VIIa/TF) to activate factor X indirectly and directly.
T TRUE: Restated, X marks the spot! True, because the extrinsic system is only a stop-gap measure. The critical, final common or unifying clotting factor that the intrinsic and extrinsic cascades utilize is factor X. CONVERSELY, The goal of the intrinsic clotting system is to replace the extrinsic tissue thromboplastin complex factor VII to activate factor X. Factor X IS critical to both the intrinsic and extrinsic clotting systems and a junction point between the intrinsic, extrisnic and common coagulation pathways.
Hemolytic uremic syndrome (HUS) is a condition that affects the blood and blood vessels and clinically characterized with the triad of microangiopathy hemolytic anemia, thrombocytopenia and acute renal damage. Lethargy, irritability and seizure are common findings. The etiology is often post-infectious. The mortality rate is 3-5% in the acute phase. HUS results in the destruction of blood platelets (cells involved in clotting), a low red blood cell count (anemia) and kidney failure due to damage to the very small blood vessels of the kidneys [(thrombotic microangiopathy (TMA)]. The signs and symptoms of this form of HUS may include bloody diarrhea, abdominal pain, cramping, bloatingand vomiting. Symptomatic uremia (uremic encephalopathy, pericarditis, hemorrhage), azotemia (BUN≥80-100 mg/dL), severe fluid loading unresponsive to diuretics (hypertension, heart failure), electrolyte and acid-base disorders unresponsive to drug medical therapy (K+>6.5 mEq/L, Na<120 mEq/L, pH<7.1) and inability to provide treatment and nutrition because of fluid restriction are the indications of dialysis treatment. Anemia frequently develops as a result of mechanical damage to erythrocytes while passing through the renal capillaries obstructed with microthrombi and fragmentation of erythrocytes. The hemoglobin is often <8 g/dLm, the platelet count is below 150000/mm3 (commonly <40 000/mm3) though bleeding is rarely observed, and the reticulocyte count is increased. T/F: The hemolytic uremic syndrome is a microangiopathic hemolytic anemia with thrombocytopenia and renal failure, that usually occurs following a severe infection and the prothrombin time (International Normalized Ratio) and activated partial thromboplastin time results typically are typically normal in hemolytic-uremic syndrome (HUS), although some series report patients with slight elevations on both tests and these tests help to distnguish it from DIC.
T TRUE: The hemolytic uremic syndrome is a microangiopathic hemolytic anemia with thrombocytopenia and renal failure. It often follows severe infection. It is most often seen in younger children, usually before age 5 years, and most often following onset of gastroenteritis. Today, possibly the most common cause is verotoxin¬producing Escherichia call 0157:H7. Prothrombin time (International Normalized Ratio) and activated partial thromboplastin time results typically are normal in both TTP and in hemolytic-uremic syndrome (HUS), although some series report patients with slight elevations on both tests. The differential diagnosis for HUS should be made with the other conditions causing to TMA. Disseminated intravascular coagulation (DIC): prothrombin and partial thromboplastin times (PT and a PTT) are prolonged. Fibrinogen, Factor V and Factor VIII levels are decreased. DIC is differentiated from HUS with these findings. Thrombotic thrombocytopenic purpura: the diagnosis is made with the finding of a ADAMTS 13 activity of <10%. Complement-related HUS: It may occur at any age starting from the neonatal period. It is differentiated from STEC-HUS with its recurrent character and familial history. Serologic and genetic tests related with the alternative complement system [serum complement 3 (C3) level, complement factor H and I level, demonstration of anti-factor H antibody, genetic mutations of the proteins related with the complement system] are valuable in the diagnosis. Decreased seum C3 level is an important finding, but a normal level does not exclude complement-related HUS. A slight decrease in C3 may be observed in some cases of STEC-HUS. Penumococcus-related HUS: Patients affected have a history of severe pneumococcus infection. The diagnosis is made definitely with growth of Streptococcus Pneumoniae in blood, pleural fluid or cerebrospinal fluid cultures or demonstration of T antigen in the erythrocytes. H1N1 and Influenza-related HUS: the diagnosis is made by demonstration of the agent with culture and polymerase chain reaction (PCR). Hereditary cobalamin metabolism disorder: although it may occur at any age, it should be especially considered in the differential diagnosis in cases of HUS which occur in the neonatal period and early infancy. The blood homocysteine level is increased and methionine level is decreased. Blood and/or urinary metyl-malonic acid levels are increased (organic acid chromatography). The definite diagnosis is made by demonstration of MMACHC mutation. Secondary HUS: History of an accompanying condition, drug usage or presence of non-STEC infection suggests the diagnosis of secondary HUS.
T/F: The intrinsic system can also be triggered by contact between inactive Factor XII in the blood and collagenous glycoproteins beneath endothelial lining (vascular injury such as a rupture atherosclerotic plaque).
T TRUE: We are digging deeper into the intricacies of the intrinsic pathway. The intrinsic system can also be triggered by a vascular injury to allow platelets adhere to specific glycoprotein surface receptors on exposed collagen and in the presence of a factor called von Willebrand's Factor (vWF), a phospholipid called platelet factor 3 and a proenzyme in serum called factor XII becomes activated due to platelet activation. Active factor XII, cofactor kiningens (a biologic sponge) and kallikrenes (serine proteases), which activate factor XII, which activates factor IX which activates factor X which converts prothrombin to thrombin.
T/F: The PTT test or APTT test is most sensitive to coagulation factor deficiencies within the intrinsic system before the prothrombin to thrombin stage.
T TRUE< The APTT is very sensitive to coagulation factor deficiencies within the intrinsic system before the prothrombin to thrombin stage because the intrinsic side factors do NOT require TF.
T/F: Tissue Factor / Factor III (TF/phospholipids or tissue thromboplastin) initiates the extrinsic system pathway in conjunction with Factor VII.
T The extrinsic clotting system is thromboplastin driven. TRUE: The extrinsic pathway is initiated upon vascular injury, which leads to activation of factor VII with TF (also rarely id'd as Factor III), a subendothelial cell-surface glycoprotein that binds phospholipids. TF is an integral transmembrane protein expressed by various cells, is a component of the factor VIIa-TF complex enzyme, and is essential for normal hemostasis. Tissue factor is the only known cellular receptor for FVII and FVIIa. Under normal circumstances cells in contact with blood do not express physiologically active TF. When mechanical or chemical damage of the vascular wall occurs, subendothelial TF is expressed/exposed to blood flow and binds plasma factor VIIa, which circulates as an enzyme and escapes the inhibition by serine proteases inhibitors because of its poor enzymatic qualities. The factor VIIa-TF/phospholipids complex initiates blood coagulation by activating the zymogens factor X (Common Pathway) and upstream using factor IX. Tissue factor is a transmembrane glycoprotein with a 219-amino acid extracellular domain, a 23-residue transmembrane region, and a 21-residue intracellular domain. The lungs and central nervous system are known to contain high levels of TF activity. In the lungs, the bronchial mucosa and alveolar epithelial cells constitutively express high levels of TF. Tissue factor is constitutively expressed on the surface of many extravascular cells, such as fibroblasts and pericytes within the blood vessel wall, but not in cells within vasculature that contact blood, such as monocytes and endothelial cells. However, under certain pathological conditions, such as sepsis, monocytes/macrophages express TF.
T/F: The major clotting factors utilized by the intrinsic clotting system include factors XI, VIII, IX and Platelet Factor-3.
T True and factor XII too. The major clotting factors utilized by the intrinsic clotting system include factor VIII, IX and PF-3. Factor VII, from the extrinsic side and cross domains and influence the intrinsic pathway too at the level of Factor IX. Life (and clotting) is tough!
T/F: When tissue thromboplastin is released from endothelial cell, it directly converts prothrombin to thrombin.
T - this makes no sense Thromboplastin or thrombokinase is a mixture of both phospholipids and tissue factor found in plasma that INDIRECTLY aids blood coagulation through catalyzing the conversion of prothrombin to thrombin. The process is NOT that simple (or direct)! When tissue thromboplastin is released from an endothelial cell, it binds with free calcium and factor VII to form thromboplastin complex. In conjunction with a phopholipid and calcium, the thromboplastin complex activates factor X that converts prothrombin to thrombin. Thrombin converts fibrinogen to fibrin and fibrin, and with factor XIII forms an insoluble strand matrix with platelet plugs, AKA a clot. This summarized how the extrinsic pathway activates the common pathway.
MC: Platelets have a major role in which of the following? Clot retraction Free calcium availability Bound calcium avaialbility Factor XII activation Fibrinogen conversion
clot retraction Platelets have a major role in clot retraction. The clot shrinks and pushes out serum that was trapped within as the blood clotted. The shrunken clot is much firmer - than it was originally.
MC: The most common platelet abnormality(ies) is thrombocytopenia and that could likely be due to all of the following, EXCEPT: Bone marrow deficiency Hepatomegaly without intrahepatic malignancy Hypersplenism Post-transfusion thrombocytopenia Drug-induced thrombocytopenia Idiopathic thrombocytopenia
hepatomegaly w/o intrahepatic malignancy Big livers are not likely to cause low platelets unless there is a cancer or enlarged spleen too. Consider: Immunologic thrombocytopeniaDrug-induced thrombocytopeniaIdiopathic thrombocytopeniaPosttransfusion thrombocytopenia Hypersplenism Bone marrow deficiency
The bleeding time test is most helpful as an indicator of which of the following? Platelets number or count Factor X activity Platelets function Thromboplastin activity None of the above.
platelet fn
All of the following describe the clinical utility that a prothrombin time (PT) test could be typically used, EXCEPT: to monitor anticoagulant therapy with Coumadin (warfarin). as part of a general screen for coagulation system disorders to monitor anticoagulant therapy with heparin as a liver function test to assess defects in the extrinsic coagulation system
to monitor anticoagulant therapy with heparin The prothrombin time (PT) is used in three ways: (1) to monitor anticoagulant therapy with Coumadin, (2) as part of a general screen for coagulation system disorders, (3) as a liver function test. PTT is commonly used in clinical practice to monitor unfractionated heparin infusion to target therapeutic range of anticoagulation and as part of coagulation panels to help elucidate causes of bleeding or clotting disorders. PTT tests the function of all clotting factors except VII (tissue factor) and XIII (fibrin stabilizing factor).
Of the major causes of bleeding in surgery (during the operation or post-operative), which of the following could be important considerations, except which of the following? Physical defect in hemostasis—improper vessel ligation, overlooking a small transected vessel or other failure to achieve adequate hemostasis, or postoperative tissue devitalization and release of a vessel ligature. The PA did not recognize a preoperative bleeding problem, such as the presence of a coagulation defect and recognized before surgery. This may be congenital (e.g., hemophilias), secondary to a disease that the patient has (e.g., cirrhosis), or due to medications. Transfusion reactions or complications from massive transfusion. Use of fresh frozen plasma rather than whole blood when hematocrit is sufficient Intraoperative DIC.
use of FFP The is a great review question. All of responses could be serious issues, except FFP. FFP is often used to provide concentrated doses of clotting factors to address some of the other issues. The others are issues are important considerations.
Which of the following is most likely to place a newborn infant at risk of intraventricular (brain) hemorrhage? Gestational age greater than 42 weeks. Anemia Fibrin degradation products Thrombocytopenia Vitamin K deficiency
vitamin K deficiency Neonatal hemorrhage due to vitamin K deficiency may occur during the first 24 hours of life, from 1-7 days after birth. Vitamin K is necessary for synthesis of factors II, VII, IX, and X. The greatest effect seems to be on prothrombin and factor VII.