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Flashcards in Chapter 2 Deck (130):
1

How does the endothelium prevent propagation of a clot?

Thrombomodulin production results in activation of protein C and subsequent inhibition of factors Va and VIIIa, while local TFPI release reversibly inhibits factor Xa
Endogenous heparin and dermatan sulfate expression results in antithrombin III binding- thus inactivating thrombin and preventing propagation of clot

2

What is an early mediator of primary hemostasis during endothelial injury?

Vasoconstriction, as a result of neuromyogenic reflexes within the vascular smooth muscle

3

How is vascular contraction further augmented?

Paracrine signaling via ADP, thromboxane A2 and serotonin from nearby adherent platelets

4

What provides an avenue for platelet and leukocyte adhesion

Exposure of subendothelial tissue factor and collagen

5

What improves coagulation protein and platelet binding?

Increased endothelial cell production of vWF
Expression of cellular TF and platelet-activating factor (PAF)
Reduced thrombomodulin activity

6

Origin of platelets and lifespan

Derived from bone marrow megakaryocytes
Lifespan of 9-12 days

7

What percentage of the body's platelet pool is stored in the spleen?

1/3

8

How is platelet adhesion further strengthened?

Presence of vWF, which mediates the binding of collagen with glycoprotein Ib/IX

9

When does platelet plug formation occur?
When does clot stabilization occur?
What is clot stabilization aided by?

Within 1-3 mins of injury
Within 10 mins of injury
Aided in part by negative feedback from endothelial cell PGI2 release

10

What occurs after platelet plug formation?

Procoagulant protein complexes (i.e, prothrombinase, tenase) form on platelet phospholipid surfaces and augment the production of thrombin via the coagulation cascade

11

What is responsible for the production of all coagulation factors with the exception of VIII and vWF?

Liver
VIII and vWF are produced by endothelial cells

12

How are factors II, VII, IX and X formed

Through vit K-dependent reactions
They are of particular importance in pharmacologic anticoagulation

13

Traditional coagulation pathway

Extrinsic (PT/INR) and intrinsic (aPTT) merge into a common pathway

14

More recent discovery of the coagulation pathway

Described in cell-based phases:
Initiation
Amplification
Propagation

15

Process of initiation

TF is released by the injured vascular endothelium
Binds to factor VII to form TF-VIIa complexes
Complex activates factors X and IX to form Xa and IXa
Factors Xa and Va form the Xa-Va complex (prothrombinase complex)
Prothrombinase complex converts small amts of factor II (prothrombin) to factor IIa (thrombin)

16

Process of amplification

Thrombin produced from initiation activates additional factor V, VIII, XI, and platelets through a pos feedback loop

17

Process of propagation

Factors IXa and VIIIa form the factor IXa-VIIIa complex (tenase complex)
Tenase complex converts additional factor X to Xa, which then forms more prothrombinase complexes
Large amts of thrombin are generated, leading to the formation of fibrin from fibrinogen
Fibrin weaves throughout the platelet plug to form a stable fibrin clot

18

What are important natural anticoagulants?

ATIII
Protein C
Protein S

19

What does ATIII do?

Directly inhibits factors IIa (thrombin), IXa, Xa, and XIa

20

What is protein C?

A vit-K dependent natural anticoagulant, which is activated by thrombin-thrombomodulin complexes on the endothelial cell surface following the formation of a clot

21

What is protein S?

A vit-K dependent cofactor in the formation of APC

22

What are important regulatory and precursor proteins necessary for fibrin degradation?

Plasminogen
tPA
a2-antiplasmin

23

What does tPA do?

Acts to convert plasminogen to plasmin, which in turn binds fibrin and degrades the polymer into soluble split products

24

What does a2-antiplasmin do?

Serves as a negative regulator of plasmin and binds and inactivates circulating excess plasmin
Binds continuously secreted plasmin, allowing early clot formation during vascular injury without immediate degradation

25

What is a nl platelet count?

150-450K/microL of blood

26

What occurs with a platelet count <50,000?

Pts are subject to easy bruising and bleeding?

27

When does spontaneous bleeding occur?

Does not typically occur unless platelet counts are <20K

28

What is considered a nl bleeding time?

Between 2-10 mins

29

What does bleeding time measure?

Qualitative platelet dysfunction

30

What is an abnormal bleeding time?
What is it associated with?

Between 10-15 mins
Associated with low-mod risk for bleeding
>15 mins is serious risk for spontaneous bleeding and severe platelet dysfunction or thrombocytopenia

31

What does prothrombin time (PT) measure?

The function of the extrinsic and common pathways of the ex vivo coagulation cascade
Measures the function of VII, V, X, II and I

32

What is a nl INR?

1.0

33

What prolongs INR? Why?

Warfarin
Due to depletion of vit K-dependent factors II, VII, IX, and X

34

What does aPTT measure?

The ex vivo intrinsic coagulation cascade, compromising high molecular weight kininogen, prekallikrein, and factors XI, IX, VIII, V, X, II, and I

35

What is activated clotting time?

ACT is a test similar to aPTT but used in clinical situations requiring high-dose heparin administration (cardiopulmonary bypass, endovascular interventions, ECMO)

36

What is TEG?

Thromboelastography
Provides a quantitative measure of all aspects of hemostasis, including:
Platelet aggregation
Clot strengthening
Fibrin cross-linking
Fibrinolysis

37

Advantages of TEG

Quantification of thrombodynamics
Ability to differentiate between platelet and plasma coagulative disorders
Rapidity of its results

38

What is the MC congenital bleeding disorder?

vWD

39

Lab findings of vWD

Prolonged bleeding time
Mildly prolonged aPTT
Abnl platelet binding as measured by a depressed ristocetin cofactor assay

40

Type I vWD inheritance pattern

Autosomal dominant
Characterized by quantitative reduction in vWF levels with nl protein structure and function

41

Type II vWD

Variable inheritance pattern
Characterized by abnl qualitative protein function

42

Type III vWD

Autosomal recessive inheritance pattern
Associated with severe bleeding with absent vWF production

43

First-line therapy for type I and II vWD

DDAVP

44

Tx for type III vWD

Surgical prophylaxis or bleeding
Transfusion with cryoprecipitate or factor VIII: vWF concentrate

45

What is Glanzmann's thrombasthenia?

A rare congenital platelet disorder that is a result of defective or decreased synthesis of glycoprotein IIb/IIIa
Platelets are unable to bind fibrinogen and lack the ability to form platelet aggregates

46

Why does platelet dysfunction occur in renal dz?

It's a result of numerous changes to protein function and intraluminal fluid dynamics

47

What bleeding problems are found in uremic pts?

Dysfunctional vWF
Decreased thromboxane A2
Altered platelet granules

48

What does anemia cause in renal dz pts?

Decreased platelet adhesion and aggregation

49

Tx of uremic pts

Depends on severity of sx/bleeding risk
Dialysis
Epo
DDAVP/cryoprecipitate

50

What is extracorporeal circuitry?
What does it give rise to?

Cardiopulmonary bypass, ECMO
Abnl platelet activation in part d/t fibrinogen accumulation within the oxygenation membrane

51

What does consumption and loss of platelets from the circulating pool result in?

Thrombocytopenia as well as qualitative dysfunction

52

How are therapeutic anticoagulation levels maintained with extracorporeal circulation?

Systemic unfractionated heparin given IV and intermittently into the extracorporeal circuit

53

Type I HIT

May occur in as many as 10% of pts receiving unfractionated heparin
Typically resolves spontaneously within 96 hrs of heparin cessation

54

Type II HIT

Unusual immunologic complication affecting 1-3% of pts

55

Pathology of HIT

Heparin binds with PF4, which is released from platelet alpha granules normally.
in HIT, IgG antibodies form against the heparin-PF4 complex within 5-10 days of exposure that in turn, strongly activates platelet adhesion and aggregation

56

When should you raise clinical concern for HIT?

When platelet counts decrease by >50% from preheparin levels

57

What does massive platelet activation and platelet plug formation predispose the pt to?

Venous thrombosis
Thromboembolism
Limb ischemia
Stroke
MI

58

Labs for HIT

Serotonin release assay (SRA)
Heparin-induced platelet aggregation assay (HIPA)
ELISA

59

What is one of the more common screening tests in clinical use for HIT?

ELISA

60

Tx of HIT

Immediate cessation of all heparin therapies
Non-heparin-based anticoagulation strategies unless clinical CI
Avoidance of platelet transfusion is appropriate to help propagation of white clot

61

Idiopathic thrombocytic purpura (ITP)

An acquired d/o rising from pathologic destruction of platelets d/t autoantibody formation

62

When does ITP commonly occur?

Time of infection (often viral) OR
altered immune homeostasis (malignancy, lymphoproliferative d/os, concurrent autoimmune dz)

63

Dx of ITP

Clinical and one of exclusion

64

Tx of ITP

With platelet count of <30K, initially prevention of bleeding
Include glucocorticoids and IVIG
2nd line is splenectomy
If surgery is CIed, rituximab

65

Pathology of hemophilia A/B

A is deficiency of factor VIII
B is deficiency of factor IX
Impaired formation of tenase (VIII-IXa) complex, impacting the amplification phase of coagulation and leading to decreased factor Xa and thrombin creation

66

Sx of hemophilia A/B

Mucosal bleeding
Excessive bleeding during circumcision
Hemarthrosis
Intracranial hemorrhage

67

Labs for hemophilia A/B

Elevated aPTT
Decreased factor VIII or IX levels

68

Tx of hemophilia A

Recombinant factor VIII
Cryoprecipitate transfusion
Desmopressin

69

Tx of hemophilia B

Recombinant factor IX
FFP or cryoprecipitate transfusion

70

DIC

Results from unchecked activation of the normal coagulation response with loss of localization
Sepsis is the MCC of DIC

71

Pathophys of DIC

Stems from systemic microvascular activation of platelets, diffuse activation of clotting factors, deposition of fibrin with microangiopathic thrombosis, and subsequent fibrinolytic pathway inactivation

72

Dx of DIC

Clinical dx of exclusion
Schistocytes on peripheral blood smear

73

Tx of DIC

Maintain an INR <1.5 and platelet count >50K

74

Tx of bleeding secondary to hepatic failure

Correction of factor and platelet deficiencies with blood component management

75

When is hypothermia commonly seen?

Altered coagulation as a result of:
Trauma
Massive resuscitation
Extended exposure to open body cavities during procedures
Iatrogenic hypothermia for cerebral or myocardial protection

76

What is hypothermia associated with?

Impaired platelet function
Decreased collagen-induced platelet aggregation

77

Tx of hypothermia

Treat underlying cause
Limit evaporative heat loss
Mild (>34 degrees Celsius)- passive rewarming techniques
Moderate (30-34 Celsius)- active rewarming
Severe (<30 Celsius)- External passive and active rewarming, internal rewarming

78

Definition of massive transfusion

Replacement of a pts blood volume with packed RBCS (pRBCs) in a 24-hr period or acute transfusion of over half the pt's blood volume per hr

79

What is the massive transfusion protocol?

1:1:1 ratio of pRBC, FFP and platelet administration

80

What is the MC hereditary procoagulant d/o?

Factor V Leiden

81

Pathology of factor V Leiden

Mutation of the factor V protein prevents APC-mediated inactivation, thereby increasing risk for uncontrolled clot formation

82

Dx of factor V Leiden

aPTT with and without APC

83

Tx of factor V Leiden

No lifelong anticoagulation, only in thromboembolic events

84

What does ATIII do?

Inactivates thrombin and factors Xa, IXa, and XIa

85

What is the MC site of thrombosis in an ATIII deficiency?

Iliofemoral DVT

86

Dx of ATIII deficiency

ATIII-heparin cofactor assay

87

Tx of ATIII deficiency

FFP transfusion or ATIII concentrate

88

Dx of protein C/S deficiency

Serum protein C and S levels below the nl limits

89

What is the MC clinical manifestation of C/S deficiency?

Venous thromboembolism

90

What is a known RF for pts with decreased protein C and S levels d/t a transient procoagulant state during initiation of the drug?

Warfarin-induced skin necrosis

91

When should postponement of surgery occur?

Postpone beyond 6 wks for bare-metal stenting and 6 mos for drug-eluting stenting for noncardiac surgery pts
If not possible, continue dual antiplatelet therapy

92

MOA of ASA

NSAID that irreversibly inhibit clyclooxygenase isoforms (COX-1 and COX-2)
Maintains its effects for the lifespan of the platelet

93

MOA of ticlopidine, prasugrel and clopidogrel

Irreversibly inhibit activity of the ADP-P2Y receptor on the platelet membrane, which in turn impairs glycoprotein IIb/IIIa-mediated platelet cross-linking and aggregation

94

When to use clopidogrel

ACS
Recent MI or CVA
Established PAD

95

When to use prasugrel

ACS during PCI
It is found to inhibit platelet aggregation more rapidly and consistently compared to clopidogrel

96

When to use cilostazol

Intermittent peripheral arterial claudication
Prevents vasoconstriction and smooth muscle proliferation
May require up to 1 yr before symptomatic relief is noticeable

97

CIs of cilostazol

Dx of heart failure

98

What are abciximab, eptifibatide, and tirofiban used for?

Adjuncts to heparin and ASA therapy

99

What do heparin and LMWH do?

Increase ATIII activity
Primarily affects intrinsic and common pathways of in vitro coagulation

100

How do you measure heparin and LMWH efficacy?

aPTT needs to be 1.5-2.5x the baseline aPTT value

101

What is the onset of therapeutic warfarin anticoagulation

Takes at least 24-72 hrs
Principally affects extrinsic and common pathways of in vitro coagulation

102

How to measure effect of warfarin

PT and INR

103

MOA of direct thrombin inhibitors (DTI)
Examples of DTI

Inactivates circulating and clot-bound thrombin
Argatroban and bivalirudin
Dabigatran

104

When to use argatroban

Those with contraindication to heparin

105

Monitoring of argatroban

aPTT

106

What is bivalirudin approved for?

Pts with ACS undergoing PCI

107

What is dabigatran used for?

Tx/prevention of DVT, PE, non-valvular atrial fibrillation-associated stroke

108

What are apixaban, roxaban, and edoxaban approved for?

VTE and nonvalvular a fib

109

Measurement of apixaban, roxaban, and edoxaban

Anti-factor Xa activity

110

What is r-tPA approved for?

Acute STEMI
Acute ischemic stroke
Acute massive PE

111

Use of oxidized regenerated cellulose products

Frequently used as topical mesh placed on sites of bleeding to promote coagulation

112

Use of gelatin matrix products

Can absorb blood up to 40x their weight and serve as the foundation of a hemostatic plug

113

Use of topical thrombin and fibrin sealants

Commonly used bioactive topicals that augment hemostasis via directed factor II (topical thrombin) or fibrinogen (fibrin) application

114

MOA of aminocaproic acid

Interferes with fibrinolysis by competitively blocking the fibrin-binding site on plasminogen, thereby preventing conversion to plasmin

115

Use of aminocaporic acid

Prevention of fibrinolytic bleeding d/t:
Cardiac surgery
Congenital hematologic dz
Cirrhosis
Malignancy

116

Use of tranexamic acid

Hemophiliac pts undergoing dental procedures
Tx of menorrhagia

117

Uses of desmopressin

DI
Nocturia
Management of bleeding secondary to hemophilia A, type I and 2 vWD, and prevention of surgical bleeding in hemophiliac pts

118

Dosing of desmopressin in perioperative vWD and hemophilia A pts

30 mins IV or 2 hrs IN prior to the procedure

119

What does protamine sulfate do?

Reverses the effects of heparin

120

What does phytonadione (vit K) do?

Antagonizes the effects of warfarin

121

What does each unit of pRBCs contain?

200 mL of RBC concentrate and an additional 100 mL of preservation solution

122

What do pRBCs do?

Raise the recipient hematocrit approximately 3-4%

123

Derivation of FFP and FP-24

Donor whole blood that has been separated and frozen within 8 (FFP) and 24 (FP-24) hrs

124

When are FFP and FP-24 indicated?

Tx of multiple coagulation factor deficiencies, massive transfusion protocols, and when specific factor concentrates are not available

125

What are components of cryoprecipitate?

Fibrinogen
Factor VIII
Factor XIII
vWF

126

Indications of cryoprecipitate

Massive transfusion protocols
Hypofibrinogenemia
Factor VIII deficiencies when factor concentrates are not available
Bleeding associated with vWD when factor concentrates or DDAVP are not available

127

Platelet concentration dose and efficacy

Contain around 7 x 10 to the 6th platelets per 50 mL
Each unit should increase platelet levels by at least 5K

128

Indications for platelet transfusions

Massive transfusion
Hereditary platelet dysfunction
Drug-induced platelet dysfunction
Cardiopulmonary bypass surgery-related platelet destruction
Platelet underproduction

129

What should platelet counts be in preparation for surgical procedures?

>50K

130

What are isolated and recombinant factors currently available?

Fibrinogen concentrate
Recombinant thrombin
Recombinant factors VIII and IX
vWF concentrate
Antithrombin concentrate
Of particular note in surgical populations: prothrombin complex concentrates (PCCs) and recombinant factor VIIa