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ACVP Phase II - Clinical Pathology > Harvey Chapter 7 Evaluation of Hemostasis PART I: Platelet Disorders (with Schalm's) AKG > Flashcards

Harvey Chapter 7 Evaluation of Hemostasis PART I: Platelet Disorders (with Schalm's) AKG Flashcards

1
Q

Where is vWF stored?

A

Endothelial Weibel-Palade bodies (only trace amounts in platelets)

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2
Q

vWF circulates in multimers of various sizes bound to ____.

A

FVIII (preserves half life of FVIII) - hence ‘factor VIII related antigen’

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3
Q

vWF binds to subendothelial collagen and undergoes a conformational change to be able to bind to _____ on platelets.

A

GP1b

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4
Q

____ multimers are most effective for wWF adhesion to platelets.

A

HMW

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5
Q

This molecule breaks down multimers of vWF into smaller ones.

A

ADAMST13

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6
Q

In type __ vWD, there is a partial quantitative deficiency (<50%) of wWF, but the remaining wWF remains in all multimer sizes with normal structure and function.

A

Type I

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7
Q

Which vWD has a functional loss in vWF (loss of large/HMW vWF multimers)?

Which assay is used to detect functional loss?

A

Type 2A

Functional assay: collagen binding assay (vWF needs to be functional in order to bind to collagen)

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8
Q

Which type of vWD results in complete vWF deficiency (<0.1%)?

A

Type 3

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9
Q

Which vWD subtypes are recessive vs dominant inheritance?

A

Type 1 – dominant

Type 2A and Type 3 – recessive

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10
Q

Type 1 vWD leads to _____ bleeding, while type 2A and type 3 lead to _____ bleeding.

A

Type 1 - mild to severe

Type 2A and 3 - severe

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11
Q

Type 1 and 2A vWD will have _____ VWF:Ag; type 3 vWD will have ____ VWF:Ag.

How do you differentiate type 1 from 2A?

A

Low

Absent

Collagen binding assay (VWF:CB) - need HMW multimers of vWF to bind to collagen. HMW multimers are present in type 1, but not in type 2A.

You can also use protein electrophoresis and western blots to look at vWF multimers - but these tests are mainly done for research, and not common clinically.

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12
Q

____ and ___ are the two best quantitative assays for measuring VWF antigen (VWF:Ag)

A

ELISA and latex immunoassay

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13
Q

What does it mean to have 120% of vWF antigen? Is this clinically significant?

A

Platelets have 20% mroe than the average pool. Not clinically significant.

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14
Q

What are the three categories of primary hemostasis disorders?

A
  1. Thrombocytopenia
  2. Platelet function (issue with platelet aggregation)
  3. vW disease
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15
Q

What are two POC assays that serve as screening tests for vWD if you suspect bleeding disorder and platelet count is normal and coag profile is normal?

A

BMBT

Platelet function analyzer (PFA-100)

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16
Q

PFA-100 measures platelet plug formation in whole blood under _____. The endpoint (closure time) is the occlusion of an aperture coated with _____ (mimics exposure of subendothelium when endothelium gets injured) and platelet clumping agonist (____ or _____).

A

High shear flow

collagen

ADP or epinephrine

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17
Q

PFA-100 will be prolonged by which subtypes of vWD?

Is this test specific?

A

all vWD types

this test is nonspecific, and will be affected by thrombocytopenia and anemia

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18
Q

What is the difference between an intrinsic and extrinsic platelet disorder?

Why is it important to classify between the two?

A

An intrinsic platelet disorder is a defect in platelets causing platelet dysfunction or thrombocytopenia.

An extrinsic platelet disorder is a defect in serum or subendothelial collagen affecting platelet adhesion (e.g., vWD, hypo/dysfibrinogenemia).

You will see petechia and ecchymotic hemorrhage and prolonged mucosal bleeding times and normal coagulation profile with both.

Transufsion products for intrinsic vs extrinscic disorders differ.

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19
Q

Inherited macrothrombocytopenia occurs in this dog breed _____, and is the result of a _____ deficiency. Is it associated with clinical bleeding?

A

Cavalier King Charles Spaniels

Beta-1-tubulin deficiency - not associated with clinical bleeding

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20
Q

Glanzmann Thrombasthenia is a mutation resulting in the absence (< 5%) of ______ receptor. This results in a functional issue with platelet ____. There is no clot retraction and platelets fail to aggregate in response to any/all agonists (even thrombin).

A

GPIIb-IIIa (aka αIIb-ßIII) –> this is the fibrinogen receptor, and results in an issue with platelet bridging.

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21
Q

Cyclic hematopoiesis is an inherited disorder of ______ that affects three cell types (____, _____, and ____). Platelet counts are _____ and platelet function is ______. There is an absence of ____ granules and defective reactivity to platelet agonists. The mutation was found in gene _____.

A

Grey collies

neutrophils, reticulocytes, platelets

Plt counts are normal, platelet function is decreased

Dense granules

AP3ß1

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22
Q

This syndrome involves abnormal leukocyte, melanocyte, and platelet granulation and results in increased infections and bleeding diathesis. It alters platelet function by having absent ___ granules. These granules contain ADP which is responsible for _____ of platelets in response to ____. The mutation is found in the ____ gene. Species affected?

A

Chediak-Higashi syndrome

Dense granules

aggregation

collagen

LYST gene (lysosomal trafficking regulator)

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23
Q

Calcium diacylglycerol guanine nucleotide exchange factor I (CalDAG-GEFI) thrombopathias is a platelet _____ disorder that results in a conformation change in ______ (therefore it does not affect #, just function).

It mostly affects ____, and often is referred to as canine thrombopathia in literature. Other breeds/species affected include ____, ____, and ____.

There is ______ platelet aggregation responses to ADP/collagen.

There is ____ platelet aggregation response to thrombin, making clot retraction assays ____ becuase they use thrombin.

A

Signal transduction

GPIIß-IIIα

Bassets (1/3rd are carriers); Eskimo, Lanseers, Simmental Cattle

absent platelet aggregation in response to ADP/collagen

mildly decreased platelet aggregation in response to thrombin; making clot retraction assays normal.

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24
Q

List the contents of platelet dense granules (5)

A

ADP

ATP

Serotonin (5-HT)

Calcium

Magnesium

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25
Q

This canine congenital platelet dissorder associated with bleeting is a _____ disorder and causes decreased/absent activation of beta-integrins on leukocytes and platelets. It is found in this canine breed.

A

kindlin-3; signal transduction disorder

German Shepherd

26
Q

This intrinsic platelet disorder is more specifically a procoagulant expression disorder that occurs in the _____ and results in lack of phosphatidylserine expression on the outer membrane, and membrane microvesiculartion failure upon activation with calcium ionophore. Platelet aggregation, BMBT, and clot retraction times are ____. It causes problems because platelets are unbale to generate and support a surface for coagulation protein activation (so kind of more a secondary hemostasis problem). Which flow cytometry marker can be used to detect it?

A

Scott syndrome

GSD

Normal

Annexin V - on flow, it is markedly reduced.

27
Q

List differntials for acquired platelet dysfunction/hypofunction:

A
  • Uremia
  • Antiplatelet antibodies
  • Infection/inflammation/neoplasia (hyperglobulinemia - globulins coat platelet surface and impaire adhesion and aggregation)
  • Increased fibrinolytic products (FDPs) - increased fibrinolysis or decreased clearance secondary to liver disease
  • Snake evenomation (modulation of ADP/TXA2 release; ROS; interaction with receptors)
  • NSAIDS: COX inhibitors (decreased TXA2 which is a potent platelet agonist), aspirin, and phenylbutazone causing transient platelet dysfunction in horses
28
Q

Platelets have an open canalicular system that is continuous with surface membrane in which veterinary species?

A

Small animals, but NOT in horses and cattle

29
Q

What is the mean platelet life span (dogs, cats, horses, cattle)?

A

4-6 days

30
Q

Splenectomy _____ lifespan of platelets.

A

increases (spleen removes aged platelets)

31
Q

Thrombocyte counts are ___ in non-mammlian than mammalian species.

A

Lower

32
Q

How do platelets generate ATP?

A

Krebs cycle and oxidative phosphorylation (have mitochondria)

AND anaerobic glycolysis

33
Q

Majority of adenine nucleotides (~ 2/3rds) is stored within ____ of platelets. ADP/ATP ratio is ___, which is opposite to the cytoplasm.

A

dense granules; 1.5; in cytoplasm you have more ATP>ADP

34
Q

Activated platelets secrete _____ from α-granules, which binds heparin-like moelcules on endothelial surfaces and displaces ______ to promote coagulation.

A

PF4 (CXCL4); displaces antithrombin

35
Q

Platelet activation results in the translocation of PS from the inner surface to the outer membrane surface. PS on the outer membrane will bind to ___ and serve as a nucleation site for the assembly of these two main coagualtion factor complexes ____ and _____. This promotes accelerated coagulation.

A

Calcium

tenase (IX + VIII) –> activates FX

prothrombinase (X+V) –> activates FII

36
Q

In addition to clotting, platelets are important for maintaining normal vascular integrity. One important protective vasoactive molecule stored and secreted from platelets is ____.

A

Sphingosine-1 phosphate

37
Q

Under high shear conditions, _____ and ____ will bind to platelet GP1b/IX/V. Under low shear/static conditions, platelets adhere directly to collagen in subendothelium using ____ and ____ receptors.

A

vWF and thormbospondin-1

GPVI and GP1a-IIa receptors

38
Q

NO and PGI2 serve as potent vaso____ and ____ platelet activation.

A

vasodilators

inhibit

39
Q

Anaplasma platys infection in dogs results in cyclic ____ and concurrent ____ that occur at 1-2 week intervals.

A

parasitemia and thrombocytopenia

40
Q

How to dx anaplasma platyis infection?

A

A. platys is cross reactive with A. phagocytophilum in Snap4Dx

PCR and 16SrRNA gene squencing

IFA for anitbodies against A. platys - will cross react with other rickettsial diseases

41
Q

Pseudothrombocytopenia is most common when using which anticoagulant? How does this occur?

A

Most commonly with EDTA

Hidden epitopes are unmasked in GpIIbIIIa d/t calcium chelation –> results in auto-antibody mediated platelet clumping.

42
Q

Thrombocytosis may result in pseudo_____ in serum becuase ___ is released during clotting. This is only significant with thrombocytosis because reference intervals of this analyte are accounted for with normal thormobocyte concentrations.

A

hyperkalemia; potassium

43
Q

TPO is involved in fragmentation from megakaryocytes. T/F

A

False

44
Q

What are causes for pseudothrombocytosis?

A
  • Small RBCs
  • Fragmented RBCs
  • Hemolyzed RBCs
  • Leukocyte fragments
  • Particulate cell debris
45
Q

What causes physiologic thrombocytosis?

A

Epinephrine release (~30% of platelets are stored in the spleen)

46
Q

List the drugs responsible for drug-induced thrombocytosis.

A

Vincristine

Epinephrine

Endogenous glucocorticoids (NOT exogenous GCs)

47
Q

Reactive thrombocytosis caused by ___ and ___ is the most common cause of thrombocytosis. What cytokine is the main mediator?

A

INflammation and neoplasia; IL-6

48
Q

Iron deficiency may result in thrombocytosis. T/F

A

True

49
Q

Thrombocytosis is a common feature of all chronic myeloproflierative diseases, so it is difficult to differentiate essential thrombocythemia from polycythemia vera or CML. T/F

A

True

50
Q

LIst the main mechanisms that can cause thrombocytopenia (give specific examples under each mechanism)

A
  1. Decreased production (hypoplastic BM, myelophthisis, FeLV, FIV)
  2. Increased platelet utilization (DIC, thromboembolism, hemangiosarcoma, vasculitis, inflammation)
  3. Increased platelet destruction (primary vs secondary IMT)
  4. Sequestration of platelets (splenomegaly from hemolytic anemia/immune-mediated dz; congestion; splenic torsion; hypothermia causes sequestration in the liver)
  5. Massive external hemorrhage (esp. with rodenticide tox, accentiuated by dilutional effect of platelet poor fluid)
  6. Infections
  7. Drug and chemical induced (chemo, cephalosproins, sulfonamides, griseofulvan, NSAIDs, methimazol and propylthiouracil, azathioprine, phenobarbital, antiviral drug ribavirin, toxins)
  8. Neoplasia (lymphomas and hemangiosarcoma MC)
  9. Inherited macrothrombocytopenia in CKC spaniel dogs
51
Q

How does hypthermia in dogs cause thrombocytopenia?

A

sequestration of platelets in the liver

52
Q

WHich inflammatory cytokines inhibit platelet production?

Which promote platelet aggregation?

Which promotes platelet production?

Which enhances platelet phagocytosis?

A

IL-10 and IFN-a

PAF

IL-6

M-CSF and GM-CSF

53
Q

List the drugs and chemicals that result in thrombocytopenia.

A
  • Cancer chemotherapeutic agents
  • Antimicrobials: cephalosporins, sulfonamides, dapsone, griseofulvin
  • NSAIDs: phenylbutazone, carprofen
  • Antithyroid drugs: methimazole, propylthiouracil
  • Immunosuppressive azathioprine
  • Exogenous or endogenous estrogens in dogs and ferrets
  • Dextroamphetamine and amphetamine
  • Phenobarbital
  • Antiviral drug ribavirin
  • Antipsoriasis cream capcipotriol
  • Toxins: Trichothecenes, bracken fern, phenol, fluoroacetate, Macrozamia seeds
54
Q

Platelet aggregate formation in cats can be decreased with ____ vacuum tubes containing platelet inhibitors.

A

CTAD (citrate, theophylline, adenosine, dipyridamole)

55
Q

Which breeds are platelet counts generally lower?

A

Polish Ogar Dogs

Greyhounds

Cavalier King Charles spaniels

56
Q

Normal to decreased MPV does not rule out thrombopoiesis. This is becuase dogs with IMT often have normal to low MPVs due to the presence of platelet ____.

A

Fragments

57
Q

MPVs are higher in ___thyroid cats and lower in ___thyroid dogs.

A

higher hyperthyroid cats

lower in hypothyroid dogs

58
Q

Platelet function analyzer (PFA-100 is an in-vitro modified bleeding time test to assess platelet function. It uses ___ plasma and depends on platelet adhesion, secretion, and aggregation. Blood is drawn through a ____ shear rate through an aperture caoted with agonists (___ and ___ or ____ and ___). The closure time is recorded as the time required for the aperture to be ____ with platelet aggregates and for blood flow to ___.

Decreased platelet counts and anemia will result in ____ closure times.

A

PAF is an in-vitro modified bleeding time test that uses citrated plasma and depends on platelet adhesion, secretion, and aggregation. Blood is drawn at a high shear rate through an aperture coated with agonists (collagen and epinephrine – CEPI; or collagen and ADP – CADP). The closure time is recorded as the time required for the aperture to be occluded with platelet aggregates and for the blood flow to stop. While this analyzer assesses platelet function, decreased platelet counts will result in prolonged “closure” times, as well as a low hematocrit – limiting the applicability of the PFA-100 in anemic patients.

59
Q

Platelet aggregometers that use platelet-rich plasma are evaluated via ____ whereas those that use whole-blood are evaluated using ______.

A

spectrometry

electrical impedence (as activated platelets aggregate to two electrodes - impedence increases)

60
Q

The three main aggregating agents used to evaluate platelet aggregateion are:

A

ADP, collagen, epinephrine

61
Q

What is the traditional gold standard platelet function test? Explain how the test works.

A

Light-transmission aggregometry (LTA) - after agonist is added to the sample, responsive platelets change shape from discoid to tiny spheres –> causes a transient decrease in light transmission. This is followed by increase in transmitted light as platelets continue to aggregate. As the size of the platelet clumps grow, more light is transmitted until a sustained plateau is reached representing maximal, irreversable platelet aggregation.

62
Q

____ is a modified technique of light-transmission aggregometry (LTA) which can detect _____ resulting from the release of ATP in the aggregation reaction mixture. ATP release is quantified through its reaction with a chemiluminsecent reagent called ____. This technique can also measure platelet _____ using whole blood in dogs.

A

Lumi-aggregometry

Chrono-lume

Secretion

ACVP Phase II - Clinical Pathology (14 decks)

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