HEMA 1 (Hemostasis) Flashcards
1
Q
What is hemostasis?
A
Derived from the Greek meaning “the stoppage of bld flow”
2
Q
What are the different hemostatic components?
A
1) Extravascular
2) Vascular
3) Intravascular
3
Q
What is extravascular hemostatic cmpt?
A
Involves the tissues surrounding a vessel, w/c become involved in hemostasis when a local vessel is injured
4
Q
What is vascular cmpt of hemostasis?
A
Involves the vessels through w/c bld flows
5
Q
What is the intravascular cmpt of hemostasis?
A
1) The key cmpts are PLTs and biochemicals (procoagulants) in the plasma
2) Such cmpts are involved in coagulation (clot / thrombus formation) / fibrinolysis
6
Q
What are the 2 types of hemostasis?
A
1) Primary hemostasis
2) Secondary hemostasis
7
Q
What is the characteristic of primary hemostasis?
A
Composed of bld vessels and PLT
8
Q
What is the purpose of primary hemostasis?
A
Formation of PLT plug
9
Q
What is the characteristic of secondary hemostasis?
A
Composed of coagulation factors
10
Q
What is the purpose of secondary hemostasis?
A
Formation of stable fibrin clot
11
Q
What are the steps in primary and secondary hemostasis after vessel injury?
A
1) Vasoconstriction
2) PLT adhesion
3) PLT activation and secretion
4) PLT aggregation
5) Fibrin-PLT plug formation
12
Q
What are the characteristics of vasoconstriction?
A
1) Controlled by vessel smooth muscle
2) Enhanced by chemicals secreted by PLTs
13
Q
What are the events that happen in PLT adhesion?
A
1) When vascular injury occurs, PLTs come in contact w/ subendothelium (collagen, fibronectin) and adhere to portions of it
2) The von Willebrwnd factor (vWF) binds to gp Ib/IX/V on the PLT membrane
14
Q
What is the other term for PLT adhesion?
A
PLT adhesiveness
15
Q
Why does PLT adhesion occur?
A
Because of the presence of vWF being deposited on the injured tissues
16
Q
What are the events that happen in PLT activation and secretion?
A
1) Following activation, the PLT undergoes a shape change caused by contraction of microtubules
2) The PLT changes from disk-shape to a spherical shape w/ the extrusion of numerous pseudopods
3) At the same time, the PLT granules are secreted
4) During activation, ADP and Ca ion activates phospholipase A2
5) Phospholipase A2 converts membrane phospholipid to arachidonic acid
6) Arachidonic acid is converted by cyclooxygenase into prostaglandin endoperoxide
7) In the PLTs, prostaglandin is converted by thromboxane synthetase into thromboxane A2
8) Thromboxane A2 causes the release of Ca ions and promotes PLT aggregation and vasoconstriction
Note:
Aspirin acetylation permanently inactivates cyclooxygenase, blocking thromboxane A2 production and impairs PLT aggregation
17
Q
What is the event that happens in PLT aggregation?
A
Interaction and adhesion of PLTs to 1 another to form initial plug at injury site
18
Q
What must happen in fibrin-PLT plug formation?
A
Fibrin clot must be stabilized by coagulation factor XIII
19
Q
What are the different bld vessel products?
A
1) Prostacyclin (PGI2)
2) Adenosine
3) Thrombomodulin
4) Heparan sulfate
5) Tissue plasminogen activator
6) vWF
20
Q
What is the metabolic product of ATP and ADP?
A
Adenosine
21
Q
What are the actions of PGI2?
A
1) Inhibits PLT activation
2) Stimulates vasodilation
22
Q
What are the hemostatic roles of PGI2?
A
1) Anticoagulant
2) Reduces bld flow rate
23
Q
What is the action of adenosine?
A
Stimulates vasodilation
24
Q
What is the hemostatic role of adenosine?
A
Reduces bld flow rate
25
What are the actions of thrombomodulin?
1) Endothelial receptor for thrombin
2) Binds and inactivates thrombin and enhances anticoagulant and fibrinolytic action pf PRO C found in the plasma
26
What are the hemostatic roles of thrombomodulin?
1) Anticoagulant
2) Fibrinolytic
27
What are the actions of heparan sulfate?
1) Coats the endothelial cell surface
2) Weakly enhances activity of antithrombin-III (w/c is a plasma anticoagulant)
28
What is the hemostatic role of heparan sulfate?
Anticoagulant
29
What are the actions of tissue plasminogen activator?
1. Converts plasminogen to plasmin, w/c plays an impt role in fibrinolysis
2. Released only on appropriate stimulus, such as vessel injury, to prevent clot formation at the site of injury
30
What is the hemostatic role of tissue plasminogen activator?
Fibrinolytic
31
What are the actions of vWF?
1. PRO secreted by endothelium into subendothelium
2. Required for PLT adhesion to site of vessel injury
32
What is the hemostatic role of vWF?
Coagulation
33
What are the characteristics of vWF?
1. Synthesized by:
a. Endothelial cell
b. Megakaryocyte
2. Stored in:
a. Endothelial cell (Weibel-Palade bodies)
b. PLTs
3. VIII/vWF
a. Entire molecule as it circulates in the plasma
b. Composed of VIII:C and VIII:vWF portions
4. VIII:vWF
a. Portion of molecule responsible for binding to endothelium and supporting normal PLT adhesion and fxn
5. VIII:C
a. Portion of molecule acting in intrinsic pathway
34
What is PLT?
1. Are not true cells because they are small fragments of megakaryocyte cytoplasm
2. Produced by megakaryocyte
3. Fxn in both primary (adhesion, secretion, aggregation) and secondary hemostasis (coagulation)
35
What are the characteristics of PLT?
1. Normal value: 150,000 - 400,000/uL
2. Size: 2 - 4 um
3. Volume (MPV): ~7 fL
4. Shape:
a. Discoid shape (**inactive**)
b. Spherical w/ pseudopod (**activated**)
5. Lifespan: 8 - 12 days
6. Storage: 1/3 in the spleen
7. Appearance in Wright-stain:
a. Violet-purple granular appearance
b. Look like specks of dust
36
What are the roles of PLT in hemostasis?
1. Adhere to injured vessel
2. Aggregate at the injury site
3. Promote coagulation on their phospholipid surface
4. Release biochemicals impt to hemostasis
5. Induce clot retraction
37
What are the events / characteristics of clot retraction for PLT?
1. Interaction of Gp IIb/IIIa w/ the PLT cytoskeleton
2. The contractile abilities of activated PLTs also result in contraction (/ retraction) of formed clots
3. Actinomysosin / thrombosthenin
4. In the test tube, clot retraction may be quantitatively assessed
5. Delayed / incomplete clot retraction:
a. Thrombocytopenia
b. Glanzamann's thrombasthenia
6. Gp IIb/IIIa is required for clot retraction
38
What is reticulated PLT?
Newly released circulated PLTs that have residual RNA
39
**Morphologic differentiation of megakaryocytic cell series**
Given stage: Megakaryoblast
1. Stage
2. Granules
3. Cytoplasmic tags
4. Nuclear features
5. PLT visibility
6. Other info
1. Megakaryoblast
2. Absent
3. Present
4. 1 nucleus
5. Not visible
6. Earliest recognizable PLT precursor
40
**Morphologic differentiation of megakaryocytic cell series**
Given stage: Promegakaryocyte
1. Stage
2. Granules
3. Cytoplasmic tags
4. Nuclear features
5. PLT visibility
6. Other info
1. Promegakaryocyte
2. Few
3. Present
4. 2 nuclei
5. Not visible
6. Formation of demarcating membrane system
41
**Morphologic differentiation of megakaryocytic cell series**
Given stage: Megakaryocyte
1. Stage
2. Granules
3. Cytoplasmic tags
4. Nuclear features
5. PLT visibility
6. Other info
1. Megakaryocyte
2. Numerous
3. Usually absent
4. 2 / more nuclei
5. Not visible
6. PLT shedding
42
**Morphologic differentiation of megakaryocytic cell series**
Given stage: Metamegakaryocyte
1. Stage
2. Granules
3. Cytoplasmic tags
4. Nuclear features
5. PLT visibility
6. Other info
1. Metamegakaryocyte
2. Aggregated
3. Absent
4. 4 / more nuclei
5. Visible
6. Last stage of thrombocyte formation
43
What is endomitosis?
Multiple mitotic division w/out cell division, generating giant multinucleated / polypoid cells
44
What is thrombopoietin?
Hormone produced in the liver that stimulates thrombopoiesis
45
What is the # of PLTs produce by each megakaryocyte?
2,000 - 4,000 PLTs
46
What is PLT shedding?
Release of PLTs into the bone marrow sinus
47
What is demarcating membrane system (DMS)?
1. Network formed by invagination of the plasma membrane
2. Fxns as the future membrane system of PLT
48
What are the zones / areas in the PLT structure?
1. Peripheral zone
2. Submembrane area
3. Sol-gel zone
4. Organelle zone
49
What is peripheral zone (of the PLT structure)?
PLT's outer membrane and related structures
50
What are the characteristics of peripheral zone (of the PLT structure)?
1. Consists of:
a. Surface coats (glycocalyx)
b. Plasma membrane
c. Submembrane area
2. Glycoproteins are incorporated in the glycocalyx
51
What are the fxns of glyocalyx?
Provides surface to w/c some coagulation factors (I, V, VIII, X, XI, XII, XIII) may adhere
52
What are the fxns of sub-membrane area (of the PLT structure)?
Links the:
1. Membrane
2. Inner cell body
53
What is the sol-gel zone (of the PLT structure)?
Matrix / muscle and skeletal portion of the PLT
54
What are the characteristics of the sol-gel zone (of the PLT structure)?
1. Influences communication of the organelles w/ the PLT's external surroundings
2. Maintains the shape of the PLT
3. Consists of microtubule and microfilaments
55
What is the fxn of microtubules?
Give the PLT structural support
56
What does microfilaments do when PLT is stimulated?
They are projected outward forming pseudopodia
57
What is the importance of microfilaments?
They are necessary for contractile process of PLT
58
What is the characteristic of microfilaments?
Consists of 2 PROs such as:
1. Actin
2. Myosin
59
What is the characteristic of organelle zone (of PLT structure)?
Consists of:
1. Granules
2. Dense bodies
3. Lysosomes
4. Mitochondria
60
What is the fxn of organelle zone (of PLT structure)?
Serves as metabolic center to influence PLT fxn in response to exogenous stimuli such as:
1. Hypercoagulation
2. Viruses
3. Foreign bodies
61
What are the glycoPROs (w/ their fxn) found in glycocalyx?
1. Gp Ib/IX/V: for PLT adhesion
2. Gp IIb/IIIa: for PLT aggregation
62
What are the PLT granules?
1. Alpha granules
2. Dense granules
63
What are the alpha granules?
1. High molecular weight kininogen (HMWK)
2. Fibrinogen (Factor I)
3. Factor V
4. vWF
5. Platelet factor 4
6. Thrombospondin
7. Platelet-derived growth factor
8. Beta thrombomodulin
9. Plasminogen
10. Alpha-2 antiplasmin
11. C1 esterase inhibitor
64
What are the dense granules?
1. Ca
2. ADP
3. Serotonin
4. ATP
5. Mg
65
What is PLT satellitism?
PLTs surrounds on:
1. Neutrophil
2. Monocyte (rare)
66
What are the causes of PLT satellitism?
1. Abnormal PROs
2. EDTA
67
Each coagulation factor (/ clotting factor) was assigned a Roman numeral in the order of its what?
Discovery
68
**True or False**
All coagulation factors are glycoPROs synthesized in the liver
False, because nearly all are glycoPROs synthesized in the liver except factor VIII complex
69
*What are the cmpts (w/ fxns and/or characteristics) of factor VIII complex?
1. VIII: coagulant (VIII:C)
2. vWF: produced by megakaryocytes and endothelial cells | activated at cold temp = VII and XI
70
What are the different coagulation factors (w/ their preferred name and synonyms)?
1. I (fibrinogen)
2. II (prothrombin | prethrombin)
3. III (tissue factor | tissue thromboplastin)
4. IV (Ca ions)
5. V (proaccelerin | labil factor, accelerator globulin [aCG])
6. VII (proconvertin | stable factor, serum prothrombin conversion accelerator [SPCA])
7. VIII (VIII:C) (antihemophilic factor [AHF] | antihemophilic globulin [AHG], antihemophilic factor A, PLT cofactor 1)
8. IX (plasma thromboplastic component [PTC] | Christmas factor, antihemophilic factor B, PLT cofactor 2)
9. X (Stuart-Prower factor | Stuart factor, Prower factor, autoprothrombin III)
10. XI (plasma thromboplastin antecedent | antihemophilic factor C)
11. XII (Hageman factor | glass factor, contact factor)
12. XIII (fibrin stabilizing factor | Laki-Lorand factor, fibrinase, plasma transglutaminase, fibrinoligase)
13. **Prekallekrein (PK)** (Fletcher factor)
14. **HMWK** (Fitzgerald factor, Williams factor, Flaujeac factor, contact activation factor)
71
What are the classifications of coagulation factors?
1. Accdg to pathway
a. Extrinsic pathway
b. Intrinsic pathway
c. Common pathway
2. Accdg to properties
a. Fibrinogen group
b. Prothrombin group
c. Contact group
72
What are the factors present in extrinsic pathway?
1. III
2. VII
73
What are the factors present in extrinsic pathway?
1. III
2. VII
74
What are the factors present in intrinsic pathway?
1. XII
2. XI
3. IX
4. VIII
75
What are the factors present in common pathway?
1. I
2. II
3. V
4. X
76
What are the factors present in fibrinogen group?
1. I
2. V
3. VIII
4. XIII
5. Ca dependent
77
What are the factors present in prothrombin group?
1. II
2. VII
3. IX
4. X
5. Vit K and Ca dependent
6. Absorbable factors in Barium sulfate (BaSO4)
78
Why are the factors present in contact group termed called as contact group?
Because they are activated by contact w/ (-)ly charged foreign particles
79
What are the factors present in contact group?
1. XII
2. XI
3. PK
4. HMWK
80
What is extrinsic pathway?
Activated by the release of tissue thromboplastin (factor III) into the plasma from the injured cells
81
What is intrinsic pathway?
Activated when a vessel is injured, exposing the subendothelial basement membrane and collagen, both surfaces that promote coagulation
82
What is common pathway?
Begins w/ the activation of factor X to factor Xa
83
What is tissue factor / tissue thromboplastin?
1. It is a transmembrane receptor for factor VIIa
2. Tissue thromboplastin = mixture of tissue factor and phospholipid *(Rodak)*
84
What are the characteristics of tissue factor?
1. Found on extravascular cells such as:
a. Fibroblast
b. Smooth muscle cells
2. Not found in endothelial cells under normal conditions
3. High lvls are found in cells of the:
a. Brain
b. Lung
c. Heart
d. Kidney
e. Testes
85
What is vit K?
It is a quinone found in green leafy vegetables
86
Vit K is produced by what?
1. Bacteroides fragilis
2. Escherichia coli
87
What is the fxn of vit K?
Catalyzes an essential post-translational modification of the prothrombin group PROs = by γ-carboxylation of amino-terminal glutamic acid
Glutamic acid is modified to γ-carboxyglutamic acid when a 2nd carboxyl grp is added to the γ carbon
88
What is vWF?
Large multimeric glycoPRO
89
What are the fxns of vWF?
1. Participates in PLT adhesion
2. Transports factor VIII
90
What are the characteristics of vWF?
1. Composed of multiple subunits of 240,000 Daltons each
=> the subunits are produced by endothelial cells and megakaryocytes, where they combine to form multimers that range from 600,000 - 20,000,000 Daltons
2. Stored in:
a. PLTs (alpha-granules)
b. Endothelial cells (Weibel-Palade bodies)
=> endothelial cells release ultra-large multimers of vWF into plasma, where they normally degraded into small multimers by a vWF-cleaving protease, ADAMTS-13 (a disintegrin-like metalloprotease w/ a thrombospondin type 1 motif, member 13), in bld vessels w/ high shear stress
=> in TTP, defective ADAMTS-13 enzyme activity is associated w/ ultralarge vWF multimers in the plasma, resulting in PLT aggregation and microvascular thrombosis
Vit K-dependents:
1. Procoagulants
a. II
b. VII
c. IX
d. X
2. Regulatory PROs
a. PRO C
b. PRO S
c. PRO Z
91
What is the purpose of Ca?
Required for the assembly of coagulation complexes on PLT / cell membrane phospholipids
Serine proteases bind to (-)ly charged phospholipid surfaces, predominantly phosphatidylserine, through (+)ly charged Ca ions
92
What are the characteristics of factor VI?
1. Obsolete
2. Activated factor (Va)
3. Was withdrawn from the naming and never reassign
93
What is serine protease?
Are proteolytic enzymes of the trypsin family
94
What are the exs of serine proteases?
1. Thrombin
2. VIIa
3. IXa
4. Xa
5. XIa
6. XIIa
7. pre-Kallekrein
95
**True or False**
Each member has a reactive seryl AA residue in its active site and acts on its substrate by hydrolyzing peptide bonds, digesting the primary backbone, and producing smaller polypeptide fragments
True
96
What is thrombomodulin?
1. Transmembrane PRO constitutively expressed by vascular endothelial cells
2. Cofactor of thrombin
97
What is the fxn of thrombomodulin?
Thrombomodulin and thrombin activate PRO C, a coagulation inhibitory PRO, and thrombin activatable fibrinolysis inhibitor (TAFI), a fibrinolysis inhibitor
=> once thrombin is bound to thrombomodulin, it loses its procoagulant ability to activate factors V and VII, and through activation PRO C, leads to destruction of factors V and VIII, thus suppressing further generation of thrombin
98
What is thrombin?
Considered as the key protease of coagulation pathway
99
What is the primary fxn of thrombin?
To cleave fibrinopeptides A and B from the α and β chains of fibrinogen molecule, triggering spontaneous polymerization
100
What are the fxns of thrombin?
1. Activates cofactors V, VIII, and XI by (+) feedback mechanism
2. Activates factor XIII, w/c forms covalent bonds between the D domains of the fibrin polymer to cross-link and stabilize the fibrin clot
3. Initiates aggregation of PLTs
4. When bounded to thrombomodulin, it activates PRO C pathway to suppress coagulation
5. Activates TAFI to suppress fibrinolysis
101
What is fibrinogen?
1. Primary substrate of thrombin, w/c converts soluble fibrinogen to insoluble fibrin to produce a clot
2. It is the most concentrated of all the plasma procoagulants
102
What is the importance of fibrinogen?
Fibrinogen is essential to PLT aggregation because it links activated PLTs through their GP IIb/IIIa PLT fibrinogen receptor
103
What is the cleaved fibrinogen called?
Fibrin monomer
104
Why is intrinsic pathway called as its term?
Because XII is present in the bld
XII -> pre-Kallekrein -> HMWK -> XI -> IX -> VIII -> X -> V -> prothrombin -> fibrinogen
105
Why is extrinsic pathway called as its term?
Because TF is not present in the bld
TF -> VII -> X -> V -> prothrombin -> fibrinogen
106
What are the labile factors?
1. V
2. VIII
107
What are the factors that are activated by cold temp?
1. VII
2. XI
108
What is the normal value of fibrinogen?
200 - 400 mg/dL
109
What is the most abundant clotting factor?
Fibrinogen
110
What are the serine proteases in:
1. Extrinsic pathway
2. Intrinsic pathway
3. Common pathway
1. VII
2. PK, XII, XI, IX (present in serum and plasma)
3. II, X
111
What is prothrombinase?
Xa-Va
112
What are the tenases in:
1. Intrinsic pathway
2. Extrinsic pathway
1. VIIIa-IXa
2. VIIa-IIIa-IV
113
What is thrombin (/ factor IIa)?
Central regulatory component of coagulation
114
What is the fxn of thrombin?
Can inhibit / accelerate coagulation
115
What is tissue factor pathway inhibitor?
Principal regulator of tissue factor pathway
116
What is the PRO C regulatory system?
Thrombin-thrombomodulin -> PRO C -> activated protein C (APC)-protein S -> inactivates factor Va and VIIIa
117
What are the members of antithrombin and other serine protease inhibitors (Serpins)?
1. Antithrombin
2. Heparin cofactor II
3. Protein Z-dependent protease inhibitor (ZPI)
4. Protein C inhibitor
5. α1-protease inhibitor (α1-antitrypsin)
6. α2-macroglobulin
7. α2-antiplasmin
8. PAI-1
118
What are the characteristics of antithrombin III?
1. Synthesized in the liver
2. 1st of the coagulation regulatory PRO to be identified
3. 1st to be assayed routinely in clinical hemostasis lab
4. SERPIN
119
What is the fxn of antithrombin III?
Inhibits thrombin
120
What is the characteristic of heparin cofactor II?
SERPIN
121
What is the fxn of heparin cofactor II?
Primarily inactivates thrombin
122
What is protein Z-dependent protease inhibitor (ZPI)?
Potent inhibitor of factor Xa
123
What are the cmpts of the fibrinolytic system?
1. Plasmin
2. Plasminogen
3. Tissue plasminogen activator (TPA)
4. Urokinase plasminogen activator (UPA)
5. Streptokinase (SK)
6. Fibrin(ogen) degradation products / fibrin(ogen) split products
7. D-dimer
8. Fragment X, Y, E
124
Fibrinolysis is dependent on what?
Enzyme plasmin
125
What is the final stage of coagulation?
Fibrinolysis
126
What are the fxns of plasmin?
1. Digest / destroy fibrinogen, fibrin, factor V, and factor VIII
2. Does not distinguish fibrinogen and fibrin
127
What is the characteristic of plasmin?
Not normally present in the bld in an active form
128
What is plasminogen?
Zymogen of plasmin
129
What are the characteristics of plasminogen?
1. Normally present in the plasma
2. Homologous to Lp (a)
130
What is the action done by plasminogen activators to plasminogen?
Plasminogen is converted to plasmin
131
What is TPA?
It is released in vivo on endothelial cell damage
132
What is the fxn of TPA?
Activates plasminogen
133
What is the characteristic of UPA?
Purified from urine
134
What may be administered to a pt to activate plasminogen?
UPA
135
What is the fxn of UPA?
Activates plasmin
136
What is the fxn of SK?
Activates plasminogen
137
Where is SK derived from?
Streptococci
138
What are the 2 fibrin(ogen) degradation products / fibrin(ogen) split products?
1. Early degradation products
2. Late degradation products
139
What are the early degradation products?
1. X
2. Y
140
What are the late degradation products?
1. D (D-D dimer)
2. E
141
What are the fxns of D-dimer?
1. Indicates fibrin (not fibrinogen) degradation products
2. Verification of in vivo fibrinolysis
3. Marker of thrombosis and fibrinolysis
142
What is D-dimer?
Sp product of digestion of cross-linked fibrin
143
How is fragment X, Y, and E produced?
Produced by digestion of either fibrin / fibrinogen by plasmin
144
What regulates fibrinolysis?
1. Plasminogen activator inhibitor 1 (PAI-1)
2. α2-antiplasmin
3. TAFI
