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Anesthesia Pharm > Week 12 - Transfusion, Coagulation, and Anticoagulants > Flashcards

Week 12 - Transfusion, Coagulation, and Anticoagulants Flashcards

1
Q

What are the normal regulators of hemostasis?

A
  • Vascular extracellular matrix and endothelial reactivity
  • Platelets
  • Coagulation proteins
  • Inhibitors of coagulation
  • Fibrinolysis
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2
Q

What does clot formation involve?

A
  • Tissue factor release
  • Factor VIIa generation
  • Platelet activation
  • Cellular and humoral activation pathways
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3
Q

What are the endogenous anticoagulants?

A
  • PGI2
  • tPA
  • Heparin sulfate
  • Antithrombin III
  • Protein C
  • Endothelium derived relaxing factor (EDRF)

-Inhibit platelet activation, fibrin formation, and provide for vascular patency

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4
Q

What are the steps of platelet activation?

A
  1. Receptors on platelets bind to the damaged blood vessel wall – form bridges with vWF to initiate platelet adhesion
  2. Once adhered, platelet surface receptor changes – causes platelet aggregation
  3. Once they aggregate, expose surface factors that activate the coagulation cascade – form an early hemostatic plug

*abnormalities in platelet number or function are an issue

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5
Q

What are the four stages of hemostasis?

A
  1. Initiation
  2. Amplification
  3. Propagation
  4. Stabilization
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6
Q

What causes the initiation of clotting during vascular injury? What does it bind to?

A

Tissue Factor expression on the subendothelial vascular basement of the blood vessel

-Tissue Factor binds factor VIIa to form factor VIIa/TF complex

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7
Q

What converts factor X to factor Xa and what is factor Xa function?

A

factor VIIa/TF complex converts factor X to factor Xa

factor Xa generates trace amounts of thrombin

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8
Q

What factors from the intrinsic cascade generate Thrombin?

A

factors XI, IX, and VIII dependent activites

also factor VIIa/TF complex which forms Xa that generates thrombin

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9
Q

What enzymatically cleaves prothrombin to produce thrombin?

A

Prothrombinase Complex (factors Xa, Va, and prothrombin) assembly

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10
Q

What are common clotting factors targeted in anticoagulation therapy?

A
  • factor Xa

- prothrombinase complex (factors Xa, Va, and prothrombin)

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11
Q

What regulates thrombin generation to localize the clot at the site of vascular injury?
(regulators of TF-trigger procoagulant response)

A

Tissue factor pathway inhibitor – neutralizes factor Xa when it is in a complex with TF-factor VIIa

Antithrombin III – neutralizes the initially formed factor Xa and thrombin

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12
Q

What is the generalization of the initiation stage of hemostasis?

A

factor VIIa in circulation searches for exposed TF at sites of vascular injury and trace quantities of factor Xa and thrombin initiate a procoagulant response

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13
Q

What is the generalization of the amplification stage of hemostasis?

A
  • vWF binds to the damaged blood vessel
  • Platelets then adhere to subendothelial collagen-vWF via their glycoprotein Ib receptor are are activated
  • Thrombin activation of platelets further amplify clot formation

*factors XI, VIII, and V further amplify and sustain procoagulant responses after thrombin-mediated activation

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14
Q

What is the function of fibrinogen? What does it bind to?

A

Critical protein for clot formation – creates a dense lattice structure

Binds to platelet glycoprotein IIb/IIIa receptors to facilitate clot formation

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15
Q

When is it recommended to treat Fibrinogen levels?

A

at 1.5-2 g/L

normal = 2-3 g/L

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16
Q

What role does Factor XIII have in the clotting cascade? How is it converted to be active?

A

Plays a major role in the terminal phase – promotes formation of cross-linked fibrin polymers and generation of a stable hemostatic plug
-protects fibrin from fibrinolysis

*converted to factor XIIIa by thrombin and calcium

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17
Q

What does t-PA do?

A

converts plasminogen to active plasmin which promotes fibrinolysis

*endothelial activation releases t-PA from endothelial stores of Weibel-Palade bodies

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18
Q

What is the function of Protein C and Protein S?

A

Exert anticoagulant and anti-inflammatory activities

Protein C is activated by thrombin – activated protein C binds protein S

Together they function as a critical anticoagulant by inhibiting factor Va and factor VIIIa

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19
Q

What is disseminated intravascular coagulation (DIC)?

A

Coagulation disorder that occurs when pathologic activation of the hemostatic system

End result is an imbalance resulting in either a hemorrhagic coagulopathy or procoagulant state

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20
Q

What are characteristics of DIC?

A
  • Thrombocytopenia (platelets <100,000 in 50-60% and <50,000 in 10-15%)
  • Coagulopathy – decreased coagulation factors (prolonged PT or aPTT, bleeding)
  • Fibrinogen consumption
  • Reduced antithrombin and Protein C levels
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21
Q

What increases tissue factor expression?

A

Surgery

Trauma

Inflammation

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22
Q

What are inherited (genetic) risk factors for hypercoagulability?

A
  • Inherited Antithrombin Deficiency – decreased levels of antithrombin
  • Prothrombin G20210A Mutation – increases prothrombin levels (2% population; Heterozygous - 3x greater risk of thrombus, Homozygous is very rare)
  • Factor V Leiden – gene mutation so that procoagulant factor V is not inactivated by activated protein C (5% population; Heter = 3x increase; Homo = 18x increase)
  • Dysfibrinogenemia – high levels or structurally defective fibrinogen (2x increase in thrombus – >450 mg/Dl = poor outcome for CVA pts)
  • Protein C Deficiency (vitamin K dependent - decrease = 5x increased risk of VTE)
  • Antithrombin III Deficiency (hetero = 50% population, homo = fatal)
  • High levels of Lipoprotein(a) – inhibits fibrinolysis
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23
Q

What are acquired coagulation risk factors?

A
  • Antiphospholipid Antibodies: causes by a disease state (Lupus anticoagulants, anticardiolipin antibody, anti-B2-GP-1 antibody) – secondary to decreased thrombomodulin expression, increased TF expression, or impaired protein C
  • Liver or Renal Failure – decreased production of anticoagulant factors (ATIII, Protein C & S, plasminogen), increases platelet activation
  • Blood Stasis – immobility, low CO, A-Fib, Virchow’s triad, metabolic syndrome, cancer, age
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24
Q

What is heparin induced thrombocytopenia (HIT)?

A
  • Heparin binds to platelet factor 4 – antibodies recognize the complex, release microparticles that stimulate thrombin aggregation, and thrombi are formed
  • Excessive thrombus formation leads to endothelial damage and tissue factor production and more prothrombosis
  • 0.5-5% incidence in pts treated with heparin in past 5 days
  • unexplained drop in platelets by 50% or more
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25
Q

How is HIT diagnosed and treated?

A

Diagnosis:

  • platelet drop by 50%
  • new thrombus in pts on heparin for 5-14 days
  • rule out sepsis, IABP destruction, drug induced thrombocytopenia
  • severe HoTN, pulmonary HTN or tachy 20-30 minutes after heparin bolus may indicate HIT

Treatment:

  • STOP heparin – eliminate ALL sources (flushes)
  • initiate anticoagulation with a direct thrombin inhibitor
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26
Q

What increases risk for bleeding?

A
  • Advanced age
  • Low preop RBC volume
  • Preop antiplatelet or antithrombotic medication
  • Redo surgery
  • Emergency surgery
  • Comorbidities
  • Thrombocytopenia (platelet <50,000)
  • Hemophilia
  • von Willebrands disease
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27
Q

Hemophilia A vs Hemophilia B

A

Hemophilia A = factor VIII deficiency
-1:5000-10,000 males

Hemophilia B = factor IX deficiency
-1:20,000-34,000 males

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28
Q

What are the types of von Willebrands disease?

A

Genetic:

  • Partial quantitative deficiency (type I) – may respond to desmopressin (DDAVP)
  • Qualitative deficiency (type II) - 4 variants
  • Total Deficiency (type III)

Acquired vW disease

Treatment: measure vWF activity, administer factor VIII/vWF concentrate; IGG; cryoppt; plasma pheresis

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29
Q

What should be considered before transfusion of RBCs?

A

Based on the individual pt risk of developing complications of inadequate oxygenation

Consider intravascular volume, whether pt is actively bleeding, and the need for improvement in oxygen transport

  • usually indicated when hbg is <6 g/dL but may be indicated in higher hgb if above conditions are deemed necessary
  • rarely admin with hbg >10
30
Q

What is the shelf life of RBCs? What happens as they age?

A

Stored for up to 42 days after donation — Biochemical changes occur as they age (storage day >14 to 21 days admin may lead to adverse effects)

As blood ages, RBCs undergo shape changes with increased fragility that may impair microcirculatory flow

*Decreases oxygen delivery and increase hemolysis

31
Q

What is the therapeutic use of a RBC transfusion?

A

increase the oxygen-carrying capacity of blood and thereby improve oxygen delivery to tissues

32
Q

What is FFP used for?

A
  • To replace volume and coagulation factors during massive transfusion
  • Treat or prevent future bleeding during surgery and invasive procedures
  • Reverse warfarin therapy
  • Treatment of coagulation factor abnormalities where specific concentrates are not available
33
Q

What does FFP contain?

A
  • Coagulation factors – procoagulants and anticoagulants
  • Fibrinogen
  • Albumin
  • Immunoglobulins

*thawed plasma maintains normal levels of all factors except factor V (falls to 80% of normal) and factor VIII (falls to 60% normal) during storage

34
Q

What is the universal FFP donor?

A

AB

35
Q

What is the dosing of FFP?

A

Usual dose 5-8 mL/kg up to 10-30 mL/kg

*No specific ratio of RBC:FFP supported by literature

  • 1-3% risk of allergic reaction
  • beware of hypocalcemia with high volume FFP – treat with Calcium Chloride 500-1000mg
36
Q

What is Cryoprecipitate? What is it used for?

A

Formed when frozen plasma is allowed to thaw slowly at 1C to 10C

Rich in fibrinogen, factor VIII, vWF, and factor XIII – also contains other factors

Used to replete fibrinogen levels during coagulopathies – each unit contains 150-200 mg of fibrinogen; each bag contains 5-10 units of cryo

37
Q

When should platelets be transfused?

A

Typical threshold for prophylactic transfusion = 10,000

Neurosurgical procedures = 100,000

Other invasive procedures or trauma = 50,000 to 100,000

*Normal range = 150,000 - 400,000

38
Q

When should Prothrombin Complex Concentrates be transfused?

A

If rapid normalization of INR after warfarin therapy is required

*FFP usually used for this in the US

39
Q

What is von Willebrand Factor used to treat?

A

treatment and prevention of bleeding in adult patients with hemophilia A

adult and pediatric patients with von Willebrand disease for a treatment of spontaneous or trauma induced bleeding episodes and prevention of excessive bleeding during/after surgery

  • in patients where desmopressin is know/suspected to be inadequate
  • not indicated for prophylaxis of spontaneous bleeding episodes
40
Q

What is TACO? What is it characterized by?

A

Transfusion Associated Volume Overload
-the rate of volume infusion of blood products is in excess of what the pt’s CV status can handle

Characterized by:

  • acute onset of dyspnea
  • HTN
  • tachypnea
  • tachycardia

*use of an Echo, TEE will reveal hypervolemia, ventricular dysfunction, and potentially exacerbation of valvular dysfunction

41
Q

What is TRALI?

A

Transfusion-Related Acute Lung Injury
-results from neutrophil and/or endothelial activation via multiple mechanisms in the lung, resulting in pulmonary vascular injury and pulmonary edema

*usually secondary to donor HLA or HNA antibodies

42
Q

What is the clinical presentation of TRALI?

A
  • Acute onset (within minutes to 6 hours after transfusion)
  • Bilateral pulmonary infiltrates
  • Hypoxia without evidence of HF
  • Pulmonary artery occlusion <18 mmHg or lack of clinical evidence of volume overload

*difficult to distinguish from ARDS

43
Q

What is the two-hit model of TRALI?

A

Priming events occur before actual blood product admin

1) an inciting inflammatory event may be required to activate and upregulate inflammatory cells and vascular endothelium
2) transfusion event that actually triggers an acute inflammatory response and injury

*priming event may be caused by lipids generated during prolonged storage of blood, recent infection, and other events such as cardiopulmonary bypass that can trigger inflammatory responses and cytokine generation

44
Q

What has been done to decrease the incidence of TRALI?

A

Use of plasma from men only

Screen female donors for leukocyte antibodies

45
Q

What is the minimum hemoglobin value to transfuse RBCs to a patient?

A

there is none

46
Q

What of the anti-Xa anticoagulants is completely reversible by prothrombin complex concentrates (PCCs) in healthy individuals?

A

Rivoraxaban (Xarelto)

47
Q

What are the two synthetic antifibrinolytic agents?

A

Epsilon Aminocaproic Acid (EACA) and Tranexamic Acid (TXA)

-Competitively inhibit activation of plasminogen to plasmin (enzyme that degrades fibrin clots, fibrinogen, and other plasma proteins)

  • Lysine analogs
  • typically used in cardiac surgery patients
48
Q

What is Protamine?

A

Reversal agent for unfractionated heparin

-it is a basic protein that inactivates the acidic heparin molecule via simple acid-base interaction

49
Q

What does desmopressin (DDAVP) do?

A

Stimulates the release of vWF

  • vWF mediates platelet adherence to vascular subendothelium
  • Shortens bleeding time of pts with mild forms of hemophilia A or von Willebrand’s disease
50
Q

What is recombinant factor VIIa used for?

A

Hemophilia patients with factor VIII, factor IX antibodies, and factor VII deficiency

recommended dose 90-120 mcg/kg
*up to 400 mcg/kg has been given without thrombosis

51
Q

What is the mechanism of action of unfractionated heparin?

A

heparin binds to antithrombin III, enhancing the rate of thrombin-antithrombin formation 1,000 to 10,000 times

*factor Xa, XII, XI, and IX are also inhibited by antithrombin

52
Q

What lab test is used to monitor heparin treatment?

A

aPTT is used on pts requiring continuous infusion

ACT is used to monitor high concentrations during bypass

53
Q

What are the clinical uses of heparin?

A
  • rapidly anticoagulate a patient and acutely reduce thrombus formation
  • prevention/treatment of venous thrombosis and pulmonary embolism
  • acute coronary syndromes
  • perioperative anticoagulation for extracorporeal circulation and hemodialysis
54
Q

What are two commonly administered low-molecular-weight heparins?

A

Enoxaparin – has an anti-Xa to anti-IIa activity ratio between 4:1 and 2:1 (heparin is 1:1)

Dalteparin

*delay surgery for 12 hours after last dose of LMWH in pts with normal renal function and even longer in pt with renal dysfunction

55
Q

What does LMWH increase the incidence of in patients with indwelling epidural catheters?

A

risk of spontaneous hematoma formation

56
Q

What is fondaparinux? What is its uses?

A

Synthetic anticoagulant that makes up the active site of heparin that binds antithrombin to inhibit factor Xa but has no direct activity against thrombin

Admin SubQ

Prevention of DVT and PE
Primarily in patients with HIT or concerns about sensitization

57
Q

What are direct thrombin inhibitors?

A

class of anticoagulants that high-risk surgery patients at risk for HIT may receive

-bind to the thrombin molecule inactivating it thus decreasing factor Va production in the final common pathway

58
Q

What is Bivalirudin? When is its use indicated?

A

Direct Thrombin Inhibitor (IV) – synthetic analog of hirudin

Indicated for use in patients undergoing PCI with unstable angina, with or at risk for HIT, or with provisional use of GP IIb/IIIa inhibitors

59
Q

What is Argatroban? What is it used for?

A

Direct Thrombin Inhibitor (IV) – synthetic, univalent

Indicated for prophylaxis or treatment of thrombosis in pts with or at risk of HIT undergoing PCI

60
Q

What are Lepirudin and Desirudin?

A

Direct Thrombin Inhibitors – Recombinant hirudins, synthetic analogs of hirudin,

Lepirudin (IV) – use in pts with HIT and associated thromboembolic disease to prevent further thromboembolic complications

Desirudin (SubQ) – prevention of VTE after total hip or knee replacement surgery (HIT)

61
Q

What is the mechanism of action of warfarin?

A

inhibits vitamin K epoxide reductase that converts the vitamin K-dependent coagulation proteins (factor II [prothrombin], VII, IX, and X) to their active form

  • onset of anticoagulation effect is delayed 8-12 hours
  • peak effects occur 36-72 hours
62
Q

What lab test evaluate warfarin treatment?

A

PT and INR

63
Q

What are the clinical uses of warfarin?

A
  • Prevention of VTE
  • Prevention of systemic embolization and resultant stroke in patients with prosthetic heart valves or a-fib
  • Treatment of pts with thrombophilia who are hypercoagulable

*must discontinue 1-3 days preop for major surgery

64
Q

What is Rivaroxaban (xarelto)? Uses?

A

Oral direct factor Xa inhibitor

  • does not require antithrombin as a cofactor
  • Inhibit free factor Xa, clot-bound Xa, and factor Xa bound to the prothrombinase complex
  • may be suitable for management of HIT
  • reduction of risk of stroke and systemic embolism in nonvalvular a-fib
  • DVT prophylaxis following hip/knee surgery
  • treatment of DVT/PE
65
Q

In patients on rivaroxaban, an epidural catheter should not be removed until how many hours since the last dose of rivaroxaban? When can the next dose be admin after removal?

A

epidural catheter should not be removed earlier than 18 hours after last admin

next dose should be admin no earlier than 6 hours after removal

66
Q

What is Apixaban and its uses?

A

Oral direct factor Xa inhibitor

  • reduction of risk of stroke and systemic embolism in nonvalvular a-fib
  • prophylaxis of DVT following hip/knee replacement
  • treatment of DVT, PE
67
Q

Which anticoagulants require dose adjustments in renal failure? Which don’t?

A

Rivaroxaban and Dabigatran require renal dose

Heparin and Warfarin do not

68
Q

What is Dabigatran? Uses?

A

Oral direct thrombin inhibitor

-reduce the risk of stroke and systemic embolism in patients with non-valvular a-fib
-treatment of DVT and PE in patients who have been
treated with a parenteral anticoagulant for 5-10 days
-reduce the risk of recurrence of DVT and PE in patients
who have been previously treated

69
Q

What are the challenges to the newer oral anticoagulants in relation to perioperative management?

A
  • may increase surgical bleeding
  • have no validated antagonists
  • cannot be monitored by simple standardized lab tests
  • pharmacokinetics vary significantly between patients
70
Q

What is the mechanism of action of aspirin?

A

Antiplatelet Agent

Irreversibly acetylates COX thus preventing formation of thromboxane A2, which is responsible for thrombocytes

Effects last the life of the platelet (7-10 days)

71
Q

What is the mechanism of action of Clopidogrel (Plavix), Prasugrel (Effient) and Ticagrelor?

A

Thienopyridines – P2Y12 receptor inhibitors

Bind P2Y12 receptors thus blocking ADP binding – inhibiting APD mediated platelet activation and aggregation due to critical role ADP plays in platelet function

  • Clopidogrel and Prasugrel bind irreversibly
  • Ticagrelor binds reversibly
72
Q

Why is it that NSAIDs don’t have anti-coagulant effect?

A

They do but it is short lived and reversible as the drug concentration falls

-inhibit thromboxane synthesis but in contrast to ASA, this effect is reversible – reason why NSAIDs are not a satisfactory substitute for low-dose ASA as a prophylactic therapy for CV events

Anesthesia Pharm (18 decks)

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