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Biotechnology > 5 - Coagulation Factors > Flashcards

5 - Coagulation Factors Flashcards

1
Q

Define Thrombosis

A

may be defined as the formation and propagation of a blood clot within the vasculature

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2
Q

What is hemostasis?

A

refers to the stoppage of blood flow

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3
Q

What is coagulation?

A

it’s a complex process where the blood forms solid clots in response to blood vessel damage

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4
Q

What is thrombosis an important part of?

A

the normal hemostatic response that limits hemorrhage caused by vascular injury

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5
Q

Under normal conditions, a thrombus is confined to the immediate areas of injury and dose not obstruct flow to critical areas, unless blood vessel lumen is already diminished, as it is in __________

A

atherosclerosis

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6
Q

What can a clot cause ?

A
  • Acute myocardial infarction (AMI)
  • Deep vein thrombosis (DVT)
  • Pulmonary embolism (PE)
  • Acute ischemic stroke (AIS)
  • Acute peripheral arterial occlusion
  • Occlusion of indwelling catheters
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7
Q

Thrombosis is a complex process and involved in which 3 factors?

A
  • Blood flow and the blood vessel
  • Platelet-vessel interactions related to the disruption of the endothelium
  • Coagulation system
    • cellular elements (platelets)
    • protein elements (coagulation factors and mediators to promote thrombus formation)
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8
Q

When a vascular injures, an immediate local cellular response takes place which attracts ______ to migrate to the area of injury.

A

platelets

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9
Q

What do platelets do?

A

Platelets secrete several cellular factors and mediators to promote thrombus formation

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10
Q

During thrombus formation, circulating prothrombin is activated to the acting clotting factor _______.

A

thrombin

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11
Q

_______ is activated to fibrin by the newly activated thrombin.

A

Fibrinogen

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12
Q

What does fibrin do?

A

It is then formed into the fibrin matrix.

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13
Q

What are the 3 main components involved in blood clotting?

A
  • platelets
  • thrombin
  • fibrin
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14
Q

Each of the 3 components (platelets, thrombin, and fibrin) can be therapeutic targets:

List 3 drugs that can inhibit platelet activation and aggregation.

A
  • aspirin
  • glycoprotein (GP) 2b/3a inhibitors
  • clopidogrel
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15
Q

______ gathers in the fibrin matrix.

A

Plasminogen

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16
Q

What does fibrin-bound plasminogen do?

A

it will be converted by thrombolytic drugs to plasmin to initiate thrombolysis

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17
Q

Thrombolysis is the ______ process of thrombosis

A

opposite

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18
Q

What does Thrombolysis involve?

A

It involves fibrin-specific activators to a activate plasminogen at the fibrin surface.

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19
Q

What are the thrombolytic agents available today?

A

They are serine proteases that work by converting plasminogen to the natural fibrinolytic agent plasmin.

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20
Q

How does plasmin lyse clots?

A

by breaking down the fibrinogen and fibrin in a clot

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21
Q

List 1 naturally occurring fibrinolytic agent.

A

Tissue plasminogen activator (tPA)

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22
Q

What is tPA involved in?

A

(it is a naturally occurring fibrinolytic agent) found in vascular endothelial cells and is involved in the balance between thrombosis and thrombolysis

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23
Q

What does thrombosis exhibit?

A

Significant fibrin specificity and affinity

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24
Q

How does the binding of tPA dissolve a clot?

A

At the site of the thrombus, the binding of tPA and plasminogen to the fibrin surface induces a conformational change that facilitates the conversion of plasminogen to plasmin and dissolves the clot

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25
Q

Fibrin specific agents produce limited plasminogen conversion in the ______ of fibrin

A

presence

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26
Q

List some examples of fibrin-specific agents

A
  • Alteplase (tPA)
  • Reteplase
  • Tenecteplase
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27
Q

What do non-fibrin-specific agents do?

A

They catalyze systemic fibrinolysis

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28
Q

List an example of a non-fibrin-specific agent

A

Streptokinase

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29
Q

What is hemophilia?

A

a rare bleeding disorder in which the blood doesn’t clot normally.

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30
Q

What is the problem in Hemophilia A?

A

genetic mutation in factor 8 gene

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31
Q

What is the problem in Hemophilia B?

A

lack of factor 9

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32
Q

What is the clinical application of recombinant coagulation factors?

A

Hemophilia (A or B)

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33
Q

What are some clinical applications of recombinant thrombolytic agents?

A
  • Acute ischemic stroke
  • Acute myocardial infarction (STEMI)
  • Acute pulmonary embolism
  • Restoration of central venous access devices (ex. dialysis)
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34
Q

Describe primary coagulation

A

Platelets from plasma bind to the exposed collagen via their surface Glycoprotein 2b/3a receptor with von Willebrand factor (vWF), platelets release their granules (ADP and TXA2) to activate more platelets. Fibrinogen crosslinks adjacent platelets forming a platelet plug at the site of injury.

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35
Q

Describe secondary coagulation

A

proteins in plasma (coagulation factors) respond in a complex cascade which eventually leads to fibrin formation (strengthens the platelet plug).

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36
Q

The coagulation cascade consists of which two pathways?

A
  • The intrinsic pathway (contact activation pathway)

- The extrinsic pathway (tissue factor pathway)

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37
Q

Describe Hemophilia

A
  • Rare condition
  • Inherited
  • Usually occurs in males
  • Involves long bleeding times. Some are internal, causing damage to organs/tissues (especially ankles, knees, and elbows)
  • Little clotting factor which is needed for normal blood clotting
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38
Q

Hemophilia A is ______ hemophilia

A

classical

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39
Q

Describe Hemophilia A

A
  • little to no clotting factor 8

- 90% of people with the disorder have this type

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40
Q

Hemophilia B is called _______ disease

A

Christmas

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41
Q

Describe Hemophilia B

A
  • missing or have low levels of clotting factor 9
  • 10% of people with the disorder have this type
  • named after Steven Christmas, a Canadian who in 1952 was the first person to be diagnosed with this distinct form of hemophilia
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42
Q

What is done if hemophilia is suspected?

A
  • Personal and family medical history
  • Physical exam
  • Blood tests
    • Prothrombin time (PT) - extrinsic pathway
    • Activated partial thromboplastin time (APTT) - intrinsic and common pathway
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43
Q

What causes hemophilia in general?

A

Defect in one of the genes that determines how the body makes blood clotting factors 8 or 9 –> located on X chromosomes

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44
Q

What causes hemophilia in males?

A

abnormal gene on X chromosome results in hemophilia

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45
Q

What causes hemophilia in females?

A

Must have abnormal gene on both X chromosomes (very rare)
-Females can be a carrier if they have an abnormal gene on one of their X chromosomes - can pass the gene onto her children

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46
Q

Describe the severity index of hemophilia

A
  • can range from mild to severe

- depends on how much clotting factor is in the blood

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47
Q

How much clotting factor is in MILD hemophilia ?

A

5-30% of normal factor

48
Q

How much clotting factor is in MODERATE hemophilia ?

A

1-5% of normal factor

49
Q

How much clotting factor is in SEVERE hemophilia ?

A

less than 1% of normal factor

50
Q

What are the symptoms of Hemophilia ?

A
  • Easy bruising

- Excessive bleeding (external or internal)

51
Q

What are external bleeding symptoms?

A

Obvious:

  • bleeding in the mouth from a cut or bite
  • unexplained nosebleeds
  • heavy bleeding from a minor cut
52
Q

What are internal bleeding symptoms?

A

Hidden within the body:

  • blood in urine or stool
  • bleeding in joints or brain
53
Q

What is factor replacement therapy?

A
  • It is the basic treatment to stop or prevent bleeding in patients with hemophilia A and B.
  • It involves the infusion of Factor 8 and 9 concentrates to prevent or control bleeding.
54
Q

Concentrates of factors 8 and 9 come from which 2 sources?

A
  • Human plasma (plasma-derived)

- Genetically engineered cell line made by DNA technology (recombinant)

55
Q

Describe Factor 8

A
  • plasma protein
  • synthesized as a single chain polypeptide for 2332 amino acids
  • circulates as an heterodimer of the 80 kDa light chain and a variable (90-210 kDa) heavy chain in a metal ion-dependent complex
56
Q

What is the risk of Recombinate (human albumin as stabilizer) ?

A

risk of human disease

57
Q

What is the risk of Kogenate or Helixate or Refacto ?

A

no risk of passing human disease but not very stable

uses sucrose as stabilizer

58
Q

What is the advantage of Advate ?

A

More stable !

uses Trehalose as stabilizer

59
Q

Dosage of recombinant Factor 9 must be individualized to the needs of the patient. It depends on which conditions:

A
  • The severity of the deficiency
  • The severity of the hemorrhage
  • The presence of inhibitors
  • The desired increase in Factor 3 activity
60
Q

There are two factor 9’s: What are they produced in?

A
  • CHO (only recombinant)

- Plasma (purified from the blood)

61
Q

What amino acids are at 148 in CHO Factor 9?

A

Ala

62
Q

What amino acids are at 148 in Plasma Factor 9?

A

Thr/Ala

63
Q

Describe the carboxylation of CHO factor 9

A

40% is under carboxylated, lacking gamma-carboxylation at Glu40

64
Q

Describe the carboxylation of Plasma factor 9

A

12 gamma-carboxyglutamic acid

65
Q

What does the dose of recombinant Factor 9 depend on?

A
  • the severity of factor 9 deficiency
  • the location and extent of bleeding
  • the clinical condition
  • patient age
  • the desired recovery of factor 9
66
Q

Why was recombinant factor 7a developed ?

A

Because:

  • 15-20% of patients with Hemophilia A
  • 2-5% of patients with Hemophilia B

will develop antibodies (inhibitors) to factor 8 or 9 respectively after using recombinant factor 8 or 9.

67
Q

Where is recombinant factor 7a produced in?

A

Baby hamster kidney cells

68
Q

Recombinant factor 7a is expressed in a _____ chain form and is spontaneously activated to factor 7a during purification.

A

single

69
Q

Recombinant factor 7a is very similar to plasma-derived factor 7a with regard to ?

A

amino acid sequence, carbohydrate composition and gamma-carboxylation

70
Q

What is tPA?

A

Tissue Plasminogen Activator

-A protein involved in the breakdown of blood clots. It is a serine protease found on endothelial cells.

71
Q

As an enzyme, what does tPA catalyze ?

A

The conversion of plasminogen to plasmin

72
Q

What does the structure of tPA include ?

A
  • consists of 527 amino acids
  • with 17 disulfide bridges
  • there are 4 N-linked glycosylation sites at residues 117, 184, 218 and 448
73
Q

tPA:

Describe the F domain

A

residues 4 to 50, homologous with the finger domain mediating the fibrin affinity of fibronectin

74
Q

tPA:

Describe the E domain

A

residues 50 to 87, homologous with epidermal growth factor

75
Q

tPA:

Describe K1 domain

A

residues 87 to 176

76
Q

tPA:

Describe K2 domain

A

residues 176 to 256

77
Q

tPA:

What do K1 and K2 domain share?

A

a high degree of homology with the 5 cringes of plasminogen

78
Q

tPA:

Describe the P domain

A

residues 276 to 527, a serine protease region with the active site residues His322, Asp371 and ser478

79
Q

tPA:

What domains are responsible for binding to fibrin?

A

F domain and K2 domain

80
Q

tPA:

What is involved in rapid clearance in vivo with an initial half life of 6 minutes in human?

A

E domain and carbohydrate side chains

81
Q

tPA:

What domain is involved in enzymatic activity ?

A

P domain

82
Q

tPA:

What is involved in rapid inhibition by plasminogen activator inhibitor-1 ?

A

Lys296-His-Arg-Arg299

**if we modify this sequence and can make it resistant to plasminogen activator inhibitor 1 or to increase half life

83
Q

tPA:

What happens if we remove F and E domain?

A

more resistant to clearance in blood, increased half life

84
Q

What are types of Alteplase?

A

rtPA, Activase, Cathflow

85
Q

What is Alteplase produced in?

A

Chinese hamster ovary cells (CHO cells)

86
Q

Alteplase is an enzyme that consists of ___ amino acids

A

527

87
Q

Alteplase contains 4 distinct regions that contribute to it’s structure-function activity. What are they?

A
  • Fibronectin Finger
  • EGF growth factor domain
  • Kringle domains
  • Proteinase domain
88
Q

What does alteplase do?

A

binds to fibrin in a thrombus (clot) and converts plasminogen to plasmin, thereby initiating local fibrinolysis

89
Q

In an Acute MI:

What is alteplase used for?

A
  • Lyses of occlusive coronary artery thrombi
  • Reduction in mortality
  • Improve cardiac function
  • Reduce incidence of congestive heart failure
90
Q

Alteplase has to be used within ___ hr of MI

A

12

91
Q

Alteplase has 2 treatment regimens: a 90 minute accelerated infusion and a 3 hour infusion

Describe the 90 minute accelerated infusion

A

**don’t need to know doses

-recommend up to 6 hours of AMI symptoms

92
Q

Alteplase has 2 treatment regimens: a 90 minute accelerated infusion and a 3 hour infusion

Describe the 3 hour infusion

A

(still 100mg total)

Effective up to 12 hours of AMI symptoms

93
Q

What is Cathflo ?

A

Used to restore the function of central venous access devices that have been occluded by thrombus formation

94
Q

What is TNKase?

A

Tenecteplase is a 527 amino acid glycoprotein

95
Q

TNKase is a modified form of ?

A

the endogenous tissue plasminogen activation (tPA) molecule

96
Q

What are the 4 domains of TNKase ?

A
  • fibronectin finger
  • EGF growth factor domain
  • kringle domains
  • proteinase domain
97
Q

TNKase is produced in ____ cells

A

CHO

98
Q

Describe the TNKase use in an AMI (acute myocardial infarction)

A
  • 40mg as a single bolus over a 5-10 second period

- Never more than 50 mg

99
Q

KNOW slide 37

A

okay

100
Q

For TNKase, replace the K with __ ______ so can be resistant to plasminogen activation inhibitor 1

A

4 alanine

101
Q

TNKase:

What substitution causes glycosylation occurs at 103 position?

A

a sub of threonine 103 with asparagine means that glycosylation occurs at 103 position

102
Q

TNKase:

What sub means that the high mannose sugar residue is absent at 117 position?

A

sub of asparagus 117 with glutamine

103
Q

TNKase:

What do mutations within the kringle 1 domain do?

A
  • increase plasma half life (T50)

- 5 to 7 times longer half life vs tPA allowing for singles 5s bolus administration

104
Q

TNKase:

What does a tetra-alanine substitution at amino acids 296-299 in the protease domain cause ?

A
  • Increased fibrin specificity (14 fold greater fibrin selectivity over tPA)
  • Greater resistance to plasminogen activator inhibitor-1 (PAL-1) - 80 fold more resistant to PAL-1 than tPA
105
Q

What are the reasons to develop the second generation of recombinant thrombolytic agents?

A
  • Rapid clearance of recombinant tPA (Alteplase) from the liver
  • The first generation of recombinant tPA may cause some general fibrinolysis although it is administered locally
  • It has relatively complicated administration procedure
106
Q

What is Reteplase?

A

It is a 355 amino acid deletion variant of natural t-PA, which consists of 527 amino acids

107
Q

What 2 domains does Reteplase have?

A
  • Protease

- Kringle 2

108
Q

Reteplase:

What leads to low fibrin binding affinity?

A

The kringle 2 domain and the lack of the finger domain lead to low fibrin binding affinity

109
Q

Reteplase:

What leads to fibrin specificity?

A

the protease domain

110
Q

Reteplase:

What type of protein is it?

A

non-glycoslylated protein

111
Q

Reteplase:

Is synthesized in ____ as a single chain about 40 kDa peptide

A

E. coli

112
Q

Reteplase:

How is it used in acute myocardial infarction in adults (STEMI) ?

A
  • Two doses of 10 unites (18.1 mg) as slow intravenous infusion not to exceed two minutes.
  • The second dose is given 30 minutes after the first dose.
113
Q

Describe the general monitoring of thrombolytic agents

A
  • aPPT - activated partial thromboplastin time
  • CBC count
  • Signs and symptoms of bleeding
  • ECG
114
Q

What is internal bleeding ?

A

Internal: intracranial, retroperitoneal sites, GI, genitourinary, or respiratory tracts

115
Q

What is superficial bleeding?

A

Superficial: observed mainly at invaded or disturbed sites. Also including epistaxis (nose bleeding) and hematuria (blood cell in urine)

116
Q

What are complications of thrombolytic therapy?

A

hemorrhage, allergic reactions, embolism, stroke, and repercussion arrhythmias, among others

117
Q

What are some risk factors for hemorrhagic complications?

A
  • Increasing age
  • Lower body weight
  • Elevated pulse pressure
  • Uncontrolled hypertension
  • Recent stroke or surgery
  • Presence of a bleeding diathesis
  • Severe congestive heart failure

Biotechnology (9 decks)

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