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Hemostasis = a process that minimizes:
1. hemorrhage when a blood vessel wall is damaged damaged
2. formation of untimely clots (thrombi) in undamaged vessels
Vasoconstriction of damaged vessels
Formation of a temporary seal by platelets
formation of a blood lot is fibrin clot (coagulation)
Platelet adherence to damaged vessel endothelium “activates”platelets by triggering
Platelet shape change resulting in interaction with other platelets and adherence to vessel endothelium
Platelet release of ADP and thromboxane A2, which bind to specific receptors on other platelets causing further platelet activatio
how do platelet get activated? (initial and advance)
by bind to vessel endothelium
by binding of ADP and throboxane A2
Adherence to vessel endothelium occurs
interaction with collagen and other proteins, e.g., von Willebrand factor (vWf)
a specific prostacyclin released by endothelial cells inhibits platelet aggregation when the vessel wall is not damaged
PG2 is pro-aggregation
drug that blocks binding of ADP to its receptor on platelets
drug inhibits synthesis of thromboxane A2
the plasma protein fibrinogen
that acts as a cross bridge by binding to specific receptors on platelets for the interaction with other platelet
fibrin clot is similar to a platelet clot
one is secondary hemostatsis and the other is primary clot
Secondary hemostasis - fibrin clot formation
fibrin mononer --> soft clot --> hard clot (transamination rxn)
how is fibrin exist in the blood and what is the implication?
so that blood wont clot in undmg vessel
Requirements of Blood Clotting
A. Rapid and efficient
B. No clotting under normal conditions
D. Removal of clots as healing occurs
Fibrinogen rxn (fibrinogen --> fibrin)
protease remove negative charge (A and B peptide) for the aggregation
Factors involved in blood clotting are synthesize in...
Clotting cascade - intrinsic pathway
all factors are present in blood; it is activated in vitro by interaction of factor XII, kininogen and kallikrein with the damaged surface of container
Deficiencies of factor XII, kininogen and kallikrein cause bleeding problem
Clotting cascade - extrinsic pathway require
requires TF, which is present in fibroblast membranes assuring that blood is exposed to TF at a damaged blood vessel site (trauma)
Clotting cascade - extrinsic pathway's main role
to initiate clotting, but this action is somewhat transient because certain inhibitors present in blood become active and inhibit factor VIIa
There is no distinction bw intrinsic and extrinsic pathway in vivo but there is one in vitro. because...
cross-talked in vitro but not in vivo
Platelet is required for clotting in vitro
what is used clinically to speed clotting?
What activates intrinsic and extrinsic pathway?
intrinsic: dmged surface (dmg endothelium)
extrinsic: trauma or TF
which one is faster, extrinsic and intrinsic?
extrinsic (1 factor vs 3)
why needs so many factor?
for amplification of clotting cascade
Roles of Thrombin
1.Cleave a thrombin receptor on platelets to activate Platelets. This is a second pathway of platelet activation (which is initiated by tissue factor.)
2.Cleave V and VIII to form active Va and VIIIa
- 3.Limit clot
- formation by eventually cleaving
- Va and VIIIa
Role of Platelets
Activated platelets also release certain growth factors that facilitate the healing of injured blood vessels.
stop clot formation at sites of injury (2 way)
Thrombin-thrombomodulin complex activate protein C which form hydrolysis product from Va and VIIIa via protein S
Heparin present in the blood inactivate protease-antithrombin complex
Role of Vitamin K in Clotting
- 1.The following coagulation factors require the binding of calcium to be active:
- II, VII, IX, X and proteins C and S
- 2. After synthesis, some glutamate residues of these factors have to
- be modified in order to bind calcium
- 3.This modification requires vitamin
- K (a fat soluble vitamin), which is a cofactor of the enzyme that catalyzes the modification reaction
Vitamin k involve in what kind of tranformation
Glu to gla transformation
wafarin, coumadin, heparin's pharm usage
prevent clotting or anticoagulant
adding coumadin/warfarin to a blood test tube, would it clot? why?
will clot because coumadin work in the liver to inactivate the factor
adding heparin to blood testube, will it clot? why?
it wont clot because of antithrombin
pt overdose on anticoagulant. dont know whether it heparin or warfarin. how to differentiate?
- mixing blood experiment
- clot --> warfarin
- wont clot --> heparin
Low molecular weight heparin (LMWH) is likely to be used more frequently because...
- 1) less non-specific binding to plasma proteins and thus better control of true
- dosage, and
2)fewer adverse side effects, eg., inhibition of platelets, and
- 3) *LMWH can be injected subcutaneously and thus can be administered at
- home by patient or nurse.
Dissolution of the clot
tPA (from endothelium) activate plasminogen (into plasmin)
Plasmin is protease for fibrin --> disease clot
what are D-dimers?
pairing of D-domain after clotting
lab finding: there has been finding and the clot broke down
Plasma levels of D-dimers are increased in:
Clinical test - bleeding time
measure primary hemostasis by nicking the pt and measure how long it take to clot
not useful very much now
clotting time in presence of added Tissue Factor
- INR = international normalization
- ratio is used to standardize results
used to assess warfarin levels
high INR --> excessive bleeding
Activated Partial Thromboplastin Time
Partial Thromboplastin Time (PTT) (clotting time in presence of added clay or kaolin, etc.)
used to assess heparin levels
pt with bleeding problem. PT is normal but prolonged APTT
problem with intrinsic pthway (factor XII, XI, IX)
pt with bleeding problem, APTT is normal and PT is abnormal
problem with extrinsic pathway (factor VII)
pt with bleeding problem, both APTT and PT are abnormal
problem with final common pathway (factor X, prothrombin, fibrinogen)
there is no crosstalk between intrinsic and extrinsic pathway of blood clotting
for LMWH, need clotting test.
what test is need to access LMWH?
antiXa activity test
- 1. X-linked recessive deficiency of
- factor VIII
2. Incidence: 1/10,000
3. Prevalent in European royal families
4. Affected patients have <5% of normal factor VIII activity
- 5. Symptoms include:
- ease of bruising
- hemorrhage into joints
- prolonged bleeding
X-linked recessive deficiency of factor IX
von Willibrand disease
Deficiency of von Willibrand factor
Thrombophilia - definition
- Untimely intravascular clot formation
- due to an imbalance between the anticoagulant and prothrombotic activities of plasma.
- 1. Factor V mutation (“Factor V
- a. Resistance to protein C
- b. Most common hereditary thrombophilia
- 2. “Prothrombin G20210A” mutation
- a. Overproduction of prothrombin
- 3. Deficiency in the level or activity of:
- protein C
- protein S, or
4. Often manifest only when other factors occur, eg., drugs (oral contraceptives), another
Acquired thrombophilia - precipitating factors
- a. Vascular infection or inflammation
- b. Severe trauma
- c. Cancer
- d. Obstetrical disorders,
- e.g., amniotic fluid embolism
- e. Antiphospholipid Syndrome
- Autoimmune production of anti- phospholipid antibodies that can cause:
- 1) thrombosis in vivo by an unknown mechanism
- 2) inhibition of coagulation vitro
- 3) fetal loss or damage during pregnancy
Acquired thrombophilia - possible cause
- a. Inflammation or cancer-induced expression of tissue factor
- 1) Certain chemicals can induce tissue factor expression by normal endothelial cells and by normal monocytes
- 2) Tissue factor exists in blood in an
- inactive state on particles derived from
- dead WBC; activation can occur by some
- unknown mechanism, e.g., lipid
- b. Reduced levels of antithrombin, protein
- C and protein S due to ongoing coagulation and inflammation.
intravascular deposition of fibrin --> throbosis of small and midsize vessels and organ failure
Depletion of platelet and coagulation factors --> bleed
acquired throbophilia - tx
anticoagulants, platelets, plasma
control of underlying condition (eg., infection).
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