Homeostasis and Treatment of Coagulation Disorders

Question 1

hemostasis

Answer 1

normal (regulated) activation of blood coagulation system in response to vascular damage (stop blood flow)

Question 2

coagulation

Answer 2

blood clot

Question 3

problems with hemostatic defects

Answer 3

1. thrombosis - blockage of vein/artery resulting from inappropriately activated/persistent blood clot
2. hemorrhage - loss of blood from arteries/veins due to injury or aneurysm

Question 4

hemostatic systems

Answer 4

1. coagulation factors: plasma proteins (serine proteases) - involved in blood clot formation after injury
2. platelets: cell fragments form primary plug - involved in blood clot formation + release mitogenic factors - aid in repairing damaged blood vessels
3. fibrinolytic system: plasma proteases: remove fibrin clots once repair to damaged blood vessel occurs

Question 5

heparin

Answer 5

natural compound = inhibit blood clot (inhibits cleavage of factors)

a form = active form

inactive form = zymogen
activated by cleavage

more selective for 2a than 5a

Question 6

clotting pathways

Answer 6

extrinsic pathway = activated in response to tissue injury
V11a (7) tissue factor + phospholipid (PL) + Ca2+
convert X >Xa (10)

intrinsic pathway: glass surface activates XII (12)
activating XII (12), XI (11), IX(9)
IXa + VIIIa + PL + Ca2+ = activate X

common pathway: Xa (Va + PL + Ca2+)
convert prothrombin (II) > prothrombin (IIa)
= converts fibrogen > firbrin monomers
= XIIIa converts > fribin polymer

Question 7

functional assessment of coagulation

Answer 7

prothrombin time (PT)

• tests extrinsic + common pathways
• addition of tissue factor, calcium, and PL
• 10-13 secs

activated partial thromboplastin time (aPPT)

• tests intrinsic + common pathways
• addition of activating surface, Ca2+, and PL
• 35-55 secs

(reproducible - store blood for future use)

whole blood clotting time

• whole blood drawn into glass tube (activating surface)
• tests for disorders in any aspect of coagulation
• 2-3 minutes (done there and then)

Question 8

inherited disorders of coagulation

Answer 8

hemophilia A - deficiency/defect factor VIII (8)

hemophilia B - deficiency factor IX (9)

Question 9

treatment for hemophilias

Answer 9

plasma factor concentrates factor 8+9

• purified from pooled human plasma donors
• risk of transmission of infectious disease (HIV/Hepatitis)

hemophilia a = RECOMBINATE

• recombinant form of factor 8
• produced in CHO cells

hemophilia b = BENEFIX

• recombinant production of factor 9
• produced in CHO

Question 10

anticoagulants

Answer 10

used to prevent occurrence/progression of deep vein thrombosis/pulmonary embolism

carefully monitored to avoid overdose with hemorrhage

effects may be increased with liver disease + antiplatelet drugs

Question 11

intravenous anticoagulants

Answer 11

HEPARIN

• activate antithrombin III
• extracted from animal tissues
• direct inhibitor of serine protease of intrinsic/common pathway factors
• rapid onset of action - monitored by aPPT
• low molecular weight = more reproducible
• rare se: osteoporosis/hypoaldosteronism/elevated K+

Question 12

oral anticoagulants

Answer 12

WARFARIN

• inhibitor of intrinsic/common pathways
• vitamin K antagonist
• interferes with activation of 9,10,7,2
• used for long-term anticoagulant therapy
• teratogenic
• monitored with PT

Question 13

PT measurements are normalized

Answer 13

. PT - measured in tandem with patient sample
. patient PT converted to International Normalized Ratio (INR) (dividing patient clotting time by standard clotting time)
. dose of warfarin adjusted to give INR between 2-4

Question 14

side effects of warfarin

Answer 14

risk of intracranial bleeding with INR>4
skin necrosis associated with genetic protein C/S deficiency
teratogenic - first trimester

Question 15

drugs that interact with warfarin metabolism by mixed-function oxidase (cytochrome P450)

Answer 15

disulfiram
fluoxetine
clopidogrel
bile acid resins

Question 16

roles of platelets in hemostasis

Answer 16

• platelets are activated by contact between glycoprotein receptors on platelet surface + collagen exposed during cell wall injury
• platelets adhere to damaged site + provide PL for the formation of 10a + 11a
• aggregation of platelets further stimulated by thromboxane + ADP
• platelets form nucleus for clot formation
• clot = cluster of platelets cross-linked by fibrin

Question 17

platelet aggregation + activation

Answer 17

adhesion of platelets to damaged surface

release of ADP

synthesis of thromboxane

expression of aggregation receptors: glycoprotein 2b/3a

crosslinking of platelets by binding of firbin to glycoproteins receptors

Question 18

antiplatelet aggregation agents

Answer 18

ASPIRIN = inhibits Cox 1 blocking synthesis of thromboxane
long-term effect = platelets cannot synthesize new cox-1

prevent atherosclerotic plaques, pulmonary embolism, strokes

contraindicated if patient is being treated with anticoagulants/liver disease

//others: TXA2 R antagonists
GP IIB/IIIa expression inhibitors/receptor antagonists

Question 19

CLOPIDOGREL

Answer 19

competes with ADP for binding to ADP receptor on platelets = prevents expression of glycoprotein R for fibrin

inactive when administered, requires metabolism by cytochrome P450

fewer problems with GI irritation than aspirin

Question 20

Optical Aggregometry

Answer 20

measures the quantity of light passing through a sample of platelet-rich plasma (PRP) using platelet-poor plasma as a reference

Addition of a platelet agonist to PRP causes
platelets to aggregate & fall out of solution producing an increase in % transmittance of the sample

Question 21

Impedance Aggregometry

Answer 21

Measures the electrical current passing between
two electrodes placed in whole blood.

Addition of a platelet agonist causes platelets to
aggregate on the electrode surface resulting in a decrease in current between the electrodes

Question 22

Quantitative Platelet Disorders

Answer 22

• Thrombocytosis*: (>700,000 platelets/µL), can
be caused by malignancies of the megakaryocyte lineage, splenectomy, anemia or rebound from thrombocytopenia

• Thrombocytopenia: (<50,000/µL), can be caused by autoimmune diseases, transfusion reactions, radiation, chemotherapies, extracorporeal circulation, and heparin

Question 23

Treatment of Platelet Disorders

Answer 23

• Thrombocytosis:
HYRDOXYUREA + APIRIN + APLHA INTERFERON
(side effect: nausea, diarrhea, seizures)

• Thrombocytopenia:
CORTICOSTEROIDS / PLATELET RICH PLASMA

Question 24

The Fibrinolytic System

Answer 24

• Initiated after coagulation occurs
• Active agent is plasmin, a serine protease = degrades fibrin and factors II, V, and VIII
• Plasminogen is inactive precursor of plasmin
• Endogenous plasminogen activators include tissue plasminogen activator (tPA) and kallikrein

Question 25

Fibrinolytic Drugs

Answer 25

• Activate plasminogen to form plasmin STEPTOKINASE • Used primarily to treat acute myocardial infarct (MI) and prevent a 2nd heart attack (must be used within 12 hrs of original MI to be effective)