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LAMP > Coagulation > Flashcards

Coagulation Flashcards

1
Q

What is hemostasis?

A

A series of physiologic processes that prevent bleeding when a blood vessel is damaged and, at the same time, keep blood in a fluid state

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2
Q

primary hemostasis

A

platelet plug formation

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3
Q

secondary hemostasis

A

coagulation cascade

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4
Q

fibrinolygsis

A

removal of clot

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5
Q

What converts prothrombin to thrombinf?

A

prothrombinase complex

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6
Q

What converts fibrinogen to fibrin

A

thrombin (IIa)

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7
Q

What does thrombin do?

A

coagulation, platelet activation, factor 8 activation, fibrinolysis, antigcoagulation etc….

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8
Q

What are natural inhibitors of coagulation? (inhibit clotting)

A

TFPI - binds factor 7a
Protein C serine protease - cleaves 5a, 8a
- cofactor protein S is crucial for its function
- both are vit K dependent
Antithrombin
- binds/inactivates serine proteases of the coaglation cascade
- activity augmented by heparin

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9
Q

What vasodilates the vessel wall?

A

nitric oxide

prostacyclins

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10
Q

What are anticoagulant properties that effect hte vessel wall?

A

heparan sulfate
thrombomodulin (protein C pathway)
TF pathway inhibotr
VW factor

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11
Q

What are components of platelets?

A

membrane receports
stored components
thromboxane

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12
Q

what is in the plasma?

A

VWF

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13
Q

What are disrdoers of primary hemostasis?

A

disoders of blood vessels
VW disease
thrombocytopenias
platelet dysfunction

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14
Q

What are bleeding sxs in disorders of primary hemostasis?

A
  • Petechiae (pinpoint, nonraised intradermal hemorrhage)
  • Easy bruising
  • Epistaxis (nose bleeding)
  • Menorrhagia (heavy menstrual bleeding)
  • Unexpected pre or post operative bleeding
  • Severe spontaneous bleeding
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15
Q

function of VWF?

A

mediates platelet adhesion at sites of vascular injury by binding to connective tissue and platelets

binds and stabilizes factor 7

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16
Q

What produces VWF?

A

vascular endothelium and stored in weibel palade bodies –> multimerization

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17
Q

What degrades VWF?

A

ADAMTS13

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18
Q

What is VW disease?

A
  • Inherited bleeding disorder caused by deficiency or dysfunction of von Willebrand factor (VWF)
  • Prevalence of symptomatic patients ~0.0023-0.01%
  • Prevalence by screening populations to identify people with ~0.6-1.3%
  • Autosomal inheritance
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19
Q

What are initial screenings assays for VWD?

A 
• VWF antigen (VWF:Ag)
– Measures the amount of protein
– Antigen level many not equal activity level
• Ristocetin Cofactor Activity (VWF:RCo)
– Activity of VWF that causes binding of VWF to platelets in the presence of ristocetin resulting in platelet agglutination
– Measured by various assays
– Large coefficient of variation
• Factor VIII
– Clot based assays

(blood doesn’t clot well)

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20
Q

What are tests for sub-typing VWD?

A 
Multimeric analysis of VWF
• Type 1, 2N – all multimers are present
• Type 2A and 2B – largest are missing
• Type 2M – all multimer are present or increased largest
• Type 3 – too little VWF to measure

Ristocetin-induced platelet aggregation (RIPA):
• Differentiates Type 2A from 2B
• Increased sensitivity to ristocetin (“gain of function”) = Type 2B

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21
Q

What is bleeding time?

A

• Cutismadeinforearm,earlobe,orfingertip blot with filter paper
measure bleeding time when bleeding stops

Disadvantages
• Labor intensive
• Accuracy depends on operator skills
• Hard to standardize
• Not a specific indicator of platelet function
• Poor indicator of surgical bleeding risk!
• ShouldnotbeusedasascreenforVWD!

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22
Q

What are the classificaitons of VWD subtypes?

A 
1 Partial quantitiative def of VWF
2 Qualittative VWF defect
2A No large multivers
2B No large multivers
2M Multivers are normal or incraesed high molecular weight
2N decreased affinity for factor 7
3 Deficiency of VWF
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23
Q

What is hte prevalence of VWD subtypes?

A

1 60-80%
2 7-30%
3 5-20%

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24
Q

14 y/o female with menorrhagia
VWF:AG 28% low
VWF:RCo 27% low
Multimer analysis: all multimer sizes present

Diagnosis?

A

T1 VWD

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25
Q

5yo boy w/ frequent nose bleeds
VWF:Ag normal
VWF:RCo LOW

Multimer analysis: large multimers are mising

Ristocetin induced platelet aggregation study POSITIVE

A

2A or 2B (large multimers missing)

2B: POSITVE ristocetin
often has decreased platelet count

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26
Q

What are the functions of platelets?

A

• Adhere to sites of vascular injury
– Glycoprotein Ia/IIa + collagen
– Glycoprotein Ib/IX/V + von Willebrand factor

• Release contents from granules
– Dense granules
• 2-7 per platelet
• ADP, ATP, calcium, serotonin

– Alpha granules=
• 50-80 per platelet
• PDGF, insulin like growth factor 1, TGFβ, platelet factor 4, thrombospondin, fibrinogen, von Willebrand factor, fibronectin, factor V
• Express P-selectin and CD63

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27
Q

Platelet functions?

A

• Aggregate together to form a hemostatic platelet plug
– Glycoprotein IIb/IIIa + fibrinogen
– Glycoprotein Ib + von Willebrand factor
• Procoagulant surface for activated coagulation protein complexes on the phospholipid membrane

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28
Q

What are antiplatelet drugs?

A

cyclooxygenase - aspirin
ADP receptor/P2Y12 inhibitors - clopidogrel, prasugrel, ticagrelor, ticlodipine
glycoprotein IIb/IIa- abciximab, epitifibatide, tirofiban
phophodisterzase - cilostazol
adenosine reuptake - dipyridamole

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29
Q

What is a PFA?

A

• Measures closure time
• Simulatesprimaryhemostasisbycreatinghigh shear flow in capillary tube
• Membrane coated with agonists: – Collagen and ADP (C/ADP)
– Collagen and epinephrine (C/EPI)
• Plateletsgetactivatedbytheagonistsatthe membraneadhere on the membrane surfaceaperture is occluded by the platelet plug
• Instrumentsensesthetimeittakesbloodflowto stop

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30
Q

What is secondary hemostasis?

A

coagulation cascade

series of enzymatic steps to amplify a minor insult into formation of a fibrin plu

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31
Q

What proteases and cofactors are responsible for secondary hemostasis?

A

• Serine proteases with different protein domains
– Factors XII, XI, X, IX, VII,II (prothrombin), XIII
• Cofactors - Factors V, VIII, tissue factor
– Enhance the efficiency of the coagulation factors

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32
Q

What initiates coagulation?

A
  • Tissue Factor (TF) and Factor VII binding
  • TF expressed on damaged or stimulated cells
  • <5% Factor VII circulates in activated (VIIa) form
  • Forms a complex in the presence of calcium
  • Converts Factor X to Xa directly or indirectly through Factor IX to IXa conversion
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33
Q

What are contact factors?

A

Prekallikrein (PK) is a serine protease that complexes with the cofactor high molecular weight kiniogen (HMWK)

PK is cleaved by factor 12a > kallikrein > activation of kinin pathway

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34
Q

What does factor XI do?

A

Activates factor 9

Activated by factor 12 and thrombin (creates a feedback loop)

35
Q

What forms the xase complex?

A
  • Factor IXa forms a complex with Factor VIIIa as cofactor
  • Calcium ions required
  • On a phospholipid surface • Activates Factor X to Xa
36
Q

What forms the prothrombinase complex?

A

Factor Xa binds to Va as cofactor • Calcium ions required
• On a phospholipid surface
• Converts prothrombin (Factor II) to thrombin (Factor IIa)

37
Q

What activates factor 8?

A

circulates as inactive form bound to VWF

activated by thrombin and factor Xa

38
Q

What activates factor 5?

A

– Activated by several factors including thrombin, Factor Xa, plasmin, and others
– Can serve as a cofactor for Factor Xa without activation

39
Q

What does thrombin do?

A

• Converts fibrinogen to fibrin
• No cofactor for enzymatic function needed
• Soluble fibrinogen cleaved by
thrombin turns to insoluble fibrin clot
– Thrombin cleaves off fibrinopeptide A and B from fibrinogen
– Fibrin monomers spontaneously polymerize to fibrin polymers
– Factor XIII stabilizes the clot by forming glutamyl-lysine bridges

40
Q

What regulates thrombin?

A
  • Positive feedback by activating Factors V, VIII, XI and XIII
  • Negative feedback by activating Protein C and fibrinolysis
  • Activates platelets
41
Q

What is the testing principle to screen for coagulation disorders?

A

• Collect sample in citrate containing tube 
binds Ca2+blocks clot formation
• Centrifuge to separate plasma from
cellular elements
• Plasma + add calcium to overwhelm
citratestarts clot formation
– Add additional factors to speed up process
and drive down a particular pathway
• Measure how long it takes to form a clot

42
Q

APTT

A

Intrinsic pathway

43
Q

PT/INR

A

Extrinsic pathwayy

44
Q

Thrombin time

A

common pathway

45
Q

What is PT

A
  • Measures the time (seconds) from VIIa/TF binding to clot formation
  • Thromboplastin reagent (Tissue factor + phospholipid) + Calcium added to citrated plasma
  • Tests the EXTRINSIC and COMMON pathways
  • Used commonly to monitor warfarin therapy
46
Q

When is hte extrinsic pathway initiated?

A

when blood is exposed to TF on damaged endothelium

–> PT assay

47
Q

What can cause a prolonged PT?

A

 Inhibitor of Factor X, VII, V, II, or fibrinogen
 Antiphospholipid antibodies, such as Lupus anticoagulants
 Medications
 Warfarin (a vitamin K antagonist)
 Heparin (only at very high levels)
 Anti-Xa inhibitors (e.g. Rivaroxaban, Apixaban, Edoxaban)
 Direct thrombin inhibitors (eg. Dabigatran, Bivalirudin, Argatroban)
 Liver disease
 Consumption of factors as may be seen with disseminated
intravascular coagulation (DIC) or bleeding  Dilution
 Vitamin K deficiency
 Dysfibrinogenemia
 “Crap in a tube” = underfill, contamination from IV fluids, contamination from heparin in line, delay in testing, collecting in wrong tube, etc.

48
Q

Why was INR developed?

A

to standardize PT testing and monitor pts on warfarin therapy

49
Q

INR formula

A

INR = sample PT/mean PT x ISI

50
Q

What is aPTT?

A
  • Measuresthetime(seconds)clotformsthrough the activation of the contact and intrinsic pathways to clot formation
  • Citratedplasmaismixedwithphospholipid (partial thromboplastin) and a contact activator + calcium
  • TeststheINTRINSICandCOMMONpathways
  • Used commonly to monitor unfractionated heparin therapy
51
Q

What initiates aPTT measurement?

A

activation of FXII and contact factors on negatively charged phospholipid surfaces

52
Q

What causes a prolonged aPTT?

A

• Inhibitor of Factor XII, XI, X, IX, VIII, V, II, or fibrinogen
• Deficiency of Prekallikrein and High Molecular Weight Kininogen (may not always be detected)
• Von Willebrand disease (due to low Factor VIII)
• Antiphospholipid antibodies, such as Lupus anticoagulants
• Medications
– Warfarin (a vitamin K antagonist) – Heparin
– Anti-Xa inhibitors (e.g. Rivaroxaban, Apixaban, Edoxaban)
– Direct thrombin inhibitors (e.g. Dabigatran, Bivalirudin, Argatroban)
• Liver disease
• Consumption of factors as may be seen with disseminated intravascular coagulation (DIC) or bleeding
• Dilution
• Vitamin K deficiency
• Dysfibrinogenemia
• “Crap in a tube” = underfill, contamination from IV fluids, contamination from heparin in line, delay in testing, collecting in wrong tube, etc.

53
Q

What is used to assess the common pathway?

A

V, X, II, fibrinogen

Russel viper venom
activates factor X directly
DRVVT assay

54
Q

What does TT measure?

A
  • Measures the conversion of fibrinogen to fibrin (last step in the aPTT, PT/INR, and DRVVT)
  • Detects abnormalities in fibrinogen to fibrin conversion
55
Q

What causes a prolonged TT?

A

– Hypofibrinogenemia
– Dysfibrinogenemia
– Unfractionated heparin
– Direct thrombin inhibitors (hirudin, argatroban, dabigatran) – Fibrin degradation products (e.g. D-Dimer)

56
Q

What has no effect on thrombin time?

A

– Warfarin
– Direct Xa inhibitors
– Factor II (factor 2) deficiency

57
Q

Ho do you determine if a pt has a factor deficiency vs an inhibitor?

A

mixing study!

Mix pt plasma w/ normal plasma.
If aPTT corrects –> factor deficiency
If aPTT does NOT correct –> inhibitor

58
Q

inheritance for hemophilia A and B?

A

x-linked recessive

59
Q

Hemophilia A

A 
def factor 8
1/5000 live male births
60
Q

hemophilia B

A 
def factor 9
1/30,000 live male births
61
Q

what percentage of hemophilia A are new spontaneous mutations?

A

30%

62
Q

What are clinical featurs of hemophilia A and B?

A

Intra-articular bleedings
– knees, elbows, ankles, shoulders, wrists
• Intramuscular hemorrhage 30% of bleeding events (compartment syndrome)
• Hematuria
• Intracranial hemorrhage (50% are spontaneous in adults)
• Gastrointestinal and oropharyngeal bleeding

63
Q

How do you diagnosis w/ lab tests hemophilias?

A

• Isolated prolongation of aPTT
• Specific clotting factor assays are used for diagnosis (Factor VIII or IX)
– Severe <1%
– Moderate 1-5% – Mild 5-30%
• Can not distinguish Hemophilia A and B without labs

64
Q

What is dyfibrinogenemia?

A

Protein does not function properly
• May be asymptomatic, hemorrhagic, or thrombotic
• Functional assays (activity) show lower level than antigen assays
• May or may not prolong clot times

65
Q

Causes of elevated fibrinogen levels?

A

increasing age, females, pregnancy, acute phase reaction, smoking, exercise

66
Q

Causes of reduced fibrinogen levels?

A

congenital, liver disease, disseminated intravascular coagulation (DIC), dilution, fibrinolysis

67
Q

What is Owren’s disease (factor V)?

A

acquired associated with exposure ot bovin thrombin in cardiac surgery

68
Q

How do you treat factor VII (alexander’s)

A

Treate with NovoSeven (recombinant FVIIa)

69
Q

How do you treat factor X def?

A

Prothrombin complex concentrates
associated wtih amyloidosis
acquired form is more common

70
Q

Factor XI def?

A

– 1 in 100,000
– Usually mild bleeding disorder
– FXI level does not correlate as well with bleeding tendency
– Bleeding
• Primarily trauma related
• Surgical bleeding at sites with fibrinolytic activity (tooth extraction, tonsillectomy, nasal surgery, prostatectomy)

71
Q

FActor XII def?

A

1 in 1 million

NO clinical signficance

72
Q

What does factor XIII do?

A

crosslinks strands of fibrin -> stabilizes clot (fbirin stabilizing factor)

73
Q

Sxs of factor XIII def

A

– Delayed bleeding, 12-36 hour after trauma
• Umbilical stump
• Bleeding after circumcision
• Spontaneous intra-cranial bleeding
• Superficial bruising, subcutaneous hematomas – Miscarriages
– Poor wound healing

74
Q

How do you test for factor XIII def?

A

• Standard screening tests (PT, aPTT,
TT) are normal!!
• Screening test: clot solubility test (dissolve the clot with 5M urea or acid)
• Confirm with FXIII antigen or activity test

75
Q

A patient has a prolonged PTT but normal PT and TT. Which of the following may explain this set of results?
A. Factor II (Factor 2) deficiency B. Factor V (Factor 5) deficiency C. Factor VII (Factor 7) deficiency D. Factor IX (Factor 9) deficiency

A

Factor 9

76
Q

A patient has a prolonged INR and PTT, but normal TT. Which of the following may explain this set of results?
A. Fibrinogen deficiency
B. Factor V (Factor 5) deficiency
C. Factor VIII (Factor 8) deficiency D. Factor XIII (Factor 13) deficiency

A

Factor 5

77
Q

Thrombin forms clot formation/thrombosis where as PLASMIN causes…

A

clot lysis/bleeding

Fibrinolysis

78
Q

What is plasmin?

A

• Plasminogen –> plasmin
• Proteolytic enzyme
• Activated by thrombin
• Degrades cross-linked fibri > fibrin degradation products (FDP) appear in circulation

79
Q

What is a d dimer?

A

a fibrin degradation product

80
Q

What regulates fibrinolysis?

A

plasminogen is activated by tPA

81
Q

What is tPA?

A

– synthesized in endothelial cells
– half life about 5 min
– inhibited by plasminogen activator inhibitor-1 (PAI-1)

82
Q

What does alpha-2 plasmin inhibiotr do?

A

inhibits plasmin in circulation

83
Q

What are the TEG parameteres?

A

• Rtime
– Measuresthetimetofibrinformationwithinaclot
– Determinedbyclottingfactorsandinhibitorbalance(eg.heparin)
•  angle
– Anglebetweentheinitialslopeofthetracingandthehorizontal – Representsspeedofclotstrengtheningbyfibrincross-linkage
•K
– TimefromtheendofRuntiltheclotreaches20mm – Representsthespeedofclotformation
• Maximum amplitude (MA)
– Thestrengthoftheclot
– Dependsontheintegrityofplateletfunctionandfibrinogenbinding
• Ly30 and Ly60
– Lysis of the clot at 30 minutes and 60 minutes
• Coagulation Index (CI)
– Overallassessmentofcoagulation
– CI = −0.6516R − 0.3772K + 0.1224MA + 0.0759α − 7.7922
– Values +3.0 = hypercoagulable

84
Q

What is platelet mapping?

A

Compares maximum amplitudes of response to various agonists
– Baseline = MATHROMBIN
– Activator (Reptilase + Factor XIII) = MAFIBRIN
– Activator +ADP = MAADP
• Used for ADP receptor inhibitors (e.g. clopidogrel)
– Activator + Arachidonic Acid = MAAA
• Used for Aspirin

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