BLOOD 3 Flashcards
“Pro-hemostatic” or
“Pro-coagulant” factors
(prevent blood loss)
“Anti-hemostatic” or
“Anti-coagulant” factors
(Keep blood fluid)
Key steps of hemostasis
- Vasoconstriction
- Primary hemostasis
- Secondary hemostasis
Primary hemostasis
platelet plug formation (“white thrombus”)
Secondary hemostasis
blood clotting or blood coagulation (“red thrombus”)
Where do platelets come from?
in the BM from cells called megakaryocytes
Strucure of platelets contain :
- Alpha granules
- Dense granules
Do platelets have a nucleus?
No,
- no DNA
- short lived
Alpha granules contain relatively large molecules:
– Adhesion molecules such as von Willebrand factor (vWF) – Growth factors – Clotting factors – Cytokines
Dense granules contain relatively small molecules
- ADP and ATP
- 5 hydroxytryptamine (5HT) or serotonin
- Ca++
Platelet plug formation (primary hemostasis)
- ADHESION of platelets
– they stick to damaged vessel wall - ACTIVATION of platelets
– they change shape, express various receptors and secrete various substances - AGGREGATION of platelets
– they stick to each other and form a plug
Activated platelets affect:
- 5HT
- TXA2
- ADP
- PL
Why does platelet plug not continuously expand?
adjacent endothelial cells are a source of chemical signals that influence platelet aggregation and alter blood flow and clot formation at the affected site.
Effects of Arachidonic acid metabolites
Disturbance in cell memb. —> Memb. Phospholipids —>
Arachidonic acid:
—> lipoxygenase pathway (inflammation)
—> cyclooxygenase pathway (hemostasis)
Effect of Aspirin on Hemostasis
Low aspirin, favours COX 1 is inhibited and COX 2 is inhibited I totally, but is then replenished because endothelial cells are nucleated, which forms prostacyclin which prevents blood clotting
COX 1 is in the _______ and COX 2 is in the ________
Platelets. Endothelial cells
COX 1
Thromboxane A2
- vasoconstriction
- increased platelet aggregation
- “PRO-hemostatic effect”
COX 2
Prostacyclin
- vasoconstriction
- decreased platelet aggregation
- “ANTI-hemostatic effect”
Secondary Hemostasis occurs following a
platelet plug formation
Secondary hemostasis involves
- a cascade of enzyme (clotting factors) activation
- Activation of enzymes occur by proteolytic cleavage
- Formation of gel-like fibrin clot
Clotting/coagulation factors
are
plasma proteins
Where are plasma proteins made
Liver
What does the synthesis of plasma proteins (clotting/ coagulation factors) require?
Vitamin K
Factors 1-4 (I-IV)
I : fibrinogen
II : Prothrombin
III : tissue factor
IV : calcium
Factors 5 and 12 (V and VII) are both
Cofactors
Activation of thrombin
- intrinsic pathway —> (
- extrinsic pathway —> (
)—> “Common activated factor” —> Prothrombin —> Thrombin
Traditional/Classical mechanism of blood clotting
Intrinsic extrinsic pathways meet up at one point. 3 pathways intrinsic, extrinsic, and common pathway. Know the sequence of activation in both pathways. Know how they are related and how they form a clot.
A deficiency in the factors _________ cause severe bleeding
- VII (7)
- VIII (9)
- XI (11) (moderate bleeding)
A deficiency in factor XII causes
No bleeding problem in vivo; failure to clot in vitro
Vivo =
Vitro =
Vivo = inside body Vitro = outside body
Blood from a healthy normal individual can clot when placed in a glass test tube ?
YES
Blood will have a delayed clot formation in a
silicone-coated test tube.
Physiological mechanism of blood clotting in vivo
- Activation of the extrinsic and intrinsic pathways happen in a sequential manner
- Initiation happens at extrinsic pathway,
small amounts of thrombin amplify the
intrinsic pathway to form a large clot - Note where V and VIII works in the pathway
Amplification of clotting protein activity by
thrombin
Wh at does Thrombin do in the clotting pathway?
- Activation of platelets
- Conversion of soluble fibrinogen to insoluble fibrin
- Activation of several other clotting factors
(factor V, VIII,XI, and XIII) - Activation of “protein C” (anticoagulant activity)
Hemophilia B: X-linked recessive gene
- Deficiency of factor IX
- Less common than Hemophilia A (Factor 8)
- Expressed in males
- No treatment available
Regulation of blood clotting
- Prevention of clot formation where and when it is not required
– Role of various anticoagulants - Breakdown of clot as tissue repair occurs
– Role of fibrinolytic system
Role of various anticoagulants
Prevention of clot formation where and
when it is not required
Role of fibrinolytic system
Breakdown of clot as tissue repair occurs
Prevention of clot formation: natural anticoagulants and wat they inhibit/change
- TFPI (inhibit X a and VII a)
- antithrombin 3 (inhibit thrombin)
- thrombomodulin (changes thrombin)
- protein C and S (inhibit V a and VIII a)
When thrombin is bound to thrombodulin, it has
PRO-coagulant activity
- increases platelet activation and fibrin formation
When thrombin is NOT bound to thrombodulin, it has
ANTI-coagulant activity
Actions of thrombin as an anticoagulant
Normal endothelial cells —-> Thrombomodulin —> Thrombin —> Protein C —> Activated protein C -> factor VIIIa -> factor Va
Prevention of clot formation: “Clinical Anticoagulants”
- Calcium chelators (eg. Na citrate) (vitro): removed ionized Ca++
- Heparin (vitro and vivo): increases effects of antithrombin 3
- antagonists of vitamin K (vivo): inhibits synthesis of II, VII, IX, and X in liver
Fibrinolysis is the
Breakdown of Fibrin Clot
Breakdown of Fibrin Clot: Fibrinolysis
We have many enzymes, but here were just mentioning one of the model enzymes, plasminogen activators, that converts inactive plasminogen to an active plasmin. For this activation to take place, it has to be in contact with the fibrin clot.
Fibrinolysis
• Natural Plasminogen activator – tissue plasminogen activator – released from endothelial cells – release increased by exercise
• Clinical clot busters or thrombolytic drugs
– used to treat patients with heart attacks
– eg., tenectaplase
Failure of hemostatic mechanisms when they ARE required
- problems with platelets
a) not enough platelets (thrombocytopenia)
b) abnormal platelet function (eg., deficiency of vWF) - problems with clotting factors
a) hereditary deficiencies (eg.hemophilias)
b) acquired deficiencies (eg. due to vit K deficiency)
Formation of blood clot when
they are NOT required
- Hereditary disorders: deficiency in anticoagulants and fibronoyltic factors
- Acquired disorders: decreased/sluggish blood flow, damage to the blood vessel wall
Abnormal hemostasis when this fine balance is broken
- Excessive bleeding Hemorrhage
- Thrombosis may lead to stroke, heart attack
