Term
| Hemostasis involves a complex interaction between which three major components? |
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Definition
1. vasculature
2. platelets
3. coagulation factors |
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Term
| Primary hemostasis definition. |
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Definition
| -involves formation of unstable platelet plug |
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Term
| Secondary hemostasis definition. |
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Definition
| -involves activation of coagulation factors and ultimately production of thrombin and cross-linked fibrin |
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Term
| Definition of coagulation cascade. |
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Definition
| Involves a series of enzymatic reactions which turn inactive proenzymes (i.e. zymogens) into activated enzymes (i.e. Factor IX to Factor IXa) |
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Term
| What does each complex for an enzymatic reaction in the coagulation cascade involve? |
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Definition
-enzyme (usually an activated coagulation factor)
-substrate (typically and inactivated proenzyme)
-cofactor (Factor Va and VIII a)
-complex is formed on a phospholipid surface (e.g. platelet or endothelial surface) and is glued together by Ca2+ ions |
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Term
| What are the end products of the coagulation cascade? |
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Definition
-formation of thrombin
-conversion of soluble fibrinogen to cross-linked fibrin which forms stable hemostatic plug. |
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Term
| Most of the coagulation factors are produced where? |
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Definition
-Liver
*note: liver failure can result in prolonged clotting times |
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Term
| Activated factors are removed by which organ? |
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Definition
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Term
| Which coagulation factors require vitamin K (i.e. vitamin-K dependent factors)for post-translational gamma-caboxylation? |
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Definition
-Thrombin (Factor II)
-Factor VII, IX, and X
*note: if carboxylation is not possible due to Vit K antagonism or deficiency, these factors are not functional and clinical bleeding can occur |
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Term
| Acitvation of either intrinsic or extrinsic pathways leads to subsequent activation of common pathway and ultimately what product? |
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Definition
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Term
| In vivo, initiation of coagulation is primarily through which which factor? |
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Definition
-tissue factor (Factor III)
*activation of extrinsic pathway and intrinsic pathway serves to amplify this signal producing a "burst" of thrombin needed for coagulation to proceed |
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Term
| Name the factors that comprise the Intrinsic pathway. |
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Definition
| Factors: XII, XI, IX, and VIII |
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Term
| Describe the properties of Factor XII. |
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Definition
| -activates intrinsic pathway when comes in contact with a negatively charged surface (diatomaceous earth or subendothelium) |
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Term
| Factor XII deficiency is the most commonly reported factor deficiency in which species? What will coagulation tests show? Will this species bleed excessively? |
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Definition
-cat (feline)
-deficiency will markedly prolong coagulation tests
-animals with this deficiency DO NOT bleed excessively |
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Term
| Deficiencies in Factors VIII and IX are sex-linked. Deficiencies in these result in what disorder? |
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Definition
| -Hemophilia A (Factor VIII) and Hemophilia B (Factor IX) |
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Term
| Name the components of the Extrinsic Pathway. |
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Definition
-Tissue factor (factor III)
-Factor VII |
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Term
| Characteristics of Tissue Factor (Factor III). |
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Definition
-initiates extrinsic pathway
-exposed/expressed at sites of tissue injury, released from damaged tissue or activated endothelial cells, monocytes, or macrophages (may be activated by endotoxins or cytokines, external injury is not required) |
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Term
| Tissue factor (factor III) complexes with and activates___________ which then is able to activate________________. |
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Definition
-Factor VII
-Factors IX adn X |
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Term
| Activation of _____________ is redundant and may be the reason that patients with Factor XII deficiency do not bleed. |
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Definition
| -Factor IX (intrinsic system) |
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Term
| Factor VII characteristics. |
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Definition
-produced in liver
-Vitamin K dependent
-very short half-life (approx 7 hours) which means that it will be first Factor depleted in cases of rodenticide toxicity (Vit K antagonism) |
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Term
| Name a negative ramification of traumatic venipuncture. |
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Definition
| -release of tissue factor and clotting of samples |
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Term
| Components of Common Pathway. |
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Definition
| -Factors X, V, prothrombin (Factor II), and XIII. |
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Term
| Characteristics of Factor X. |
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Definition
-first factor in the common pathway
-activated by both intrinsic and extrinsic pathways
-converts Prothrombin (Factor II) to thrombin (Factor IIa) |
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Term
| Characteristics of Factor V |
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Definition
| -critical cofactor, activated by thrombin |
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Term
| Characteristics of prothrombin (Factor II) |
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Definition
| -cleaved to thrombin by a complex of Factor Va and Xa |
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Term
| Thrombin activates many substrates including: |
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Definition
| -fibrinogen, V, VIII, XI, XIII, protein C |
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Term
| Thrombin also has many other functions including: |
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Definition
1. Direct induction of platelet aggregation and secretion
2. Activation of endothelial cells to generate adhesion molecules, cytokines, and fibrinolytic mediators
3. Activation of mononuclear inflammatory cells. |
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Term
| Factor XIII characteristics. |
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Definition
-cross-links fibrin and reinforces secondary hemostatic plug
-formation of cross-linked fibrin results in formation of neoantigen termed D-dimer |
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Term
| Which processes help to keep the hemostatic process where it is needed? |
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Definition
-constant blood flow
-removal of activated factors by hepatocytes
-removal of particulate matter by mononuclear cells
-restriction of clotting process to phorpholipid membranes (i.e. platelets) |
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Term
| List the specific anticoagulant proteins that help maintain hemostatic homeostasis: |
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Definition
1. Antithrombin III
2. Proteins C and S
3. Other (Fibrin(ogen)) degradation products |
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Term
| Characteristics of anticoagulant Antithrombin III |
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Definition
-major inhibitor of coagulation, produced by liver
-decreased concentrations due to increased loss (e.g. protein losing nephropathy or enteropathy) or increased consumption (DIC)
-may be an acute phase reactant in rabbits and cats (therefore, increased concentrations with inflamm dz in these species)
-Heparin and Heparin-like compounds markedly enhance antithrombin III activity and allow direct inhibition of thrombin formation
-Antithrombin III also indirectly inhibits thrombin formation through inactivation of several coagulation factors |
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Term
| Characteristics of proteins C and S. |
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Definition
-Protein C is a Vit K dependent proenzyme produced in hepatocytes
-activated by thrombin especially when thrombin bound to thrombomodulin (produced by endothelial cells)
-in presence of Protein S and Factor V (produced by endothelial cells), will inactivate Factors Va and VIIIa |
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Term
| Characteristics of other anticoagulants (i.e. Fibrin(ogen) degradation products) |
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Definition
-have weak anticoagulant activity
-compete with fibrinogen for active site of thrombin inhibiting further fibrin production
-compete with fibrinogen for platelet binding sites inhibiting platelet aggregation
-associate with fibrin monomers disrupting normal polymerization |
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Term
| Fibrinolytic proteins: Plasmin characteristics. |
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Definition
-fibrinolysis proceeds when proportion of plasminogen activators exceeds proportion of plasminogen activator inhibitors
-plasmin may degrade fibrinogen, fibrin monomers/polymers, and cross-linked fibrin to form fibrin(ogen) degradation products and D-dimers |
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Term
| Primary hemostasis: abnormalities in platelets or blood vessels result in: |
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Definition
-Petechiae
-Ecchymoses
-Spontaneous bleeding from mucosal surfaces (epistaxis, gingival bleeding, hematuria, melena, ocular bleeding)
-prolonged bleeding from incision and/or injection sites
*Note: may bleed from one, several, or all of these sites |
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Term
| Secondary hemostais is caused by: |
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Definition
| -congenital or acquired disorders of coagulation factors |
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Term
| Coagulation factor abnormalities in secondary hemostasis result in: |
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Definition
-hematomas
-bleeding into muscles or hemarthrosis
-injection sites may initially clot but bleeding will recur due to failure of primary hemostatic plug to stabilize |
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Term
| List congential causes of secondary hemostatic abnormalities. |
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Definition
1. Hemophilia A (Factor VIII deficiency)-most commonly reported inherited canine coagulopathy; sex-linked
2. Hemophilia B (Factor IX deficiency), Factor VII, Factor X, Factor XI also reported but are rare
3. Factor XII reported in cats, severe prolongation of APTT but no clinical bleeding |
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Term
| List acquired causes of secondary hemostatic abnormalities: |
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Definition
1. Marked impaired liver function
2. Vitamin K antagonism |
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Term
| Describe characteristics of the marked impaired liver function as an acquired cause of secondary hemostatic abnormality. |
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Definition
-decreased production of coagulation factors
-decreased clearance of activated factors by hepatocytes and liver macrophages
-altered production of plasma proteins that regulate coagulation
-altered blood flow in a very vascular organ leads to blood stasis
-altered absorption of Vitamin K (requires bile) or altered intestinal microflora that impair digestion/absorption |
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Term
| Describe characteristics of Vitamin K antagonism/deficiency as an acquired cause of secondary hemostatic abnormalities. |
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Definition
-rodenticide toxicity
-moldy sweet clover (dicoumarol)
-post-hepatic biliary obstruction that prevents vitamin K absorption
-severe enteric disease that prevents vitamin K absorption (e.g. exocrine pancreatic insufficiency, infiltrative bowel disease)
-antibiotic use |
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Term
| List the methods used to evaluate secondary hemostatic abnormalities. |
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Definition
1. PTT-partial thromboplastin time
2. Activated clotting time (cage-side test, less sensitive than PTT)
3. PT-prothrombin time
4. Fibrinogen concentration/Thrombin time
5. Individual factor assays are available if a congenital absence of a factor is suspected |
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Term
| Characteristics of mixed hemostatic defect (i.e. DIC) |
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Definition
1. Complex disorder, ALWAYS secondary to another process (i.e. neoplasia, sepsis, heat stroke)
2. Platelets are often decreased due to consumption or concurrent immune-mediated destruction (often a moderate decrease)
3. Systemic process culminating in both thrombosis and hemorrhage |
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Term
| How is DIC evaluated/diagnosed? |
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Definition
-evaluation involves measurement of both primary and secondary hemostasis
-A diagnosis of DIC is often considered when THREE of FIVE coagulation tests are outside of RIs (use routine coagulation panel) |
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Term
| What does a routine coagulation panel usually involve? |
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Definition
1. measurement of platelet numbers
2. fibrinogen
3. partial thromboplastin time
4. prothrombin time
5. FDPs |
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Term
| Notes on "cell-based model of coagulation" |
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Definition
-increased focus on importance of celular elements involved in coagulation (i.e. monocytes, endothelial cells) and interaction with coagulation factors and pro and anti-thrombotic substances
-traditional laboratory dx tests used to evaluate hemostasis fail to adequately incorporate this element (newer tests i.e. thromboelastography-TEG are designed with this in mind)
-coagulation/hemostasis is a complex and dynamic process that involves input from many influencing factors |
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Term
| List routine coagulation tests: |
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Definition
1. Platelet count
2. Buccal Mucosal Bleeding Time (BMBT)
3. Activated Clotting Time (ACT)
4. Activated Partial Thromboplastic Time (APTT)
5. Prothrombin Time (PT)
6. Thrombin time (TT)
7. Fibrin(ogen) Degradation Products (FDPs)
8. Antithrombin III
9. Ancillary Coagulation Tests (i.e. D-dimer, Specific Factor Assays, Platelet function tests, vWF assay, and TEGs) |
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Term
| Characteristics of Activated Clotting Time. |
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Definition
-assesses the intrinsic and common pathways
-diatomaceous earth and glass tube provide negatively charged surface required for activation of intrinsic pathway and platelets in whole blood provide phospholipid surface
-requires whole blood and grey top tube (contains diatomaceous earth) |
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Term
| Characteristics of Activated Clotting Time (2). |
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Definition
-no special equipment necessary, bed-side test
-ACT is prolonged if activity of a given factor is approx 5% of normal whereas milder deficiencies (10-30% normal) will cause prolongation of APTT (therefore, ACT is less sensitive than APTT)
-ACT may also be prolonged by: marked thrombocytopenia (<10,0000/uL) |
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Term
| What type of collection tube and what ratio of sample: anticoagulant is used for the APTT, PT, TT, FDPs, Antithrombin III, and Ancillary Coagulation Tests? |
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Definition
-blue-top 3.2% trisodium citrate tube
-ratio of blood to trisodium citrate= 9 parts blood: 1 part trisodium phosphate (fill to yellow line) |
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Term
| What are the consequences of traumatic venipuncture? Of collecting too little blood for the previously mentioned tests? |
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Definition
-activation of platelets, hemolysis, and contamination of blood with tissue fluid containing Tissue Factor. All of these may affect test results.
-too little blood will result in falsely prolonged clotting times
Also: avoid sampling through heparinized catheters. Marked anemia may result in undercitrated plasma because there is more plasma with the same amount of citrate (this will shorten coag times). |
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Term
| Characteristics of Activated Partial Thromboplasin Time (APTT) |
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Definition
-screening tests for the intrinsic and common pathways
-citrated plasma is incubated with an activator of Factor XII and a phospholipid, then Ca2+ added-> time required to form fibrin clot is APTT |
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Term
| What can cause a prolonged APTT? |
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Definition
When one or more factors in the intrinsic or common pathways are reduced to <30% normal.
-factor XII deficiency will cause markedly prolonged APTT with no clinical evidence of hemorrhage |
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Term
| Does thrombocytopenia affect PT? Why or why not? |
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Definition
| No, because the test reagents include phospholipid. |
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Term
| Is shortened APTT a reliable test for detecting hypercoagulability? |
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Definition
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Term
| Causes of prolonged APTT. |
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Definition
1. Deficiencies of functional intrinsic or common pathway coagulation factors (acquired and hereditary)
2. Inhibition of intrinsic or common pathway coagulation factors: heparin, FDPs, antibodies to phospholipids, or coagulation factors
3. Inhibition of common pathway coagulation factors: heparin, FDPs, antibodies to phospholipids or coagulation factors |
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Term
| Describe the acquired deficiencies of functional intrinsic or common pathway coagulation factors that cause prolonged APTT. |
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Definition
Decreased production:
1.Hepatic disease (necrosis, cirrhosis, portosystemic shunts)
2.Vitamin K Antagonism or Deficiency(a. Decreased Vitamin K recycling in hepatocytes: anticoagulant rodenticide ingestion, coumadin overdose, moldy sweet clover ingestion; b. decreased vitamin K absorption: biliary obstruction, infiltrative bowel disease, chronic oral antimicrobials, EPI)
3. Increased coagulation factor inactivation/consumption (a. DIC, b. Localized consumptive coagulopathy)
4. Dilution of coagulation factors: acute, massive blood loss treated with crystalloid and colloid fluids, including Oxyglobin solution |
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Term
| Describe the hereditary deficiencies of functional intrinsic or common pathway coagulation factors that cause prolonged APTT. |
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Definition
(usually a single coagulation abnormality)
1. intrinsic pathway: XII, XI, IX, VIII
2. common pathway: X, V, II, I |
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Term
|
Definition
-screening test for extrinsic and common pathways
-citrated plasma is incubated with Ca2+, phospholipids, and excess tissue factor
-usually a single factor must be reduced to below 30% of normal before the PT is prolonged
-due to the short half-life of Factor VII, test is sensitive to vitamin K deficiency or antagonism an may be prolonged prior to other tests
-thrombocytopenia does not affect PT b/c test reagents include phospholipid
-shortened PT is not reliable for detecting hypercoagulability |
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Term
| Characteristic of TT (Thrombin time) |
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Definition
| -assesses the thrombin induced conversion of fibrinogen to an insoluble fibrin clot by adding thrombin to test plasma |
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Term
| Prolonged TT suggests what? |
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Definition
| Hypofibrinogenemia or afibrinogenemia secondary to increased consumption (DIC), congenital deficiciency, or decreased production due to hepatic insufficiency. |
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Term
| What effect do high concentrations of heparin or FDPs have on TT? |
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Definition
| -inhibit reaction and result in spuriously low values |
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Term
| Describe general characteristics of fibrinogen concentrations offered by heat precipitation. |
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Definition
-used by VMC
-not generally sensitive enough to detect decreases and if thrombin time is available, it is preferable for hemostatic testing. |
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Term
| Describe FDPs (fibrin(ogen) degradation products)test |
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Definition
-detected increased fibrinolysis and increased fibrinolysis
-involves latex agglutination of particles coated with antibody against fragments D and E |
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Term
| Increased concentrations of FDPs are seen with: |
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Definition
-localized intravascular coagulation (thrombosis, thromboembolism)
-DIC
-internal hemorrhage in body cavities or tissues
-surgical trauma
-decreased clearance of FDPs due to liver or renal disease
-Note: FDPs are weakly anticoagulant and may prolong PT, PTT, TT, ACT, and impair platelet function |
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Term
| Describe Antithrombin III test |
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Definition
-reported as percent of normal (compared to a species specific plasma pool considered to have 100% activity)
-foals may have lower plasma activities than adults
-patients with concentrations less than 70% of normal are at increased risk for thrombosis |
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Term
| Causes of decreased concentrations are acquired and include: |
|
Definition
-severe liver disease
-protein losing nephropathy/enteropathy, or consumption (DIC)
-increased ATIII activity has been suggested to reflect an acute phase response in rabbits and cats |
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Term
| List: Ancillary Coagulation Tests |
|
Definition
1. D-dimer
2. Specific Factor Assays
3. Platelet function tests
4. vWF assay
5. Thromboelastography (TEG) |
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Term
| Describe D-dimer (the ancillary coagulation test) |
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Definition
-detects increased fibrinolysis and NOT increased fibrinogenolysiss
-assays detect presence of D-dimer, the neoantigen formed when fibrin is cross-linked by Factor XIIIa |
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Term
| Describe specific factor assays (the ancillary coagulation test) |
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Definition
-assayed in specialized veterinary laboratories
-asses the ability of patient plasma to correct the PT or PTT of specific factor-deficient plasmas |
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