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Hemostasis/Coagulation/Inflammatory Response Flashcards

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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
Negative acute phase proteins
-Albumin is the main one
26
Positive acute phase proteins
- 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
27
C-reactive protein
-Positive acute phase protein -Binds to bacteria and promotes activation of complement
28
Bradykinin
-endothelial prostacyclin synthesis -superoxide formation -tissue plasminogen activator release -venous dilation through NO release -increases vascular permeability -produces associated pain response
29
Substance P
-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
30
31
Cryoprecipitate involves
vWf, factors V and VIII
32
Acute Traumatic Coagulopathy
Caused by endothelial glycocalyx disruption, hemodilution, hypothermia, academia, systemic inflammation, hypo perfusion
33
DIC vs ATC
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
Virchow's triangle
Includes endothelial dysfunction, hypercoagulability of blood, and blood stasis/altered blood flow Can lead to a predisposition to thrombotic disease
35
Endothelial glycocalyx
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
Activation of endothelial cells can be done by...
TNF-alpha, bradykinin, thrombin, histamine, and vascular endothelial growth factor.
37
Once activated, endothelial cells release...
Ultra large multimers of vWF, p - selectin, IL8, tPA, factor VIII
38
Role of tissue factor in coagulation
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
What happens when platelets activate?
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
What is found in feline alpha granules?
vWF
41
Microparticles
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
NETS
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
Primary anticoagulant proteins:
1) AT 2) protein C 3) TFPi
44
Antithrombin
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
Protein C
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
TFPI
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
Plasmin
Plasmatogen is the precursor Converted into plasmin by fibronolytic activators including tPA and urokinase Breaks down fibrin meshwork of formed clots
48
Plasminogen activator inhibitor
PAI-1 Decreases the effects of plasminogen
49
Septic dogs have a lower ______ and ______ That support a consumptive coagulopathy.
Protein C AT
50
Septic dogs demonstrate what on their blood work showing consistency with consumptive coagulopathy?
-prolonged aPTT and/or PT -higher FDP -higher d-dimer concentrations -lower fibrinogen concentration -lower platelets
51
Are proteins C and S increased or decreased during hypercoagulability?
Decreased, thought to be more likely a response to widespread activation of coagulation
52
Factors that lead to an increased MA (maximal amplitude) on TEG include:
Fibrinogen, platelet count and function, hematocrit
53
Propose mechanism of ITP in dogs and cats
Increased phagocytosis by splenic macrophages due to autoantibodies found to platelet integrin (fibrinogen receptor) or glycoprotein (vWF receptor)
54
Sepsis mediated thrombocytopenia caused by
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
Canine platelets directly interact with pathogens by expressing functional ____, which augments platelet activation in the presence of ____ and _____.
- toll-like receptor 4 - lipopolysaccharides - ADP
56
Canine platelets directly interact with pathogens by expressing functional ____, which augments platelet activation in the presence of ____ and _____.
- toll-like receptor 4 - lipopolysaccharides - ADP
57
Acquired platelet disorders
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
Cyclooxygenase (COX)
Rate limiting enzyme that converts arachidonic acid to eicosanoids COX-1: prostaglandins, thromboxane (platelets) COX-2: Prostaglandins (inflammatory sites and macrophages)
59
Do platelets express Cox 1 or Cox 2? What is the MOA?
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
HES effects on platelets
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
Classification of platelet dysfunction
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
Von Willebrands disease
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
Glanzmann thrombasthenia
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
P2RY12 gene
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
DDAVP
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
Intrinsic pathway
Factors 12, 11, 9, 8 aPTT
67
Extrinsic pathway
Tissue factor activates factor VII PT
68
Primary hemostasis
Platelet number and function, vWF
69
Secondary hemostasis
Clotting factors Cofactors (calcium, vit K)
70
Fibrinolysis
Plasmin, tPA
71
Cell base model of hemostasis
Initiation, amplification, propagation
72
Hyperfibrinolysis associated with
Massive trauma Acute liver dysfunction Spontaneous hemoperitoneum
73
Vitamin k dependent factors
2,7,9,10 Seven has the shortest half life of these factors PT will be more prolonged than PTT
74
Fibrinolysis is evaluated using
FDP and d-dimer assays
75
Platelet inhibitors
NO Prostacyclin (PGI2) ADPase
76
Anticoagulants
Antitheombin Thrombomodulin TFPI
77
Fibrinolysis activators
tPA
78
Normal hemostasis
-Reflex vasocontriction -Primary hemostasis -Secondary hemostasis -Fibrinolysis
79
Primary hemostasis
Initiation -> extension -> stabilization
80
Initiation
Endothelial disruption exposes prothrombotic substances (vwf, tf, collagen) in the subendothelium. Vwf binds GP-I -IX-V platelet receptor leads to tethering and rolling of platelets Collagen binds to the GP-VI receptor leading to further slowing down of the platelets and activation
81
82
Extension
Platelets are activated and go through a shape change leading to the formation of a procoagulant membrane that allows recruitment of additional platelets. Requires thrombin, thromboxane A2, and ADP Instagrams are essential to platelet aggregation
83
Cell membrane
-Anticoagulant -Have lipid membrane bilayers -inactive membrane state: -PC, sphingomyelin, sphingolipids EXTERNAL -PS, PE INTERNAL
84
Enzymes involves in maintaining cell resting state
-Flippase: transports PS from the external to internal leaflet -Floppase: PC from internal to external leaflet
85
Scramblase
When cells are activated or injured, scramblase shuffles PS and PE to OUTER leaflet
86
87
88
Platelet granules
Alpha, delta Alpha integral for hemostasis, thrombosis, inflammation, vascular healing. Delta contains ADP, serotonin, histamine
89
Stabilization
Platelets of platelet interactions allow for platelet aggregation and stabilization of the initial clot. Involves integrin which binds to fibrinogen.
90
91
Intrinsic pathway
12,11,9,8 These factors are contained within blood aPTT/ACT
92
Extrinsic pathway
VII, TF Contained within tissues/endothelium PT
93
Vitamin k dependent factors
2,7,9,10, protein C, protein S
94
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96
Cell based model of coagulation
Three phases: -initiation -amplification -propagation Requires tissue factor and platelets
97
What factor circulates in the blood and it's active form?
VIIa Binds to tissue factor, which then activates additional VIIa
98
How do factors 9 and 10 become active?
By the tenase complex (TF-VIIa)
99
What does factor 10 activate?
Xa activates V in small amounts. Xa and Va together form the prothrombinase complex, which cleaves prothrombin to thrombin. Any dissociated Xa is an activated by TFPI and AT
100
Amplification of the cell-based model
Thrombin binds to platelets that causes shape change, which then causes shuffling of the membrane phospholipids and the release of granules. Thrombin activates factors 5, 8, 11 It cleaves vwf from VIIIa
101
Propagation
A thrombin burst results in conversion of fibrinogen to fibrin to form the clot
102
Anticoagulant properties of endothelial cells
-HSPGs: is a binding site for antithrombin -TM: combines with thrombin to activate protein c, which is an anticoagulant -TFPI: Inhibits Xa and VIIa, prevents participation in thrombin formation
103

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