week 2- hemostasis Flashcards

(76 cards)

1
Q

• What is hemostasis?

A

o Rapid, localized process; balance bw bleeding and clotting
o Body stops bleeding after injury, maintains blood in fluid state in vascular compartment
o Controlled activation of plts and soluble clotting factors, form stable fibrin clots

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2
Q

• What are the major constituents of the hemostatic pathway?

A

o Coagulation proteins, plts, endothelium

o Each interacts and influences all others

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3
Q

• What are the 3 simultaneous pathways that cause stable hemostatic plug after BV injury?

A

o Neural → BV constriction → reduced blood flow
o TF → coagulation activation → thrombin, fibrin
o Plt activation → primary hemostatic plug → plt fusion

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4
Q

• What are the 2 stages of hemostasis?

A

o Primary: response to BV injury, form plt plug adhere to endothelium, immediately limit bleeding
o Secondary: stable clot formation, enzymatic activation of coagulation proteins, produce fibrin, reinforce plt plug, gradual fibrinolysis dissolves plug

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5
Q

• What is the main purpose/advantage of the endothelium vascular system?

A

o Smooth endothelium helps blood flow
o Intact endothelial cells inhibit plt adherence and coagulation
o Endothelial injury promotes local clot formation

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6
Q

• What role does vasoconstriction play in hemostasis?

A

o Narrows lumen to reduce blood loss
o Brings plts and proteins closer to vessel wall
o Enhance contact activation of plts (VWF, collagen, plt membrane glycoprotein Ib)
o Activated plts enhance activation of coagulation proteins

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7
Q

• How quickly does coagulation occur after BV injury?

A

o Normally, coagulation initiated within 20 seconds of injury

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8
Q

• What are plts?

A

o Small, anucleated, cytoplasmic fragments of megakaryocytes
o Normal: 150-400 x 10E9 /L
o Live 9-12 days
o old cells removed by spleen and liver
o ~2/3 circulate in peripheral blood
o ~1/3 sequestered in spleen (2 pools constantly exchanging, equilibrium)
o Spontaneous hemorrhage <10 x 10E9 /L

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9
Q

• Where do plts come from?

A

o released from BM by megakaryocytes
o Megakaryocyte proliferation stimulated by thrombopoietin (TPO)
o TPO: humoral factor; produced by liver, kidney, spleen, BM; made at constant rate

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10
Q

• How does plt adhesion happen?

A

o Damaged endothelium exposes blood to subendothelial (SE) tissue matrix w adhesive molecules
o Plt receptor GPIb binds SE collagen fibers via VWF
o Plt adherence stops initial bleeding

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11
Q

• What is VWF?

A

o Multimeric glycoprotein
o Parts made in endothelial cells and megakaryocytes
o Stored in endothelial cells (Weibel-Palade Bodies) and Plt alpha-granules
o Circulate in plasma, 7-10 mg/mL
o Ligand for Plt receptor Ib/IX

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12
Q

• What happens to plts after aggregation?

A

o Undergo a shape change

o Oval → dendrites → more dendrites → fried egg

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13
Q

• What things are necessary for plt-plt interaction in aggregation?

A

o Dense granule release from adhering plts

o Requires Ca2+ and ATP; fibrinogen; fibrinogen recptors GPIIB and IIIA

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14
Q

• What plt-plt interaction happens in aggregation?

A

o Begins 10-20 sec after injury and adhesion
o ADP released from plt cytoplasm → expose GIIb and GIII, fibrinogen binds
o EC Ca2+-dependent fibrinogen bridges form bw plts, promote agg
o = primary/reversible aggregation
o 2nd/irreversible: begins w release of dense granules

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15
Q

• What is the purpose of secretion of dense granules?

A

o Begin 2nd agg
o Have lots of ADP, binds plt membrane triggering synthesis and release of TXA2
o Amplifies initial plt agg into big plt mass
o = primary hemostatic plug

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16
Q

• What is the primary plt plug?

A

o Dt plt interaction with vessel wall, each other

o Plug: fragile, can easily be dislodged from vessel wall

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17
Q

• What are some inherited plt defects?

A
o	Bernard soulier dz: def GPIb
o	Von Willebrand dz: def VWF
o	Glanzmann’s Thrombasthenia: GPIIb, GPIIIA
o	Storage pool dz: dense body
o	Gray plt syndrome: alpha granule
o	Defective procoagulant activity
o	COX deficiency: dense tubular system
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18
Q

• What is von Willebrand dz?

A

o Most frequent inherited bleeding disorder, ~1/100
o many clinical manifestations
o Clinically significant vWD : 125/1 million
o Severe dz in 0.5-5/ 1 million
o Autosomal inheritance pattern
o M=F

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19
Q

• Who discovered vWD? What did he find? Future findings?

A
o	1931-Erik von Willebrand
o	Hereditary pseudohemophilia
o	Prolonged BT, normal plt ct
o	Mucosal bleeding
o	M=F
o	1950s: prolonged BT assoc w def fx VIII
o	1970s: discover VWF
o	1980s: VWF gene cloned
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20
Q

• What is the classification of vWD?

A

o Type I: partial quant def; 70%; mild-mod dz
o Type II: qual def; 25%; mild-mod dz
o Type III: near/total def; 5%; severe dz
o Additional subclass: acquired vWD

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21
Q

• What is bleeding time? Recommended criteria prior to testing?

A

o Test adequacy of primary hemostasis or plt fxn
o 1. Plt ct: >75,000/mm3
o 2. Only I BT/24 hrs, unless excuse
o 3. stop heparin 6 hrs prior

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22
Q

• How is bleeding time done?

A

o BP cuff on arm (@40 mm Hg)
o 2 incisions made on inner forearm
o Blot w filter paper every 30 sec
o Record time for clotting to occur (bleeding stops)

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23
Q

• What are sources of error giving false + results in BT?

A
o	BP cuff too high (>40) or too low 
o	lo fibrinogen (<100 mg/dl) or plt ct (100,000 /mm3).
o	Drugs that affect plt fxn (aspirin)
o	Incision too shallow/deep
o	disturb clot w filter paper
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24
Q

• what are the ref ranges for BT?

A

o 1-3 mins (duke method)

o 2-7 mins (template Ivy method)

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25
• What is clinical sig of BT?
o Usu very long in congenital or acquired plt defects | o Thrombasthenia, Bernard-soulier, storage pool dz, aspirin, VWD, uremia, liver failure, plt ct <75,000
26
• What is the plt fxn screen?
o Replaces BT as a test of plt fxn o PFA-100; ordered as “plt fxn screen” o Blue top tube o Measures time for blood to block membrane coated w collagen/epi or col/ADP
27
• How would you interpret plt fxn screen results?
o Norm epi, N ADP: normal plt fxn o Abn epi, N ADP: “aspirin effect” o A epi, A ADP: abn plt fxn, valvular heart dz, renal failure, VWD
28
• What is aspirin’s role in primary hemostasis?
o =acetylsalicylic acid o Limits blood clotting o = “blood thinner” for ppl at risk for life-threatening clots o Inhibits plt activation by irreversible inhibition (acetylation) of plt enzyme COX, inhibiting TXA (need for plt agg, adhesion unaffected) o Lasts at least 7 d (lifetime of plt) o So pts should avoid aspirin 7 d if doing plt fxn test o Also acetylate fibrinogen, alter clot formation, enhance fibrinolysis
29
• What is 2nd hemostasis?
o Coagulation factors form fibrin strands, strengthen plt plug o Activated plt release granules, stim more activation, enhance hemostasis
30
• What is the coagulation cascade?
o Contact activation pathway (intrinsic) o Tissue factor pathway (extrinsic), primary for initiation of coagulation o Zymogen of serine protease and its glycoprotein co-factor activated…
31
• What are clotting factors, and how are they named?
o Circulate in zymogen/inactive forms o Roman numeral (order of discovery) o “a” once activated
32
• What are the numbers, names, source, and pathway of all the clotting factors?
o I- fibrinogen, liver, common o II- prothrombin, liver (vit K dep), common o III- tissue factor/thromboplastin, released by damaged cells/extrinsic, by plts/intrinsic o IV- calcium ions, bone and gut, entire process o V- proaccelerin/labile factor, liver and plts, E and I o VI- dne o VII- proconvertin/stable factor, liver (K), E o VIII- anti-hemolytic factor, plts and endothelium, I o IX- Christmas factor, liver (K), I o X- stuart-prower factor, liver (K), E and I o XI- plasma thromboplastin antecedent, liver, I o XII- Hageman factor, liver, I, also activates plasmin o XIII- fibrin-stabilizing factor/VWF, liver, slows fibrinolysis
33
• What is the extrinsic/TF pathway?
o Initiated by release of tissue thromboplastin (TP, III), exposed to blood after vessel injury o Circulating VII forms complex w TP and Ca → VIIa o Rapidly converts X → Xa o Xa and Va catalyze prothrombin (II) to thrombin (IIa), to convert fibrinogen (I) to fibrin
34
• What is the intrinsic pathway?
o Initiated after exposure to neg charge foreign substances (collagen, subendothelium, phospholipids) o XII → XIIa o W contact factors (prekallikrein, kininogen), XI -→XIa o IX → IXa, in presence of Ca2+ o IXa, VIII, protein C, Ca2+, PF3 (source of phospholipids) =tenase complex o → Xa, → thrombin
35
• What is the common pathway?
o Fibrin clot formation o End products of intrinsic or extrinsic, X → Xa o Xa and Va: II → IIa (thrombin) o Thrombin enzymatically converts fibrinogen → fibrin monomer, polymerize into insoluble strands o Thrombin activates XIII → XIIIa → crosslinks, stabilize fibrin clot o This occurs on plt surface
36
• What is thrombin? Its roles?
o Central role of bioregulation of hemostasis in normal and pathologic conditions o Potent plt agg and secretion agent o Amp coagulation by activating V, VIII, XI (Activating V and VIII = positive feedback to amplify more thrombin) o Make XIIIa for fibrin stabilization (soft vs hard clot) o Complex w endothelial thrombomodulin to activate protein C (Active C inactivates Va, VIIIa, slow thrombin formation) o Stimulation of tissue repair
37
• What are the 3 phases of the coagulation cascade?
o Initiation: injury, blood contacts SE, TF exposed, VII → VIIa, activate IX and X, Xa binds Va on cell surface o Amplification: Xa/Va convert little pro → thrombin, activates VIII, V, XI and plts locally, XIa activates IXa, activated plts bind Va, VIIIa, IXa o Propagation: VIIIa/IXa activates X on plt surface, Xa/Va convert lots of pro → thrombin (“thrombin burst”) → stable fibrin clot
38
• What are the d/os of 2nd hemostasis? Sxs? sxs common to 1st and 2nd hemostatic dos?
o Dos of proteins of fibrin formation, or assoc w fibrinolysis o Sxs: delayed bleeding, deep mm bleed, spontaneous jt bleed o Common: Ecchymoses, GI bleed, hematuria, hypermenorrhea, gingival bleed, inc bleed after tooth extraction, intracranial bleed, epistaxis o Mb deep spreading hematomas, bleed into jts, hematuria, dt failure to reinforce plt plug
39
• What is prothrombin time (PT)? results?
o Evaluates extrinsic path o Prolonged: def VII, X, V, II (prothrombin), or I (fibrinogen) o Or: vit K def (needed for synthesis of II, VII, IX, X) o Liver dz, warfarin, DIC, excessive heparin
40
• What is the international normalized ratio (INR)? Effects of heparin?
o PT value = patient PT/ PT for control plasma o INR= correction factor applied (international sensitivity index) o = (PT pt / PT control) ^ISI o 1.0= pt’s PT is normal o > 1.0 = clotting time elevated
41
• What is the therapeutic interval for oral anticoagulant therapy? Application?
o 2.0-4.5 (target 2.0 – 3.0) o 3 = hemorrhagic o App: monitor oral anticoag tx (warfarin, etc) o Heparin won’t prolong INR o For heparin tx, monitor aPTT or aPTT ratio
42
• What is coumadin (warfarin, dicoumarol)?
o Oral anticoagulant o Takes few days for effects to show o Inhibit production of vit k dep factors (II, VII, IX, X) and Protein C and S o Monitored w PT (since VII has shortest 1/2 life and becomes deficient first)
43
• What is activated partial thromboplastin time (aPTT)? Results?
o Eval intrinsic o Prolonged aPTT, normal PT: def VIII, IX, XI, or XII o Prolong both aPTT and PT: def X, V, II, or I (all rare) o Normal aPTT: XIII def or VII def (PT prolonged) o Heparin: most common cause of prolonged aPTT
44
• What is heparin?
o Administered IV o Immediate inhibition of blood clotting o Accelerates action of ATIII to inactivate IIa (thrombin) o Monitored w PTT
45
• What are normal PT and aPTT times?
o PT: 9.9-13 sec | o aPTT: 25-35 sec
46
• what are the types of dos of proteins of fibrin formation? Tests?
o Hereditary vs acquired o Quantitative vs qualitative deficiencies (not differentiated by PT or aPTT) o Qualitative: prolong clotting test, found by Ig tests o Activity assays are essential to screen for deficiencies
47
• What is thrombin time?
o Measures conversion of fibrinogen to fibrin o Add thrombin to pt’s plasma o Measure time to clot
48
• What are some factor assays used for?
o IX: x-linked Hemophilia B | o VIII: X-linked Hemophilia A
49
• What are the hemophilias?
o A: VIII def, antihemophilic factor, x-link recessive, most common o B: IX, Christmas factor (family name), x-linked o C: XI, AR, Ashkenazi, mild-severe sxs
50
• How is hemophilia diagnosed?
o Readily: in severe dz, or FHx | o Dx: unusual bleeding sxs early in life (age varies w severity), FHx, PE, Lab eval
51
• Congenital def: Plt N, PT N, aPTT N, PFA N, TT N:
o XIII, mild def of any factor, plasminogen activator inhibitor-1, a2 anti-plasmin
52
• Congenital def: Plt N, PT A, aPTT N, PFA N, TT N:
o VII
53
• Congenital def: Plt N, PT N, aPTT A, PFA N, TT N:
o XII, XI, IX, VIII, prekallikrein, high molecular weight kininogen
54
• Congenital def: Plt N, PT A, aPTT A, PFA N, TT N:
o X, V, II
55
• Congenital def: Plt N, PT A, aPTT A, PFA N, TT A:
o Fibrinogen
56
• Congenital def: Plt N, PT N, aPTT N/A, PFA N/A, TT N:
o VWF
57
• What are acquired coagulation dos?
``` o More common that hereditary o Usu defects of mult factors o Often bleeding from mult sites o Mb dt another dz o Many mechanisms ```
58
• What is DIC?
o Altered hemostasis o Uncontrolled formation and lysis of fibrin in vessels o Systemic, rather than local site of injury o Fibrin deposited diffusely in capillaries, arterioles, venules o Factors/plts/proteins consumed faster than synthesized o Too much clotting followed by too much bleeding
59
• What is vit k? def?
o Lipophilic, hydrophobic; posttranslational modification of II, VII, IX, X, C, S o Quinone: green leafy veg, fish, liver, intestinal organisms (B fragilis, E coli) o Adds 2nd C=O group to y carbon of glutamic acid at end of II, VII, IX, X (pocket for Ca2+ promotes phospholipid binding) o Def: mb dt warfarin (antagonist); non-active II, VII, IX, X, C, S
60
• What may cause K def? tx?
o Malnutrition, biliary obstruction, malabsorption, Abx tx | o Tx: vit k, fresh frozen plasma
61
• Why is excessive clotting inhibited? How?
o Would be dangerous o Clotting factors rapidly inactivated by circulating proteins o So clotting only at site, not systemically o Fibrin inhibits thrombin = neg feedback loop
62
• How is fibrinolysis activated?
o Gradual enzymatic cleavage of fibrin to soluble fragments o Limits extent of hemostatic process, re-establish normal blood flow o Important: local activation of plasminogen (PLG) to plasmin o Plasmin enzyme system =fibrinolytic system
63
• What is plasmin?
o Responsible for degradation of fibrin (or fibrinogen) o → fibrin degradation products (FDPs) o Sites of plasmin cleavage: similar in fibrin and fibrinogen o Also destroy V, VIII, others
64
• What is the Proteins C and S regulatory pathway of coagulation?
o Excess thrombin binds thrombomodulin on endothelium surface → activate C o C + S → complex degrades Va and VIIIa -> clotting stays local o C and S are vit K dep
65
• What is the antithrombin III regulation pathway?
``` o Inhibit thrombin (IIa) o Inactivate Xa o In most cells, esp basophilic granules and plt surface o Limited anticoag effect on its own o Activity ↑ 1000x w heparin ```
66
• What is factor V Leiden mutation?
o 3-8% of Caucasians o Resistant to degradation by C-S complex o → hypercoagulable state, risk venous thrombosis o Women w OB complications: preeclampsia, still-born, IU growth retardation, repeat preg losses o Females: BCP inc risk of thrombosis 35x
67
• What happens w imbalance of hemostasis?
o Thrombi: excessive local/systemic coag activation | o Sustained bleeding: excess local/systemic fibrinolytic activity
68
• What is usu cause of delayed hemostasis? Sx?
o Either plt do or coag defect o Imbalance bw: abn slow hemostasis, normal rate fibrinolysis o Bleeding episode mb prolonged
69
• What happens with an inadequate fibrinolytic response?
o May retard lysis of thrombus, or contribute to extension
70
• What are the 3 categories of clotting/bleeding dos?
o Vascular and plt dos o Coag factor def, or specific inhibitors o Fibrinolytic dos
71
• What tests are used to differentiate clot/bleed dos?
``` o Plt ct o Peripheral blood smear o Ivy BT (N=2.5-9.5 min) or PFA o PT- contains thromboplastin and CaCl, extrinsic and common (N=11-13 sec) o aPTT: contact activators, plt sub, CaCl added, intrinsic and common (23-35 sec, varies) o TT: add thrombin, common (15-22 sec) o PT and aPTT abn studies o Coag factor assays ```
72
• What would you do after PT and aPTT studies were abn?
o mix pt plasma and normal plasma, distinguish bw factor def and coag inhibs o if assay is corrected: dt fx def o if partially corrected or uncorrected: dt inhibitor
73
• what are CBC and smear tests for bleeding dos?
o Plt ct: thrombocytopenia | o RBC and plt morph: TTP, DIC, etc
74
• What are coagulation tests for bleeding dos?
o PT: extrinsic/common pathways o PTT: intrinsic/common pathways o Coagulation factor assays: specific factor deficiencies o 50:50 mix: inhibitors (like Abs) o Fibrinogen assay: dec fibrinogen o TT: qual/quantitative fibrinogen defects o FDPs or D-dimer: fibrinolysis (DIC)
75
• What are the plt fxn tests for bleeding dos?
o VWF: VWD o BT: in vivo test (non-specific) o PFA: qualitative plt dos and VWD o Plt fxn tests: qualitative plt dos
76
• Swollen tender knee, after falling. Hx prolonged bleeding after tooth extraction. Never hospitalized. No meds. PT=10sec (8-14). aPTT=57sec(24-36). Plt=450k (130-350k). mix PTT=32 sec (24-36). VIII=5% (50-150). IX=132%. XI=112%
o Hemophilia A= factor VIII deficiency