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Duncan and Prasse > Chapter 4: Hemostasis > Flashcards

Chapter 4: Hemostasis Flashcards

1
Q

What are the antithrombotic properties of endothelial cells?

A

1) PGI1 release (activates adenylate cyclase & increases cAMP production–> vasodilation & platelet inhibition)
2) NO release (similar fx as PGI2)
3) Thrombomodulin expression (binds thrombin so can’t activate platelets and turns it into anticoagulant by having it activate protein C–> with protein S inhibits V & VII)
4) tPA release (converts plasminogen to plasmin)
5) Heparan sulfate expression (accelerates AT3 binding and inactivation of thrombin and X)
6) TFPI synthesis (inhibits TF)
7) EctoADPase release (degrades ADP to platelets can’t aggregate)

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2
Q

What are the procoagulant properties of endothelial cells?

A

1) TF synthesis
2) vWF synthesis
3) PAI-1 synthesis (inhibits fibrinolysis)
4) loss of endothelial lining and exposure of subendothelium when damaged

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3
Q

What do platelet alpha granules contain? (#6)

A

fibrinogen
factor V
VWF
thrombospondin
platelet factor 4
PDGF

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4
Q

What do platelet dense granules contain? (#4)

A

adenine nucleotides
calcium
inorganic phosphates
serotonin

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5
Q

Megakaryocytes are derived from _____.

A

bipotent megakaryocyte-erythroid progenitor (MEP)

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6
Q

2 distinct colonies that lead exclusively to megakaryocyte production identified in vitro

A
  1. burst-forming unit (BFU-MK)– primitive progenitor that makes colonies, divides into several hundred megas
  2. colony-forming-unit-megakaryocyte (CFU-MK)– more mature progenitor, divides into 3-50 megas
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7
Q

Stages of megakaryocyte maturation

A

Stage 1 megakaryocyte– 15-50 um, intense basophilic cytoplasm, oval, round, idney bean shaped nuclei

Stage 2 megakaryocyte– 75 um, increased lobulation, basophilic cytoplasm, few granules

Stage 3 megakaryocyte– 150 um, lobulated nuclei, variable eosinophilic cytoplasm, many granules (now can make platelets)

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8
Q

Platelet circulating lifespan in most species

A

5-9 days

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9
Q

The _____ normally contains 30-40% of circulating platelet mass.

A

Spleen

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10
Q

Specific TPO receptors on megas and platelets are referred to as ____.

A

c-Mpl

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11
Q

Platelets adhere to exposed __, ___, ___, and ___.

A

subendothelial collagen, VWF, fibronectin, and vitronectin

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12
Q

Membrane glycoproteins on platelets that participate in platelet adhesion include ___, ___, ____ and ___.

A

GPIb-IX-V, GP-VI, integrin a2B1 and integrin aIIbB3/GPIIb-IIIa

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13
Q

Which platelet glycoprotein which interacts indirectly with collagen is critically important in initiation of platelet contact with collagen under high shear stress? How is it important?

A

GPIb-IX-V complex
It mediates transient arrest of platelets from flowing blood and weak tethering of platelets onto exposed subendothelial surfaces through binding of VWF.

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14
Q

Platelets are tethered to exposed endothelial surfaces by platelet surface ____. The tethered platelets roll and encounter collagen which bind to ___. This leads to inside-out signaling and activation of integrins ___ and ___, release of ___, and ___ formation which in turn reinforces the ___/collagen interaction.

A

GPib-IX-V complex
GPVI
a2B1 and aIIbB3
ADP
thromboxane
GPVI/collagen

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15
Q

Which platelet surface integrin allows firm platelet adhesion and spreading?

Which one reinforces platelet adhesion and aggregation by binding to fibrinogen?

A

activated a2B1

activated aIIbB3

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16
Q

How are platelet granules released?

A

Agonists bind–> activates platelet phospholipases–> Ca and diacylglycerol mobilization–> synthesis of TXA2–> induces irreversible platelet aggregation and release

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17
Q

What facilitates assembly of coagulation complexes on platelet surfaces?

A

platelet activation and phosphatidylserine translocation to the outer membrane

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18
Q

3 examples of automated platelet count methods

A
  1. Aperture impedance flow automated hematology instruments
  2. Quantitative buffy coat analysis
  3. Flow cytometry
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19
Q

Which platelet count method is not affected by platelet clumping?

A

Quantitative buffy coat analysis (still only fair to good accuracy though)– impedance and hemocytometer are

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20
Q

For platelet counting via impedance, collection of cat blood samples in ____ decreases platelet aggregation and pseudothrombocytopenia.

A

citrate-based anticoagulant containing platelet inhibitors such as throphylline, adenosine, and dipyridamole

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21
Q

What is the quantitative buffy coat analysis for platelet counts based on?

A

differential centrifugation of blood components in samples of anticoagulated whole blood by use of modified microhematocrit tubes

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22
Q

Explain the QBC method of platelet counting.

A

A plastic cylindrical float with a density similar to that of the platelets and leukocytes expands the buffy coat, which allows quantification of platelets and leukocytes based on their differential fluorescence. DNA primarily stains green, while RNA, lipoproteins, and granules containing glycosaminoglycan primarily stain orange to red.

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23
Q

Which type of animal blood cannot be used for platelet counts via QBC?

A

ruminants

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24
Q

Which breed of dog has lower platelet counts in health?

A

Greyhound

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25
Q

Spontaneous petechial to ecchymptoc hemorrhage usually doesn’t occur until the platelet count is below ___.

A

20,000/uL

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26
Q

Thrombocytosis associated with ___ usually is not associated with increased risk of thrombosis. However, thrombocytosis associated with ____ may increase risk of thromboembolic disease.

A

inflammation
myeloproliferative disease

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27
Q

Less than __ platelet/__erythrocytes in the monolayer denotes thrombocytopenia (but presence of anemia needs to be considered to evaluate severity)

A

1 platelet/50 erythrocytes

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28
Q

Formula for estimating platelet count/uL on a blood smear

A

(number of platelets/WBC observed) x (WBC count/uL) = estimated platelet count/uL

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29
Q

In healthy birds, thrombocyte counts range from ____ to ___/uL.

A

20,000 to 30,000/uL

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30
Q

What are the causes of platelet fragments?

A

iron-deficiency anemia, bone marrow aplasia, IMTP, artifact of in vitro storage and aging in EDTA for more than 24 hours

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31
Q

What is the unit for MPV? What kind of counters is it determined by?

A

femtoliters, impedance and optical particle counters

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32
Q

What does MPV reflect?

A

average size of platelets in the circulating population

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33
Q

Increased MPV with thrombocytopenia suggests ___.

A

responsive thrombopoiesis

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34
Q

What 3 things are most commonly associated with decreased MPV?

A

lack of mega response (bone marrow failure), early immune-mediated thrombocytopenia, insufficient megakaryocytes

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35
Q

What might cause an artifactually high MPV?

A

Swelling in EDTA samples that are stored more than 4 hours, cooled to room temp, or refrigerated

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36
Q

What does PDW measure?

A

platelet size variation (unitless)

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37
Q

What are reticulated platelets and what do they suggest?

A

they contain increased RNA and are less than 24 hours old from the bone marrow, suggest responsive thrombopoiesis

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38
Q

What are some ways that have been developed to detect antiplatelet antibodies?

A

Numerous assays that are insensitive and non-specific, direct determination of platelet surface-associated immunoglobulin (PSAIg) by fluorescence labeling and flow cytometry

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39
Q

What is the gold standard for assessment of platelet function and which diseases are these helpful in diagnosing?

A

Platelet aggregation assessment with aggregometers

Hereditary platelet functional defects (i.e. canine thrombopathia, Glanzmann thrombasthenia) and acquired disorders of platelet function secondary to disease or drugs (i.e. uremia, aspirin, NSAIDs)

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40
Q

What are 2 platelet function assays?

A

Platelet aggregation with aggregometers and aperture closure instruments

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41
Q

How do aperture closure instruments for assessing platelet function work?

A

The instrument aspirates citrated whole blood under high shear through a capillary tube and a compartment containing test cartrudge membranes (have a central aperture coated with either ADP or collagen and epinephrine–epi isn’t a good agonist in dogs). Blood flows under shear stress across the membrane and through the aperture and platelets become activated and adhere and aggregate which closes the aperture. It measures decrease in flow rate with time until flow completely stops. Final closure time is recorded.

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42
Q

Bleeding time measures ___.

A

length in time required for platelets to plug a small laceration in blood vessels– evaluates primary hemostasis or platelet status

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43
Q

In what situation would a prolonged BMBT not add additional information?

A

When the patient is already thrombocytopenic.

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44
Q

What conditions will prolong BMBT?

A

VWD, acquired or congenital, and acquired platelet disorders from effects of medications or immune-mediated disorders

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45
Q

Do coagulation factor deficiencies prolong BMBT?

A

No

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46
Q

What disease causes loss of vascular collagen integrity which can cause prolonged bleeding times in guinea pigs and people?

A

Vitamin C deficiency (scurvy)

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47
Q

What does the clot retraction test measure?

A

Platelet function

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48
Q

Describe the clot retraction test.

A

0.5 mL of blood is drawn directly into a plastic syringe that contains cold saline (4.5 mL) and is mixed. A portion of the blood/saline mixture (2 mL) is placed in glass tubes (duplicate test) that contain a small amount of thrombin, capped, mixed, and refrigerated for 30 minutes. The tubes are put in a 37 degree C water bath, and clot retraction is graded +1 to +4 at one and two hours.

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49
Q

What platelet functional defect will not be detected with the clot retraction test and why?

A

The canine thrombocytopathias (CalDAG-GEFI platelet disorders) because these platelets can interact with thrombin and express fibrinogen receptors.

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50
Q

The clot retraction test depends on the interaction between ____, ____, and ____.

A

platelet receptors, thrombin, and fibrinogen

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51
Q

Will dogs with VWD have an abnormal clot retraction test?

A

No, because platelets from dogs with VWD react normally with platelets

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52
Q

What diseases will cause an abnormal clot retraction test?

A

Glanzmann thrombasthenia

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53
Q

What kind of tests are the assays for VWD?

A

quantitative ELISA assays

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54
Q

What is the proper collection method when testing via assay for VWD?

A

require citrated or EDTA plasma (NOT SERUM!), frozen in plastic tubes after immediate separation from erythocytes, and shipped frozen within 2 weeks after collection

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55
Q

What is the collagen-binding assay and what does it test for?

A

It is an ELISA that uses collagen-coated microtiter plates to assess for VEF binding capacity. Calculations of ratios of VWF-antigen to VWF-CBA can be used to distinguish type 2 VWD from types 1 and 3.

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56
Q

What will the collagen-binding activity assay results look like in a dog with type 2 VWD?

A

they have VWF antigen assays that are discordant with their CBA results due to reduced presence of the more functional high molecular weight multimers of VWF. Ratios of VEF-antigen to VWF-CBA greater than 2 are consistent with the diagnosis of type 2 VWD. Can’t tell difference between acquired and inherited forms.

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57
Q

How is flow cytometry useful in identifying platelet function disorders?

A

It can determine if platelets lack major glycoproteins such as GPIIb and GPIIIa if species-specific antibodies are available; it can also detect binding of fibrinogen to activated platelets via CAP1 antibody binding.

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58
Q

What is an example of an extrinsic platelet disorder?

A

VWD

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59
Q

VWF stabilizes ___ in circulation.

A

FVIII:C

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60
Q

Which multimers of vWF are most active in hemostasis?

A

Large

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61
Q

Why is FVIII usually decreased in VWD? Does it cause abnormal clotting tests?

A

Because VWF stabilizes it, and so with insufficient VWF, the protein is degraded by proteases. It doesn’t cause a prolonged APTT becqause usually more than 30-40% FVIII:C activity exists in affected dogs.

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62
Q

Describe Type 1 VWD

A

A partial quantitative deficiency of VWF
Plasma VWF concentrations are below 20%
VWF is structurally and functionally normal (just not enough of it!)
Autosomal inheritance
Severity varies

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63
Q

Describe Type 2 VWD.

A

Qualitative abnormalities of VWF structure and function
Lose more high molecular weight multimers than the others
Autosomal recessive inheritance
Rare

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64
Q

Describe Type 3 VWD.

A

Severe quantitative deficiency of VWF (basically a more severe form of type 1)– VWF conc usually <0.1% of normal
Reduced FVIII but APTT usually not prolonged
Autosomal recessive inheritance

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65
Q

What type of conditions do you see acquired VWD and what is the mechanism?

A

High shear stress conditions like aortic stenosis
VWF unfolds and is cleaved by ADAMTS13

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66
Q

What does ADAMTS13 do?

A

it is an enzyme that cleaves VWF into smaller, less functional, multimers when VWF is under high shear stress or involved in platelet aggregates– necessary to prevent excessive platelet adhesion or aggregation mediated by large VWF multimers

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67
Q

Examples of intrinsic platelet disorders?

A

Chediak-higashi syndrome
Glanzmann thrombasthenia
CalDAG-GEFI
Dense granule defect in American Cocker Spaniels
Cyclic hematopoiesis
LADIII
P2Y12 mutation
Scott syndrome
Macrothombocytopenia of CKCS

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68
Q

Describe Chediak-Higashi syndrome

A

Autosomal recessive
Abnormal leukocyte, melanocyte, and platelet granulation
Platelets lack discernable granules and are deficient in storage pools of adenosine nucleotides, serotonin, and divalent cations
Dilute coat color

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69
Q

What has Chediak-Higashi syndrome been linked to in cattle, mice, and people?

A

Mutations in the lysosomal trafficking regulator (LYST) gene

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70
Q

Describe Glanzmann thrombasthenia.

A

Deficiency of GPIIb-IIIa (integrin aIIbB3) on platelet surfaces
Platelets can’t bind to fibrinogen
Causes impaired platelet aggregation and clot retraction

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71
Q

What glycoprotein on platelets is affected in Glanzmann thrombasthenia?

A

GPIIb-IIIa (aIIbB3)

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72
Q

Describe CalDAG-GEFI platelet disorder.

A

Signal transduction platelet disorder
Platelets display abnormal fibrinogen receptor exposure and impaired dense granule release
The abnormality is caused by absent or dysfunctional calcium diacylglycerol guanine nucleotide exchange factor-I (signal transduction protein important in the pathway leading to the change in conformation of GPIIb-IIIa necessary for fibrinogen binding)
Platelet aggregation and flow abnormal; clot retraction normal

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73
Q

Describe the dense platelet granule defect in American Cocker Spaniels.

A

Platelet counts and morpholopgy normal
ADP concentration decreased so not as functional

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74
Q

Describe cyclic hematopoiesis.

A

Described in Grey Collies
Cyclic fluctuations in numbers of circulating neutrophils, reticulocytes, and platelets
From a bone marrow stem cell defect which causes neutropenic episode every 12 days.
Mortality high
Platelet numbers usually normal but fluctuate
Platelet reactivity to colagen, PAF, and thrombin defective
Clot retraction and adhesiveness impaired
Mutation in gene for adaptor protein complex 3 (AP3) linked

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75
Q

Describe LADIII.

A

Due to Kindlin-3 deficiency/dysfunction (key signal transduction protein for activateion of beta integrins on hematopoietic cells
Platelets and leukocytes can’t activate their beta-subunit type integrins
Bleed, persistent leukocytosis, susceptible to infections

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76
Q

Describe P2Y12 platelet disorder and what breed has it been described in?

A

Platelets can’t bind CAP1 in response to high concentrations of ADP
P2Y12 is one of 2 key platelet ADP receptors– associated with platelet aggregation and granule release, thromboxane generation, expression of procoag activity, and inhibition of adenylate cyclase
Described in a Greater Swiss Mountain dog

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77
Q

Describe Scott syndrome and what breed has it been described in?

A

Lack of procoagulant expression on the surface of platelets (lack of phophatidylserine exposure) so impaired assembly of coag factors complexes
Described in a family of German Shepherds

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78
Q

Describe Macrothrombocytopenia of CKCS.

A

Mutation in beta1-tubulin that affects microtubule stability and alters mega proplatelet formation and release
Platelet counts usuallt 30,000-100,000/uL
Plateletcrit normal
No bleeding tendencies

79
Q

What are some acquired functional platelet disorders that cause hyporesponsive platelets? (6)

A

Drugs (COXi, B-lactam antibiotics, Ca channel blockers)
Uremia
DIC
Liver disease
Infectious diseases (FELV, Ehrlichia canis)
Misc (paraproteinemia of MM, leukemia and other myeloproliferative disorders, snake venoms)

80
Q

How do COX inhibitors cause hyporesponsive platelets?

A

Aspirin irreveribly acetylates COX in platelets and megas –> inhibition of TXA2
Ibuprofen and other NSAIDs reversibly inactivate COX

81
Q

How do B-lactam antibiotics cause platelet hypofunction?

A

reversibly inhibit platelet function by binding agonist receptors which impairs agonist-induced Ca flux across the platelet membrane (not usually clinically relevant)

82
Q

How do Ca channel blockers cause hyporesponsive platelets?

A

prevent Ca movement across membranes which impairs platelet activation

83
Q

What conditions are associated with enhanced platelet function?

A

Nephrotic syndrome
Epo administration
FIP
Heartworm disease

84
Q

4 basic mechanisms of thrombocytopenia

A
  1. Decreased production
  2. Increased consumption
  3. Sequestration
  4. Excessive loss
85
Q

Four categories that cause decreased platelet production or failure of platelet production (decreased BM megas with concurrent thrombocytopenia)

A
  1. Pure megakaryocytic hypoplasia
  2. Bone marrow panhypoplasia (pancytopenia, aplastic anemia) of any cause
  3. Neoplastic or inflammatory myelophthisis
  4. Infectious (ehrlichia, FeLV, FIV, EIA, African swine fever, BVD
86
Q

What causes pure megakaryocytic hypoplasia?

A

autoantibodies directed against megakaryocytes

87
Q

What 5 categories cause bone marrow panhypoplasia (pancytopenia, aplastic anemia)?

A
  1. Drugs (chloramphenicol, sulfas, estrogen, griseofulvin (cats)
  2. Chemicals (trichloroethylene, benzene)
  3. Mycotoxins/plant toxins (aflatoxin B, bracken fern)
  4. Ionizing radiation
  5. FeLV or parvo
88
Q

Three categories that cause platelet consumption or destruction in excess of platelet production.

A
  1. IMTP
  2. Drug induced thrombocytopenia
  3. Conditions that cause increased activation and removal of platelets (intravascular parasites (Plasmodium, Dirofilaria), bacterial, rickettsial, viral infections, DIC)
89
Q

What is the difference between primary IMTP and secondary?

A

Primary- autoantibodies are produced against specific platelet autoantigens (usually GPIIb-IIIa and GPIb-IX), megas may be targeted too
Secondary- antibody production is secondary to another condition like SLE, neoplasia, infectious disease, or drugs. The platelet nonspecifically adsorbs the antibody.

90
Q

Which platelet membrane glycoproteins are usually target in primary IMTP?

A

GPIIb-IIIa
GPIb-IX

91
Q

What are the 3 categories of thrombocytosis?

A 
Physiologic thrombocytosis (splenic contraction)
Essential/primary thrombocythemia (myeloproliferative disorder)
Reactive/secondary thrombocytosis (inflammation, malignancy, iron-deficiency, splenectomy)
92
Q

Describe bloodwork and bone marrow changes seen in essential thrombocythemia.

A

Platelet count persistently, markedly increased
Platelets have varying sizes, shapes, and granulation
BM megas are increased and abnormal
Hemorrhage/thrombosis may occur

93
Q

2 most common causes of reactive thrombocytosis?

A

Inflammation and malignancy

94
Q

How does inflammation or tumor cells cause thrombocytosis?

A

IL-6, IL-3, IL-11 stimulate mega proliferation and maturation
IL-6 stimulates TPO production

95
Q

What is dysthrombocytopoiesis and what is it associated with?

A

Disordered productin of platelets
Megakaryocytic leukemia and myelodysplastic syndromes

96
Q

What are the 3 principle coagulation complexes and what do they include?

A
  1. Intrinsic factor X activation complex (aka intrinsic tenase complex)– IX, VIII, X
  2. Extrinsic factor X activation complex (aka extrinsic tenase complex)– VII, III (TF), X
  3. Prothrombinase complex– X, V, II
97
Q

What factors can the extrinsic factor VII-tissue factor complex activate?

A

X (common) and IX (intrinsic)

98
Q

Factor XII is aka?

A

Hageman factor

99
Q

Factor XI is aka?

A

Plasma thromboplastin antecedent

100
Q

Prekallikrein is aka?

A

Fletcher factor

101
Q

Which factors make up most of the contact activation system in coagulation?

A

XII, XI, prekallikrein

102
Q

Factor II is aka?

A

prothrombin (activated is thrombin)

103
Q

Factor VII is aka?

A

Proconvertin

104
Q

Factor IX is aka?

A

antihemophilic factor B, Christmas factor

105
Q

Factor X is aka?

A

Stuart factor

106
Q

How are factors II, VII, IX, and X activated by Vitamin K?

A

Vitamin K carboxylates glutamic acid residues on the molecules so they have a negative charge and can bind to phosphatidylserine on platelets in the presence of Ca

107
Q

Why is Ca important in coagulation?

A

It allows the electrostatic interaction to occur between negatively charged coag factors and negatively charged platelet surface.

108
Q

What are PIVKAs?

A

Coagulation factors made without sufficient carboxylation beacuse of Vit/ K deficiency so aren’t functional (can’t bind to platelet surfaces)

109
Q

Factor XIII is aka?

A

fibrin stabilizing factor

110
Q

Why is factor XIII important?

A

it is converted to an active transglutaminase by thrombin and cross-links and stabilizes fibrin monomers

111
Q

What is the major function of AT?

A

Inhibit thrombin activity by forming thrombin-AT complexes that are cleared by the mononuclear phagocytic system

Also inactivates IX, X, XI and XII

112
Q

AT activity is enhanced by ___.

A

heparin

113
Q

Once thrombin binds to thrombomodulin, it’s substrate specificity changes from ____ to ____.

A

Fibrinogen to protein C

114
Q

What are the non enzymatic protein factors?

A

Factor V, VIII, and I

115
Q

Factor V is aka?

A

Proaccelerin

116
Q

Factor VIII is aka?

A

Antihemophilic factor A

117
Q

Which factors are acute phase proteins?

A

I (fibrinogen) and VIII

118
Q

How does protein C play an anticoagulant role?

A

It degrades activated factors V and VIII.

119
Q

Which factor is found in sub endothelial fibroblasts, pericytes, macrophages, and monocytes but not on unperturbed endothelial cells?

A

TF

120
Q

When TF is exposed to blood, TF binds to ___ and ___ and then this complex activates ___ to make the extrinsic tense complex.

A

factor VII and factor VIIa
factor X

121
Q

How does TFPI work?

A

it binds activated X and then this complex binds membrane bound FVIIa/TF complex to inactivate it (Ca dependent)

122
Q

Disorders of the extrinsic clotting pathway include which factors?

A

III and VII

123
Q

What is the severity and clinical outcome of dogs with hereditary deficiency of factor VII?

A

Mild disease associated with easy bruising but lacks serious bleeding tendencies.

124
Q

The intrinsic clotting pathway includes which molecules/factors? (6)

A

HMWK, prekallikrein, factors XII, XI, IX, VIII

125
Q

Contact activation of the intrinsic pathway involves which molecules/factors?

A

XII, XI, prekallikrein, HMWK

126
Q

The product of contact activation in the intrinsic system is ____.

A

activated factor XI

127
Q

Which tense complex is not susceptible to TFPI and is 50 times more efficient in activation of factor X?

A

intrinsic tense complex (initial production of Xa is by extrinsic but sustained activation depends on intrinsic)

128
Q

Activated factor ___ activates platelets via formation of a small amount of thrombin in their vicinity.

A

X

129
Q

Activated factor ___ enhances production of thrombin on surfaces of activated platelets by activating more X to sit on the surface of platelets with the prothrombinase complex.

A

IX

130
Q

What is the clinical outcome of dogs/horses with hereditary deficiency of prekallikrein?

A

Not reported to have clinical bleeding

131
Q

What is the clinical outcome of dogs/cats with hereditary factor XII deficiency (Hageman’s disease)?

A

Not reported to have clinical bleeding

132
Q

What is the clinical outcome of dogs/cattle with hereditary factor XI deficiency?

A

Retracted bleeding after surgery, otherwise mild

133
Q

What is the clinical outcome of dogs/cats with hereditary, sex-linked, factor IX deficiency? What is it otherwise known as?

A

Hemophilia B

Usually have <10% normal factor IX activity

Males only

Tend to be internal hemorrhages only

Smaller animals (cats) tend to have longer lifespan than bigger animals

134
Q

What is the clinical outcome of dogs/cats/horses/sheep/cattle with hereditary, sex-linked, factor VIII:C deficiency? What is it otherwise known as?

A

Hemophilia A

Most common inherited coagulopathy because factor VIII gene mutates easily

Smaller animals (cats) tend to have longer lifespan than bigger animals

135
Q

What coagulation proteins are consumed in DIC?

A

fibrinogen, factor V, and factor VIII

136
Q

Starting with factor X activation, how is fibrin eventually made and stabilized?

A

Xa–> binds V, Ca, and phospholipid to make the prothrombinase complex–> cleaves peptide bonds in prothrombin–> prothrombin fragment 1+2 and pre thrombin 2 made–> pre thrombin 2 cleaved to make thrombin–> thrombin comes of the platelet and converts soluble fibrinogen to monomeric fibrin (fibrinopeptides A & B released)–> XIIIa polymerizes and cross-links fibrin monomers to make insoluble fibrin

137
Q

2 examples of anticoagulation disorders

A 
AT deficiency (PLN, PLE, sepsis)
Protein C deficiency (horses with colic syndrome, DIC in dogs)
138
Q

What 3 species/breeds have inherited Vitamin K-dependent multi factor coagulopathies been described in, and do they respond to Vitamin K treatment?

A

Devon Rex cats– yes, they make carboxylase protein thats defective but still responds
Rambouillet sheep– no, they don’t make the carboxylase
Labrador retrievers– unknown

139
Q

3 activators of plasminogen?

A

kallikrein, tPA, uPA

140
Q

Describe the heavy (A) and light (B) chains of plasmin

A

A chain- mediates plasmin’s interaction with fibrin and its inhibitor a2-antiplasmin
B chain- enzymatic site

141
Q

Inhibitor of plasmin?

A

a2AP main one
a2-macroglobulin, a1-antitrypsin, AT, C1-esterase inhibitor

142
Q

What is thrombin activatable fibrinolysis inhibitor’s (TAFI) role?

A

As thrombin is being made, TAFI is made which keeps the clot that’s being made from being broken down by fibrinolysis (cleaves lysine binding sites on fibrin for plasminogen and tPA and prevents conversion of Glu to Lys-plasminogen).

143
Q

What is the terminal degradation product make bib plasmin-mediated hydrolysis of cross linked fibrin?

A

D-dimers

144
Q

What is an intrinsic activator of plasminogen?

A

Factor XII directly and indirectly (it also activates kallikrein which activates uPA which activates plasminogen)

145
Q

What are extrinsic activators of plasminogen?

A

tPA and uPA

146
Q

How does tPA work to promote fibrinolysis?

A

Sits on fibrin and activates fibrin-bound plasminogen to plasmin–> fibrin digested by plasmin–> more binding sites for plasmin exposed

147
Q

uPA is mostly responsible for activation of plasminogen where?

A

cell surfaces

148
Q

What do plasminogen activator inhibitors (PAI) do?

A

binds plasminogen and keeps it from being activated

149
Q

What are 5 imbalances in fibrinolysis that favor hyper coagulation?

A
  1. decreased plasminogen concentration
  2. lack of plasminogen activators
  3. lack of protein C or protein S
  4. factor V mutations results in resistance of factor V to inactivation by protein C
  5. excess PAI
150
Q

What are 2 imbalances in fibrinolysis that favor hypo coagulation?

A
  1. lack of a2 antiplasmin and other plasmin inhibitors
  2. systemc uncontrolled plasminogen activation
151
Q

What does the activated clotting time (ACT) measure and what is it evaluating?

A

Measures the time (s) required for fibrin clot formation in fresh whole blood after exposure to a contact activator.
Evaluates the intrinsic and common pathways.

152
Q

Activity of a given factor has to be <___% in order to prolong the ACT.

A

10% (less sensitive than APTT for intrinsic and common pathway)

153
Q

What concurrent hematological abnormality can prolong ACT and why?

A

thrombocytopenia because platelets are the phospholipid surface required to assemble the coagulation complexes

154
Q

Citrate blood tubes need ___parts fresh whole blood/1 part 3.8% trisodium citrate anticoagulant.

A

9

155
Q

Plasma refrigerated at 4 degrees C is usually stable for ___.

A

48 hours

156
Q

What does the APTT measure and what is it evaluating?

A

measures the time (s) required for fibrin clot formation in citrated plasma after addition of a contact activator of the intrinsic system, phospholipid that substitutes for platelet-derived phospholipid, and Ca
Evaluating the intrinsic and common pathways

157
Q

What diseases would you expect a prolonged APTT? (8)

A

hemophilia A, hemophilia B, XII deficiency, prekallikrein deficiency, DIC, Vit K antagonism, liver failure

158
Q

For APTT, factor activity must be <__% to prolong the test.

A

30%

159
Q

Will hemophilic carriers have prolonged APTT?

A

No–their factor activity is still 40-60% of normal

160
Q

Will VWD patients have prolonged APTT?

A

No– even though they usually have decreased VIII, it’s usually not less than 40% normal

161
Q

Does thrombocytopenia affect APTT?

A

No– the test provides a phospholipid substitute, so platelets not needed for it

162
Q

Does prekallikrein deficiency affect APTT?

A

usually not because ellagic acid used in the test bypasses need for kallikrein (other activators are sometimes used and that would affect the APTT)

163
Q

What does PT measure and what is it evaluating?

A

measures the time (s) required for fibrin clot formation to occur in citrated plasma after addition of thromboplastin (III) and calcium
Evaluating the extrinsic or common pathways

164
Q

What kind of thromboplastin must be used for reliable determination of PT in birds?

A

Chicken brain tissue

165
Q

What diseases would you expect a prolonged PT? (4)

A

VII deficiency, DIC, Vit K antagonism, liver failure

166
Q

Factor activity must be <___% to prolong the test.

A

30%

167
Q

What is the preferred test for evaluation of Vit K therapy response?

A

PT

168
Q

Does thrombocytopenia affect PT?

A

No– test reagents include phospholipids for assembly of coagulation factors

169
Q

What does TT measure and what is it used to evaluate?

A 
measures functional fibrinogen concentration
evaluates hypofibrinogenemia (prolonged) like in DIC, hereditary deficiencies, or dysfunctional fibrinogen disorders
170
Q

Would a Vit K deficiency/antagonism affect TT?

A

No–exogenous thrombin is added before the test is performed.

171
Q

What does the Russell viper venom test evaluate?

A

Prolongation implies deficiency in one or more factors in the common pathway

172
Q

How are FDPs made?

A

plasmin-mediated degradation of fibrinogen and fibrin

173
Q

How are FDPs measured?

A

Latex agglutination assay (antibody to fibrinogen added and agglutinate when FDPs there)

174
Q

When will FDPs be increased?

A

DIC, severe internal bleeding, localized thrombosis (like jugular thrombosis in horses)

175
Q

Are FDPs specific for primary versus secondary fibrinolysis?

A

No– FDPs include degradation products from both fibrinogen and fibrin

176
Q

Are D-dimers specific for primary versus secondary fibrinolysis?

A

Yes– they are made from just fibrin degradation so indicate secondary fibrinolysis

177
Q

How are d-dimers measured?

A

Either semi-quantitative (latex agglutination) or quantitative (immunoturbidimetric)– both use a monoclonal antibody that recognizes d-dimers

178
Q

How is AT activity measured?

A

on automated chemistry instruments using a chromogenic substrate

179
Q

Animals with <___% the control values of AT activity are at risk for thrombosis.

A

80%

180
Q

Animals with <___% he control value of AT activity may not be responsive to heparin therapy.

A

70%

181
Q

How can protein C be measured?

A

chromogenic and Laurell rocket techniques

182
Q

Protein C concentrations increase or decrease in hypercoagulative disorders and Vit K antagonism?

A

decrease

183
Q

Patients with homozygous protein C deficiency develop ___.

A

fatal neonatal purpura fulminans (fulminant thrombosis)

184
Q

What does TEG measure?

A

measures viscoelastic changes in blood during polymerization of fibrin

185
Q

What kind of sample is TEG measured on and why is it an advantage?

A

whole blood (anti coagulated with sodium citrate)–provides an assessment of the influence of cellular elements as well as plasma coagulation factors

186
Q

In a TEG tracing, what does R represent?

A

In a TEG tracing, what does R represent?

187
Q

In a TEG tracing, what does K represent?

A

K= clotting time/time from initial clot formation until a predetermined clot strength is reached

188
Q

In a TEG tracing, what does MA represent?

A

MA= maximum clot strength

189
Q

In a TEG tracing, what does alpha represent?

A

alpha= angle/rate of clot formation

190
Q

In a TEG tracing, which parameter depends on coagulation factor activity, fibrinogen, and platelets?

A

alpha

191
Q

In a TEG tracing, which parameter is determined by platelet number and function?

A

MA

192
Q
A
193
Q
A

Duncan and Prasse (2 decks)

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