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Biochemistry > Chapter 9 & 10: Hemostasis > Flashcards

Chapter 9 & 10: Hemostasis Flashcards

1
Q

Overview of Hemostasis

A

• Hemostasis is the cessation of bleeding following damage to a blood vessel (e.g. repair of leaks in the vasculature) •

Hemostasis involves:

  • Blood coagulation (clot formation) which has three stages
    • Vasoconstriction (vessel spasm): immediate reflex that reduces the flow and diminishes blood loss. This is the first line of defense.
    • Platelet plug formation
    • Fibrin clot production

Fibrinolysis (clot degradation): fibrin clot is dissolved by the enzyme plasmin. Can be induced by fibrinolytic drugs (e.g. tPA)

• Repair of vessel wound

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2
Q

Vasoconstriction and Platelet Plug Formation

A
  • Hemostasis is activated when the endothelial cells are damaged
  • The damaged exposes two triggers:
  • 1) Platelet plug formation is triggered by the exposure of collagen in the subendothelium.
  • This is known as primary hemostasis.
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3
Q

Fibrin Clot Formation and Thrombosis

A
  • 2) Fibrin clot formation is triggered by the exposure of tissue factor on the surface of exposed subendothelial cells
  • This is known as secondary hemostasis.

Thrombus: clot that forms in vessel

Thrombosis: process of forming a thrombus

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4
Q

Overview: Platelet Plug Formation

A
  • The major function of the platelet plug is to “act like a sandbag in a leaky dike”
  • Sequence of events after damage to vessel wall:

1) Adhesion (to collagen)
2) Activation (increase in intracellular Ca+2)
3) Secretion (degranulation)
4) ShapeChange(interlocking platelets)
5) Aggregation (to one another)

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5
Q

Platelet Adhesion

A
  • Damage to the endothelium and exposure of collagen beneath the endothelium is the initial trigger that signals adhesion and the first step in formation of the platelet plug.
  • von Willebrand Factor (vWF) is a linker protein found in blood that binds to collagen. This binding results in a conformational change that allows vWF to bind to the platelet integrin GPIb
    • GP = glycoprotein
    • Integrins are transmembrane proteins that are linked to the cytoskeleton inside the cell

Thus, vWF anchors the platelet cytoskeleton to the collagen of the subendothelium Patients with defects in vWF or GPIb present with hemorrhages

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6
Q

Von Willbrand Disease

A
  • vWD is the most common hereditary coagulation abnormality described in humans
  • Due to a quantitative or qualitative abnormality in vWF
  • vWF functions in both primary and secondary hemostasis
  • primary: platelet adhesion
  • secondary: binds Factor VIII
  • Deficiency in vWF –> decreased adhesion of platelets and increased turnover in Factor VIII
  • Symptoms are similar to those of a hemophiliac but tend to be milder
  • Tendency to bleed (bruising, nosebleeds, heavy menstrual periods)
  • Severe internal or joint bleeding is rare
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7
Q

Platelet Adhesion

A
  • Adhesion culminates with a monolayer of platelets adhering to the wound site
  • Note: Collagen can also directly contribute to platelet adhesion by interacting with platelet integrin GPIa/IIa
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8
Q

Platelet Activation

A
  • The second step in platelet plug formation is platelet activation.
  • Platelet activation is initiated by platelet agonists* binding their receptors
  • Platelet agonists include:
  • Thrombin
  • Thromboxane A2 (TxA2)
  • ADP
  • Epinephrine
  • Collagen
  • Binding of platelet agonists triggers an increase in [Ca+2] in the platelet.
  • This is an “activation step” as it generates a second messenger.
  • Platelet activation leads to granule secretion, shape change, and aggregation.

* Agonist: a substance that binds to a specific receptor and triggers a response

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9
Q

Eiconosoids

A
  • Eicosanoids: signaling compounds made from the essential fatty acids omega-6 and omega-3
  • Act as autocrine and paracrine signaling compounds

– Local mediators that are rapidly degraded that are involved in inflammation and immunity

• Two eicosanoids are important in hemostasis

– Thromboxane A2: produced by platelets to promote platelet plug formation

– PGI2: produced by intact vessel wall to inhibit platelet plug formation

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10
Q

Health Benefits of Omega 3 EFA

A

• Eicosanoids made from Omega 3 (rather than Omega 6) essential fatty acids are less potent in promoting inflammation and platelet plug formation

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11
Q

COX Enzyme Inhibitors

A
  • The enzyme cyclooxygenase (COX-1 and Cox-2) catalyzes the first committed step in PGI2 and TxA2 biosynthesis
  • Drugs that inhibit the synthesis of PGI2 and TxA2 include
  • Aspirin (Salicylic acid) irreversibly inhibits both COX-1 and COX-2
  • Actaminophen (Tylenol) and ibuprofen (Motrin and Advil) are competitive (reversible) inhibitors of cyclooxygenase
  • Celebrex selectively inhibits COX-2 at the site of inflammation
  • Steroids also inhibit COX-2 as part of their anti-inflammatory activity
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12
Q

Platelet Activation: Aspirin and TxA2

A
  • The rising Ca+2 in activated platelets increase the synthesis of thromboxane A2 (TxA2)
  • TxA2, a potent platelet agonist, acts to recruit additional platelets to form the platelet plug
  • Aspirin acts by inhibiting the formation of TxA2
  • Aspirin irreversibly inhibits cyclooxygenaseinhibition of TxA2 production
  • Because cyclooxygenase is not regenerated in the circulation within the life-span of the platelet one aspirin may affect platelet function for a week
  • Low dose aspirin has been shown to be effective in the prevention of acute myocardial infarction
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13
Q

Platelet Activation: Plavix and ADP

A
  • ADP is released from platelet dense-granulesand acts to recruit additional platelets –> formation of platelet plug
  • Plavix binds ADP receptors receptors and prevents ADP from promoting platelet plug formation
  • Plavix is three times more effective than aspirin at inhibiting platelet plug formation Result: Plavix and Aspirin are useful in anti-coagulant therapy because they inhibit Platelet activation
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14
Q

Secretion or Degranulation

A

Increase in [Ca+2] triggers exocytosis of

1) Stored platelet agonists (e.g.Ca+2, ADP)
2) Clotting factors (e.g. factor V).
3) Growth factors (e.g. PDGF or platelet- derived growth factor)
4) Adhesive proteins (e.g. von Willebrand factor (vWF), fibrinogen)
5) Serotonin to aid vasoconstriction

Thus, platelet activation –> activation of more platelets (positive feedback)

• Degranulation increases the surface area of the platelet membrane by 60% and aids in the subsequent shape change

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15
Q

Shape Change

A
  • Resting platelets have a discoid shape
  • Increased intracellular [Ca+2] –> conversion to spiculated spheres that strengthen the platelet plug via interdigitation and later play a role in clot retraction
  • Additional membrane added in degranulation has a role in both fibrin clot formation and platelet aggregation
  • Platelet activation exposes sites on the surface of platelets for clotting factors which form the enzyme complexes needed to generate the fibrin clot
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16
Q

Platelet Aggregation: Fibrinogen

A
  • As a result of [Ca+2] and degranulation, active GpIIb-IIIa is present in the membrane
  • Platelets are aggregated by fibrinogen binding to active GpIIb- IIIa on two different platelets
  • Fibrinogen is a long fibrous molecule composed of two identical halves, each half is recognized by GPIIb/IIIa
  • The two binding sites allows one fibrinogen molecule to tether two platelets together
  • Thus, fibrinogen bound to GPIIb/IIIa acts as a bridge between the actin cytoskeleton two platelets
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17
Q

Intact Endothelium is Antithrombotic

A
  • To prevent thrombosis, the intact vessel wall inhibits platelet plug (and fibrin clot) formation.
  • Platelet plug formation (or extension of the platelet plug beyond the site of injury to the vessel wall) is inhibited by:
  • 1) The negative charge of the endothelial cell membrane repels the negatively charged platelet membrane
  • 2) ADPase bound to the endothelial cell surface hydrolyzes ADP, preventing further platelet activation
  • 3) Secreted compounds
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18
Q

Intact Endothelium –> decrease of platelet activation

A
  • Compounds secreted by the intact endothelial cells inhibit platelet activation
  • Prostacyclin PGI2 is the most important natural inhibitor of platelet activation

– PGI2 is made and released by healthy endothelial cells and is a potent inhibitor of platelet degranulation

– PGI2 functions by lowering [Ca+2] inside the platelet

• NO or nitrous oxide is a strong vasodilator that provides functions similar to PGI2 (NO is aka EDRF – endothelial-derived relaxing factor)

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19
Q

Summary: Platelets in Hemostasis

A
  • Platelets form a physical plug to temporarily stop bleeding at the site of vascular injury
  • Platelet activation leads to promotion of platelet plug and fibrin clot formation (positive feedback)
  • The platelet is stabilized by the fibrin clot
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20
Q

Fibrin Clot Overview

A
  • The platelet plug is not stable but is held in place by the fibrin clot
  • The fibrin clot is formed via the coagulation cascade which involves
  • A series of proteolytic enzyme reactions
  • Assembly of three enzyme membrane-anchored complexes

– The three complexes forming an amplifying cascade which activate more clotting factors (e.g. positive feed-back)

– The coagulation cascade results in the activation of thrombin which is responsible for the conversion of fibrinogen to fibrin

• Fibrin forms a protein meshwork among and over aggregated platelets to form a thrombus (combination of platelet plug + fibrin)

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21
Q

What are coagulation factors?

A
  • 12 coagulation factors compose the coagulation cascade that results in the formation of the fibrin clot
  • 11 proteins and Ca+2, numbered I to XIII (there is no VI) •
  • Most clotting factors circulate in the blood (known as intrinsic)
  • Only Tissue Factor (aka TF III) is not found in circulation (it’s extrinsic)
  • Each clotting factor exists in circulation as a zymogen*.
  • In order to be activated, they must undergo limited proteolysis by a particular activated protease in the coagulation system.
  • Activated forms of coagulation factors are designated with subscript “a”. For example XXa when the zymogen is activated. The exceptions are fibrin (Ia) and thrombin (IIa)
  • The activated clotting factors activate additional clotting factors by proteolysis

*Zymogen: an inactive enzyme precursor that requires a biochemical change, such as a hydrolysis reaction revealing the active site, for it to become an active enzyme.

22
Q

Complexes in Coagulation

A
  • Serine proteases (Factors VII, IX, X) do not work in isolation but in conjunction with protein, mineral (Ca+2), and phospholipid (PL) cofactors to form ACTIVE protease complexes
  • There are 3 complexes anchored to the membrane:
  • Initiation complex
  • Tenase Complex*
  • Prothrombinase Complex*
23
Q

Vitamin K Dependent Clotting Factors

A
  • Several clotting factors require a unique post- translational modification to function
  • Several Glutamate (Glu) residues on clotting factors VII, IX, X, and II are carboxylated in the liver by an enzyme which requires vitamin K as a co-enzyme
  • The carboxylated glutamate residues contain two carboxyl groups and are called g-carboxyglutamate residues (Gla)
  • Warfarin (coumadin), a vitamin K analog, acts as a competitive inhibitor of the carboxylation of the clotting factors
  • Without the modified Gla residues, clotting factors are nonfunctional
24
Q

Gla residues

A
  • Gla residues are ideal for chelating Ca+2
  • Ca+2 (factor IV) serves as a bridge between the Gla residues of activated clotting factors and the membrane phospholipids of the activated platelets.
  • This localizes the enzymes for clot formation to the membrane of activated platelets
  • If active factors are washed away from the site of injury, the factors will be unable to form a clot without activated platelets

— This increases safety and represents a check on the coagulation cascade

Note: Calcium chelators (EDTA, citrate, oxalate, fluoride) act as anti-coagulants by reducing available calcium which interrupts the formation of these complexes

25
Q

Initiation of Coagulation

A
  • Physiologically, the principal means of initiating the coagulation cascade at an injury is the exposure of tissue factor (TFIII), a membrane protein on the surface of subendothelial cells
  • Factor VIIa binds the newly exposed tissue factor in a Ca+2 dependent fashion to form the initiation complex
26
Q

Where Does VIIa Come From?

A
  • Small amounts (<1%) of factor VII continually circulate in the blood as VIIa
  • Although VIIa is a protease (not zymogen), it is not active until bound to its cofactor, TFIII, which only comes into contact with blood following vessel injury
  • This is an example of the “idling” nature of coagulation that allows the coagulation cascade can respond rapidly to any vessel injury

–Coagulation is not an “on” or “off” process but rather an “idling” system in a continual state of activity held in check by anticoagulants.

27
Q

Initiation Complex: TF, VIIa, PL, & Ca+2

A
  • Factor VIIa, when bound to tissue factor (TFIII), catalyzes the limited proteolysis of additional VII as well as factors IX and X
  • IXa and Xa are the proteases used to form the other two complexes in coagulation
28
Q

Protease Complexes

A
  • Two additional protease complexes form in the coagulation cascade.
  • To form these complexes, the proteases IXa and Xa bind their cofactors VIIIa and Va respectively, in a Ca+2 dependent fashion on the surface of activated platelets
  • Small amounts of VIIIa and Va are also always present in circulation (like VIIa)

• The next two complexes are named after their substrates

  • Tenase (IXa + VIIIa + Ca+2) activates factor X
  • Prothrombinase (Xa + Va + Ca+2) activates factor II

• Prothrombinase generates thrombin (IIa) the protease that cleaves fibrinogen to fibrin

29
Q

Fibrin

A
  • Thrombin catalyzes the conversion of fibrinogen to fibrin removing four fibrinopeptides from the center of each fibronogen molecule
  • Fibrin monomers spontaneously polymerize in a staggered fashion to form the fibrin clot. Initial polymer is called a soft clot as it is only held together by ionic bonds
30
Q

Cross-linking Soft Clot –> Hard Clot

A
  • Thrombin also catalyzes the conversion of factor XIII to XIIIa
  • Factor XIIIa (aka fibrin stabilizing factor or transglutaminase) catalyzes th formation of peptide bonds between lysine and glutamine residues in neighboring fibrin monomers

-Cross-linked fibrin is termed the hard clot which is more resistant to degradation

31
Q

Limiting Coagulation

A
  • Thrombin, Xa, and IXa which diffuse away from the injury site form an irreversible covalent complex with antithrombin III (ATIII)
  • Heparan sulfate (GAG on the surface of intact endothelial cells) forms a complex with ATIII increasing the effectiveness of ATIII 1000 fold

ATIII inhibits proteases in the intrinsic clotting cascade

32
Q

Proteins C and S

A
  • Excess thrombin will bind to its receptor, thrombomodulin (abbreviated TM) on the surface of endothelial cells (preventing it from cleaving more fibrinogen). The thrombin/TM complex binds to a substrate called Protein C, converting it into activated protein C (APC).
  • APC works in conjunction with its cofactor, Protein S, to convert Factors Va and VIIIa into their inactive forms Vi and VIIIi. APC with Protein S –> inactivation of protein cofactors V & VIII
33
Q

Tissue Factor Pathway Inhibitor (TFPI)

A

• TFPI binds and inactivates factors Xa and VIIa while they are bound to Tissue Factor.

TFPI inhibits proteases in the extrinsic clotting cascade

34
Q

Fibrinolysis

A
  • Removes the clot as part of wound repair
  • Initiated by the release of tissue-plasminogen activator (t-PA) from endothelial cells
  • t-PA initiates fibrinolysis by cleaving plasminogen to plasmin (t-PA only acts on the plasminogen bound to fibrin)
  • Plasmin degrades fibrin, clearing the clot by cleaving peptide bonds
35
Q

Regulation of Thrombosis

A

• Platelet activation and the formation of the fibrin clot are feed-forward or positive feed-back loops

  • Advantage: rapid coagulation
  • Disadvantage: increased risk for pathology.

• Thus, clotting must be suppressed when not needed

36
Q

Pharmaceuticals & Hemostasis

A
  • Anticoagulants: inhibit Thrombosis
  • Aspirin: inhibits platelet plug formation via inhibition of COX enzymes
  • Coumadin / Warfarin: inhibits fibrin clot formation via inhibiting synthesis of post-translationally modified (active) serine protease clotting factors VII, IX, X, II
  • Heparin / Heparan Sulfate: inhibits fibrin clot formation via activation of ATIII
  • Thrombi
  • Venous thrombi are rich in fibrin due to increased blood stasis. The fibrin traps red blood cellsred clot. Treat with Heparin
  • Arterial thrombi tend to be rich in platelets because they are areas with their high shear force and are white clots. Treat with Aspirin
  • Fibrinolytics: promote fibrin clot breakdown
  • tPA: tissue plasminogen activator
  • Streptokinase
37
Q

Therapeutic Anticoagulants: Heparin

A
  • The drug, heparin provides a binding site for the endogenous anticoagulant, ATIII, to bind in close proximity to thrombin.
  • Since ATIII-heparin complex is 1000x better at inhibiting thrombin than ATIII alone, Heparin is used to inhibit fibrin clot formation.
  • Heparin is administered IV and acts rapidly (within 30 min) and becomes ineffective after 6 hours.
  • Low and high molecular weight (MW) heparin available. These clear the body at different rates.
  • Heparin is administered prophylactically during surgery and in bolus to treat acute myocardial infarction and venous thrombosis.

Note: EDTA and other calcium chelators are lethal in vivo and only used in vitro

38
Q

Coumarin (aka Warfarin / Coumadin)

A
  • Coumarins / Warfarins belong to a family of Vitamin K antagonists. They inhibit g-glutamyl carboxylase and prevent posttranslational modification of clotting factors VII, IX, X, and II with Gla residues, rendering them ineffective.
  • As Factor VII has the shortest half- life of these four factors, Coumarin exerts its greatest effect on VII, followed by IX, X, and II.
  • Thus, Coumarins inhibit fibrin clot formation but act in the liver (site of Gla incorporation) not at the site of clot formation.
  • Warfarins are fat-soluble and administered orally. The initial effect is observed 1.5 – 2 days post administration and maximal effects are seen within 3 – 5 days. Total duration of effect is 4 – 5 days. The effect of warfarin is reversed by intake of Vitamin K.
  • Warfarin is used for chronic oral anticoagulation therapy to prevent fibrin clot formation to treat and prevent heart disease and venous thrombosis.
39
Q

Overview Hemostasis Tests

A
  • Laboratory hemostasis tests assay blood coagulation and are designed to identify deficiencies in hemostasis
  • The tests discussed here can detect defects in the formation of the platelet plug and fibrin clot production
  • Platelet function is assayed by the Bleeding Time test
  • Different deficiencies of clot formation are assayed by
  • aPTT or Activated partial Thromboplastin
  • PT or Prothrombin time
  • Clot Solubility in 5M Urea

• Other aspects of hemostasis including vasoconstriction, fibrinolysis, and repair of vessel wall are not directly addressed by these tests

40
Q

5M Urea and Hard Clots

A
  • Factor XIIIa is required to cross-link the fibrin clot, transforming the soft clot formed by the coagulation cascade into a hard clot
  • Soft clots are soluble in 5 M urea but hard clots are not

– The fibrin in soft clots is linked together only by non-covalent bonds that are disrupted by 5 M Urea.

– The fibrin in the hard clot is linked by covalent bonds that are not dissolved by 5 M Urea

41
Q

Bleeding Time

A

• Bleeding time is used to assess platelet plug formation.

  • Bleeding time test is initiated by performing a forearm incision on the patient that is reproducible in dimensions and executed under constant capillary pressure. The time it takes to cease bleeding is measured.
  • Prolonged bleeding times may indicate problems with platelet number (thrombocytopenia), platelet function, and vWF. Bleeding time is also affected by intake of aspirin.
  • Bleeding time tests are rarely performed.
42
Q

Clinical Note: vWF and GPIb

A
  • Bleeding time is a screening test for inherited or acquired disorders of platelet function and for von Willebrand factor diseases
  • Examples:
  • Deficiencies in GPIb cause Bernard-Soulier disease
  • Von Willebrand’s disease is caused by a quantitative or qualitative abnormality in vWF. It is the most common inherited abnormality of hemostasis

• Both result in hemorrhage, especially in areas of high shear rates where platelet plug formation is particularly important in hemostasis

  • High shear forces seen in arteries favor vWF – GP1b interactions. Thus, arterial thrombi usually have high levels of platelet plugs
43
Q

Prothrombin Time: PT Test

A
  • The PT test measures the time it takes a starting sample of citrated plasma to clot upon addition of Ca+2 and purified tissue factor (thromboplastin).
  • By adding TF and Ca+2, the PT test bypasses the intrinsic pathway. The purified tissue factor contains phospholipid which serves as a platelet substitute in the initiation of clotting.
  • Thus, the PT test is used to assess the extrinsic and common pathways of the coagulation cascade. In other words, prothrombin time (PT) is used as a screen to identify acquired or inherited deficiencies of factors VII, X, V, prothrombin, and fibrinogen.
44
Q

Activated Partial Thromboplastin Time

A
  • The aPTT test essentially involves initiation of coagulation in vitro by CONTACT with a negatively charged surface (the aPTT reagent) in the test-tube.
  • The coagulation factor that gets activated by contact is Factor XII, a vascular (and thus intrinsic) factor.
  • Activated Factor XIIa promotes cleavage of factor XI into XIa, which in turn promotes formation of Factor IXa.

-The contact pathway is not physiologically necessary for efficient hemostasis. Factor XIIa deficiency has little or no effect on coagulation.

• The aPTT test is used to assess the Intrinsic and Common Pathway factors of the coagulation cascade.

45
Q

Summary: Fibrin Clot

A
  • There are 12 clotting factors. Four of which are vitamin K dependent: VII, IX, X, II
  • The coagulation cascade is series of 3 enzyme complexes
  • Coagulation is initiated by injury and exposure of TF (on subendothelial cells) which forms the initiation complex along with VIIa. This complex catalyzes the formation if IXa and Xa
  • Two other protease complexes form on the surface of activated platelets
  • Tenase (IXa and VIIIa) catalyze the activation of X –> Xa
  • Prothrombinase (Xa and Va) catalyze the activation of prothrombin
  • Thrombin cleaves fibrinogen into fibrin
  • Coagulation is inhibited by ATIII
  • t-PA cleaves plasminogen to plasmin which degrades fibrin into fibrin degradation products
46
Q

Summary: Platelet Plug Formation

A
  • The platelet plug acts like a sandbag in a leaky dike
  • Sequence of events
  • Adhesion (to collagen)
  • Activation (increasing intracellular Ca+2)
  • Secretion (degranulation) • Shape Change (interdigitate)
  • Aggregation (to one another)
47
Q

Summary: Platelet Plug

A
  • Formation of the platelet plug is the first phase of hemostasis
  • Following vessel damage, resting platelets adhere to exposed collagen via GPIa/IIa directly or via vWF and GPIb
  • Platelet agonists (thrombin, TxA2, ADP, epinephrine, collagen) activate platelets by binding receptors and increasing intracellular [Ca+2]
  • The events associated with platelet activation are calcium dependent
  • Secretion (aka degranulation)
  • Shape change (filapodia formation)
  • Aggregation (activation of integrin GPIIb/IIIa which binds fibrinogen)
48
Q

Platelet Activation (with Diagram)

A

• Platelet activation is a central step in the formation of the platelet plug

• It is the key site for physiological (e.g. TxA2, ADP, thrombin, collagen) and pharmacological (e.g. aspirin, plavix) regulation of the platelet plug

49
Q

Summary: Platelets in Primary Hemostasis

A
50
Q

Thrombin

A
51
Q

Regulation of Thrombosis

A
  • Physical factors that affect the balance between clotting and thrombosis:
  • Endothelial cells serve as a barrier between the blood and the subendothelium
  • Circulating clotting factors are inactive zymogens
  • Assembly of clotting factor complexes
  • Serine proteases aren’t active when they aren’t in a complex
  • “Escaped” active clotting factors are diluted in circulation

• Healthy endothelial cells inhibit platelet plug and clot formation to prevent Thrombosis in absence of injury

  • Factors that inhibit platelet plug formation include PGI2, NO, ADPase
  • TM (thrombomodulin) and heparin sulfate (which activates ATIII) act to inhibit thrombin
52
Q

Summary Chart

A

Biochemistry (5 decks)

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