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Lab Dx 2 > week 2- hemostasis > Flashcards

week 2- hemostasis Flashcards

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
Q

• What is clinical sig of BT?

A

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

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26
Q

• What is the plt fxn screen?

A

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

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27
Q

• How would you interpret plt fxn screen results?

A

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

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28
Q

• What is aspirin’s role in primary hemostasis?

A

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

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29
Q

• What is 2nd hemostasis?

A

o Coagulation factors form fibrin strands, strengthen plt plug
o Activated plt release granules, stim more activation, enhance hemostasis

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30
Q

• What is the coagulation cascade?

A

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…

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31
Q

• What are clotting factors, and how are they named?

A

o Circulate in zymogen/inactive forms
o Roman numeral (order of discovery)
o “a” once activated

32
Q

• What are the numbers, names, source, and pathway of all the clotting factors?

A

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
Q

• What is the extrinsic/TF pathway?

A

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
Q

• What is the intrinsic pathway?

A

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
Q

• What is the common pathway?

A

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
Q

• What is thrombin? Its roles?

A

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
Q

• What are the 3 phases of the coagulation cascade?

A

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
Q

• What are the d/os of 2nd hemostasis? Sxs? sxs common to 1st and 2nd hemostatic dos?

A

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
Q

• What is prothrombin time (PT)? results?

A

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
Q

• What is the international normalized ratio (INR)? Effects of heparin?

A

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
Q

• What is the therapeutic interval for oral anticoagulant therapy? Application?

A

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
Q

• What is coumadin (warfarin, dicoumarol)?

A

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
Q

• What is activated partial thromboplastin time (aPTT)? Results?

A

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
Q

• What is heparin?

A

o Administered IV
o Immediate inhibition of blood clotting
o Accelerates action of ATIII to inactivate IIa (thrombin)
o Monitored w PTT

45
Q

• What are normal PT and aPTT times?

A

o PT: 9.9-13 sec

o aPTT: 25-35 sec

46
Q

• what are the types of dos of proteins of fibrin formation? Tests?

A

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
Q

• What is thrombin time?

A

o Measures conversion of fibrinogen to fibrin
o Add thrombin to pt’s plasma
o Measure time to clot

48
Q

• What are some factor assays used for?

A

o IX: x-linked Hemophilia B

o VIII: X-linked Hemophilia A

49
Q

• What are the hemophilias?

A

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
Q

• How is hemophilia diagnosed?

A

o Readily: in severe dz, or FHx

o Dx: unusual bleeding sxs early in life (age varies w severity), FHx, PE, Lab eval

51
Q

• Congenital def: Plt N, PT N, aPTT N, PFA N, TT N:

A

o XIII, mild def of any factor, plasminogen activator inhibitor-1, a2 anti-plasmin

52
Q

• Congenital def: Plt N, PT A, aPTT N, PFA N, TT N:

A

o VII

53
Q

• Congenital def: Plt N, PT N, aPTT A, PFA N, TT N:

A

o XII, XI, IX, VIII, prekallikrein, high molecular weight kininogen

54
Q

• Congenital def: Plt N, PT A, aPTT A, PFA N, TT N:

A

o X, V, II

55
Q

• Congenital def: Plt N, PT A, aPTT A, PFA N, TT A:

A

o Fibrinogen

56
Q

• Congenital def: Plt N, PT N, aPTT N/A, PFA N/A, TT N:

A

o VWF

57
Q

• What are acquired coagulation dos?

A 
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
Q

• What is DIC?

A

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
Q

• What is vit k? def?

A

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
Q

• What may cause K def? tx?

A

o Malnutrition, biliary obstruction, malabsorption, Abx tx

o Tx: vit k, fresh frozen plasma

61
Q

• Why is excessive clotting inhibited? How?

A

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
Q

• How is fibrinolysis activated?

A

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
Q

• What is plasmin?

A

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
Q

• What is the Proteins C and S regulatory pathway of coagulation?

A

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
Q

• What is the antithrombin III regulation pathway?

A 
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
Q

• What is factor V Leiden mutation?

A

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
Q

• What happens w imbalance of hemostasis?

A

o Thrombi: excessive local/systemic coag activation

o Sustained bleeding: excess local/systemic fibrinolytic activity

68
Q

• What is usu cause of delayed hemostasis? Sx?

A

o Either plt do or coag defect
o Imbalance bw: abn slow hemostasis, normal rate fibrinolysis
o Bleeding episode mb prolonged

69
Q

• What happens with an inadequate fibrinolytic response?

A

o May retard lysis of thrombus, or contribute to extension

70
Q

• What are the 3 categories of clotting/bleeding dos?

A

o Vascular and plt dos
o Coag factor def, or specific inhibitors
o Fibrinolytic dos

71
Q

• What tests are used to differentiate clot/bleed dos?

A 
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
Q

• What would you do after PT and aPTT studies were abn?

A

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
Q

• what are CBC and smear tests for bleeding dos?

A

o Plt ct: thrombocytopenia

o RBC and plt morph: TTP, DIC, etc

74
Q

• What are coagulation tests for bleeding dos?

A

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
Q

• What are the plt fxn tests for bleeding dos?

A

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
Q

• 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%

A

o Hemophilia A= factor VIII deficiency

Lab Dx 2 (8 decks)

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