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Coagulation Tests (view source)

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Also known as: '''''coagulation profile — clotting profile — clotting tests — tests of haemostasis
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{{OpenPagesTop}}Also known as: '''''coagulation profile — clotting profile — clotting tests — tests of haemostasis
 
[[Image:Coagulation Cascade.jpg|thumb|right|350px|Coagulation cascade. Source: Wikimedia Commons; Author: Joe D (2007)]]
 
[[Image:Coagulation Cascade.jpg|thumb|right|350px|Coagulation cascade. Source: Wikimedia Commons; Author: Joe D (2007)]]
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==Introduction==
   
[[Image:LH_Platelet_Histology.jpg|thumb|right|<center><p>'''Platelets'''</p><sup>©RVC 2008</sup></center>]]
 
[[Image:LH_Platelet_Histology.jpg|thumb|right|<center><p>'''Platelets'''</p><sup>©RVC 2008</sup></center>]]
 
Normally, [[Normal Mechanisms of Haemostatic Control|haemostastis]] is maintained by three key events:   
 
Normally, [[Normal Mechanisms of Haemostatic Control|haemostastis]] is maintained by three key events:   
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*'''Fibrinolysis''' is the final stage of restoring haemostasis - it prevents uncontrolled, widespread clot formation and breaks down the fibrin within blood clots.  The two most important anticoagulants involved in fibrinolysis are antithrombin III (ATIII) and Protein C. The end products of fibinolysis are fibrin degratation products (FDPs).
 
*'''Fibrinolysis''' is the final stage of restoring haemostasis - it prevents uncontrolled, widespread clot formation and breaks down the fibrin within blood clots.  The two most important anticoagulants involved in fibrinolysis are antithrombin III (ATIII) and Protein C. The end products of fibinolysis are fibrin degratation products (FDPs).
 
    
 
    
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Abnormalities can develop in any of the components of haemostasis. Disorders of primary haemostasis include [[Haemorrhagic_Disease_Pathophysiology#Vascular_Fragility|vessel defects]] (i.e. vasculitis), [[Platelet_Abnormalities#Thrombocytopaenia|thrombocytopenia]] (due to decreased production or increased destruction) and [[Platelet Abnormalities|abnormalities in platelet function]] (e.g. congenital defects). These lead to the occurence of multiple minor bleeds and prolonged bleeding times; petechial or ecchymotic [[Haemorrhage|haemorrhages]] may be seen for example, on the skin and mucous membranes, or ocular bleeds may arise. Generally, intact secondary haemostasis prevents major haemorrhage in disorders of primary haemostasis. When secondary haemostasis is abnormal, [[Haemorrhage|larger bleeds]] are frequently seen. Haemothorax, haemoperitoneum, or haemoarthrosis may occur, in addition to subcutaneous and intramuscular haemorrhages. Petechiae and ecchymoses are not usually apparent, as intact primary haemostasis prevents minor capillary bleeding. Examples of secondary haemostatic disorders include [[:Category:Coagulation Defects|clotting factor deficiencies]] (e.g. hepatic failure, vitamin K deficiency, hereditary disorders) and circulation of substances inhibitory to coagulation (FDPs in [[Disseminated Intravascular Coagulation|disseminated intravascular coagulation]], [[Systemic Lupus Erythematosus|lupus]] anticoagulant). If fibrinolysis is defective, thrombus formation and infarctions may result. Thrombus formation may be promoted by vascular damage, circulatory stasis or changes in anticoagulants or procoagulants. For example, ATIII may be decreased. This can occur by loss due to glomerular disease or accelerated consumption in disseminated intravascular coagulation or sepsis.
 
Abnormalities can develop in any of the components of haemostasis. Disorders of primary haemostasis include [[Haemorrhagic_Disease_Pathophysiology#Vascular_Fragility|vessel defects]] (i.e. vasculitis), [[Platelet_Abnormalities#Thrombocytopaenia|thrombocytopenia]] (due to decreased production or increased destruction) and [[Platelet Abnormalities|abnormalities in platelet function]] (e.g. congenital defects). These lead to the occurence of multiple minor bleeds and prolonged bleeding times; petechial or ecchymotic [[Haemorrhage|haemorrhages]] may be seen for example, on the skin and mucous membranes, or ocular bleeds may arise. Generally, intact secondary haemostasis prevents major haemorrhage in disorders of primary haemostasis. When secondary haemostasis is abnormal, [[Haemorrhage|larger bleeds]] are frequently seen. Haemothorax, haemoperitoneum, or haemoarthrosis may occur, in addition to subcutaneous and intramuscular haemorrhages. Petechiae and ecchymoses are not usually apparent, as intact primary haemostasis prevents minor capillary bleeding. Examples of secondary haemostatic disorders include [[:Category:Coagulation Defects|clotting factor deficiencies]] (e.g. hepatic failure, vitamin K deficiency, hereditary disorders) and circulation of substances inhibitory to coagulation (FDPs in [[Disseminated Intravascular Coagulation|disseminated intravascular coagulation]], [[Systemic Lupus Erythematosus|lupus]] anticoagulant). If fibrinolysis is defective, thrombus formation and infarctions may result. Thrombus formation may be promoted by vascular damage, circulatory stasis or changes in anticoagulants or procoagulants. For example, ATIII may be decreased. This can occur by loss due to glomerular disease or accelerated consumption in disseminated intravascular coagulation or sepsis.
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The reference range given for platelet number is usually around 200-500x10<sup>9</sup> per litre, although this varies depending on the laboratory equipment used. Clinical signs due to thrombocytopenia are not commonly encountered until the platelet count drops below 50x10<sup>9</sup>/l, when increased bleeding times may be seen. Haemorrhage during surgery becomes a concern with counts lower than 20x10<sup>9</sup>/l, and spontaneous bleeding arises when platelets are fewer than 5x10<sup>9</sup>/l<sup>2</sup>. These cut-offs are lowered if platelet function is concurrently affected by other factors such as the use of non-steroidal anti-inflammatory drugs<sup>1</sup>.
 
The reference range given for platelet number is usually around 200-500x10<sup>9</sup> per litre, although this varies depending on the laboratory equipment used. Clinical signs due to thrombocytopenia are not commonly encountered until the platelet count drops below 50x10<sup>9</sup>/l, when increased bleeding times may be seen. Haemorrhage during surgery becomes a concern with counts lower than 20x10<sup>9</sup>/l, and spontaneous bleeding arises when platelets are fewer than 5x10<sup>9</sup>/l<sup>2</sup>. These cut-offs are lowered if platelet function is concurrently affected by other factors such as the use of non-steroidal anti-inflammatory drugs<sup>1</sup>.
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===Buccal Mucosal Bleeding Time===
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The buccal mucosal bleeding time is a simple test that gives a rapid assessment of platelet function, providing platelet numbers are normal. If platelet numbers are below 50x10<sup>9</sup>/l, this test should not be performed since the results will be affected by thrombocytopenia, making them unreliable. The small wound inflicted may also not stop bleeding easily.
 
The buccal mucosal bleeding time is a simple test that gives a rapid assessment of platelet function, providing platelet numbers are normal. If platelet numbers are below 50x10<sup>9</sup>/l, this test should not be performed since the results will be affected by thrombocytopenia, making them unreliable. The small wound inflicted may also not stop bleeding easily.
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Acquired platelet function abnormalities can be drug induced, for example by [[NSAIDs|non-steroidal anti-inflammatory drugs]]<sup>2,3</sup>, or can be secondary to [[Uraemia|uraemia]]. Hereditary defects in platelet function also exist, and [[Coagulation_Factor_Deficiency#Von_Willebrand.27s_Disease|von Willebrand's disease]] is the most common of these.
 
Acquired platelet function abnormalities can be drug induced, for example by [[NSAIDs|non-steroidal anti-inflammatory drugs]]<sup>2,3</sup>, or can be secondary to [[Uraemia|uraemia]]. Hereditary defects in platelet function also exist, and [[Coagulation_Factor_Deficiency#Von_Willebrand.27s_Disease|von Willebrand's disease]] is the most common of these.
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The BMBT is influenced by all the aspects of this phase, including vasoconstriction, platelet adherence and plately aggregation. Although this makes BMBT an effective screening test for the vascular/platelet (primary) phase of haemostasis, it also means it is not purely a test for thrombocytopathia, as it is often considered: BMBT depends on an intact vasospastic response and adequate platelet numbers as well as platelet function<sup>3</sup>. BMBT is a fairly crude test, and has been found to be
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The BMBT is influenced by all the aspects of this phase, including vasoconstriction, platelet adherence and plately aggregation. Although this makes BMBT an effective screening test for the vascular/platelet (primary) phase of haemostasis, it also means it is not purely a test for thrombocytopathia, as it is often considered: BMBT depends on an intact vasospastic response and adequate platelet numbers as well as platelet function<sup>3</sup>. BMBT is a fairly crude test, and has been found to be normal in some patients with a known platelet function disorder and vice versa<sup>3</sup>. The results of this test therefore should be interpreted with some caution.
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normal in some patients with a known platelet function disorder and vice versa<sup>3</sup>. The results of this test therefore should be interpreted with some caution.
      
==Tests Evaluating Secondary Haemostasis==
 
==Tests Evaluating Secondary Haemostasis==
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===Activated Clotting Time===
 
===Activated Clotting Time===
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The activated clotting time (ACT) allows rapid evaluation of secondary haemostasis. The ACT is the time taken for 2ml of fresh whole blood to clot in a tube with a contact activator (diatomaceous earth<sup>2</sup>), but an automated analyser can perform a test with a similar principle. The reaction must occur at body temperature to give a reliable indication of haemostatic ability: this can be achieved by the use of a warm water bath, or in an emergency by holding the tubes under an arm. The normal ACT is 90-120 seconds and <75 seconds in dogs and cats respectively<sup>2</sup>.
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The activated clotting time (ACT) allows rapid evaluation of secondary haemostasis. The ACT is the time taken for 2ml of fresh whole blood to clot in a tube with a contact activator (diatomaceous earth<sup>2</sup>), but an automated analyser can perform a test with a similar principle. The reaction must occur at body temperature to give a reliable indication of haemostatic ability: this can be achieved by the use of a warm water bath, or in an emergency by holding the tubes under an arm.  
    
The contact activator used in the ACT test triggers the intrinsic pathway, and so ACT allows assessment of the intrinsic and common pathways. ACT will therefore be prolonged when factors I, II, V, VIII, IX, X, XI or XII are deficient or abnormal, such as in DIC, liver disease, vitamin K antagonist toxicosis or haemophilia A or B<sup>2</sup>. Thrombocytopenia may also increase ACT.
 
The contact activator used in the ACT test triggers the intrinsic pathway, and so ACT allows assessment of the intrinsic and common pathways. ACT will therefore be prolonged when factors I, II, V, VIII, IX, X, XI or XII are deficient or abnormal, such as in DIC, liver disease, vitamin K antagonist toxicosis or haemophilia A or B<sup>2</sup>. Thrombocytopenia may also increase ACT.
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The APTT measures the time necessary to generate fibrin from activation of the intrinsic pathway<sup>3</sup>. It therefore assesses functionality of the components of the intrinsic and common pathways of coagulation. The test is performed on citrated plasma, and so blood should be collected into a sodium citrate tube if the APTT test is to be undertaken. Once a sample is obtained, factor XII is activated by an external agent that will not also activate factor VII, such as kaolin<sup>1, 3</sup>. Since the intrinsic arm of the cascade requires platelet factors to function, the test also provides a phospholipid emuslion in place of these factors. Calcium is added, the preparation is incubated, and the time for clumping of kaolin is measured. Classically, partial thromboplastin time was measured after activation by contact with a glass tube, but use of an external activating agent in the newer, "activated" partial thromboplastin time method makes results more reliable<sup>3</sup>.
 
The APTT measures the time necessary to generate fibrin from activation of the intrinsic pathway<sup>3</sup>. It therefore assesses functionality of the components of the intrinsic and common pathways of coagulation. The test is performed on citrated plasma, and so blood should be collected into a sodium citrate tube if the APTT test is to be undertaken. Once a sample is obtained, factor XII is activated by an external agent that will not also activate factor VII, such as kaolin<sup>1, 3</sup>. Since the intrinsic arm of the cascade requires platelet factors to function, the test also provides a phospholipid emuslion in place of these factors. Calcium is added, the preparation is incubated, and the time for clumping of kaolin is measured. Classically, partial thromboplastin time was measured after activation by contact with a glass tube, but use of an external activating agent in the newer, "activated" partial thromboplastin time method makes results more reliable<sup>3</sup>.
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APPT evaluates the same pathways as ACT, and so will be prolonged by abnormalities or deficiencies in factors XII, XI, IX, VIII, X, V, II or I. However, APTT is not affected by thrombocytopenia and is also considered to be a more sensitive test than ACT: APTT becomes prolonged when 70% of a factor is depleted, compared to 90% depletion required to prolong the ACT. APTT can also be prolonged in the presence of a circulating inhibitor to any of the intrinsic pathway factors. To differentiate factor deficiency from inhibition, a "mixing study" can be performed where the test is repeated on a 1:1 mix of patient and normal plasma. Complete correction indicates a deficiency, and partial or no resolution shows that an inhibitor is present. This difference stems from the above mentioned fact that the APTT will be normal in the presence of 50% normal activity<sup>3</sup>.
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APPT evaluates the same pathways as ACT, and so will be prolonged by abnormalities or deficiencies in factors XII, XI, IX, VIII, X, V, II or I. However, APTT is not affected  
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Conditions in which APTT is prolonged include inherited disorders, such as haemophilia A and B and other congential absences of intrinsic and common factors. Acquired factor deficiency also occurs, for example with vitamin K deficiency, liver dysfunction, prolonged bleeding or disseminated intravascular coagulation. The most common inhibitors found to prolong APTT are the antithrombins, which inhibit the activity of thrombin on the conversion of fibrinogen to fibrin. Examples include heparin and fibrin degradation products.
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Occasionally, a shortened APTT is seen. This may reflect increased levels of activated factors in a hypercoagulable state, for example in the early stages of DIC<sup>3</sup>.
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===Prothrombin Time===
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Prothrombin time (PT) gives an assessment of the extrinsic and common pathways by measuring the time necessary to generate fibrin after activation of factor VII<sup>3</sup>. It is performed manually or by an automated analyser<sup>2</sup> using citrated plasma<sup>1, 3</sup>. Blood should therefore be collected into a sodium citrate tube if prothrombin time is to be performed. For the manual test, as a quality control measure it is normal to undertake the test in a sample from an unaffected patient to compare the time taken to clot between the two samples - this will account for variables such as variations in the technique of performing the manual test. The test procedure involves adding rabbit brain thromoplastin to the patient's plasma once it has been warmed to 37<sup>0</sup>C and recording the time taken for the sample to clot<sup>1</sup>.
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A prolonged PT may reflect a factor deficiency or the presence of a circulating inhibitor of coagulation. Repeating the test using a mix of test plasma and "normal" plasma can help differentiate these possibilities: PT returns to normal limits when normal plasma is added to factor-deficient plasma, but no change is seen when this is added to plasma containing inibitors<sup>3</sup>. PT is more sensitive than APTT for factor deficiencies.
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PT is affected by abnormalities or deficiencies in coagulation factors I, II, VII or X, for example in DIC, liver disease, endotoxaemia or poisoning with vitamin K antagonists. Inherited defects are possible. PT is also prolonged by the presence of circulating anticoagulants.  Inhibitors are often directed at factor X or thrombin and include fibrin degradation products and heparin<sup>3</sup>. As factor VII has the shortest half-life of all the coagulation factors, if a patient is suffering a coagulation factor deficiency a prolonged PT is seen before a prolonged PTT as this factor is depleted most rapidly.
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===Tests for Individual Clotting Factors===
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Some specialised laboratories offer tests for specific clotting factors. A sodium citrate sample is required.
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===Proteins Induced by Vitamin K Antagonism Test===
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Factors II, VII, IX and X are produced in the liver as non-functional precursors which become activated by carboxylation of their glutamic acid residues in the presence of vitamin K. The inactive precursors are absent from the circulation of normal animals, as they are stored in the microsomal system of the liver. However, the absence of vitamin K results in an increase in these precursors, which spill into the circulation and become known as Proteins Induced by Vitamin K Antagonism (PIVKA). Concurrently, the levels of active factors II, VII, IX and X are depleted.
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The PIVKA test is modified version of PT that is designed to be more sensitive than PT for abnormalities in the vitamin-K dependent clotting factors. Diluted plasma is used to give longer clotting times, and a test-specific reagent is added. The PIVKA test is reported to be sensitive to both increases in PIVKAs and decreases in the functional coagulation factors II, VII, IX and X, although there is some debate as to whether PIVKAs actually inhibit the reaction. Although intended to be more sensitive than the PT for factors of interest, studies in dogs have shown that a PIVKA test offers little diagnostic advantage<sup>4</sup>. Additionally, only certain laboratories offer the test and the turnaround time is longer than PT.
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The PIVKA test is prolonged in vitamin K deficiency. This can result from anticoagulant rodenticide toxicity or cholestasis. Some animals in disseminated intravascular coagulation also have a prolonged PIVKA test.
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==Tests Evaluating Fibrinolysis==
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===Fibrin Degradation Products===
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A latex agglutination test is available for fibrin degradation products (FDP). To perform the test, anti-FDP antibodies attached to latex particles are added to serial dilutions of test serum. If agglutination is seen at a particular dilution, the test is positive. The most dilute sample that agglutinates gives the overall result of the test. Normal values are between 1/4 and 1/16.
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Although the test is simple to perform, interpretation may be challenging. This is because other small fragments involved in the homeostasis of fibrinogen and fibrin are measured by the test in addition to ''bona fide'' fibrin degradation products. In general, an increase in FDP corresponds to increased fibrinolysis. This can be due to a local problem of fibrin generation such as thrombosis, trauma or chronic bleeding, or be related to a systemic process, usually DIC<sup>3</sup>.
      
{{Learning
 
{{Learning
 
|literature search = [http://www.cabdirect.org/search.html?rowId=1&options1=AND&q1=%22Coagulation%22&occuring1=title&rowId=2&options2=AND&q2=tes*&occuring2=title&rowId=3&options3=AND&q3=&occuring3=freetext&x=65&y=9&publishedstart=yyyy&publishedend=yyyy&calendarInput=yyyy-mm-dd&la=any&it=any&show=all Coagulation Tests publications]
 
|literature search = [http://www.cabdirect.org/search.html?rowId=1&options1=AND&q1=%22Coagulation%22&occuring1=title&rowId=2&options2=AND&q2=tes*&occuring2=title&rowId=3&options3=AND&q3=&occuring3=freetext&x=65&y=9&publishedstart=yyyy&publishedend=yyyy&calendarInput=yyyy-mm-dd&la=any&it=any&show=all Coagulation Tests publications]
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|flashcards = [[Equine Internal Medicine Q&A 03]]
 
}}
 
}}
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#[http://ahdc.vet.cornell.edu/clinpath/modules/coags/pivka.htm Cornell University Clinical Pathology Modules: Tests of Haemostasis - PIVKA]
 
#[http://ahdc.vet.cornell.edu/clinpath/modules/coags/pivka.htm Cornell University Clinical Pathology Modules: Tests of Haemostasis - PIVKA]
 
#Howard, M R and (2008) '''Haematology: an illustrated colour text''', ''Elsevier Health Sciences''.
 
#Howard, M R and (2008) '''Haematology: an illustrated colour text''', ''Elsevier Health Sciences''.
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#Mair, TS & Divers, TJ (1997) '''Self-Assessment Colour Review Equine Internal Medicine''' ''Manson Publishing Ltd''
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{{review}}
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{{OpenPages}}
 
[[Category:Blood Samples and Coagulation Tests]]
 
[[Category:Blood Samples and Coagulation Tests]]
 
[[Category:Clinical Pathology]]
 
[[Category:Clinical Pathology]]
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[[Category: To Do - Siobhan Brade]]
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[[Category:Expert Review]]
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[[Category:To Do - Manson review]]
 
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