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Biochem Diseases > Blood Coagulation > Flashcards

Blood Coagulation Flashcards

1
Q

Hemophilia A

A
  • Factor VIII def.
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2
Q

Hemophilia B

A

Factor IX def.

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3
Q

Hemophilia C

A

Factor XI def.

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4
Q

Hemophilia clinical Sx

A
  • tendency towards easy bruising
  • massive hemorrhage after trauma & surgical procedures
  • spontaneous hemorrhages, particularly in joints - Hemarthrosis
  • Bleeding time (platelet fx): nl
  • Platelet count: nl
  • Prothrombin time: nl
  • APTT: increased
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5
Q

von Willebrand Disease

A
  • vWF mutation leads to instability of VIII
  • Inheritance can be AR or AD
  • Clinical Sx:
    • presents with same clinical features as hemophilia A
    • increased mucosal bleeding
    • epistaxis
    • mennorhagia
    • increased post-op bleeding
  • Dx:
    • bleeding time: increased
    • Platelet counts: nl
    • APTT: increased
    • PT: nl
    • prolonged bleeding time & prolonged APTT in the presence of nl factor VIII levels is highly indicative of vW disease
      *
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6
Q

Thrombocytopenia

A
  • low platelet count
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7
Q

Thrombasthenia of Glanzmann & Naegeli

A
  • Glycoprotein IIb/IIIa gene mutation (AR)
  • Fibrinogen binding cannot occur; bleeding time significantly prolonged
  • Clinical Sx:
    • increased mucosal bleeding
    • epistaxis
    • menorrhagia increased bleeding post-op
    • bleeding tendency variable but may be severe
  • Dx:
    • prolonged bleeding time in presence of nl platelet counts
    • nl Prothrombin time & partial thromboplastin time
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8
Q

Bernard-Soulier Syndrome

A
  • Glycoprotein Ib gene mutation on platelet plasma membrane
  • GP1b composed of 4 subunits encoded by 4 genes
  • results in deficiency binding of platelets to vWF and defective platelet adhesion
  • defective platelet plug formation -> increased bleeding time
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9
Q

Extrinsic pathyway

A
  • III & VIIa & thromboplastin & Ca2+ & phospholipids
  • more important physiologically
  • activated by Factor III released at site of tissue injury
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10
Q

Instrinsic pathway

A
  • Factors XII, XI, IX, VIII, platelet phospholipids & Ca2+, activate Factor X
  • more important in pathology
  • initiated by activation of Hageman factor (XII) -> exposure of collagen -> activation of factor XII
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11
Q

Common pathway

A

Fibrinogen (I), Prothrombin (II), V, X, XIII

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12
Q

Prothrombin Time (PT) aka INR

A
  • tests the Extrinsic & Common coagulation pathways. Measures defects in:
  • Thromboplastin
  • Factor VII
  • Factor V
  • Factor X
  • Prothrombin
  • Fibrinogen
  • Factor XIII
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13
Q

Activated Partial Thromboplastin Time (APTT)

A
  • tests Intrinsic & Common pathways
  • Measures defects in
  • Factor V
  • Factor VIII
  • Factor IX
  • Factor X
  • Factor XI
  • Factor XII
  • Prothrombin
  • Fibrinogen
  • Factor XIII
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14
Q

Hemostasis is complex process & involves the following phaes

A
  • vascular spasm/vascular constriction
  • formation of platelet plug (primary hemostasis)
  • formation of a blood clot as a result of coagulation (secondary hemostasis)
  • dissolution of fibrin clot (tertiary hemostasis)
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15
Q

Vascular spasm brought about by:

A
  • local myogenic spasm: initiated by direct damage to vascular wall
  • factors released from injured vessel wall: Endothelin is the most important factor responsible for this response, being one of the most potent vasoconstrictors known
  • TXA2 released by platelets also help in vasoconstriction
  • nervous impluses: these reflexes are initiated by pain nerve impulses or other sensory impulses that originate from traumatised vessel or nearby tissues
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16
Q

Endothelin

A
  • binds to target tissues (adjacent smooth muscles) through GPCR
  • GPCR -> IP3 -> Ca2+ release -> smooth muscle construction
17
Q

Platelet plug formation (primary hemostasis)

A
  • form mechanical plugs at site of injury & secrete regulators of clotting process and vascular repair
  • if cut in blood vessel is small, it is often sealed by platelet plug, rather than a blood clot
  • 3 stages of platelet plug formation:
    • Adhesion
    • Activation
    • Aggregation
18
Q

Platelet Adhesion & vWF

A
  • Platelet-subendothelial interaction that occurs when platelets initially adhere to sites of the blood vessel injury
  • under nl conditions, this adhesion is prevented by -ve charges present on both the platelets and the intact endothelium, causing repulsion
  • Endothelial injury exposes
    • subendothelial collagen
    • vWF
  • Platelet Glycoprotein Ia (GP1a) binds to collagen -> structural changes to promote platelet interactions
  • vWF binds to platelet receptor, GP1b -> changes in platelet membrane
  • platelets activate
  • binding also exposes GPIIb/IIIa for binding of fibrinogen
  • this adhesion leads to platelet activation which results in more platelets aggregating at site of injury & releasing their contents
19
Q

vWF

A
  • def. of vWF leads to a problem in both primary hemostasis by affecting platelet adhesion, and secondary hemostasis by affecting the stability of factor VIII
  • large Cys-rich glycoprotein
  • Synthesized by: endothelial cells & megakaryocytes
  • Stored in:
    • subendothelial matrix
    • alpha granules of the platelets
  • Fx:
    • acts as bridge b/w specific glycoproteins on the surface of platelyets & collagen fibres - platelet adhesion to the vessel wall & platelet aggregation
    • complexed with factor VIII
20
Q

Platelet activation

A
  • morphological & functional changes in the attached platelets
    • shape change to promote platelet-platelet interactions:
      • irregular outline with many cytoplasmic projections (pseudopods)
      • cell signaling events cause release of intracell stores of Ca2+ which generate shape transformation
      • Ca2+ diffuses out of cell to enhance vasoconstriction
    • release of granule contents, which activate other platelets promoting aggregation
    • increased surface receptor expression ex. thrombin, ADP, & GPIIb/IIIa receptor
    • synthesis & release of TXA2 & platelet activating factor
      *
21
Q

Platelet granules

A

Dense granules

  • ADP: aggregation of platelets
  • ATP: provides ADP
  • 5HT: vasoconstriction & platelet activation
  • Calcium: coagulation, platelet fx

alpha Granules

  • vWF: adhesion molecule, factor VIII stabiliser
  • Fibrinogen: clotting factor
  • PDGF: mitogen, chemotactic agent
  • Thrombospondin: promotes platelet-platelet interaction
22
Q

Role of ADP

A
  • potent platelet activator
  • induces:
    • swelling of activated platelets
    • promotes platelet-platelet contact
    • promotes platelet adherence
  • binding of ADP to its receptor on the platelet surface leads to a further unmasking of GPIIb/IIIa receptors which are required to bind fibrinogen for the formation of a platelet plug
  • ADP stimulates P2Y1 & P2Y12 platelet receptors causing shape change, aggregation, and secretion & further unmasking
    • P2Y1 -> releases intracell Ca2+ stores -> platelet shape change, aggregation (transient)
    • P2Y12 -> decreased adenyl cyclase & cAMP -> aggregation (sustained) secretion
23
Q

Platelet activating factors

A
  • Platelet activating factors (PAF)
  • ADP
  • Collagen & vWF
  • Thrombin
  • TXA2
  • Epinepherine
  • 5HT
24
Q

Platelet Aggregation

A
  • platelet aggregation mainly mediated by fibrinogen
  • characterised by cross-linking of platelets thru active GPIIb/IIIa receptors with fibrinogen bridges
  • ADP & TXA2 very important stimuli for platelet aggregation
  • ADP & TXA2 -> increase intracell Ca2+ -> activation of PLA2 -> conversion of GPIIb/IIIa from low affinity to high affinity receptors
  • formation of platelet plug/white thrombus
25
Q

Surface receptor expression

A
  • activation of platelets results in expression of PhosphatidylSerine (PS) & Phosphatidylinositol (PI) on platelet surfaces
  • allow platelets to contribute to secondary hemostasis (coagulation cascade) as they provide binding sites for coagulation factors
  • ex. VIIIa binds to PS & PI on platelet surfaces -> recruit Ca2+, IXa & X during coagulation cascade
26
Q

Blood coagulation (secondary hemostasis)

A
  • white thrombus (soft clot) + fibrin (from fibrinogen cleaved by thrombin) = red thrombus (hard clot)
  • Fibrin enmeshes the platelet aggregates at the sites of injury & converts the unstables primary platelet plugs to firm, definitive & stables hemostatic plugs
  • soft clot converted to hard clot by Fibrin stabilizing factor (XIII) which needs to be activated by thrombin before it can act on soft clot
  • 2 pathways can lead to the formation of thrombin:
    • Intrinsic
    • Extrinsic
  • after activation, Factor XIII acts as enzyme to cause covalent bonds b/w fibrin monomer molecules and also multiple cross-linkages b/w adjacent fibrin fibres adding to the 3-D strength of fibrin meshwork
27
Q

Role of Vit. K

A
  • required for hepatic synthesis of factors, i.e post-translationaly mod:
  • II (prothrombin)
  • VII
  • IX
  • X
  • Protein C & S
  • serves as co-enzyme in the carboxylation of certain glutamate residues present in these factors leading to formation of mature clotting factors capable of subsequent activation
  • gamma-carboxylation of these residues allows more efficient Ca2+ binding b/c of 2 adjacent -ve charged carboxylase groups. This clotting factor Ca2+ complex can then bind to phospholipids on platelet membrane
    *
28
Q

Fibrinolysis (tertiary hemostatis): dissolution of fibrin clot

A
  • Inactive plasminogen gets incorporated in the developing clot
    • Inhibitors: Plasminogen activator inhibitor 1 & 2
    • Activator: Tissue-type Plasminogen Activator, Urokinase, Streptokinase, FXIIa
  • Active plasmin (proteolytic) degrades Fibrin
    • Inhibitor: alpha2-antiplasmin
    • Plasmin is a Ser protease
    • Plasminogen has a high affinity for fibrin, promoting its incorporation in the developing clot
  • Fibrin degradation product levels are icnreased in Pt with DVT. They are used in clinical practice to estimate the extent and rate of fibrinolysis and in follow up of Pt with thrombosis
29
Q

alpha2-antiplasmin (alpha2-AP)

A
  • circulating protease inhibitor which rapidly inactivates circulating plasmin
  • when plasmin is NOT bound to fibrin (free in soln). alpha2-AP complexes with plasmin and thereby inactvates plasmin
  • when plasmin is attached to Lys residues on fibrin, this inhibition is greatly reduced.
30
Q

Tissue Plasminogen Activator (tPA)

A
  • important route for plasminogen activation
  • released from endothelial cells
  • Inactive until bound to fibrin
  • upon binding to fibrin, t-PA cleaves plasminogen to generate plasmin, which in turn digests fibrin to produce fibrin degradation activator inhibitor
31
Q

Control of hemostasis

A
  • variety of mechanisms exist which act to limit coagulation to the site of injury & prevent its dissemination
  • normal endothelium is anti-thrombotic
  • endothelial cells maintain an environment conducive to liquid blood flow by mechanisms that block platelet adhesion and aggregation and also interfere with the coagulation cascade
  • smoothness of endothelium prevents contact activation of clotting process while a layer of absorbed glycocalyx repels platelets and clotting factors
  • chemical mediators such as prostacyclin and NO are released by healthy endothelium and prevent platelet aggregation
  • many required coagulation factors for clotting are concentrated by their selective absorption to activated platelet at injury sites
  • macrophages have a high affinity for circulating coagulation factors & selectively remove them from the circulation
  • coagulation automatically initiates fibrinolysis
  • endothelium and blood also contain very powerful anticoagulant factors, which combine with and inactivate specific clotting factors including antithrombin III, proteins C & S, alpha-1 antiprotease, and alpha1-antitrypsin
32
Q

Antiothrombin III

A
  • binds to & inhibits factor Xa & thrombin
  • causes the formation of a complex b/w thrombin and activated Ser protease, inactivating both compounds
  • activated by binding to heparin like molecules on endothelial cells
  • antithrombin III also known as heparin co-factor I
  • Heparin acts by activating this factor & preventing coagulation
33
Q

Protein C & S

A
  • act together to inactive cofactors Va & VIIIa
  • enhance fibrinolysis
  • Protein C is activated by binding of thrombomodulin to thrombin
  • Thrombomodulin-thrombin complex activates protein C which localises to the endothelial surface and is able to destroy activated factors V & VIII
  • action of protein C is enhanced by protein S, which binds it to platelet surface
    *
34
Q

Other anti-coagulant factors

A
  • alpha1-antiprotease/alpha-1 antitrypsin, alpha-2 macroglobulin: inhibit many proteolytic enzymes
  • PGI2 aka Prostacyclin: synthesised by endothelium; increases cAMP levels within platelets and inhibits platelet activation. TXA2 antagonist
  • Tissue Factor Pathway Inhibitor (TFPI): limits the action of tissue factor & prevents TF-mediated activation of factor X
35
Q

Role of thrombin in coagulation

A
  • critical fx in generating the hard clot
  • thrombin directly induces platelet aggregation and secretion
  • Thrombin (proteolytic) acts on many other clotting factors including:
    • Prothrombin
    • V
    • VIII
    • XI
    • XIII
    • Fibrinogen
  • binding of thrombin to thrombomodulin is essential for activation of protein C, which is important in regulating the coagulation process

Biochem Diseases (33 decks)

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