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Transfusion Medicine Fellowship > Coagulation > Flashcards

Coagulation Flashcards

1
Q

Why is FFP a poor choice for correcting mild INR abnormalities?

A

FFP itself has an INR > 1.0; mild INRs also do not predict significant bleeding.

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2
Q

What is the preferred choice to rapidly reverse warfarin effect?

A

4-factor prothrombin complex concentrate. Also add vitamin K.

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3
Q

What is a normal fibrinogen level? In a pregnant patient?

A

2-4g/dL&raquo_space; 6g/dL in pregnancy.

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4
Q

Fibrin sealants

A

Topical treatments mostly for intraoperative use.

Downsides include antibody formation, viral transmission, and excessive clotting.

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5
Q

What drives coagulopathy in bypass circuits?

A

Contact with non-endothelial surfaces causes release of tissue factor (prothrombotic). Patients also acquire deficiencies of platelets, fibrinogen, fXIII and vWF (pro-bleeding) and must be on systemic anticoagulation.

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6
Q

What is the mainstay of anticoagulation in bypass, and how is it monitored?

A

Heparin; monitor with aPTT or anti-factor-Xa (note: need to ensure no acquired antithrombin deficiency!)

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7
Q

Thrombin-activatable fibrinolysis inhibitor (TAFI)

A

Endothelial protein that is activated by thrombin-thrombomodulin complex to cleave lysine residues from fibrin, making it less recognizable as a plasmin substrate.

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8
Q

PAI-1

A

Endothelial prothrombotic protein which inhibits plasminogen activator’s ability to activate plasmin.

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9
Q

Tissue factor pathway inhibitor (TFPI)

A

Endothelial antithrombotic protein. Partially secreted. Inhibits the extrinsic Tenase and prothrombinase but can be displaced by heparin.

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10
Q

Endothelial protein C receptor

A

Endothelial antithrombotic protein that facilitates the activation of protein C by thrombin.

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11
Q

PAR-1

A

Endothelial antithrombotic receptor that upregulates PGI2 and NO synthesis following cleavage activation by thrombin. Also releases tPA from Weibel-Palade bodies?

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12
Q

What complications are associated with use of topical bovine thrombin products?

A

Antibodies to thrombin but also factor V.

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13
Q

What coagulation factors are affected by use of oral contraceptives?

A

Factor VIII and von willebrand factor levels may increase wiht OCPs.

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14
Q

What isolated factor deficiencies may be ween with the lupus anticoagulant? With myelodysplastic or myeloproliferative disorders? Amyloidosis? Gaucher disease?

A

Lupus anticoagulant - Factor II
MDS, MPN - Factor V
Amyloidosis - Factor X
Gaucher disease - Factor XIT

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15
Q

Why do hemophilia A/B carriers often have lower levels of those factors?

A

Lyonization of X chromosomes.

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16
Q

Is PNH associated with bleeding or thrombotic complications?

A

Thrombotic; usually venous thrombi of visceral organs.

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17
Q

What pathophysiologic mechanisms cause acquired von willebrand disease?

A

Autoantibodies against vWF (as in lymphoma/myeloma), decreased production (as in hypothyroidism), or increased destruction (as in cardiac valve abnormalities)

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18
Q

What lab assays can (maybe) distinguish acquired from congenital von willebrand disease?

A

Von willebrand propeptide (decreased in congenital forms).

Ristocetin cofactor mixing studies (no correction upon mixing if inhibitor is present).

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19
Q

Pre-test risk assessments for HIT

A

HIT Expert Probability (HEP)

4T: Thrombocytopenia, Timing, Thrombosis, oTher causes

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20
Q

How can EIA specificity of HIT be improved?

A

Use IgG-specific test (IgA, IgM do not cause significant HIT).

Use confirmatory high-dose heparin second step (inhibition is confirmatory)

Use high OD cutoffs.

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21
Q

Rapid HIT immunoassays

A

“HemosIL” latex particle agglutination or chemiluminescence assays

“PaGIA” Particle gel immunoassay

Akers particle immunofiltration assay

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22
Q

Heparin-induced platelet aggregation

A

A disfavored confirmatory assay for diagnosis of HIT. Essentially platelet light transmission aggregometry; very labor intensive, but requires donor platelets and

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23
Q

How are argatroban and bivalirudin monitored?

A

aPTT
ACT
*Prone to underdosing because of nonlinearity of these tests.

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24
Q

What coagulation factors are merely cofactors? What do they do?

A

Factor V, VIII

Serve as serine protease binding sites to coordinate substrate docking.

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25
Q

What genetic polymorphisms can affect the metabolism and effect of warfarin?

A

CYP2C9 - Metabolism

Mutation in VKORC1 can affect response

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26
Q

What drive neonatal vitamin K deficiency, and how is it treated?

A

Lack of gut flora to produce vitamin K

Treat with prophylactic IM supplementation

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27
Q

What processes contribute to feedback amplification of the coagulation cascade?

A

Thrombin-based feedback activation of factor V, VIII, and XI. Polyphosphate secreted from activated platelets.

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28
Q

What is the structure of fibrinogen?

A

Dimer composed of three pairs of protein chains (Aa, Bb, and gamma). Can be divided into a central E globular domain flanked by two D globular domains.

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29
Q

What is the mechanism of action of factor XIIIa?

A

Crosslinks adjacent fibrin monomers in a covalent fashion through glutaminase function. Links E+D domains, but also D+D.

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30
Q

How does thrombin interact with platelets and endothelial cells?

A

Platelets: Activates PAR-1, PAR-4
Endothelium: Activates PAR-1, TAFI, and protein C (when bound to thrombomodulin).

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31
Q

What is EPCR?

A

Endothelial protein C receptor; an endothelial surface marker that concentrates protein C enough to be activated by the thrombin-thrombomodulin complex.

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32
Q

In what form is circulating protein S found?

A

40% unbound

60% bound to C4b

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33
Q

How does antithrombin prevent clotting?

A

Binds serine proteases (thrombin, but also many others) to form an inactive complex. It is potentiated by a heparin pentasaccharide.

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34
Q

What is heparin cofactor II?

A

Another serpin similar to antithrombin but more specific to inhibition of thrombin.

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35
Q

What are usual causes of pre-analytical errors in coag testing?

A 
Specimen underfilling
Hemolyzed/clotted specimen
Old or mistimed specimen
Improper transport
Thrombophilia testing in acute setting or on anticoagulation...
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36
Q

What are the relevant binding domains on VWF?

A

A1 (binds platelets, collagen) and A3 (binds collagen), D’ (fVIII)

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37
Q

What is the ratio of vWF to fVIII binding?

A

50:1. Most fVIII is bound to vWF, but vWF is hardly saturated.

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38
Q

What platelet interactions dominate at high and low shear?

A

High-shear: Gp1b-VWF

Low-shear: Gp1a/IIa-Collagen

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39
Q

What compounds are in alpha granules?

A

VWF, fV, fVIII, fXIII, fibrinogen, fibronectin, P-selectin, GpIIb-IIIIa, PDGF

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40
Q

What compounds are in dense granules

A

ADP/ATP, Ca2+, Mg2+, polyphosphate, histamine, serotonin

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41
Q

How do red cells facilitate hemostasis?

A

Improve plt-endothelial interactions, contribute to hemostatic plug, increase blood viscosity (and by extension, shear force), secrete ADP

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42
Q

What is the cutoff value of VWF antigen used to diagnose VWD?

A

<30%; although normal range is generally 50-200%, some group O patients will naturally fall under 50%.

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43
Q

What conditions can increase von willebrand levels?

A

Pregnancy
Acute phase reaction
Non-white race

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44
Q

How is VWF RCO testing performed?

A

Mix PPP with REAGENT plts and add ristocetin to mimic shear force function (binding of Gp1b to vWF)

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45
Q

What is the “VWF functional antibody”?

A

Antibody against A1 domain. Note that the antigen tested in VWF antigen levels is a structural, not binding domain.

46
Q

How is VWF Collagen binding testing performed?

A

Benchtop ELISA using microtiter wells coated with collagen. Note, same method applies to Gp1b bnding.

47
Q

What is the benefit of a VWF propeptide test?

A

Propeptide is a cleaved byproduct of mature vWF. It is cleared more quickly than vWF. In patients with Type 1 VWD due to increased clearance (1C, Vicenza) the pp:vWF ratio will be increased.

48
Q

What VWF test is useful to detect Type 2N vWF?

A

VWF:FVIII binding assay

49
Q

Describe the utility of genetic von willebrand disease testing?

A

Challenging to sequence due to size and presence of a pseudogene.

Large deletions predict a higher rate of inhibitors or analphylactic reactions.

50
Q

To what conditions is the PFA-100 sensitive?

A

Anemia (affected by hematocrit)
Thrombocytopenia (need >100k/uL to use PFA)
Qualitative defects (duh)
VWD (normal study rules out VWD?)

51
Q

Compare the lumiaggregometry profiles of BS and GT.

A

BS: Responds to all agonists except Ristocetin.
GT: Responds only to ristocetin agonists.

52
Q

How does the VerifyNow work? What testing cartridges exist?

A

Fibrinogen coated beads are aggregated by platelets that are activated by either AA (to detect ASA), ADP (to detect P2Y12 inhibs), or TRAP (to detect IIb/IIIa inhibs).

53
Q

What is the use of electron microscopy in coag testing?

A

For assessing granule (particularly dense granule) structure.

54
Q

What NON-COAGULATION-FACTOR targets are activated by thrombin?

A

Protein C, platelet activating receptor (PAR), TAFI. tPA release?

55
Q

What are the longest and shortest lived coagulation factors?

A

Longest: Factor XIII (144hrs)
Shortest: Factors VII (6hrs), VIII (12hrs)

56
Q

What is the function of these domains in coagulation factors: Kringle, Discoidin, GLA, Kunitz

A

Kringle: Bind positively-charged residues (especially in fibrin[ogen])
GLA: Binds calcium, requires VKORC
Discoidin: Found on cofactors V/VIII
Kunitz: Protease inhibitors, for feedback inhibition and found on SERPINs

57
Q

How do the extrinsic and intrinsic pathways actually probably contribute to clotting in vivo?

A

Extrinsic is usually the spark (note that VIIa is rapidly shut down by TFPI), then the intrinsic feeds forward the cascade.

58
Q

What is the “Josso loop”?

A

The extrinsic Tenase can also activate factor IX, promoting the intrinsic Tenase.

59
Q

What are the five components of the tenase or prothrombinase?

A 
Enzyme
Cofactor
Calcium
Substrate zymogen
Negatively-charged surface
60
Q

What is the relative affinity of antithrombin for activated coagulation factors?

A

IIa, Xa > XIIa, XIa, IXa

61
Q

How are different detection methods of PT/aPTT affected by H/I/L?

A

Optical detection methods are affected by all 3 in the usual fashion.

Mechanical detection methods are affected by hemolysis (releases phospholipid) and lipemia (activates factor VII?).

62
Q

What are the Quick and Owren methods?

A

Methods of PT; Quick method is common and uses a 1:3 dilution of plasma to buffer. Owren method is a 1:21 dilution which uses bovine reagent and is insensitive to factor V and I levels.

63
Q

Batroxobin time

A

AKA reptilase time, directly cleaves fibrinogen and so is unaffected by direct thrombin inhibitors. Note, only generates fibrinopeptide A.

64
Q

For what factors do chromogenic assays exist?

A

8, 9, 10

65
Q

What is a Bethesda unit? How is it calculated from the residual activity level?

A

The amount of inhibitor needed to reduce activity level by half. BU = (2-log[residual]/.301)

66
Q

How are protein C levels measured?

A

Activate plasma with protac venom, mix with C-deficient plasma, and compare to a standard curve. A chomogenic protac venom assay also exists.

67
Q

How are protein S levels measured?

A

Add APC to patient plasma (and S-deficient plasma) and compare the rate of prolongation of aPTT to a standard curve.

68
Q

How are antithrombin levels measured?

A

Add heparin and activated Xa or IIa to PPP with a chromogenic substrate. Compare rate to a standard curve.

69
Q

What is the function of factor XIII and where is it found?

A

It crosslinks fibrin D-domains and also incorporates alpha-2 antiplasmin into the clot. It is found half-bound to fibrinogen, and half in platelet alpha granules (and cytoplasm?)

70
Q

What is the structure of factor XIII?

A

Composed of subunit A (the transglutaminase) which is made in megakaryocytes, and subunit B (the zymogen) which is made by hepatocytes

71
Q

How does t-PA promote degradation of fibrin(ogen)? How do most antifibrinolytics work?

A

Binds fibrin surface using kringle domains (at lysine residues) to attract and activate plasminogen. Most antifibrinolytics work by mimicing soluble lysine analogues.

72
Q

What proteins regulate plasmin activity?

A

Alpha-2 antiplasmin (inhibits plasmin at clot)
PAI-1 (inhibits tPA)
TAFI (cleaved by thrombin&raquo_space; cleaves lysine domains)

73
Q

Urea clot lysis

A

Form clot, try to dissolve in 5M urea. A surrogate marker of factor XIII activity which is not recommended by ISTH.

74
Q

How are factor XIII levels detected?

A

Urea clot lysis (old, irrelevant)
Antigenic assays
Functional assays (detect ammonia release)

75
Q

What is a D-dimer? What are the units?

A

Soluble fibrin fragment which was cross-linked by fXIIIa. A sensitive but nonspecific assay. Can be reported as 1 FEU (1 of which equals 0.5 DDU).

76
Q

Euglobulin clot lysis

A

Form euglobulin fraction (which lacks serpins) by using acetate. If clot lyses in <120min, suggests hyperfibrinolysis.

77
Q

How is alpha-2 antiplasmin measured?

A

Add pt plasma and plasmin to a normal sample, measure degree of inhibition and compare to standard curve.

78
Q

What is the effect of anemia on VET?

A

Actually improves clotting MA/MCF on TEG/ROTEM (RBCs disrupt plt-fibrinogen interactions)

79
Q

How can clot retraction be ruled in on ROTEM?

A

Use aprotinin (stops fibrinolysis)

80
Q

Activated Clotting Time

A

Whole blood POC test using a contact activator (kaolin, celite). Variable and unreliable but reportable over high levels of UFH&raquo_space; used in bypass

81
Q

Tachyphylaxis

A

Rapid resistance to treatment, applicable to von willebrand disease response to DDAVP

82
Q

How should Type 1 VWD ideally respond to DDAVP challenge?

A

Expect threefold increase in VWF levels.

83
Q

How is von willebrand factor dosed?

A

No agreed upon dosing level. Aim for a minimum activity level of 30%, up to 80% for major surgeries. Example loading dose 30-60 U/kg.

84
Q

Why is it not recommended to prophylactically transfused qualitative platelet disorders?

A

Many will be prone to developing antibodies against missing antigens (eg, BSS&raquo_space; Gp1b antibodies).

85
Q

What are the lab features of BSS?

A

Macrothrombocytopenia
Lack of activation with ristocetin
Absent Gp1b on flow

86
Q

What are the lab features of Glanzmann’s thrombasthenia?

A

Lack of activation with all agonists except ristocetin

Resembles afibrinogenemia, but fails to correct with PNP mix?

87
Q

Grey platelet syndrome

A

No alpha granules (compare with dense granule deficiency).

88
Q

Genetic thrombocytopenias

A

MYH9
MPL/MECOM
RUNX1/ANKRD26/ETV6

89
Q

What are some causes of acquired von willebrand disease?

A 
Inhibition by paraprotein
Clearance by autoantibody
Neoplastic clearance (ie, essential thrombocythemia)
Shear stress (defects, cardiac hardware)
Hypothyroidism (decreased synthesis)
90
Q

How does uremia cause bleeding? How can it be treated?

A

Causes abnormalities of the von willebrand factor multimers. Treat with cryo/desmopressin, estrogens, and maintaining hematocrit above 30%. IE, not platelet transfusion.

91
Q

What severity of hemophilia is most common?

A

Severe (<1% factor activity)

92
Q

How many cases of hemophilia are de novo?

A

1/3

93
Q

What is the goal activity level desired with factor repletion in hemophilia?

A

30%

94
Q

How are factors VIII and IX dosed?

A

1U fVIII per kilogram&raquo_space; +2% activity level

1U fIX per kilogram&raquo_space; +1% activity level

95
Q

How are severe hemophilias with inhibitors treated?

A 
Bypass agents (FEIBA, NovoSeven)
Emicizumab (do not mix with FEIBA)
(porcine factors may be less cross-reactive)
96
Q

How do hemophilia A and B differ clinically?

A

A is more common, and is generally more severe (arthropathy).
DDAVP is not an option in hemophilia B.
Factor IX dosing is 2x that of factor VIII.
Hemophilia B has fewer inhibitors, but patients may have anaphylactic reactions.

97
Q

How is RiaSTAP dosed?

A

Divide (difference in desired level) by 1.7 mg/dL per mg/kg bodyweight. Just, divide by 1.7

98
Q

What treatments exist for deficiencies of…
Factor V
Factor XI
Factor XIII

A

fV: FFP, plts (contain fV)
fXI: FFP only (EU has concentrate available)
fXIII: Plasma-derived (Corifact) or recombinant (novo13)

99
Q

How does liver disease cause thrombocytopenia?

A

Splenism due to portal hypertension
Decreased liver production of TPO
Direct bone marrow suppression by EtOH

100
Q

How is coagulopathy of liver disease managed perioperatively?

A

Correct vitamin K deficiency pre-op.
Transfuse to TEG, not PT/aPTT.
Consider antifibrinolytics.

101
Q

What are some general transfusion goals in DIC?

A

Plt: 30k/uL
PT: 150mg/dL

102
Q

How does hypothermia affect coag factor function?

A

-10% factor activity per -1 degree C

103
Q

How does acquired factor VIII inhibitor present?

A

Usually elderly patient with severe subcutaneous, muscle, or GI bleeding. Not hemearthrosis!

104
Q

How rapidly is heparin cleared?

A

During the initial phase, it is cleared rapidly by endothelium with a half-life of 1.5hrs.

Once endothelium is saturated, half-life extends to 4-6hrs depending on renal function

105
Q

How do LMWH and fondaparinux compare to UFH?

A

More Xa activity, less IIa activity. Cannot be monitored with aPTT (use anti-Xa for LMWH; no consensus for fondaparinux).

106
Q

What is the purpose of the heparin bridge when starting warfarin therapy?

A

To cover for prothrombotic state caused by loss of protein C and S (VKORC-dependent, first to go)

107
Q

How are DTIs metabolized?

A

Argatroban is hepatically metabolized

Dabigatran and bivalirudin are renally excreted.

108
Q

How are DTIs monitored?

A

Can follow aPTT, ACT, or DTT. Ecarin clotting time can be used for Dabigatran.

109
Q

What are the antidotes for DOACs and DTIs?

A

DOACs: Adnexanet-alfa, 4F-PCCs
Dabigatran: Idaricizumab, FEIBA

110
Q

What isoforms of COX does aspirin block?

A

At low dose, blocks COX-1 (in plts)

At high dose, blocks COX-2 (inflammatory/pain)

111
Q

Compare the thienopyridines antiplatelet drugs

A

Plavix: Slow, irreversible, prone to polymorphisms in metabolism
Prasugrel: Faster, no resistances from cytochromes
Ticagrelor, cangrelor: Fast and reversible.

Transfusion Medicine Fellowship (34 decks)

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