MBM > Hemostasis > Flashcards

Hemostasis Flashcards

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1
Q

hemophilia?

A

tendency to bleed

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2
Q

thrombophilia?

A

tendency to clot

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3
Q

hemostasis?

A
  • stoppage of blood flow through blood vessel through balance of procoagulants and anticoagulants
  • when injured vessel, the goal is to produce a platelet and fibrin plug (thrombosis) in order to seal an injured blood vessel wall
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4
Q

blood vessel structure?

A
  • tunica intima- endothelium, interior of blood vessel, have opposite of clotting effects
  • tunica media- smooth muscle is in middle, constrict vessel to decrease flow of blood and inhibits loss of blood, elastic fibers
  • tunica adventitia- collagen fibers, allows for platelets to adhere to site of injury and initiate formation of platelet plug
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5
Q

what happens after a vessel is injured?

A
  1. immediately vascular spasm (constriction)
  2. formation of platelet plug
  3. blood coagulation (fibrin>thrombin), clot 3-6 mins
  4. growth of fibrous tissue into the clot to close hole permanently
    - 3 simultaneous reactions:
  5. platelet aggregation
  6. fibrin formation
  7. vessel contraction
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6
Q

What things are flowing through a blood vessel?

A
  • RBC- don’t clot, just make it look red
  • WBC (leukocytes)- surface for clotting cascade to occur on
  • platelets- main component of clots -plasma
  • clotting factors- enable formation of fibrin mesh to cover platelet plug
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7
Q

process of formation of clot and restriction of clot

A
  1. blood vessel is injured, blood is lost through the wound
  2. first step is to inhibit loss of blood
    - vasoconstriction
    - regulated by reflex neurogenic mechanisms
    - and by local secretion factors (endothelium), thromboxane A2 and serotonin (from platelets)
  3. formation of platelet plug
    - temporary block of the flow of blood from wound
    - platelets attach to injured vessel and to each other
    - aggregation and activation of platelets (recruit more, clotting factors)
  4. clotting factors induce production of fibrin mesh around platelet plug
    - fibrin cross links the platelets
    - forms a hard clot that completely blocks loss of blood from wound
    - thrombin mediates the conversion of fibrinogen to fibrin, (also plays role in degrading clot after clot is no longer necessary)
  5. RBC and WBC stick to clot, gives it red color
  6. the size of the clot must be restricted
    - enzymes restrict growth of the clot
    - others dissolve the clot after tissue is repaired
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8
Q

properties of platelets (thrombocytes)?

A
  • small, disk shaped clear cell fragments
  • no nucleus
  • 2-3 micrometer in diameter
  • derived from fragmentation of precursor megakaryocytic
  • normal lifespan 5-9 days
  • source of growth factors
  • circulate in blood of mammals
  • involved in hemostasis, leading to formation of blood clots
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9
Q

platelete microparticles (PMP)?

A
  • submicron size (dust)
  • released mainly from platelets also from monocytes and other cells after activation or during apoptosis
  • platelet derived PMP have procoagulant activity, monocyte particles contain encrypted tissue factor
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10
Q

How are platelets the first responders?

A
  • they become activated by outside signal
  • signal transduction to alert cell
  • platelet undergoes abrupt shape change
  • granule contents spill into surrounding area
  • platelet adhesion and aggregation
  • prostaglandins synthesized
  • surface negatively charged
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11
Q

Where are platelets formed?

A

-in bone marrow from megakaryocytes

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12
Q

Function of thrombopoietin (TPO)?

A
  • targets megakaryocytes (MK) for platelet synthesis
  • TPO is a hematopoietic growth factor, a cytokine and a hormone which specifically targets MK
  • made in liver, some in kidney
  • recombinant human TPO may be a way to increase the number of platelets in cancer patients receiving chemotherapy
  • potential regulation: platelets can remove TPO from circulation
  • TPO receptor, polypeptide from protooncogene MPL
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13
Q

Activation of platelets?

A
  1. when platelets come into contact with a damaged vascular surface
    - collagen fibers in vascular wall
  2. platelets immediately change their characteristics
    - begin to swell
    - assume irregular forms with numerous irradiating pseudopods
    - their contractile proteins contact forcefully and cause release of granules that contain multiple active factors (degranulation)
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14
Q

Degranulation? (21)

A
  • alpha granules have fibrinogen (inactive) to make fibrin
  • vWF factor- platelet adhesion, adhesion to factor 8
  • dense granules- help with vasoconstriction such as with serotonin, ATP is necessary, contains calcium to act as positive bridge between clotting factors and negative charged surface of platelets
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15
Q

prostaglandin, leukotriene production?

A
  1. phospholipids are cleaved by phospholipase to create arachidonic acid
  2. arachidonic acid can form into leukotrienes for inflammation and immunology
    - or can form into prostaglandins
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16
Q

process of prostaglandin formation? (23)

A
  • enzyme cyclooxyganse (COX2) converts prostaglandins from arachidonic acid
  • in endothelial cells, will convert to prostacyclins and has opposite effect of platelet aggregation
  • or can go to thromboxane A2 which causes vasoconstriction and promotes platelet aggregation
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17
Q

Enzyme that converts arachidonic acid to prostaglandins? inhibitors?(24)

A
  • cyclooxygenase (COX1, COX2)
  • COX1 constitutive
  • COX2 inflammation induced
  • aspirin inhibits cyclooxygenase irreversibly
  • NSAIDS inhibit COX reversibly, reduces clotting
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18
Q

what prostaglandins cause vasoconstriction?

A
  • serotonin from platelets
  • thromboxane A2 from platelets
  • endothelins from endothelial cells
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19
Q

what prostaglandins cause vasodilation?

A
  • nitric oxide from endothelial cells
  • prostacyclin from endothelial cells
  • bradykinin from high molecule weight kininogen
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20
Q

procoagulant phospholipids become exposed on platelet surface how?

A
  • arachidonic acid is cleaved from membrane phospholipids by PLA2
  • phospholipids flip from inside to outside of membrane leaflet
  • platelet surface becomes negatively charged (good for clot formation)
  • important for calcium to bind so that clotting factors are concentrated around area of injury
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21
Q

why are surface bound reactions important?

A
  • concentrate reactants (clotting factors)
  • achieve two dimensional diffusion of factors, usually within lipid raft
  • orient reactants for enzymatic reaction
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22
Q

why is platelet plug important?

A
  • temporary blocks blood flow out of injured vessel
  • concentration of platelets at site of injury necessary for coagulation
  • this begins first, but continues throughout the rest of the coagulation cascade
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23
Q

process of formation of platelet plug?

A
  1. platelet recruitment to site of injury
    - collagen is exposed on injured vessel
    - platelets adhere directly to collagen via glycoprotein IV receptor (GpIV) expressed on the platelet
  2. when platelets adhere to damaged vessel, they undergo degranulation and release cytoplasmic granules, which contain serotonin, a vasoconstrictor, and ADP and thromboxane A2
    - ADP attracts more platelets to the area
    - thromboxane A2 promotes platelet aggregation, degranulation, and vasoconstriction
    - positive feedback promotes formation of plug
  3. Von Willebrand factor (VWF)
    - component of alpha granules
    - vWH is produced by endothelial cells and platelets
    - is normally folded but when vessel is injured, the sheer stress from injury, vWF unfolds to expose certain protein components that will bind to collagen
    - vWH binds Gp1b receptor on platelet
    - acts as bridge from collagen to platelets
  4. phosphatidylserine (PS)
    - PS exposed on dying cells and activated platelets
    - platelets bind to PS
  5. platelets bind to each other
    - platelets bind to each other via Glycoprotein IIb/IIIa receptor (with fibrinogen as intermediate)
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24
Q

How Gp IIb/IIIa help platelets bind to each other? (36)

A

pic

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25
Thrombobasthenia?
1. Glanzman - platelet aggregation disorder - lack Gp IIb/IIIa receptors on platelets to bind fibrinogen between 2 platelets, less fibrin formation 2. Bernard Soulier - platelet adhesion disorder - lack GpIb/IX/V receptors to bind vWF to sub cellular surface - both bind via RGD 3 AA sequence (arginine, glycine, aspartate) found on fibrinogen and vWF
26
Von Willebrand Disease (vWD)?
- presents as nose bleeds, skin bruises, hematomas - most common hereditary coagulation disorder - vWF required for adhesion to protect Factor VIII from degradation - deficiency in vWF means that Factor VIII is also deficient - less platelet adhesion and coagulation
27
vWF and ADAMTS-13? (40)
1. vWF is a multimeric protein produced in endothelial cells 2. ADAMTS-13 produced in hepatocytes (liver) - a disintegration and metalloproteinase with thrombi spendin 1 like domains - a metalloprotease that cleaves vWF under high shear stress - keeps vWF in check - major regulator of vWF final size in plasma - congenital deficiency found in patients with thrombotic thrombocytopenia purpura (TTP)
28
conditions that favor thrombosis?
- endothelial cells are damaged - promoting platelet activation and adhesion - exposing tissue factor is one of the main components to start clot cascade
29
what is blood coagulation?
- ordered series of reactions - specificity of enzymes (clotting factors) - amplification effects
30
human coagulation cascade through the years? (43)
- extrinsic vs intrinsic in lab, earlier model - in 2000s, cell based model - initiation, amplification, propagation happens in vivo - clotting factors are interrelated - cell surfaces are important for clotting factor activation
31
what are clotting factors? where synthesized?
- most synthesized in liver - most are enzymes - require calcium for their function - some require Vit K - a few are cofactors, bind to and help enzyme - active form denoted with a (Xi -\> Xa)
32
How calcium ions act as a bridge? (45)
-certain clotting factors have extra carboxyl groups to aid in binding to surface
33
Adding a gamma carboxyl to glutamate residues? (46)
- factors that need carboxyl group are prothrombin (II), factors 7, 9, 10, C, S - Vit K dependent
34
Function of Warfarin (coumadin)? (47)
-blocks reductases and inhibit the recycling of Vit K so that certain clotting factors are not able not function properly
35
What is thrombin?
- serine protease - inactive form is pro thrombin - active form is thrombin
36
why is thrombin important?
- plays critical role in blood coagulation: 1. activates clotting factors XI, VIII, V, XIII 2. activates platelets 3. converts fibrinogen to fibrin monomers (fibrin clot)
37
3 steps of the new model of coagulation?
1. initiation (activation) 2. amplification 3. propagation
38
Step 1: initiation new model? (55)
- tissue factor bearing cells are exposed to blood 1. injured fibroblast or monocyte with tissue factor exposed - TF is receptor for active factor VIIa 2. factor VIIa floats around in inactive form, some is activated by thrombin 3. active factor VIIa binds to TF 4. this complex allows factor X to be activated Xa 5. factor Xa combines with cofactor Va (prothrombinase XaVa) 6. cleaves prothrombin to thrombin (very little) 7. factor VIIa activates some factor IX to IXa - IXa diffuse to activated platelets
39
Role of tissue factor (TF) in initiation of clot formation?
1. TF is found both outside, inside the blood vessels - TF is integral membrane protein, normally expressed by extravascular cells (especially heart, lungs, testis, uterus, placenta) - separated by 1 degree hemostatic barrier around all blood vessels, but following injury, rapidly activates blood coagulation 2. also present in blood encrypted form, circulating on monocyte derived microparticles (dust) - not clear how TF becomes un-encrypted
40
Step 2 amplification new model? (58)
- amplification of clotting factor activation - thrombin produced on TF bearing cells activates platelets and additional clotting factors 1. a little bit of thrombin is being made from step 1, thrombin starts to add up 2. vWF is bound to factor VIII to block its degradation, thrombin comes in and causes them to separate 3. vWF binds to collagen to recruit more platelets 4. factor VIIIa is now activated 5. thrombin also activates factor XI to XIa and V to Va which is a cofactor that interacts with factor X 6. thrombin also activates more platelets
41
Step 3: propagation new model? (60)
- occurs on surface of platelets - during amplification, increased platelets and clotting factors - high level of tenase (VIIIa -IXa) activate Xa (8,9,10) - large burst of thrombin formation to form fibrin clot 1. activated platelet has calcium bound, factor IXa comes in and binds to VIIa to make more factor Xa - factor XIa activates IXa to make more factor Xa 2. factor VIIIa forms with IXa to make tenase complex to activate factor Xa 3. factor Xa binds factor Va (prothrombinase) 4. prothrombin is cleaved by factor Xa (Va is cofactor) to create a huge burst of thrombin 5. thrombin creates fibrin mesh over injury
42
Cofactor V?
- cofactor, not enzyme - activated by thrombin to Va - binds to receptors on platelet surface - helps to properly align all components - is inactivate by activated protein C (APC) - factor V is activated by thrombin, later thrombin activates APC to inhibit factor V
43
Fibrin and the stable blood clot new model?
1. burst of thrombin increases fibrinogen to convert to fibrin monomer (soft clot) 2. Factor XIII is fibrin stabilizing factor (activated by thrombin) 3. factor XIII cross links fibrin (hard clot)
44
earlier models of coagulation? (67)
- XII is not primarily important in hemostasis - deficiencies do not significantly affect clotting ability
45
Hemophilia A and B?
- X linked disorders of coagulation - mutations of clotting factor VIII (A) or IX (B) - factor VIII is a cofactor and factor IX is the enzyme in the reaction to activate factor Xa (same reaction) - deficiency in either results in decreased clotting - characterized by bleeding into soft tissue, muscle, and weight bearing joints, hours to days after trauma and continuing days to weeks - management: intravenous replacement of deficient factor
46
post coagulation?
- want to get rid of clot so vessel does not get clogged - thrombin - protein C - thrombolytic pathway - SERPINS - Heparin and Warfarin (coumadin)
47
How do thrombin and endothelial cells inhibit thrombosis? (73)
1. ECs produce thrombomodulin (TM) which complexes with thrombin (T) 2. T-TM complex activates protein C -\> APC 3. factors Va and VIIIa are cleaved and inactivated by active protein C (APC) - depresses clot cascade
48
proteolysis of clot? (74)
1. plasminogen inactive form, is activated by plasminogen activator (PA) to form plasmin (protease) - PA is inhibited by PAI - plasmin is inhibited by alpha 2 AP 2. plasmin degrades and its up the clot, cleared in blood
49
cross linked fibrin degradation? (75)
- D dimers are break down of fibrin clot - a lot of D dimers shows that active clot process is going
50
Thrombolytic therapy?
- plasminogen activators (PA) are approved by FDA for thrombotic diseases - for those with strokes - streptokinase (SK) - urokinase - alteplase (tissue plasminogen activator tPA) - recombinant tPA - they are usually delivered directly to clot via catheters - not used in pulmonary embolisms (PE)
51
Kringles in plasminogen and apolipoprotein A?
- kringle domains are autonomous protein domains that fold into large loops stabilized by 3 disulfide linkages - kringles help it to bind to clot so plasminogen (plasmin) can digest it - apolipo a can make a person more prone to clot because it has cringes can bind to clot and compete with plasminogen, reducing fibrinolysis - too much of apolipo a can cause more clots
52
Inhibitors of proteases (including clotting enzymes)?
- most are serine proteases inhibitors (SERPINS) - produced in liver - circulate in blood - either inactivate or trap protease enzymes - suicide substrate- complex of inhibitor and clotting factor tightly bound, clears clotting factor from circulation
53
SERPINS?
- inhibitors of serine proteases - irreversible inhibitors - fit into serine active site - results in complex that is stable and doesnt dissociate - suicide substrate
54
Central triad of serine proteases?
- 3 AA in active site (aspartate, histidine, serine) - serine proteases are factors XII, XI, IX, II, VII, plasmin, complement C1r, C1s, elastase, trypsin - 1/3 of all known proteases are serine proteases
55
Types of hemostatic inhibitors?
1. inhibitors that block clotting - ATIII, C1inh, alpha 1 protease inhibitor 2. inhibitors that block fibrinolysis - plasminogen activator inhibitors (PAI) - plasmin inhibitors 3. inhibitors that shift reactions - TFPI inhibits tissue factor (TF)
56
Tissue Factor pathway inhibitor (TFPI)? (82)
1. secreted from endothelial cells - reduces coagulation 2. TFPI acts as serine proteases inhibitor (SERPIN) - inactivates TF, VIIa, Xa 3. TFPI causes shifts 4. thrombin formed from extrinsic coagulation will feed back to activate the intrinsic coagulation side (initiation to amplification)
57
Action of heparin? (83)
- it is a mucopolysaccharide chain - antithrombin III (ATIII) is a SERPIN - Heparin reduces clotting 1. Heparin binds to ATIII to enhance its inhibitory activity 2. helps guide to inactivate its target 3. conformational change in ATIII, inhibits factors Xa, thrombin (IIa), IXa, XIa, XIIa
58
Tests for primary hemostasis?
- platelet vascular problems - do platelet count - bleeding time, a test of platelet vessel wall interactions
59
PTT? (90)
- partial thromboplastin time - measure intrinsic and common paths - used to test effect of heparin - also used for severe deficiencies
60
Why use PTT test to measure effects of heparin?
- hepain greatly enhances inhibitory activity of ATIII - ATIII primarily inhibits factor Xa and thrombin (IIa) - also inhibits factors IXa, XIa, XIIa
61
PT? (91)
- prothrombin time - patients calcium, plasma, phospholipid, TF - measures extrinsic and common paths - used to test effect of warfarin (coumadin) - also used for deficiencies
62
INR?
-international normalized ratio
63
Summary of warfarin (coumadin)?
1. post translational modification 2. alpha carboxylation of: - factors VII, IX, X, S, C, thrombin (II) 3. actions of warfarin take time - when you first administer, there are plenty of normal proteins, it takes time to recycle with new proteins being made in liver - dont use in hospital setting, takes too much time
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