- XI, XII, PK, HMWK - II, VII, IX, X - I, V, VIII, XIII

Secondary Hemostasis Flashcards by Queenie Mae

• Is a process whereby on vessel injury, plasma proteins, tissue factors, and calcium interact on the surface of platelets to form a ___________. Platelets also interact with fibrin to form a stable platelet-fibrin clot.
o __________ = Coagulation factors
o __________ = released when there is vessel
injury
o ________ = co-factor that interacts on the surface platelets.
• This is a mechanism consisting of a series of cascading reactions involving development of enzymes from their precursors (_______) which will further be converted to an activated state (_________)

COAGULATION
stable fibrin clot
Plasma proteins
Tissue factors
Calcium
zymogen
serine protease

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• _______ (_____________) – inactivated form
o Example: Factor II, VII, IX, X, XI, XII,Prekallikrein
o No biological activity
• ___________ – activated form
o Has biological activity
• If there’s letter next to the roman numeral, it is in activated form (ex. Ia – fibrin, IIa – thrombin)

Zymogen (Coagulation Factors)
Serine proteases

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• Culprit: Vessel Injury
• The upper part involves the primary hemostasis and the lower part involves the secondary hemostasis.
• Once there is injury, there will be a release of the Tissue Factor to activate the Factor VII. The activated Factor VII will then activate the Factor X, which will be the start of the common pathway.
• Thrombin is the activated form of Prothrombin, which is responsible for the activation of Fibrinogen to become Fibrin.
• Thrombin also activates Factor XIII to become XIIIa to stabilize the fibrin platelet plug.

OVERVIEW OF BLOOD COAGULATION

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• Involves the enzymatic activation of series of plasma proteins in the coagulation system to form a fibrin meshwork.

SECONDARY HEMOSTASIS

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• Coagulation factors interact on platelet surface to produce fibrin; fibrin-platelet plug then forms at site of vessel injury.

STEP 4: FIBRIN-PLATELET PLUG FORMATION

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• Fibrin clot must be stabilized by coagulation factor XIII
o Factor XIII stabilizes the platelet clot. Fibrin
meshwork.

STEP 5: FIBRIN STABILIZATION

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COAGULATION FACTORS

Factor I Fibrinogen
Factor II Prothrombin
Factor III Tissue Thromboplastin
Factor IV Calcium Ions (Ionized Calcium)
Factor V Labile Factor, Proaccelerin
Factor VII Stable Factor, Proconvertin
Factor VIII Antihemophilic Factor
Factor IX Christmas Factor
Factor X Stuart-Prower Factor
Factor XI Plasma Thromboplastin Antecedent
Factor XII Hageman Factor
Factor XIII Fibrin Stabilizing Factor
- Prekalikrein
- High Molecular Weight Kininogen (HMWK)

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• _______ is written as Fibrinogen, as well as _____ which is written as Calcium.
• _______ and ___ are both labile factors, meaning they easily deteriorate. Both are soluble plasma proteins.
• ______ – omitted or unassigned. It is previously activated Factor V.
• ______ belongs in the extrinsic pathway
• ______ is a contact factor
• _________
o Hemophilia A – _______________
o Hemophilia B – _______________
o Hemophilia C – _______________
• All cofactors are synthesized in the ____ except pre-kal, HMWK, calcium, and tissue factor.
o ___ is synthesized in the endothelial cells or
platelets.
• ________________ are mostly proteins.

Factor I
Factor IV
Factor V and VIII
Factor VI
Factor VII
Factor XII
Hemophilia
Factor VIII Deficiency
Factor IX Deficiency
Factor XI Deficiency
liver
vWf
Coagulation factors

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Will act upon the enzyme

CATEGORIES OF COAGULATION FACTORS
SUBSTRATE

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• Aids to activate a coagulation factor
o Assist in activation
o Examples: Factor V, VIII, TF, and HMWK.

COFACTORS

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_________ Fibrinogen (Factor I)
_________ Factor V (Labile Factor), Factor VIII:C
(AHF)
_________ Serine Protease Ia, Ixa, Xa, Xia,
Transaminase, Factor XIIIa Prekalikrein

CLASSIFICATION OF COAGULATION FACTORS BY HEMOSTATIC FUNCTION
Substrate
Cofactors
Enzymes

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____________ XII, XI, Prekalikrein, HMWK
____________ X, IX, VII, II (1972)
____________ I, V, VIII, XIII

CLASSIFICATION OF COAGULATION FACTORS BY PHYSICAL PROPERTIES
Contact Group
Prothrombin Group/Vitamin K Dependent Group
Fibrinogen Group

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• If there’s a deficiency in Factor XI, there will be _________ because this is a contact factor.
• ____________ – needs Vitamin K for their synthesis.
o _____________: Protein Z, Protein C, Protein S (Vitamin K dependent)

no bleeding
Prothrombin Group
Regulatory Proteins

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FACTORS

XI, XII, PK, HMWK
II, VII, IX, X
I, V, VIII, XIII

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ABSORBED BY AL3OH/BaSO4

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VIT K DEPENDENT

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CONSUMED IN CLOTTING

NO
NO (ll)
YES

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FOUND IN SERUM OR PLASMA

BOTH
BOTH
PLASMA

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• ___________ – most labile (deteriorates immediately)
o ___________ deteriorates/decreases upon
storage.
o ___________ is increased in pregnancy, inflammation, and the use of contraceptives.
o Act as a substrate for plasmin.
o Reference Value for Fibrinogen: _________
➢ <200 g/dl – ___________
➢ Non-functional – __________
➢ No Fibrinogen – __________
• Fibrinogen such as I, and V are usually found in the _______, specifically ________________. Except for Factor XIII, which is seen in ____________. Factor VIII is ______________.
• ___________ are absorbed by glass. They slow down the conversion of XII to XIIa.
o Involved in Intrinsic Pathway
• ________ – barium sulfate
• ________ – has 20% residue

Fibrinogen Group
Factor V and VIII
Fibrinogen
200-400 g/dl
hypofibrinogenemia
dysfibrinogenemia
afibrinogenemia
platelets
alpha-granules
platelet cytoplasm
not seen in the platelets
Contact Groups
BaSO4
Factor II

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FACTOR XIII

• Fibrin Stabilizing Factor
• This protein stabilizes the linkage between the
fibrin monomers of the blood clot.
• It is present in the plasma, platelets and
apparently synthesized by megakaryocytes.
o Stabilizes the fibrin clot
o Can be seen in only in the Common Pathway that is initiated by Intrinsic or Extrinsic Pathway
• HALF LIFE: 150 hours (6 days)

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FACTOR XII

• Factor XII – Hageman Factor serine protease
• A stable globulin that is not consumed
• This factor is activated by contact with foreign surfaces, and initiates the intrinsic system.
o Prekalikrein will be activated into kallikrein via HMWK to activate the Factor XII then it will loop again to the contact factors to activate more Factor XII
o Factor XII bonds to the Phosphatidyl Serine start the Intrinsic Pathway
o Factor XII is the first factor to initiate in the Intrinsic Pathway
• It is also involved in the activation of fibrinolysis
• HALF LIFE: 48-70 hours

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FACTOR XI

• Serine protease beta or gamma globulin partly consumed in clotting found in serum and plasma
o It is activated by Factor XIIA/Activated Factor XII
o Activated Factor XI reacts with Calcium to activate Factor IX/Factor IXa
• HALF LIFE: 48-84 hours (2-3.5 days)
*Same illustration used as XII

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FACTOR X

• Serine protease not consumed in the clotting process found in both serum and plasma.
o Not consumed
• Pptd by 55%-65% ammonium sulfate.
• Activated by the products of both extrinsic and intrinsic
o Activated by the product of either
intrinsic or extrinsic
o Initiates the common pathway
• HALF LIFE: 48-52 hours (2 days)

FACTOR IX

• Present in both serum or plasma • Vit K dependent. • Not consumed during clotting • Essential component of the intrinsic thromboplastin generating system o Factor IX is activated via Factor XIa and Calcium o Activated Factor IX/Factor IXa reacts upon Calcium, Activated VIII/Factor VIIIa and Phospholipid to activate the common pathway = Factor X • HALF LIFE: 24 hours

FACTOR VIII

• Name: Anti- hemophilic factor / antihemophilic factor A • Source: Endothelium lining blood vessel and platelet • Activator: Thrombin • Actions: Works with Factor IX and calcium to activate Factor o Activated Factor VIII/Factor VIIIa will react to Calcium and Phospholipid to activate Factor X

FACTOR VII

• Stable factor; is activated by tissue thromboplastin which activates Factor X o Involves in extrinsic pathway o Factor III reacts with Calcium to activate the Factor VII to form activated Factor VII/Factor VIIa • Vit. K dependent • HALF LIFE: 6 hours

FACTOR V

• Synthesized in the liver; unstable when stored in citrated plasma. o PT/APTT = STAT procedure for Factor V • Consumed during clotting process not found in the serum. •HALF LIFE: 24 hours o Activated Factor V/Factor Va reacts with Calcium and Phospholipid to activate the Prothrombin to form Thrombin or Factor II. •MEAN PLATELET COMPONENT: 1mg/dl

FACTOR IV

•An active form of calcium that is required for the activation of thromboplastin and for conversion of prothrombin o Most factors utilizes Factor IV • MEAN PLATELET COUNT: 8-l0 mg/dl

FACTOR III

• Tissue factor cofactor (Thromboplastin) • Half-life insoluble used to designate the clot accelerating action of extract of tissue • Thromboplastin is required for the conversion of prothrombin to thrombin o We won't lose Factor 3

FACTOR II

• Proenzyme, precursor of thrombin 10-20 mg/dl. • Vit k is important for the production of prothrombin by the liver. o Activated Factor X/Factor Xa reacts with Calcium, Factor VIIIa and Phospholipid to activate Factor II to form Thrombin/Factor IIA • Vit K dependent • HALF LIFE: 60 hours (2.5days)

FACTOR I

• The substrate for thrombin and precursor of fibrin. •Function is to be converted into a soluble protein • Absent in serum 75% • Present in the plasma 200-400 mg/dl • HALF LIFE: 100-150 hours (4-6 days)

PREKALLIKREIN – FLETCHER FACTOR

• This is a plasma protein with a molecular weight of approximately 85,000 daltons. • It is partially adsorbed by barium sulfate but not adsorbed by aluminium hydroxide. Activator of factor xi in conjuction with w/ HMWK • HALF LIFE: 35 hours

HIGH MOLECULAR WEIGHT KININOGEN – FITZGERALD FACTOR

• Activator of Factor XI in effect with prekallikrein • Contact Factor

• __________ – longest lifespan • __________ – shortest life span • __________ – activated by thrombin • __________ – dissolution of fibrin • Pre-kal + Kallikrein = _______ • __________ – activated by HMWK • __________ – no fibrinogen • __________ – low fibrinogen level • __________ – non-functional fibrinogen • Deficiencies of _______, _______, or ______ do not cause clinical bleeding disorders.

- Factor XIII and I - Factor VII - Factor XIII - Factor XII - Factor XII - Pre-kal - Afibrinogenemia - Hypofibrinogenemia - Dysfibrogenemia - Factor XII, HMWK, or pre-K

• Activation occurs when a _________, exposing the ________________ and _______. • This will lead to the activation of the “Contact Factor”, together with _______, _____ and _______. o __________ o Exposure of collagen and subendothelial cells = it will activate the Factor XII

- INTRINSIC PATHWAY - vessel is injured - subendothelial basement membrane - collagen - Factor XII - HMWK - prekallikrein - 4-6 Minutes

COAGULATION FACTORS INVOLVED IN INTRINSIC PATHWAY:

✓ Factor XII ✓ Factor XI ✓ Factor IX ✓ Factor VIII

• Activated by the ____________ (TF/Tissue Thromboplastin) into the plasma from injured tissue. o ________ are needed to activate all the coagulation factors o _____________ takes place for 30 seconds/shorter than intrinsic pathway

- EXTRINSIC PATHWAY - release of Factor III - Co-factors - Extrinsic Pathway

COAGULATION FACTORS INVOLVED IN EXTRINSIC PATHWAY:

✓ Factor III ✓ Factor VII

• This pathway starts with the ____________ by either intrinsic or extrinsic pathway.

- COMMON PATHWAY - activation of Factor X to Factor Xa

COAGULATION FACTORS INVOLVED IN EXTRINSIC PATHWAY:

✓ Factor X ✓ Factor V ✓ Factor II ✓ Factor I

• _______ formation marks a critical event in the hemostatic process.

- MAINTENANCE OF BLOOD IN LIQUID STATE INSIDE BLOOD VESSELS - Thrombin

ACTIONS OF THROMBIN

1 Converts fibrinogen to fibrin 2 Activates Factor XIII 3 Enhances the activity of Factors V & VIII:C 4 Induces platelet aggregation

• Induces ________ and _______ • Activates cofactor VIII to VIIIa • Converts Factor XIII to XIIIa • Via autocatalysis converts ________

- THROMBIN-MEDIATED REACTIONS IN HEMOSTASIS - PROCOAGULANT - platelet activation - aggregation - Prothrombin to Thrombin

• Binds antithrombin to inhibit _______ • Binds to thrombomodulin to ____________ (inhibits Va & VIIIa)

- COAGULATION INHIBITOR - serine proteases - activate protein C

• Induces ______ • Stimulates __________ and ________

- TISSUE REPAIR - cellular chemotaxis - proliferation of smooth muscle - endothelial cells

• To maintain balance to ______________.

- INHIBITORS OF COAGULATION (ANTICOAGULANTS) - PHYSIOLOGIC INHIBITORS - avoid thrombosis/bleeding

• Glycoprotein that is produced by the liver and is a ________________. • This ________________ and __ in the presence of cofactor Protein S. o Protein C = Vitamin K o Protein C work synergistically with Protein S/Tandem o Without Protein S, it cannot inactivate coagulation factors.

- PROTEIN C - major inhibitor of blood coagulation - inactivates Factors VIII:C and Va

• A vitamin K dependent protein and also produced by the liver. This functions to _______________________ and increase the rate of Factors Va and VIIIa inactivation by Protein C. o Enhancement of Protein C

- PROTEIN S - enhance binding of Protein C to phospholipid surfaces

• __________ and ________________. o Inactivates V and VIII o Slows down the process of coagulation cascade.

- THROMBOMODULIN - Inhibits thrombin - inactivates the clotting cascade

• Major inhibitor of Thrombin and Factor Xa

ANTITHROMBIN II

• ____________; activity is enhanced by heparin

- HEPARIN COFACTOR - Inhibits thrombin

• Forms complex with _______, ________, thus _____________. o If there’s no kallikrein, the Factor XII won’t be able to activate more Factor XII

- ALPHA 2 MACROGLOBULIN - thrombin - kallikrein - inhibiting their activities

• Lipoprotein associated inhibitor (LACI) that inhibits VIIa which is a __________.

- EXTRINSIC PATHWAYS INHIBITOR - tissue complex factor

• Inactivates _______ and _________, _______ and ________. o Plasmin – activated form of plasminogen o Reacts with the fibrinolysis

- C1 INHIBITOR - Factor XIIa - plasma kallikrein - Factor XIa - plasmin

• A slow reacting thrombin inhibitor which inhibits Factor XIa and Xa

- ALPHA 1 ANTITRYPSIN

• Inhibits Protein C. This is more active when heparin is present.

ACTIVATED PROTEIN C INHIBITORS

• Coagulation control factors are ________, protein ___, and _________. • _______ is a cofactor to Z-dependent protease inhibitor (ZPI). Protein S works synergistically with Protein C. • _______ plays a role in coagulation (fibrin), platelet activation, coagulation control (protein C), and in controlling fibrinolysis (TAFI). Thrombin is considered the key protease of the coagulation pathway. • Acquired or inherited deficiencies of these proteins may be associated with an increased incidence of venous thromboembolic disease, as the hemostatic balance is shifted more toward coagulation than termination of the activated pathway. • ________ and ___________ both require heparin for effective anti-coagulant activity. • _____________ is a nonspecific, heparin-binding serpin that inhibits a variety of proteases, including ___, ______, _______, ________, and ______.

- thrombomodulin - S - protein Z - Protein Z - Thrombin - Antithrombin - heparin cofactor II - Protein C inhibitor - APC - Thrombin - Factor Xa - Factor XIa - Urokinase