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E4.MHD > L1&2.Normal Hemostasis/Thrombosis I&II > Flashcards

L1&2.Normal Hemostasis/Thrombosis I&II Flashcards

1
Q

What is the nml hemostasis?

A

ruptured vessels change=PREVENTS blood LOSS

**hemostatic plug: fills leakage site in injured vessel

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2
Q

What is NML state of blood?

A

blood in vascular system in LIQUID and CLOT-FREE, but solid clots can rapidly form to plug holes/defects in ruptured/injured blood vessels

  • cellular components NOT activated/physiologically altered
  • endothelial cells inert
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3
Q

What is the abnml state?

A

THROMBOSIS=blood forms clot in INTACT blood vessels (SAN vessel rupture)

  • PATHOLOGICAL activation of clotting system SANS rupture
  • can also result in loss of blood into:
  • ->surrounding soft tissues
  • ->body cavity
  • ->from the body
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4
Q

What are THREE entities that HEMOSTASIS is dependent upon?

A
  1. BLOOD VESSEL WALL: endothelium and subendothelial components
  2. PLATELETS and platelet release products
  3. COAGULATION and FRIBRONOLYTIC systems
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5
Q

What happens if there is dz of any of the THREE entities that are crucial for HEMOSTASIS?

A
  • dz of any of these 3->ABnml Hemostasis

- cancer, sepsis, congenital coagulation defects may lead to bleeding disorders

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6
Q

What is THROMBOGENESIS and when does it occur?

A

in pathological condition, functional state of these is altered:

  • endothelial damage, platelet activation, and release of T from cells=THROMBOGENESIS
  • once thrombus is formed it can obstruct blood flow + produce an inflamm resp
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7
Q

What is Hemostatic Response A/VASOCONSTRICTION?

A

occurs IMMEDIATELY and BRIEFLY through REFLEX NEUROGENIC MECHANISMS

  1. endothelin release causes VASOCONSTRICTION
    - endothelin=potent vasoconstricting agent released from endothelial cells in DISTRESS
  2. reflex vasoconstriction at sire of injury to REDUCE blood LOSS
    - release of various mediators
  3. ECM-contractile fibers
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8
Q

What is hemostatic Response B/PRIMARY HEMOSTASIS?

A
  • pre: vessel injury damages endothelial cells and EXPOSES SUBENDOTHELIAL COLLAGEN
  • overall: adhere, activate, aggregate
    1. platelets quickly ADHERE to damaged vessels
  • GP1b binding to vWF
    2. shape change/collagen ACTIVATION step 1
  • from discoid–>NON-discoid formation (extending pseudopods)
    3. granule release/collagen ACTIVATION step 2
  • light granules (alpha): PF4, PDGF, other proteins…etc
  • dense granules (beta): ADP, Ca2+, histamine, serotonin, epinephrine…etc
  • TXA2 (thromboxane A2)
    4. recruitment of additional platelets (by substances)
  • activated platelets recruit other platelets
    5. Hemostatic plug formation
  • several platelets AGGREGATE and for a plug
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9
Q

What is hemostatic response C/Secondary hemostasis?

A
  1. Tissue Factor is release at the site of injury from the endothelial cells
  2. TF combines with platelet factors (procoagulant) to initiate the plasma coagulation cascade
  3. Phospholipid complex expression
    surface phospholipids are expressed and promote coagulation process
  4. Thrombin generation by the activation of coagulation cascade generates THROMBIN
  5. Fibrin polymerization-formed fibrin is polymerized by factor 13a.
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10
Q

What is Hemostatic Response D: Formation of platelet-thrombin (permanent plug)?

A
  • thrombin stimulates recruitment and activation of additional platelets
  • thrombin enzymatically converts FIBRINOGEN to FIBRIN
  • FIBRIN polymerizes and binds/stabilizes/anchors the aggregated platelets
  • permanent plug seals the hole in the vessel wall
  • –erythrocytes (RBC) + leukocytes (N) become part of the thrombus (get trapped)
  • once clot is formed it is subject to endogenous lysis by fibrinolytic enzymes
  • –clot size can also be increased by CELLULAR RECRUITMENT
  • clot composition depends on:
    a. vascular site at which it is formed
    b. patients own pathophysiological state
  • stationary clot (thrombus) can also BREAK APART and travel to another location in the vasculature=EMBOLUS
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11
Q

What are two possible pathways that endothelial cells use to modulate elements of the hemostasis?

A

a. ANTI-thrombotic effect (normal state)

b. PRO-thrombotic effect (response to injured endothelium)

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12
Q

What are the three components of the ANTI-thrombotic effect?

A

NORMAL. NO CLOTS.

i. ANTI-platelet effect
- -INTACT endothelium prevents platelets and coagulation proteins from coming into contact with SUB-endothelial collagen
- -nml endothelial cells secrete PROSTACYCLIN and NITRIC OXIDE that prevent platelet aggregation
ii. ANTI-coagulant effect
- -endothelial cell membrane contains receptors that play n INDIRECT role in ANTI-coagulation
- -HEPARIN-LIKE MOLECULES + ANTI-THROMBIN III (naturally occurring anti-coagulation protein) = combo to inhibit thrombin and other coagulation factors (10a and 9a)
- -THROMBOMODULIN binds to thrombin=complex that activates Protein C (naturally occurring anti-coagulant)
- -endothelium also secretes Protein S (co-factor for Protein C)
iii. Fibrinolytic effect
- -endothelial cells also secrete PLASMINOGEN ACTIVATORS (t-PA) which promote FIBRINOLYSIS.
- -PLASMINOGEN is converted into PLASMIN and dissolves the clot

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13
Q

What is the overall role of platelets?

A

platelets=discoid, ANUCLEAR cells. play major role in HEMOSTASIS

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14
Q

Platelet Structure: PM

A

PM contains many glycoprotein receptors which play a role in:

  • attachment of platelets to SUB-ENDOTHELIAL proteins (vWF)
  • inter-adherence between platelets (via FIBRINOGEN)
  • secretion of substances from intra-cytoplasmic platelet granules
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15
Q

Platelet Structure: cytoplasm

A

Light granules (alpha):

  • fibrinogen
  • fibronection
  • coagulation Factors 5 and 8
  • platelet factor 4 (heparin-binding chemokine)
  • growth factors
  • –PDGF (platelet derived growth factor)
  • –TGFβ (transforming growth factor beta)

Dark granules (beta)

  • ADP
  • ATP
  • ionized calcium
  • histamine
  • serotonin
  • epinephrine
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16
Q

What are the 5 platelet receptors?

A
  1. Glycoprotein 2b/3a (GP 2b/3a)
  2. Glycoprotein 1b (GP 1b)
  3. Thrombin
  4. Serotonin
  5. ADP
17
Q

Platelet Function (Hemostatic Response B and C: PRIMARY and SECONDARY)

A

overall: with vessel injury, circulating platelets exposed to SUBENDOTHELIAL proteins (collagen, proteoglycans, fibronectin) and undergo THREE reactions:
1. ADHESION
- platelets attach to SUB-endothelial through molecular bridge
- GP 1b attaches to vWF, vWF attaches to collagen
- critical because it prevents the blood flow from dislodging the adherent platelets and unplugging
2. ACTIVATION (and secretion)
- initiated by molecules binding with GP 2b/3a
- platelet-platelet aggregation occurs via GP 2b/3a and a fibrinogen bridge between platelets
- upon activation platelets release granular contents
- phospholipid complex activated when negatively charged phospholipids become EXPOSED
- –complex=site on which coagulation factors combine with ionized calcium to activate INTRINSIC pathway of coagulation cascade to form THROMBIN
3. AGGREGATION
- release of ADP and TX A2 initiates reaction which serves to recruit, activate, an aggregate more platelets into PRIMARY hemostatic plug (TEMPORARY)
- serotonin and TX A2 VASOCONSTRICT the vessel:
- -decreases size of injury
- -reduces blood flow
- -reduces likelihood of plug detaching from vessel wall
- (simultaneously) THROMBIN is formed by activation of INTRINSIC pathway
- -THROMBIN converts fibrinogen to fibrin
- -FIBRIN surround and structurally holds platelets in a SECONDARY (IRREVERSIBLE) hemostatic plug

18
Q

network of proenzymes (zymogens), cofactors, activators and inhibitors.

A
  • extrinsic OR intrinsic forms THROMBIN (fibrinogen->FIBRIN)
  • fibrinogen group: 1,5,8,13
  • prothrombin: 2,7,9,10
  • –all these proteins contain gamma-carboxy glutamic acid which helps bind Ca2+
  • –all synthesized in the liver and are Vit K-dependent
  • contact group: 11, 12, Fletcher factor (PRE-kallikrein), Fitzgerald factor (HMW Kininogen)
  • Other: Protein C, Protein S, Fibronectin
19
Q

overall role of the coagulation system

A
  • network of PRO-enzymes which are activated to their functional form
  • eventually make THROMBIN which converts FIBRINOGEN (soluble structural plasma protein) to FIBRIN (clot)
  • FIBRIN clot is stabilized by TRANSAMIDASE ENZYME (13a) and THROMBIN ACTIVATABLE FIBRINOLYTIC INHIBITOR (TAFI)
20
Q

plasma proteins capable of inhibiting the formed serine protease enzymes involved in regulation of the clotting process

A

-ANTI-thrombin (AT)
–also mediates the anticoagulant actions of heparin
–congenital deficiencies–> THROMBOPHILIA
-heparin cofactor II (HC II)
weak inhibitor of thrombin
-tissue factor pathway inhibitor (TFPI)
–potent TF inhibitor and conducts some of the anti-coagulant effects of heparin
-clotting factor inhibitors
-lupus ANTI-coagulant and ANTI-phospholipid antibodies
-antibodies to specific coagulation factors (RARE)

21
Q

Fibrinolytic System

A
  • overall: network of enzymes responsible for dissolution of a formed clot, comprised of PROENZYMES
  • -when activated, enzymatic form can digest a formed clot AND facilitate FIBRINGOGEN digestion
  • Step 1: plasmingoen (profibrinolysis) is converted by plasminogen activators (PA) into plasmin
  • Step 2: Plasmin digests the clot (fibrin)
  • there are physiological and pharmacological plasminogen activators and natural and acquired inhibitors
  • important inhibitors of fibrinolytic system:
  • –plasminogen activator inhibitor (PAI)
  • –α2-antiplasmin
  • –α2-macroglobulin
  • –thrombin activatable fibrinolytic inhibitor (TAFI)
22
Q

Thrombosis=pathological transition of blood from fluidity to NON-fluidity. What are the main steps?

A
  1. stationary THROMBUS is formed
  2. stationary clot (THROMBUS) may progress and eventually break into smaller pieces
    - -when released into the blood circulation=EMBOLI
    - thrombogenic mechanisms differ in the arterial and venous systems; influenced by: blood flow, endothelial cell composition, blood vessel size, degree of oxygenation
23
Q

Pathogenesis of Thrombosis (Virchow’s Triad)

A
  1. endothelial injury–>resulting in release of TF
  2. abnormal blood flow; alterations in blood composition and flow
    - hypercoagulability (stasis)
24
Q

What is the hypercoaguable state?

A

-imbalance of blood coagulation mechanisms leading to thrombotic transitions
-age, smoking, oral contraception, and diet are important
-thrombotic stroke, MI, and peripheral arterial thrombosis are the result
A. Primary (genetic)
–molecular thrombophilias
–inhibitor deficiency
B. Secondary (Acquired)
i. High risk: sepsis, cancer, and trauma
ii. Lower risk: pregnancy, hyperlipidemia, and drugs
C. Thrombophilia
-molecular basis
—Factor V Leiden
—Prothrombin 20210
—MTHFR mutation
-Clinical manifestations of thrombophilia
—DVT
—microvascular angiographic condition

E4.MHD (7 decks)

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