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Immunology and Haematology - Veterinary Internal Medicine > Coagulation > Flashcards

Coagulation Flashcards

1
Q

Thromboelastography / Thromboelastometry - What is tested?

A
  • Tests global coagulation
    • From initial clot formation through to fibrinolysis
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2
Q

What are the measured variables with TEG/TEM?

What do each of the variables relate to in vivo?

A
  1. R value (reaction time)
    • Time until first evidence of clot formation
    • This provides an indication of clotting time
  2. K
    • Time from clot initiation (end of R) to clot reaching 20 mm
    • Measures the speed of clot formation and is a reflection of polymerization or clot kinetics
  3. Angle
    • measures the tangent of clot length over time - similar information to K
  4. MA
    • Maximal ampiltude
    • Provides an indication of overall clot strength
  5. Fibrinolysis
    • EPL - estimated percent lysis
    • % lysis after 30 minutes
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3
Q

TEM / ROTEM - Pros and Cons

A

Pros:

  • Includes cells in evaluation of clotting

Cons:

  • Poor reproducibility without a strong tissue factor
  • Results altered by platelet number and red cell mass
    • Increased time to clot formation with increased HCT
  • Longer handling times with lead to activation of the contact pathway, leading to erroneous results
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4
Q

Thrombin-antithrombin complexes - what is tested

A

A marker of in vivo thrombin activity * Thrombin half life in vivo is extremely short. Stable TAT complexes is an indirect indicator of thrombin generation

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5
Q

Thrombin-antithrombin complexes - Pros and Cons

A

Pros: * Uses plasma, thus eliminates effect of variable HCT and platelet number Cons: * Expensive and not readily available * Multi-well plate design necessitates batch processing

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6
Q

D- dimers - What is tested?

A

Degradation of insoluble cross-linked fibrin Increased D dimers indicate: * thrombin generation - fibrin generation, cross linking of fibrin via factor XIII(a) and plasmin activity (to degrade cross linked fibrin.

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7
Q

D-Dimers - Pros and Cons

A

Pro: * Specific for breakdown of cross-linked fibrin - ie. fibrinolysis * Short half-life (5 hours) means results consistent with recent fibrinolysis. Cons: * Not available widely * Some human assays do not cross react with animal D-Dimers

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8
Q

Fibrinogen degradation products (FDPs) - what is tested?

A

Specifically tests plasmin activity Breakdown products of fibrinogen, insoluble fibrin, soluble fibrin monomers and cross-linked fibrin

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9
Q

Fibrin degradation products - Pros and Cons

A

Pros: * Inexpensive and simple to run * In-house testing available Cons: * Not specific for breakdown of cross-linked fibrin * Non specific - can be increased with large number of disorders

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10
Q

Callibrated automated thrombography - What is it?

A

Evaluates thrombin generation in vitro in response to specific stimuli. The test is run on PRP or PPP but not whole blood

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11
Q

Calibrated automated thrombography - Pros and Cons

A

Pros: * sensitive evaluation of enzyme contribution to clot formation * can assess platelet contribution with PRP Cons: * Not widely available * Mainly used for research at this time

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12
Q

What tests are available to assess platelets and their function?

A
  1. Platelet count - automated and manual 2. Platelet function testing - impedence whole blood platelet aggregometry (Multiplate) * Platelet function analyser (PFA-100)
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13
Q

Describe the function of the PFA-100

A

PFA-100 measures cessation of while blood flow through an aperture under high shear conditions. * Measures closing time * Membrane coated with collagen and adrenalin or ADP. * Uses sodium citrated blood held at room temperature * Platelet aggregation is dependent on platelet number,, platelet function and functional vWF.

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14
Q

PFA-100: Pros and Cons

A

Pros: * Simple to use * Accurate and reproducible results * Screening test to exclude severe platelet dysfunction or vWD Cons: * Non-specific for underlying disease process * Will not exclude milder forms of disease

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15
Q

Prothrombin Time (PT) - What is tested

A

PT evaluates the tissue factor pathway (extrinsic) and common pathway. PT assesses FVII (extrinsic pathway) * citrated plasma is added to CaCl2 and tissue factor in a lipid membrane. PT is the time to first fibrin strands Prolonged PT (normal APTT) indicated FVII deficiency

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16
Q

Activated partial thromboplastin time (APTT) - what is tested

A

APTT evaluates with contact pathway, intrinsic pathway and common pathway. Does not assess FVII or FXIII. * Citrated plasma incubated with a contact activator (celite, kaolin) and lipids to allow for generation of FXIIa and XIa. Then re-calcified to allow for downstream coagulation APTT in the time from re-calcification to first fibrin strands. Prolonged APTT (normal PT): deficiency of * FXII * FXI (haemophilia C) * FIX (haemophilia B) * FVIII (haemophilia A) * also seen with heparin therapy

17
Q

Activated Clotting Time - What is tested?

A

Similar to the APTT, except that is uses whole blood, not citrated plasma. * Tube contains a contact activator * Platelets in the blood provide the lipid surface * Blood must be placed directly in the tube after venepuncture * Tube must be at 37 degrees C * end point is time to visible clot formation

18
Q

Describe the Contact Activation (intrinsic) pathway for coagulation

A
  • Surface contact leads to activation of FXII-FXIIa
  • FXIIa activates FXI to FXIa
  • FXIa activates FIX to FIXa
  • FIXa together with VIIIa, PL (activated platelets), and Ca++ = intrinsic tenase FX activated to FXa
19
Q

Describe the Tissue Factor (extrinsic) pathway for coagulation

A

Tissue damage lead to exposure of TF (tissue factor) TF binds to FVIIa TF:FVIIa and Ca++ = extrinsic tenase Tenase activates FX to FXa

20
Q

Describe the common pathway for coagulation.

A

Factor Xa combines with FV, PL (activated platelets) and Ca++ to cleave prothrombin (FII) to thrombin (FIIa) Thrombin cleaves fibrinogen (F1) to fibrin (F1a). Thrombin activates FXIII to FXIIIa FXIIIa crosslinks fibrin to stabilise the clot.

21
Q

Describe amplification of coagulation

A

Thrombin activates FV, FVII, FXI and FXIII FVa and FXa combine on the platelet surface to stimulate burst production of further thrombin. Thrombin also stimulates activation of FXIII to enhance cross linking of generated fibrin strands. FXIa catalyses production of IXa when combined with VIIIa on the platelet surface (tenase) ensures further production of Xa. Xa catalyses production of more thrombin.

22
Q

Describe mechanisms of auto-regulation of coagulation

A

* Tissue factor pathway inhibitor (TFPI) binds to FXa, inactivating FXa. * TFPI: FXa inhibits TF:FVIIa - which limits further activation of FX. * Antithrombin III - binds to multiple factors cause inhibition * Thrombin combines with Thrombomodulin to activate Protein C * Protein C inactivates FVa and FVIIIa

23
Q

List the actions of Antithrombin III

A

ATIII binds to the following: * FII (thrombin) * FX, IX, XI and XII of the contact pathway * FVII of the tissue factor pathway Inactivates kallikrein - reduces activation of contact pathway Inactivates plasmin thereby reducing fibrinolysis Net result is inhibition of coagulation and reduced degradation of clots already formed.

24
Q

List acquired causes for a hypercoagulable state

A

* IMHA * Cardiac disease * Protein losing disorders - especially PLN * Neoplasia * Endocrinopathies * Inflammation / sepsis * Antiplatelet, anticoagulant and thrombolytic therapy

25
Q

List mechanisms for hypercoagulability in: IMHA

A
  • Increase platelet reactivity
  • Increased expression of tissue factor - on monocytes and endothelial cells
  • Exposure of RBC membrane phosphatidylsterine
  • Circulating procoagulant particles
  • Diminished endogenous anticoagulant activity
  • Systemic inflammation
26
Q

List mechanisms for hypercoagulability in: Cardiac Disease

A
  • Left atrial enlargement - blood stasis and turbulent blood flow
  • Endomyocardial injury and exposure of tissue factor
  • Platelet hyper-reactivity
  • Endocarditis and heart worm also cause endothelial injury and altered blood flow.
27
Q

List mechanisms for hypercoagulability in: Protein losing nephropathy

A
  • Loss of Antithrombin III (controversial)
  • Increased platelet reactivity
  • Hyperfibrinogenaemia
  • Decreased fibrinolysis
  • Note: degree of hypercoagulability is not correlated with levels of albumin and antithrombin.
28
Q

List endocrine diseases from which hypercoagulability has been documented

A
  • Hypercoabulability has been described in HAC, DM and hypoT
    • Mechanism unknown
  • Atherosclerosis may contribute in DM and HypoT
29
Q

List mechanisms for hypercoagulability in: Neoplasia

A

Common finding and multiple mechanisms likely involved

  • Increased cellular expression of tissue factor
  • Increased soluble tissue factor
  • Platelet hyper-reactivity +/- thrombocytosis
  • Vasscular endothelial fragility
  • Systemic inflammation
  • Increased fibrinogen concentration with carcinoma
30
Q

List mechanisms for hypercoagulability with: Sepsis / inflammatory disease

A
  • Pro-inflammatory cytokines increase platelet production
  • Increased platelet reactivity
  • Increased expression of tissue factor on endothelial cells and monocytes
  • Anti-coagulant activity is diminished
  • Fibrinolysis is diminished
  • Hypercoagulability together with micro-thrombi formation can contribute to MODS
  • Hypercoagulability together with inflammation can lead to DIC which eventually contributes to hypocoagulability
31
Q

List acquired causes for a hypocoagulable state

A
  1. Vitamin K antagonism
  2. Hepatic failure
  3. DIC
  4. Acquired anticoagulants
32
Q

List mechanisms of hypocoagulability in: Vitamin K deficiency

A
  • Vitamin K can be reduced due to antagonism or reduced production in the GIT (by resident bacteria) and decreased absorption
  • Important co-factor in production of Vitamin K dependent coagulation factors (II, VII, IX, X)
  • Important co-factor in production of anti-coagulant protein C and protein S
  • Rodenticides antagonize vitamin K epoxide reductase –> reduced vitamin K –> rapid depletion of the factors with a short half life (VII and IX in particular)
    • Reduced ability to form a stable clot due to depleted coagulation factors
33
Q

List mechanisms of hypocoagulability in: Hepatic Failure

A
  • Liver is responsible for production of most pro-coagulant and anti-coagulant proteins
  • Early disease causes a balanced loss of both proteins and stable in vivo haemostasis
  • In vitro haemostasis often affected (PT/PTT prolonged)
  • Liver failure can also cause vitamin K deficiency
  • Can see reduced levels of: factors II, V, VII, IX, X, XI, dysfibrinogenaemia, and decreased alpha2-antiplasmin
  • Elevated levels of factor VIII and VWF
  • Decreased levels of protein C, protein S, antithrombin and plasminogen.
34
Q

List mechanisms of hypocoagulability in: DIC

A
  • Consumptive coagulopathy
  • Systemic inflammation –> intravascular fibrin deposition and thrombosis
  • Tissue factor mediated
  • TF expression is increased by pro-inflammatory cytokines and endotoxin
  • High concentration of TF can be found on monocytes, endothelial cells, neoplastic cells, microparticles and other sources
  • TF binds to circulating FVIIa with subsequent activation of the tissue factor pathway and fibrin formation
  • Anti-coagulant proteins are consumed in the process - further promotes thrombosis
  • Platelets become entrapped within micro- and macro-thrombi causing thrombocytopenia
  • Excessive thrombin activates plasminogen to plasmin
  • Circulating plasmin cleaves fibrinogen and fibrin to form FDP’s which have anti-coagulant properties
  • Excessive plasmin also activates complement and kinin systems - shock, hypotension, increased vascular permeability.
35
Q

List mechanisms of hypocoagulability with: Aquired anti-coagulants

A
  • Aantibodies (typically IgG) bind to and inhibit a coagulation factor or promote increased clearance of the factor
  • Anti-phospholipid protein antibody (lupus anticoagulant) inhibits interaction between coagulation proteins and the cell membrane

Immunology and Haematology - Veterinary Internal Medicine (10 decks)

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