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1

Three initial responses to vascular injury

Vascular vasoconstriction, platelet adhesion, thrombin generation

2

Intrinsic coagulation cascade

Exposed collagen + prekallikrein + HMW kiniogen + Factor 12 -> activate factor 11 -> activate 9, then 8 -> activate 10, then add 5 -> Convert prothrombin (factor II) to thrombin -> thrombin then converts fibrinogen to fibrin

3

Extrinsic coagulation cascade

Tissue factor (injured cells) + factor 7 -> activate 10, then add 5 -> convert prothrombin to thrombin -> thrombin then converts fibrinogen to fibrin

4

Prothrombin complex (for intrinsic and extrinsic pathways)

- 10, 5, Ca, platelet factor 3, prothrombin.
- Forms on platelets
- Catalyzes the formation of thrombin

5

Convergence point for intrinsic and extrinsic pathway

Factor 10

6

Inhibits factor 10

Tissue factor pathway inhibitor

7

Links platelets together (binds GpIIb /IIIa molecules) to form platelet plug -> hemostasis

Fibrin

8

Helps crosslink fibrin

XIII

9

- Key to coagulation
- Converts fibrinogen to fibrin and fibrin split products
- Activates factors 5 and 13
- Activates platelets

Thrombin

10

- Key to anticoagulation
- Binds and inhibits thrombin
- Inhibits factors 9, 10, and 11
- Heparin activates AT-III (up to 1000x normal activity)

Antithrombin III (AT-III)

11

Vitamin-K dependent; degrades factors 5 and 8; degrades fibrinogen

Protein C

12

Vitamin K dependent, protein C cofactor

Protein S

13

Released from endothelium and converts plasminogen to plasmin

Tissue plasminogen activator

14

Degrades factors 5 and 9, fibrinogen, and fibrin -> lost platelet plug

Plasmin

15

Natural inhibitor of plasmin, released from endothelium

Alpha-2 antiplasmin

16

Components of fibrinolysis

Tissue plasminogen activator, plasmin, alpha-2 antiplasmin

17

Factor: shortest half life

Factor 7

18

Factors: labile factors, activity lost in stored blood; activity not lost in FFP

Factors 5 and 8

19

Factors: only factor not synthesized in the liver (synthesized in the endothelium)

Factor 8

20

Factors: 2, 7, 9, 10, protein C and protein S

Vitamin-K dependent factors

21

Takes 6 hours to have effect

Vitamin K

22

Effect is immediate and lasts 6 hours

FFP

23

Prothrombin

Factor II

24

Half life: RBCs

120 days

25

Half-life: platelets

7 days

26

Half life: PMNs

1-2 days

27

- From endothelium
- Decreases platelet aggregation and promotes vasodilation (antagonistic to TXA2)

Prostacyclin (PGI2)

28

- From platelets
- Increases platelet aggregation and promotes vasoconstriction
- Triggers release of calcium in platelets -> exposes Gp2b/3a receptor and causes platelet-to-platelet binding; platelet-to-collagen binding also occurs (Gp1b receptor)

Thromboxane (TXA2)

29

Contains highest concentration of vWF-VIII; used in von Willebrand's disease and hemophilia A (factor 8 deficiency), also has high levels of fibrinogen

Cryoprecipitate

30

Has high levels of all coagulation factors, protein C, protein S, and AT-III

FFP

31

Causes release of VIII and vWF from endothelium

DDAVP and conjugated estrogens

32

Measures 2, 5, 7, and 10; fibrinogen; best for liver synthetic function

PT

33

Measures most factors except 7 and 13 (thus does not pick up factor 7 deficiency); also measures fibrinogen

PTT

34

What do you want PTT for routine anticoagulation?

60 - 90 sec

35

ACT

activated clotting time

36

What do you want ACT (activated clotting time) for routine anticoagulation?

Want ACT 150 - 200 sec for routine anticoagulation, > 460 sec for cardiopulmonary bypass

37

INR: relative contraindication to performing routine procedures

INR > 1.5

38

INR: relative contraindication to central line placement, percutaneous needle biopsies, and eye surgery

INR > 1.3

39

Most common cause of surgical bleeding

Incomplete hemostasis

40

Most common congenital bleeding disorder

Von Willebrand's disease

41

- Reduced quantity of vWF
Tx: recombinant VIII:vWF, DDAVP, cryoprecipitate

Type 1 von Willebrand's disease

42

- Defect in vWF molecule itself, vWF does not work well
Tx: recombinant VIII:vWF, cryoprecipitate

Type 2 von Willebrand's disease

43

- Complete vWF deficiency (rare)
Tx: recombinant VIII:vWF, cryoprecipitate; (DDAVP will not work)

Type 3 von Willebrand's disease

44

Lab findings of von Willebrand's disease

PT normal; PTT can be normal or abnormal. Prolonged bleeding time (ristocetin test).

45

- VIII deficiency
- Sex linked recessive
- Prolonged PTT, normal PT

Hemophilia A

46

Why may hemophilia A newborns not bleed at circumcision?

Factor 8 crosses the placenta

47

Treatment for hemophiliac joint bleeding

- Do not aspirate
- Ice, keep joint mobile with ROM exercises
- Factor 8 concentrate or cryoprecipitate

48

Treatment for hemophiliac epistaxis, intracerebral hemorrhage, or hematuria

Recombinant factor 8 or cryoprecipitate

49

Goals for hemophilia A pre and post op

Need levels 100% pre-op, keep at 80-100% for 10-14 days after surgery

50

- Sex-linked recessive
- Prolonged PTT and normal PT
Tx: Recombinant factor 9 or FFP

Hemophilia B - Factor 9 deficiency - Christmas Disease

51

Goals for Hemophilia B pre and post op

Need levels 100% pre-op, keep at 30-40% for 2-3 days after surgery

52

Prolonged PT.
Normal PTT.
Bleeding tendency.
Tx: Recombinant factor 7 concentrate or FFP

Factor 7 deficiency.

53

Causes bruising, epistaxis, mucosal bleeding, petechiae, purpura.

Platelet disorders

54

Platelet disorder: caused by H2 blockers, heparin

Acquired thrombocytopenia

55

Platelet disorder: Gp2b/3a receptor deficiency on platelets (cannot bind to each other).
- Fibrin normally links the Gp1b/3a receptors together.
Tx: ?

Glanzmann's thrombocytopenia
Tx: Platelets

56

Gp1b receptor deficiency on platelets (cannot bind to collagen)
- vWF normally links Gp1b collagen.
Tx: ?

Bernard Soulier
Tx: Platelets

57

How does uremia affect platelets?

Uremia inhibits platelet function.
Tx: hemodialysis (1st), DDAVP, platelets

58

Thrombocytopenia due to antiplatlet antibodies (IgG PF4 antibody) results in platelet destruction.
- Can also cause platelet aggregation and thrombosis.
- Forms a white clot.
- Can occur with low doses of heparin.

Heparin-induced thrombocytopenia (HIT)

59

Treatment for heparin-induced thrombocytopenia (HIT)

Stop heparin, start argatroban (direct thrombin inhibitor) to anticoagulate

60

- Decreased platelets, low fibrinogen, high fibrin split products, and high d-dimer
- Prolonged PT and prolonged PTT
- Often initiated by tissue factor
Tx: need to treat the underlying cause

Disseminated intravascular coagulation (DIC)

61

Inhibits cyclooxygenase in platelets and decreases TXA2

Aspirin

62

Aspirin pre-op recommendations

Stop 7 days before surgery; patients will have prolonged bleeding time

63

Plavix pre-op recommendations

Stop 7 days before surgery; ADP receptor antagonist.
Tx: platelets

64

Coumadin pre-op recommendations

Stop 7 days before surgery; consider starting heparin while Coumadin wears off

65

Platelet pre-op recommendations

Want them > 50,000 before surgery, > 20,000 after surgery

66

Surgery: can release urokinase, activates plasminogen -> thrombolysis.
Tx: e-aminocapropic acid (Amicar)

Prostate surgery

67

Best way to predict bleeding risk

H & P

68

Does normal circumcision rule out bleeding disorders?

No, they can still have clotting factors from the mother

69

Picks up 99% of patients with bleeding disorder

Abnormal bleeding with tooth extraction or tonsillectomy

70

Common with vWF deficiency and platelet disorders

Epistaxis

71

Common with bleeding disorders

Menorrhagia

72

Present as venous or arterial thrombosis / emboli (e.g., DVT, PE, stroke)

Hypercoaguability Disorders

73

- 30% of spontaneous venous thromboses
- MC congenital hypercoaguability disorder.
- Causes resistance to activated protein C; the defect is on factor 5.
Tx: heparin, warfarin

Factor V Leiden mutation

74

Treatment for hyperhomocysteinemia

Folic Acid.
B12

75

Tx: prothrombin gene defect G20210A

Heparin, warfarin

76

Tx: protein C or S deficiency

Heparin, warfarin

77

- Heparin does not work in these patients
- Can develop after previous heparin exposure
Tx: recombinant AT-III concentrate or FFP (highest concentration of AT-III) followed by heparin, then warfarin

Antithrombin H1 deficiency

78

Tx: dysfibrinogenemia, dysplasminogenemia

Heparin, warfarin

79

- Defect in platelet function; can get thrombosis
- Keep Hct

Polycythemia vera

80

Causes of polycythemia vera

Primary: JAK2 mutation
Secondary: low oxygen tension (e.g.: living at high altitudes, smoking, carbon monoxide exposure)

81

- Procoagulant (get prolonged PTT, but are hyper coagulable)
- Caused by antibodies to cardiolipin and lupus anticoagulant (phospholipids)

Anti-phospholipid antibody syndrome)

82

Prolonged PTT (not corrected with FFP).
Positive Russell viper venom time, false-positive RPR test for syphillis.
Tx: heparin, warfarin

Anti-phospholipid antibody syndrome

83

MC factor causing acquired hypercoagulability

Tobacco

84

Causes of acquired hyper coagulability

Tobacco. Malignancy. Inflammatory states. IBD. Infections. OCPs. Pregnancy. Rheumatoid arthritis. Post-op patients. Myeloproliferative disorders.

85

How does cardiopulmonary bypass result in hyper coagulability?

Activates Factor 12 (Hageman factor). Tx: heparin to prevent.

86

Why does warfarin-induced skin necrosis occur?

Short half-life of proteins C and S, which are first to decrease in levels compared with the pro coagulation factors; results in relative hyperthrombotic state.
- Occurs when placed on coumadin without being heparinized first.

87

Who is at risk for warfarin-induced skin necrosis?

Patients with relative protein C deficiency are especially susceptible.

88

Key elements in the development of venous thromboses

Virchow's triad (stasis, endothelial injury, hyper coagulability)

89

Key element in the development of arterial thrombosis

Endothelial injury

90

Risk factors for DVT

Stasis. Venous injury. Hypercoaguability.

91

Post-op DVT Tx:
1st:
2nd:
3rd:

1st: Warfarin for 6 mo.
2nd: Warfarin for 1 yr.
3rd or significant PE: Warfarin for life.

92

Indications for Greenfield filter

- Contraindications to anticoagulation
- Documented PE while on anticoagulation
- Free-floating IVC, ilio-femoral, or deep femoral DVT
- Recent pulmonary embolectomy

93

When are temporary IVC filters indicated?

Can be inserted in patients at high risk for DVT (e.g. head injury patients on prolonged bed rest)

94

Most common origin of PE

Ilio-femoral region

95

Tx pulmonary embolism

Shock (despite massive interpose, pressors) -> OR.
No shock -> Heparin (thrombolytics have not shown an improvement in survival) or suction catheter-based intervention.

96

- Inhibits fibrinolysis by inhibiting plasmin
- Used in DIC, persistent bleeding following cardiopulmonary bypass, thrombolytic overdoses

Aminocaproic acid (Amicar)

97

Prevents vitamin-K dependent decarboxylation of glutamic residues on vitamin K dependent factors

Warfarin

98

Improve venous return but also induce fibrinolysis with compression (release of tPA (tissue plasminogen activator) from endothelium.

SCDs.

99

- Binds and activates anti-thrombin III
- Reverse with protamine
- Cleared by the reticuloendotehlial system
- Does not cross placental barrier

Heparin

100

Risks of long-term heparin

Osteoporsis. Alopecia.

101

Half-life / goal PTT of heparin

Half-life: 60-90 minutes.
Goal PTT: 60-90 seconds

102

Cross reacts with NPH insulin or previous protamine exposure; 1% get protamine reaction (hypotension, bradycardia, and decreased heart function).

Protamine

103

- Lower risk of HIT compared to unfractionated heparin
- Binds and activates antithrombin III but increases neutralization of just 10a and thrombin
- Not reversed with protamine

Low molecular weight heparin (ex, enoxaparin, fondaparinux)

104

- Reversible direct thrombin inhibitor
- Metabolized in the liver
- Half life: 50 minutes
- Often used in patients with HITT

Argatroban

105

- Reversible direct thrombin inhibitor
- Metabolized by proteinase enzymes in the blood
- Half life: 25 minutes

Bivalirudin (Angiomax)

106

- Irreversible direct thrombin inhibitor
- Most potent direct inhibitor or thrombin
- High risk for bleeding complications

Hirudin (Hirulog; form leeches)

107

Malayan pit viper venom; stimulates tPA release

Ancrod

108

- Activate plasminogen
- Need to follow fibrinogen levels: fibrinogen

Thrombolytics: Streptokinase, urokinase, tPA

109

Treatment for thrombolytic overdose

e-aminocaproic acid (Amicar)

110

Absolute contraindications to TPA

Active internal bleeding. Recent CVA or neurosurgery (

111

Major contraindications to TPA.

Recent (

112

Minor contraindications to TPA.

Minor surgery. Recent CPR. A fib with MV disease. Bacterial endocarditis. Hemostatic defects (i.e. renal or liver disease). Diabetic hemorrhage retinopathy. Pregnancy.