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Residency > Hemostasis/Coagulation/Inflammatory Response > Flashcards

Hemostasis/Coagulation/Inflammatory Response Flashcards

1
Q

Platelets

A

-derived from karyocytes
-forms initial hemostatic plug that provides a surface for the assembly of activated coagulation factors leading to formation of fibrin stabilized platelet aggregates
-adhere to injured subendothelial tissue to undergo morphological change (aka degranulation)

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2
Q

Platelet alpha granules

A
  • P-selectin
  • fibrogen
  • fibronectin
  • factor V
  • factor VII
  • platelet factor IV
  • Platelet derived growth factor
  • THF- alpha
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3
Q

Platelet delta granules (dense granules)

A
  • ATP
  • ADP
  • Ca2+
  • serotonin
  • histamine
  • epi
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4
Q

Effects of ADP

A

ADP binding causes a confirmational change in GpIIb/IIIa receptors preserve on platelet surface causing deposition of fibrinogen

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5
Q

Initiation phase

A

-injury occurs, blood exposed to tissue factor bearing cells -> FVIIa binds to the exposed tissue factor -> activates more FVII to FVIIa -> activates FIX and FX.

-FXa activates FV

-FXa and FVa combine to form prothrombinase complex -> cleaves prothrombin to thrombin

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6
Q

Which is the only coagulation protein that routinely circulates in blood in its active form?

A

FVIIa

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7
Q

Vasodilation in acute vascular response induced by

A

-NO
-histamine
-leukotrienes
-prostaglandins
-complement factors

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8
Q

Vascular permeability caused by

A

-histamine and serotonin: increase the number and size of intracellular endothelial gaps
-interendothelial gaps formed by endothelial cell retraction caused by hypoxia, endothelial injury, cytokines, and other inflammatory mediators
-Direct trauma
-Leukocyte-mediated endothelial damage

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9
Q

Selectins

A

-Adhesion molecules on endothelial cells

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10
Q

Neutrophil extravasation

A

1) Margination and rolling of leukocytes along the vascular endothelium are mediated through interactions between endothelial selectins with their corresponding leukocyte ligands
2) Chemokines stimulate increased expression and enhanced binding affinity of leukocytes integrins, leading to firm adherence to endothelial cell integrins
3) Leukocyte diapedesis is facilitated by adhesion molecule, platelet-endothelial cell adhesion molecule-1 and leukocytes follow chemokine gradients to the site of injury.

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11
Q

Neutrophils produce which chemokines?

A

-IL-1 alpha
-IL-1
-IL-6
-IL-1 beta
-TNF alpha

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12
Q

Macrophages produce which cytokines?

A

M1:
-INF- gamma
-TNF- alpha
(debride affected site by phagocytosis of foreign material, pathogens, and damaged cells)
-IL-1 beta
-IL- 6
-TNF-alpha
(pro-inflammatory cytokines)

M2:
-IL-4
-IL- 13
-IL-10
(anti-inflammatory cytokines, secrete growth factors to simulate and wound repair and healing)

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13
Q

Mast cells release

A

-Histamine, serotonin, leukotrienes, prostaglandin metabolites, heparin, cytokines
-Mast cell degranulation enhances local inflammatory response

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14
Q

How do endothelial cells become active?

A

Cytokines and bacterial products (endotoxins) activate endothelial cells
-Rapid, transient upregulation of preformed and stored vWF and P-selectin
-This is followed by de novo expression of pro-inflammatory cytokines, chemoattractants, and adhesion molecules.

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15
Q

TLR

A

-pattern recognition receptors
-Type 1 transmembrane proteins that initiate intracellular signaling cascades -> activate NFKB -> leads to altered gene transcription
-Play a role in the release of inflammatory cytokines from the innate immune system

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16
Q

Histamine

A

-Vasoactive amine
-Released in response to physical injury, antibody binding, complement protein binding
-interacts with H1 receptors on endothelial cells during inflammatory response to cause vasodilation and increase endothelial permeability

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17
Q

TNF-alpha

A

-Activated M1 macrophages are a major source of TNF-alpha
-Initiates production of proinflammatory cytokines, reactive oxygen intermediates, chemotaxins, and endothelial adhesion molecules, which all facilitate recruitment of cells to the site of inflammation

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18
Q

IL-6

A

-Produced by macrophages, T-cells, epithelial cells, enterocytes
-initiates compensatory anti-inflammatory responses and downregulates pro-inflammatory cytokine production
-Considered a prognostic biomarker of inflammation

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19
Q

IL-1

A

-Denotes several cytokines produced by macrophages and other cell types
-IL-1beta has pro-inflammatory functions similar to TNF-alpha -> further enhances inflammation

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20
Q

IL-10

A

-Anti-inflammatory cytokine produced by CD4+ Th2 T-cells, monocytes, B-cells
-Depresses the production of pro-inflammatory cytokines and chemokines -> inhibits translocation of NFKB

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21
Q

Arachidonic acid

A

-Stored in the cell membranes of endothelial cells, leukocytes, and other cells
-Released by activated phospholipase A2
-Inhibited by glucocorticoids because they inhibit phospholipase A2 and upregulate genes encoding antiinflammatory proteins

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22
Q

Prostaglandins

A

-Produced by the cyclooxygenase pathway, where arachidonic acid metabolism is catalyzed by enzymes, COX-1 and COX-2.
-Prostaglandins mediate many inflammatory responses primarily through GPCR on a number of cell types.
-They are chemotactic agents that cause
leukocyte recruitment and vasodilation, contributing to the pathogenesis of pain and fever during
inflammation
-COX enzymes are inhibited by aspirin and NSAIDS

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23
Q

Platelet activating factor

A

-Metabolized by cell membrane phospholipids by phospholipase A2
-Synthesis modulated by MAPK intracellular signaling pathways
-Platelet activating factor binds to GPCR on various cells where it stimulates arachidonic acid release and increases eicosanoid production
-Proinflammatory
-Platelet aggregation and degranulation

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24
Q

Nitric Oxide

A

-Synthesized from amino acid L-arginine by the enzyme nitric oxide synthase
-Causes vasodilation by diffusing into smooth muscle cells and indirectly initiating intracellular signaling events leads to smooth muscle relaxation
-antagonizes the vasoconstrictive effects of angiotensin II, endothelins, and ROS

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25
Q

Negative acute phase proteins

A

-Albumin is the main one

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26
Q

Positive acute phase proteins

A
  • In response to pro-inflammatory cytokines, peak within 24-48 hours
    -remain elevated while inflammatory persists
    -enhance protective host functions by minimizing tissue damage and enhancing repair
    -C-reactive protein, serum amyloid A, serum amyloid P, complement proteins
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27
Q

C-reactive protein

A

-Positive acute phase protein
-Binds to bacteria and promotes activation of complement

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28
Q

Bradykinin

A

-endothelial prostacyclin synthesis
-superoxide formation
-tissue plasminogen activator release
-venous dilation through NO release
-increases vascular permeability
-produces associated pain response

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29
Q

Substance P

A

-Secreted by inflammatory leukocytes and by neurons in the respiratory tract, GI tract, CNS, skin, and genitourinary system
-Binds to GPCR (NK-Rs) and transmits pain and pro-inflammatory signals on effector cells, including neurons, endothelial cells and leukocytes

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30
Q
A
31
Q

Cryoprecipitate involves

A

vWf, factors V and VIII

32
Q

Acute Traumatic Coagulopathy

A

Caused by endothelial glycocalyx disruption, hemodilution, hypothermia, academia, systemic inflammation, hypo perfusion

33
Q

DIC vs ATC

A

DIC is considered a hypokable condition with an early prothrombotic and anti-fibrinolytic tendency that progresses to a consumptive coagalopathy and fibrinolytic state.

ACT is a process at limits thrombin generation early on there’s lack of microthrombin lack of clotting platelet sparing

34
Q

Virchow’s triangle

A

Includes endothelial dysfunction, hypercoagulability of blood, and blood stasis/altered blood flow

Can lead to a predisposition to thrombotic disease

35
Q

Endothelial glycocalyx

A

Composed of a large network of negatively charged glycominoglycans (GAGs), proteoglycans, and glycoproteins.

Heparin sulfate accounts for 50 to 90% of the proteoglycans and facilitates binding of antithrombin which increases the efficiency of antithrombin mediated inhibition of thrombin.

Other important anticoagulants that bind to glycocalyx include heparin cofactor II and TM.

Tissue factor pathway inhibitor localizes to the glycocalyx.

Glycocalyx also serves as a mechano receptor which can release nitric oxide during conditions of interested sheer stress

36
Q

Activation of endothelial cells can be done by…

A

TNF-alpha, bradykinin, thrombin, histamine, and vascular endothelial growth factor.

37
Q

Once activated, endothelial cells release…

A

Ultra large multimers of vWF, p - selectin, IL8, tPA, factor VIII

38
Q

Role of tissue factor in coagulation

A

Endothelial disruption exposes procoagulant substances such as tissue factor to the circulating blood.

Coagulation is initiated through the interaction of TF with activated factor VII.

TF can also be found on monocytes and macrophages that have been activated by inflammation and have also been identified on some neoplastic cells. TF perpetuates inflammation through the activation of NFKB, leading to the production of TNF alpha

39
Q

What happens when platelets activate?

A

They increase the number of copies of the active fibrinogen receptor on their surface (glycoprotein IIbIIIa or integrin alphaIlbbeta3). The contents of the alpha and dense granules are secreted releasing procoagulant elements such as calcium, factor 5A, serotonin, fibrinogen, p - selectin, and ADP

40
Q

What is found in feline alpha granules?

A

vWF

41
Q

Microparticles

A

Circulating small vesicles released from activated or apoptotic cells.

Can be derived from platelets, and othelial cells, leukocytes, erythrocytes, and neoplastic cells.

Like platelets, MPs can provide an asymmetric phospholipid membrane for thrombin generation. They express TF on their surface and some that express PS and TF on their surface are considered pro-coagulant MPs.

Possibly induces coagulation through activated VII-TF pathway

Pro-coagulant MPs may have vWF sites that can tether and activate circulating platelets

42
Q

NETS

A

Neutrophil extracellular traps

Released from activated neutrophils and consist of nuclear contents including DNA, histones and some extra nuclear proteins.

Thought to immobilize and sequester microbial elements as a response to septicemia. Also released following interaction with PAMPs.

Nets can be antimicrobial and also procoagulant.

43
Q

Primary anticoagulant proteins:

A

1) AT
2) protein C
3) TFPi

44
Q

Antithrombin

A

Acts primarily to inhibit thrombin and factor Xa

It is most effective when bound to heparin like GAGs (heparin sulfate) or when exposed to exogenous heparins.

Typically decreased in systemic inflammation or critical illness via consumption, decreased production, or degradation.

Patients with glomerulonephritis may also lose AT through urine.

45
Q

Protein C

A

Important inhibitor of factor Va and VIIIa.

Becomes activated when trace amounts of thrombin bind TM on the endothelium of the microcirculation.
This reaction also prevents thrombin from acting on fibrinogen and platelets and generates thrombin activitable fibrinolysis inhibitor.

Protein C is less functional during systemic inflammation due to decreased hepatic synthesis of proteins CNS.

46
Q

TFPI

A

Tissue factor pathway inhibitor

Released from endothelial cells and acts to inhibit fVIIa-TF complex and factor Xa

Also released from platelets, mononuclear cells, vascular smooth muscle, cardiac myocytes, fibroblast and megacaryocytes

47
Q

Plasmin

A

Plasmatogen is the precursor

Converted into plasmin by fibronolytic activators including tPA and urokinase

Breaks down fibrin meshwork of formed clots

48
Q

Plasminogen activator inhibitor

A

PAI-1

Decreases the effects of plasminogen

49
Q

Septic dogs have a lower ______ and ______ That support a consumptive coagulopathy.

A

Protein C
AT

50
Q

Septic dogs demonstrate what on their blood work showing consistency with consumptive coagulopathy?

A

-prolonged aPTT and/or PT
-higher FDP
-higher d-dimer concentrations
-lower fibrinogen concentration
-lower platelets

51
Q

Are proteins C and S increased or decreased during hypercoagulability?

A

Decreased, thought to be more likely a response to widespread activation of coagulation

52
Q

Factors that lead to an increased MA (maximal amplitude) on TEG include:

A

Fibrinogen, platelet count and function, hematocrit

53
Q

Propose mechanism of ITP in dogs and cats

A

Increased phagocytosis by splenic macrophages due to autoantibodies found to platelet integrin (fibrinogen receptor) or glycoprotein (vWF receptor)

54
Q

Sepsis mediated thrombocytopenia caused by

A

Increase platelet consumption due to direct microbial platelet interactions, platelet leukocyte aggregate formation, increase platelet sequestration secondary to microvascular thrombus.

Bacteria such as e coli and streptococcus can directly interact with platelets through a variety of molecular interactions leading to platelet activation and aggregation

55
Q

Canine platelets directly interact with pathogens by expressing functional ____, which augments platelet activation in the presence of ____ and _____.

A
  • toll-like receptor 4
  • lipopolysaccharides
  • ADP
56
Q

Canine platelets directly interact with pathogens by expressing functional ____, which augments platelet activation in the presence of ____ and _____.

A
  • toll-like receptor 4
  • lipopolysaccharides
  • ADP
57
Q

Acquired platelet disorders

A

Uremia: causes defects in platelet adhesion, secretion, aggregation. Mechanism unclear.

Liver disease: dogs with hepatic malignancy and cirrhosis have a lower platelet count than those with hepatitis leading to decreased platelet cycloocygenase and thromboxane synthetase activities. These enzymes are crucial for converting arachidonic acid to platelet agonist thromboxane A.

Heart disease: platelets are hyperactive in response to adenosine diphosphate (a potent platelet agonist)

Medications

58
Q

Cyclooxygenase (COX)

A

Rate limiting enzyme that converts arachidonic acid to eicosanoids

COX-1: prostaglandins, thromboxane (platelets)

COX-2: Prostaglandins (inflammatory sites and macrophages)

59
Q

Do platelets express Cox 1 or Cox 2?
What is the MOA?

A

Platelets Express mainly Cox-1 which is irreversibly inhibited by acetyl salicyclic acid thereby modulating the biosynthesis of thromboxane a2 and prostaglandin.

NSAIDs are selective Cox-2 inhibitors. Will not inhibit platelet function.

60
Q

HES effects on platelets

A

Binding of the colloid molecules on the extracellular domains of integrin alphaIIbbeta3 or glycoprotein 1B inhibits their confirmational changes and subsequently platelet aggregation and
adhesion.

Binding of colloid molecules interferes with factor VIII/vWF complex leading to accelerated elimination.

HES may exert inhibitory effects in platelets by interfering with intracellular signaling function.

61
Q

Classification of platelet dysfunction

A

A: defect in platelet receptors for adhesion
B: defect in platelet receptors for agonists
C: platelet granule defect
D: defect in signal transduction
E: defect information of pro-coagulant membrane

62
Q

Von Willebrands disease

A

Deficiency or dysfunction in vWF, which is produced by endothelial cells.

Type 1: reported in Dobermans, autosomal recessive disorder caused by mutations in the gene

Type 2: qualitative abnormalities in vWF (2A, 2B, 2M, 2N)

Type 3: most severe form, complete absence of vWF, can cause life-threatening hemorrhage following trauma or procedures

63
Q

Glanzmann thrombasthenia

A

Mutations in ITGA2B gene -> abnormal expression of alphaIIb subunit

Subunit required for platelet aggregation and thrombus formation. Without it, hemorrhage has been reported

Prolonged bugle mucosal bleeding times, definitive diagnosis requires flow cytometry or Western plot analysis or DNA testing

Great Pyrenees

64
Q

P2RY12 gene

A

Black or deficiency in receptors for this gene significantly diminishes ADP induced activation an integrin activation

Leads to impairment in the ADP induced fibrinogen binding on the platelet surface and diminished platelet aggregation

In cats it may lead to clopidogrel resistance

65
Q

DDAVP

A

Can shorten vehicle mucosa bleeding time in dogs with aspirin induced platelet dysfunction as well as clotting times and dogs with chronic liver disease

66
Q

Intrinsic pathway

A

Factors 12, 11, 9, 8

aPTT

67
Q

Extrinsic pathway

A

Tissue factor activates factor VII

PT

68
Q

Primary hemostasis

A

Platelet number and function, vWF

69
Q

Secondary hemostasis

A

Clotting factors

Cofactors (calcium, vit K)

70
Q

Fibrinolysis

A

Plasmin, tPA

71
Q

Cell base model of hemostasis

A

Initiation, amplification, propagation

72
Q

Hyperfibrinolysis associated with

A

Massive trauma
Acute liver dysfunction
Spontaneous hemoperitoneum

73
Q

Vitamin k dependent factors

A

2,7,9,10

Seven has the shortest half life of these factors

PT will be more prolonged than PTT

74
Q

Fibrinolysis is evaluated using

A

FDP and d-dimer assays

Residency (14 decks)

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