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Hematology > Weeks 8/9 > Flashcards

Weeks 8/9 Flashcards

Hemostasis & Fibrinolysis

1
Q

What is the main goal of hemostasis?

A

To stop bleeding by forming a clot and eventually breaking it down to restore circulation after healing is complete.

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2
Q

Why must clot breakdown occur at the right time?

A

If clot breakdown happens too fast, circulation is restored before healing is complete, potentially leading to further bleeding.

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3
Q

What are the three main steps in hemostasis?

A
  1. Bleeding
  2. Clotting
  3. Clot Breakdown
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4
Q

Why is it important to balance clot formation and breakdown in hemostasis?

A

To ensure that bleeding stops initially and that normal circulation resumes only after the wound has healed.

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5
Q

What does clot breakdown ensure in the hemostatic process?

A

It restores circulation, but only after healing is complete.

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6
Q

What is a primary cause of errors in hemostasis?

A

Missing components necessary to produce a clot.

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7
Q

What happens in hemostasis when clot formation is impaired?

A

Bleeding continues without the formation of a stable clot.

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8
Q

How does the absence of clotting impact clot breakdown in hemostasis?

A

Without clot formation, the process of clot breakdown cannot occur, preventing circulation restoration.

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9
Q

What is the consequence of missing clotting components in hemostasis?

A

The inability to progress from bleeding to clotting, leading to continuous blood loss.

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10
Q

What is the role of regulation in hemostasis?

A

Regulation ensures a balance between clot formation and clot breakdown, preventing excessive clotting or prolonged bleeding.

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11
Q

What are the three systems that interact to provide hemostasis?

A

Vascular Intima, Platelets, and Plasma Coagulation System.

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12
Q

What activates primary hemostasis?

A

Desquamation and small injuries to blood vessels.

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13
Q

What activates secondary hemostasis?

A

Large injuries to blood vessels and surrounding tissues.

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14
Q

What components are involved in primary hemostasis?

A

The vascular intima and platelets.

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15
Q

What components are involved in secondary hemostasis?

A

Platelets and the plasma coagulation system.

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16
Q

How does the response time differ between primary and secondary hemostasis?

A

Primary hemostasis is a rapid, short-lived response, while secondary hemostasis is a delayed, long-term response.

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17
Q

What triggers the procoagulant substances in primary hemostasis?

A

They are exposed or released by damaged or activated endothelial cells.

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18
Q

What is the key activator in secondary hemostasis?

A

Tissue factor, which is exposed on cell membranes.

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19
Q

What type of cells line the inner layer of blood vessels and play a role in hemostasis?

A

Endothelial cells (EC).

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20
Q

What are the main components of the normal intimal layer that suppress hemostasis?

A

Smooth surface
Prostacyclin
Heparan sulfate
Tissue factor pathway inhibitor
Thrombomodulin

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21
Q

What feature of endothelial cells helps prevent spontaneous clotting?

A

Endothelial cells present a smooth, contiguous surface that inhibits platelet adhesion.

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22
Q

What platelet inhibitor is secreted by endothelial cells?

A

Prostacyclin.

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23
Q

Which vascular “relaxing” factor is secreted by endothelial cells to prevent clotting?

A

Nitric oxide.

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24
Q

What anticoagulant glycosaminoglycan is secreted by the endothelium?

A

Heparan sulfate.

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25
Q

What regulator does the endothelium secrete to inhibit the coagulation extrinsic pathway?

A

Tissue factor pathway inhibitor.

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26
Q

What protein on the endothelial cell membrane activates the protein C coagulation control system?

A

Thrombomodulin.

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27
Q

What is the primary role of these anticoagulant properties of intact endothelium?

A

To prevent spontaneous clotting and maintain blood fluidity.

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28
Q

What happens to the vessel’s properties after an injury?

A

The vessel’s properties switch from anti-coagulant to pro-coagulant.

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29
Q

What is the procoagulant property of smooth muscle cells in arterioles and arteries?

A

They induce vasoconstriction.

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30
Q

What does exposed subendothelial collagen do in the coagulation process?

A

It binds von Willebrand factor (VWF) and platelets.

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31
Q

How do damaged or activated endothelial cells contribute to coagulation?

A

They secrete von Willebrand factor (VWF) and adhesion molecules like P-selectin, ICAMs, and PECAMs.

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32
Q

What is the role of exposed smooth muscle cells and fibroblasts in coagulation?

A

They expose tissue factor on cell membranes.

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33
Q

How do endothelial cells contribute to coagulation during inflammation?

A

They induce tissue factor.

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34
Q

What are ICAMs, PECAMs, and P-selectin, and what is their role in hemostasis?

A

These are adhesion molecules secreted by endothelial cells to promote platelet adhesion and aggregation.

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35
Q

What triggers the exposure of tissue factor on cell membranes?

A

Damage to the vascular intima or inflammatory processes.

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36
Q

What is the function of platelet adhesion?

A

Platelets roll and cling to non-platelet surfaces.

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37
Q

What are the characteristics of platelet adhesion?

A

It is reversible, seals endothelial gaps, involves secretion of growth factors, and requires von Willebrand factor (VWF) for adhesion in arterioles.

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38
Q

What is the function of platelet aggregation?

A

Platelets adhere to each other to form a plug.

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39
Q

What are the characteristics of platelet aggregation?

A

It is irreversible, requires fibrinogen, and involves the secretion of platelet contents.

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40
Q

What is the function of platelet secretion?

A

Platelets discharge the contents of their granules.

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41
Q

What are the characteristics of platelet secretion?

A

It is irreversible, occurs during aggregation, and is essential for coagulation.

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42
Q

Why is von Willebrand factor (VWF) important for platelet function?

A

VWF is necessary for platelet adhesion to endothelial surfaces, especially in arterioles.

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43
Q

At what stage is platelet function reversible?

A

During adhesion, when platelets initially bind to non-platelet surfaces.

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44
Q

Through which receptor do platelets bind to von Willebrand factor (VWF) during adhesion?

A

The GP Ib/IX/V receptor.

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45
Q

What are the key events during the release reaction of platelet aggregation and secretion?

A

Activation of platelet receptor GP IIb/IIIa.
Secretion of granules.
Attraction of more platelets to the damaged area.

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46
Q

What does the platelet receptor GP IIb/IIIa do during aggregation?

A

It facilitates the binding of fibrinogen, allowing platelets to adhere to each other and form a stable plug.

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47
Q

What are the contents of alpha granules in platelets?

A

Fibrinogen
von Willebrand factor (vWF)
Factor V and VIII
Plasminogen
High molecular weight kininogen (HMWK)
Protein S

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48
Q

What are the contents of dense granules in platelets?

A

ADP
ATP
Calcium
Serotonin
Epinephrine
Thromboxane

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49
Q

What are zymogens in the coagulation system?

A

Inactive precursor proteins that become active enzymes in the coagulation cascade.

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50
Q

List some examples of zymogens in the coagulation system.

A

Prekallikrein
Factor XII (FXII)
Factor XI (FXI)
Factor IX (FIX)
Factor X (FX)
Prothrombin (FII)
Factor XIII (FXIII)

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51
Q

What is the role of cofactors in the coagulation system?

A

They enhance the activity of coagulation factors and are essential for the cascade to progress.

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52
Q

List some key cofactors in the coagulation system.

A

High molecular weight kininogen (HMWK)
Tissue factor
Factor VIII (FVIII)
Factor V (FV)
Protein Z
Protein S
Thrombomodulin

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53
Q

What are control proteins, and why are they important in coagulation?

A

Control proteins regulate the coagulation cascade to prevent excessive clotting or thrombosis.

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54
Q

List some control proteins involved in the coagulation system.

A

Antithrombin
Heparin cofactor II
Tissue factor pathway inhibitor (TFPI)
Protein C
α2-macroglobulin
α1-antitrypsin
ZPI

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55
Q

What is the function of antithrombin in coagulation control?

A

It inhibits thrombin and other serine proteases to prevent excessive clot formation.

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56
Q

What role does thrombomodulin play in coagulation?

A

It binds thrombin and activates protein C, which inhibits clotting factors Va and VIIIa.

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57
Q

How does tissue factor pathway inhibitor (TFPI) contribute to coagulation regulation?

A

It inhibits the tissue factor-FVIIa complex, blocking the initiation of the coagulation cascade.

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58
Q

What initiates the extrinsic pathway of the coagulation cascade?

A

Exposed tissue factor (TF) combines with Factor VIIa (FVIIa).

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59
Q

What initiates the intrinsic pathway of the coagulation cascade?

A

Activation of Factor XII (FXII) by contact with negatively charged surfaces, along with prekallikrein (Pre-K) and high molecular weight kininogen (HMWK).

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60
Q

What is the role of platelet membrane phospholipids in coagulation?

A

They provide a surface for the assembly of vitamin K-dependent clotting factors, facilitated by Platelet Factor 3.

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61
Q

Which factors are part of the common pathway in the coagulation cascade?

A

Factor Xa, Factor Va, thrombin (Thr), and Factor XIIIa.

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62
Q

What is the function of thrombin (Thr) in the coagulation cascade?

A

Thrombin converts fibrinogen into fibrin, forming the fibrin polymer.

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63
Q

How does Factor XIIIa contribute to clot formation?

A

It cross-links fibrin polymers to form a stable clot.

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64
Q

What is the function of Platelet Factor 3?

A

It acts as an assembly point for vitamin K-dependent factors, essential for coagulation.

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65
Q

What is the end product of the coagulation cascade?

A

Cross-linked fibrin, which stabilizes the blood clot.

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66
Q

Which vitamin K-dependent factors are assembled on the platelet membrane?

A

Factors II (prothrombin), VII, IX, and X.

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67
Q

What is the link between the extrinsic and intrinsic pathways?

A

Factor VIIa from the extrinsic pathway can activate Factor IX in the intrinsic pathway.

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68
Q

Which regulatory proteins in the coagulation pathway are Vitamin K-dependent?

A

Protein C and Protein S.

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69
Q

What are the three key coagulation complexes?

A

Extrinsic Tenase
Intrinsic Tenase
Prothrombinase

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70
Q

What components are required for each coagulation complex?

A

Each complex involves:

A protease
A co-factor
Calcium ions (Ca²⁺)
A phospholipid surface

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71
Q

What is the role of the extrinsic tenase complex?

A

It activates Factor X (FX) to Factor Xa (FXa) in the presence of tissue factor and Factor VIIa (FVIIa).

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72
Q

What factors make up the intrinsic tenase complex?

A

The intrinsic tenase complex consists of Factor IXa (FIXa), Factor VIIIa (FVIIIa), calcium, and a phospholipid surface.

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73
Q

What is the role of the intrinsic tenase complex?

A

It amplifies the activation of Factor X (FX) to Factor Xa (FXa).

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74
Q

What components form the prothrombinase complex?

A

The prothrombinase complex includes Factor Xa (FXa), Factor Va (FVa), calcium, and a phospholipid surface.

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75
Q

What is the function of the prothrombinase complex?

A

It converts prothrombin (Factor II) into thrombin (Factor IIa), which is essential for clot formation.

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76
Q

What is the role of calcium ions (Ca²⁺) in coagulation complexes?

A

Calcium ions stabilize the complexes and enable the binding of clotting factors to the phospholipid surface.

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77
Q

How does the phospholipid surface contribute to coagulation?

A

It provides a platform for the assembly and stabilization of coagulation complexes, ensuring efficient clot formation.

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78
Q

What triggers the initiation phase of coagulation?

A

Tissue factor (TF) on tissue factor-bearing cells binds to Factor VIIa (FVIIa), activating Factor X (FX) to Factor Xa (FXa).

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79
Q

What is the role of the tissue factor-VIIa complex in coagulation?

A

It activates Factor X to Xa and Factor IX to IXa, starting the coagulation cascade.

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80
Q

What happens during the amplification phase of coagulation?

A

A small amount of thrombin activates platelets and cofactors (FVIII and FV), increasing the local concentration of activated clotting factors.

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81
Q

How does thrombin (Thr) contribute to the amplification phase?

A

Thrombin activates Factor VIII to VIIIa, Factor V to Va, and platelets, preparing them for the propagation phase.

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82
Q

What occurs during the propagation phase of coagulation?

A

Activated platelets (COAT platelets) provide a surface for the assembly of intrinsic tenase (IXa + VIIIa) and prothrombinase (Xa + Va) complexes, resulting in a thrombin burst.

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83
Q

What is a thrombin burst, and why is it important?

A

The thrombin burst is a rapid generation of large amounts of thrombin, which converts fibrinogen to fibrin, stabilizing the clot.

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84
Q

What is the role of von Willebrand factor (vWF) in the coagulation process?

A

vWF stabilizes Factor VIII and supports platelet adhesion to the site of vascular injury.

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85
Q

Which factors are activated by thrombin during the amplification phase?

A

Factors VIII, V, and XI, along with platelets.

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86
Q

What is the role of activated COAT platelets in the propagation phase?

A

They provide a phospholipid surface for the assembly of coagulation factor complexes, leading to efficient thrombin generation.

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87
Q

What is the primary substrate of thrombin in the coagulation process?

A

Fibrinogen.

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88
Q

What is the structure of fibrinogen?

A

Fibrinogen has a trinodular structure with two outer D domains and a central E domain.

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89
Q

How does thrombin act on fibrinogen?

A

Thrombin cleaves fibrinogen, releasing fibrinopeptides A and B, and converting fibrinogen into fibrin monomers.

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90
Q

What happens to fibrin monomers after thrombin cleavage?

A

Fibrin monomers polymerize to form a fibrin network, which is the basis of a stable clot.

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91
Q

What regions of fibrinogen are cleaved by thrombin?

A

The Aα and Bβ chains near the E domain.

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92
Q

What domains are responsible for the cross-linking of fibrin polymers?

A

The D domains are involved in cross-linking to stabilize the fibrin polymer.

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93
Q

What enzyme strengthens the fibrin clot after thrombin cleavage?

A

Factor XIIIa cross-links the fibrin monomers to form a stable clot.

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94
Q

What happens to the E domains of fibrinogen after thrombin cleavage?

A

Thrombin-cleaved E domains develop an affinity for adjacent D domains, enabling fibrin polymer formation.

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95
Q

What is the sequence of events in fibrin mesh formation?

A

Thrombin cleaves fibrinogen to fibrin monomers.
Fibrin monomers spontaneously polymerize via interactions between E and D domains.
Factor XIIIa cross-links the fibrin polymers, stabilizing the clot.

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96
Q

Which clotting factors are activated by thrombin?

A

Thrombin activates Factor XIII (FXIII) and Factor XI (FXI).

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97
Q

How does thrombin enhance the coagulation process?

A

It enhances the activity of Factor V (FV) and Factor VIII (FVIII), amplifying the coagulation cascade.

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98
Q

What is thrombin’s role in platelet function?

A

Thrombin induces platelet aggregation, which strengthens the initial platelet plug.

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99
Q

How does thrombin participate in feedback inhibition of coagulation?

A

Thrombin binds to thrombomodulin, activating Protein C, which inhibits Factors Va and VIIIa.

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100
Q

In addition to coagulation, what other processes is thrombin involved in?

A

Thrombin plays roles in fibrinolysis, cellular migration, and vascular endothelial cell activation.

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101
Q

How does thrombin affect the fibrinolytic pathway?

A

Thrombin indirectly regulates fibrinolysis by modulating the balance between clot formation and breakdown.

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102
Q

What cellular processes are influenced by thrombin?

A

Thrombin influences cellular migration, monocyte activation, and endothelial growth processes.

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103
Q

What is the reagent used in the Prothrombin Time (PT) assay?

A

The PT reagent consists of tissue factor suspended in phospholipid, diluted in buffered calcium chloride.

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104
Q

Which pathways does the PT assay evaluate?

A

The PT assay evaluates the extrinsic and common pathways of the coagulation cascade.

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105
Q

Which coagulation factor has the greatest effect on the PT?

A

Factor VII has the greatest effect on the PT due to its short half-life of approximately 6 hours.

106
Q

Why is calcium chloride included in the PT reagent?

A

Calcium chloride is included to provide calcium ions necessary for the activation of the coagulation cascade.

107
Q

What is the clinical significance of the PT assay?

A

The PT assay is used to assess coagulation disorders, monitor warfarin therapy, and evaluate liver function.

108
Q

How does the short half-life of Factor VII affect PT results?

A

A deficiency in Factor VII, due to its short half-life, can result in a prolonged PT, making it a sensitive marker of extrinsic pathway function.

109
Q

What does the PTT reagent in the aPTT assay contain?

A

Phospholipid (partial thromboplastin) and an activator, which are negatively charged particles like silica.

110
Q

What is the purpose of the second reagent in the aPTT assay?

A

The second reagent, calcium chloride, is added to provide calcium ions necessary for coagulation.

111
Q

Which pathways are evaluated by the aPTT assay?

A

The aPTT assay evaluates the intrinsic and common pathways of the coagulation cascade.

112
Q

What role do negatively charged particles like silica play in the aPTT assay?

A

They act as activators, triggering the intrinsic pathway by initiating contact activation.

113
Q

What is the clinical significance of the aPTT assay?

A

It is used to monitor heparin therapy and to detect deficiencies or inhibitors in the intrinsic and common pathways.

114
Q

What is the purpose of the Thrombin Time test?

A

To measure the time it takes for a clot to form after thrombin is added to plasma.

115
Q

How is the Fibrinogen Assay conducted?

A

By adding thrombin to diluted plasma and producing a standard curve of time versus fibrinogen concentration.

116
Q

What is the outcome of the Fibrinogen Assay?

A

The patient’s fibrinogen concentration is determined from the standard curve graph.

117
Q

What is the key difference between the Thrombin Time test and the Fibrinogen Assay?

A

Thrombin Time measures clotting time directly, while the Fibrinogen Assay calculates fibrinogen concentration using a standard curve.

118
Q

What are the two main regulators of the coagulation pathway?

A

The vascular intima and regulatory proteins.

119
Q

What is the primary goal of coagulation pathway regulation?

A

To prevent uncontrolled thrombosis.

120
Q

What is the role of Tissue Factor Pathway Inhibitor (TFPI) in coagulation regulation?

A

TFPI inhibits the Tissue Factor (TF)-VIIa complex and limits the initiation of coagulation.

121
Q

How does Antithrombin (AT) contribute to coagulation regulation?

A

AT inhibits factors Xa, IXa, and thrombin (Thr), reducing clot formation.

122
Q

What is the function of Activated Protein C (APC) in coagulation?

A

APC inactivates factors Va and VIIIa to regulate clot propagation.

123
Q

What role does ZPI (Z-dependent protease inhibitor) play in coagulation?

A

ZPI inhibits factor Xa and XIa, working with Protein Z to regulate coagulation.

124
Q

Which factors are directly inhibited by Antithrombin (AT)?

A

Factors Xa, IXa, and thrombin.

125
Q

What are the critical regulatory checkpoints in the coagulation pathway?

A

Regulation at TF-VIIa by TFPI, inhibition of Xa, IXa, and thrombin by AT, and inactivation of Va and VIIIa by APC.

126
Q

What is the function of Tissue Factor Pathway Inhibitor (TFPI)?

A

With Factor Xa, TFPI binds tissue factor-VIIa complex to regulate coagulation.

127
Q

What is the role of Thrombomodulin in coagulation?

A

Thrombomodulin serves as an endothelial cell surface receptor for thrombin.

128
Q

What is the function of Protein C in coagulation regulation?

A

Protein C acts as a serine protease that deactivates factors Va and VIIIa.

129
Q

What is the role of Protein S in coagulation?

A

Protein S acts as a cofactor for Protein C in regulating coagulation.

130
Q

How does Antithrombin (AT) regulate coagulation?

A

Antithrombin inhibits thrombin and factors Xa and IXa.

131
Q

What is the function of Heparin Cofactor II?

A

Heparin Cofactor II acts as a serpin that inhibits thrombin in the presence of heparin.

132
Q

What is the role of Z-dependent protease inhibitor (ZPI)?

A

ZPI inhibits factors Xa and XIa in conjunction with Protein Z.

133
Q

What is the role of α₁-Protease Inhibitor (α₁-Antitrypsin) in coagulation regulation?

A

It inhibits serine proteases, contributing to the control of clot formation.

134
Q

What is α₂-Macroglobulin’s function in coagulation?

A

α₂-Macroglobulin acts as a broad-spectrum inhibitor for proteases, including thrombin.

135
Q

What system activates Factor X (FX) in coagulation?

A

The Extrinsic System activates Factor X (FX).

136
Q

How does TFPI regulate coagulation?

A

TFPI inactivates FXa and binds with it to inactivate FVIIa, preventing further FXa production.

137
Q

Why is the pathway regulated by TFPI considered short-lived?

A

The regulation by TFPI quickly inhibits further production of FXa, making the pathway short-lived.

138
Q

Through which factor does most thrombin amplification occur?

A

Most amplification of thrombin occurs through FIXa.

139
Q

What is the role of FVIIa in the extrinsic pathway?

A

FVIIa, in complex with tissue factor, activates FX to FXa, initiating the coagulation cascade.

140
Q

What does thrombin bind to in the Protein C Pathway to prevent uncontrolled clotting?

A

Thrombin binds to thrombomodulin (TM).

141
Q

What is Protein C, and how does it function in the coagulation pathway?

A

Protein C is a zymogen that, when activated, helps regulate clot formation by degrading factors Va and VIIIa.

142
Q

What is Protein S, and what are its two forms in plasma?

A

Protein S is a cofactor for Protein C and exists in two forms: free and bound to C4b-Binding Protein (C4bBP).

143
Q

What percentage of Protein S is free, and what percentage is bound?

A

40% of Protein S is free, while 60% is bound to C4b-Binding Protein.

144
Q

Are Protein C and Protein S dependent on Vitamin K for their function?

A

Yes, both Protein C and Protein S are Vitamin K-dependent.

145
Q

What happens to factors Va and VIIIa in the presence of Activated Protein C (APC)?

A

Activated Protein C (APC) degrades factors Va and VIIIa, inhibiting further coagulation.

146
Q

What activates Protein C (PC) in the Protein C pathway?

A

The thrombin-thrombomodulin (TM) complex activates Protein C (PC) to Activated Protein C (APC).

147
Q

What is the role of Activated Protein C (APC) in the Protein C pathway?

A

APC binds to free Protein S, forming the APC-PS complex.

148
Q

Where is thrombomodulin (TM) located in the Protein C pathway?

A

Thrombomodulin (TM) is located on the endothelial cell membrane.

149
Q

What is the primary function of Antithrombin (AT)?

A

Antithrombin is the major inhibitor of Thrombin (FIIa).

150
Q

Which coagulation factors are inhibited by Antithrombin (AT)?

A

Antithrombin inhibits FXa, FXIIa, FXIa, FIXa, and thrombin (FIIa).

151
Q

Besides coagulation factors, what else does Antithrombin (AT) inhibit?

A

Antithrombin inhibits prekallikrein and plasmin.

152
Q

Is Antithrombin’s inhibition of thrombin reversible or irreversible?

A

Antithrombin inhibits thrombin irreversibly.

153
Q

What is Antithrombin’s (AT) baseline activity level as an inhibitor?

A

Antithrombin is a slow-acting and weak inhibitor.

154
Q

Does Antithrombin (AT) interfere with normal clotting under baseline conditions?

A

No, Antithrombin does not interfere with normal clotting until activated by heparin.

155
Q

How does heparin enhance the activity of Antithrombin (AT)?

A

Heparin activates Antithrombin by binding to its heparin binding site, increasing its ability to inhibit thrombin and other coagulation factors.

156
Q

What complex is formed when Antithrombin (AT) inhibits thrombin?

A

The Thrombin-Antithrombin (TAT) complex is formed.

157
Q

What does Antithrombin (AT) require to bind and inhibit thrombin?

A

Heparin.

158
Q

What are the sources of heparin for Antithrombin (AT) activation?

A

Mast cell granules.
Heparan sulfate from endothelial cells (EC).
Therapeutic heparin.

159
Q

What happens to Antithrombin-Thrombin (AT-Thr) complexes after formation?

A

They are rapidly removed from circulation.

160
Q

What does Heparin Cofactor II (HCII) require for effective anticoagulant activity?

A

Heparin.

161
Q

What is the primary function of Heparin Cofactor II (HCII)?

A

It inactivates thrombin in the presence of heparin.

162
Q

How does Heparin Cofactor II (HCII) prevent clot formation?

A

By preventing the conversion of fibrinogen to fibrin.

163
Q

What family does Z-dependent protease inhibitor (ZPI) belong to?

A

The SERPIN family.

164
Q

What is the function of ZPI with its cofactor, protein Z?

A

It is a potent inhibitor of factor Xa.

165
Q

Which coagulation factor can ZPI inhibit, especially in the presence of heparin?

A

Factor XIa.

166
Q

What enhances ZPI’s activity as a protease inhibitor?

A

The presence of protein Z and heparin.

167
Q

What is fibrinolysis?

A

The process of breaking down a stabilized fibrin clot to restore blood flow.

168
Q

What is the primary result of fibrinolysis?

A

Fibrin Degradation Products (FDP).

169
Q

What does thrombin cleave to initiate the formation of fibrin monomers?

A

Fibrinopeptides A and B from fibrinogen.

170
Q

How are fibrin polymers stabilized during clot formation?

A

By cross-linking D domains through the action of Factor XIIIa.

171
Q

What is the precursor protein involved in fibrinolysis?

A

Plasminogen.

172
Q

Which activators convert plasminogen into plasmin?

A

Tissue Plasminogen Activator (tPA) and Urokinase.

173
Q

What inhibits tissue plasminogen activators?

A

Plasminogen Activator Inhibitor-1 (PAI-1).

174
Q

Which inhibitor prevents plasmin activity in fibrinolysis?

A

α2-Antiplasmin.

175
Q

Where is plasminogen produced?

A

In the liver as a circulating zymogen.

176
Q

How is plasminogen activated?

A

It is activated to plasmin by Tissue Plasminogen Activator (TPA).

177
Q

What does plasminogen co-precipitate with at the site of injury?

A

Tissue Plasminogen Activator (TPA).

178
Q

Where do plasminogen and TPA bind during fibrin polymerization?

A

Both bind to fibrin.

179
Q

When does fibrin-bound plasminogen become active plasmin?

A

When cleaved by bound TPA or urokinase.

180
Q

What are the breakdown products formed when fibrin is degraded by plasmin?

A

FDPs (Fibrin Degradation Products) and D-dimer.

181
Q

What type of enzyme is plasmin?

A

Plasmin is a serine protease.

182
Q

What does plasmin degrade in circulation?

A

Plasmin degrades fibrinogen and clotting factors V and VIII.

183
Q

What does plasmin degrade in a clot?

A

Plasmin degrades the fibrin polymer.

184
Q

How is plasmin activity regulated?

A

Plasmin is regulated by α₂-antiplasmin.

185
Q

What is the primary plasminogen activator?

A

Tissue Plasminogen Activator (TPA).

186
Q

Where is Tissue Plasminogen Activator (TPA) secreted from?

A

Endothelial cells.

187
Q

Why is TPA considered more potent and efficient than urokinase?

A

It has a higher affinity for fibrin than fibrinogen and cleaves fibrin-bound plasminogen.

188
Q

How is TPA used therapeutically?

A

It is used as a thrombolytic therapy, often in a synthetic recombinant form.

189
Q

What is Urokinase and where is it secreted?

A

Urokinase is a plasminogen activator secreted by urinary tract (kidney) epithelial cells, monocytes, and macrophages into plasma.

190
Q

What is the primary role of Urokinase?

A

It acts as the primary plasminogen activator within the genitourinary system.

191
Q

How specific is Urokinase as an activator?

A

Urokinase is highly specific.

192
Q

What happens to Urokinase during clot formation?

A

It gets caught up in fibrin-bound plasminogen and TPA but is not bound to fibrin.

193
Q

During which conditions is Urokinase released more?

A

Increased release is observed during urological surgery and prostate cancer.

194
Q

What is Streptokinase?

A

Streptokinase is a bacterial endotoxin and a product of β-hemolytic streptococci.

195
Q

What conditions is Streptokinase associated with?

A

It is usually pathogenic and often triggers Disseminated Intravascular Coagulation (DIC).

196
Q

Is Streptokinase a serine protease?

A

No, it is not a serine protease. Instead, it forms a complex with plasminogen to activate it.

197
Q

Why is Streptokinase considered highly antigenic?

A

Because it can induce an immune response when used therapeutically, forming antigen-antibody complexes.

198
Q

How does Streptokinase relate to sepsis?

A

As a bacterial endotoxin, it can be involved in sepsis caused by β-hemolytic streptococci.

199
Q

What does thrombin cleave from fibrinogen?

A

Thrombin cleaves A and B fibrinopeptides from fibrinogen.

200
Q

What fragments does plasmin cleave from fibrinogen?

A

Plasmin cleaves E and D fragments from fibrinogen.

201
Q

What happens when plasmin acts on fibrin?

A

Plasmin cleaves the same E and D fragments from fibrin but forms different fragment complexes (e.g., D-dimers).

202
Q

How are fibrin and fibrinogen cleavage products different?

A

Fibrin cleavage results in unique complexes like D-dimers, which are not produced during fibrinogen cleavage.

203
Q

What process results in the formation of D-dimers?

A

D-dimers are only formed as a result of fibrin degradation by plasmin.

204
Q

What is the role of Plasminogen Activator Inhibitor 1 (PAI-1) in the fibrinolytic system?

A

PAI-1 stops the activation of plasma plasminogen by inhibiting tissue plasminogen activator (TPA).

205
Q

What are the two primary plasmin inhibitors in the fibrinolytic system?

A

α₂-antiplasmin - Neutralizes free plasmin effectively.
α₂-macroglobulin - Acts as a secondary plasmin inhibitor.

206
Q

How do plasmin inhibitors contribute to the fibrinolytic system?

A

They neutralize free plasmin to prevent excessive fibrin degradation and maintain balance.

207
Q

What triggers the release of tissue plasminogen activator (tPA) in fibrinolysis?

A

Endothelial cells release tPA, which initiates the fibrinolysis process.

208
Q

What inhibits tPA in fibrinolysis?

A

Plasminogen Activator Inhibitor (PAI) prevents tPA from activating plasminogen.

209
Q

How is plasminogen activated during fibrinolysis?

A

tPA converts plasminogen (PLG) into plasmin when bound to fibrin threads.

210
Q

What is the role of plasmin in fibrinolysis?

A

Plasmin breaks down fibrin threads into fibrin degradation products (FDPs), restoring blood flow.

211
Q

How is plasmin activity regulated to prevent excessive clot breakdown?

A

α₂-antiplasmin and other inhibitors deactivate plasmin to maintain balance in the fibrinolytic system.

212
Q

What is the function of α₁-antitrypsin in relation to plasmin?

A

α₁-antitrypsin acts as a plasmin inhibitor, regulating its activity.

213
Q

How does antithrombin (AT) inhibit plasmin?

A

Antithrombin inhibits plasmin, especially when enhanced by the presence of heparin.

214
Q

What is the role of C1 esterase inhibitor in the regulation of plasmin?

A

C1 esterase inhibitor acts as a plasmin inhibitor, preventing excessive plasmin activity.

215
Q

How is thrombin generated?

A

Thrombin is generated as a result of activation of the coagulation system.

216
Q

What role does thrombin play in initiating fibrinolysis?

A

Thrombin initiates fibrinolysis by inducing the release of tissue plasminogen activator (tPA).

217
Q

How does thrombin inhibit fibrinolysis?

A

Thrombin inhibits fibrinolysis by stimulating endothelial cells to release plasminogen activator inhibitor-1 (PAI-1).

218
Q

What is DIC?

A

DIC stands for Disseminated Intravascular Coagulation, a hypercoagulable state caused by excess thrombin in the plasma and a weakened plasmin response.

219
Q

What overwhelms normal inhibitory mechanisms in DIC?

A

Excess thrombin and a delayed/weak plasmin response overwhelm normal inhibitory mechanisms.

220
Q

What is the effect of DIC on coagulation factors and platelets?

A

DIC leads to the consumption of coagulation factors and platelets.

221
Q

What does diffuse clotting in DIC result in?

A

Diffuse clotting in DIC results in bleeding and shock.

222
Q

How does fibrinolysis relate to DIC?

A

Fibrinolysis in DIC is delayed or weakened, contributing to clot persistence and excessive bleeding.

223
Q

What is the first triggering mechanism of DIC?

A

Activation of the extrinsic coagulation pathway by the release of Tissue Factor (TF).

224
Q

What is the second triggering mechanism of DIC?

A

Direct activation of Factors X or II.

225
Q

What is the third triggering mechanism of DIC?

A

Activation of the intrinsic pathway.

226
Q

What is the first triggering mechanism of DIC?

A

Activation of the extrinsic coagulation pathway by the release of Tissue Factor (TF).

227
Q

What events can trigger the release of Tissue Factor (TF) leading to DIC?

A

Trauma/surgery
Obstetrical complications
Tumor/leukemia
Bacterial infection
Sepsis

228
Q

How does Tissue Factor (TF) contribute to DIC?

A

Tissue Factor activates the extrinsic clotting pathway, leading to thrombin generation, fibrin deposition, and platelet activation.

229
Q

What role do monocytes and endothelial cells play in DIC?

A

They release Tissue Factor (TF) in response to infection, malignancy, or vascular injury.

230
Q

What are the downstream effects of Tissue Factor activation in DIC?

A

Activation of platelets, thrombin generation, fibrin formation, and eventual formation of fibrin degradation products (FDPs) and D-dimers.

231
Q

What is the second triggering mechanism of DIC?

A

Activation of Factors X and II.

232
Q

What are some causes of activation of Factors X and II in DIC?

A

Snake venom
Liver disease

233
Q

What is the third triggering mechanism of DIC?

A

Activation of the intrinsic system.

234
Q

What are some causes of activation of the intrinsic system in DIC?

A

Liver disease
Heat stroke
Sepsis
Burns
Immune complex disease

235
Q

How does the clinical presentation of primary fibrinolysis compare to DIC?

A

It is similar to DIC.

236
Q

How is plasmin formed in primary fibrinolysis?

A

In the absence of clot formation.

237
Q

What is a key difference between primary fibrinolysis and DIC?

A

Unlike DIC, uncontrolled clotting does not occur in primary fibrinolysis.

238
Q

What are the triggers for primary fibrinolysis?

A

Enzymes in plasma capable of activating plasminogen
Urological procedures
Metastatic prostatic carcinoma
Hepatic disorders

239
Q

What is the platelet count reference interval, and how does it change in DIC?

A

Reference interval: 150,000–450,000/μL. In DIC: <150,000/μL.

240
Q

What is observed in a peripheral blood film exam in DIC?

A

Schistocytes (MAHA) are present in 50% of DIC cases, and leukocytosis is common.

241
Q

What is the normal reference range for PT (Prothrombin Time), and how does it change in DIC?

A

Reference range: 11–14 sec. In DIC: >14 sec.

242
Q

What is the normal reference range for PTT (Partial Thromboplastin Time), and how does it change in DIC?

A

Reference range: 25–35 sec. In DIC: >35 sec.

243
Q

How does thrombin time and reptilase time change in DIC?

A

Both are prolonged due to fibrinogen levels <80 mg/dL, elevated FDPs, and soluble fibrin monomer.

244
Q

What is the normal reference range for D-dimer, and how does it change in DIC?

A

Reference range: 0–240 ng/mL DDU or 0–500 ng/mL FEU. In DIC: >240 ng/mL DDU or >500 ng/mL FEU, often 10,000–20,000 ng/mL.

245
Q

What is the normal fibrinogen reference range, and how does it change in DIC?

A

Reference range: 220–498 mg/dL. In DIC: <220 mg/dL, often higher due to fibrinogen being an acute-phase reactant.

246
Q

What type of methods are used in the D-Dimer test?

A

Quantitative or semi-quantitative immunoassay methods.

247
Q

What technologies are involved in the D-Dimer test?

A

Automated methods and monoclonal antibodies against D-dimers on microlatex particles.

248
Q

What does the D-Dimer test specifically indicate?

A

It is a specific marker for thrombosis.

249
Q

Under what condition are D-Dimers formed?

A

Only when fibrin is broken down by plasmin.

250
Q

What is the typical value of Protein C, Protein S, and AT activity assays in DIC?

A

Less than 50%.

251
Q

Why are Protein C, Protein S, and AT activity assays used in DIC?

A

To monitor plasma and AT concentrate levels.

252
Q

What is the typical value of Serum FDP in DIC?

A

Greater than 10 µg/mL.

253
Q

Which test has largely replaced Serum FDP measurements in DIC diagnosis?

A

Quantitative D-dimer tests.

254
Q

How are Plasminogen, Tissue Plasminogen Activator, and Plasminogen Activator Inhibitor-1 levels affected in DIC?

A

They are decreased.

255
Q

Why are assays for Plasminogen and its activators useful in DIC?

A

They help analyze systemic fibrinolysis, but specimen management protocols must be strictly observed.

256
Q

How does the platelet count differ in DIC vs. Primary Hyperfibrinolysis?

A

DIC: Low; Primary Hyperfibrinolysis: Normal.

257
Q

What is the fibrinogen level in DIC and Primary Hyperfibrinolysis?

A

Both have low fibrinogen levels.

258
Q

How do FDP levels compare in DIC and Primary Hyperfibrinolysis?

A

FDP is elevated in both conditions.

259
Q

What is the D-dimer level in DIC and Primary Hyperfibrinolysis?

A

Elevated in both conditions.

260
Q

How does ATIII (Antithrombin III) differ in DIC vs. Primary Hyperfibrinolysis?

A

DIC: Decreased; Primary Hyperfibrinolysis: Normal.

261
Q

Is schistocytosis present in DIC and Primary Hyperfibrinolysis?

A

DIC: Present; Primary Hyperfibrinolysis: Absent.

262
Q

How are clotting times affected in DIC and Primary Hyperfibrinolysis?

A

Clotting times are prolonged in both conditions.

Hematology (6 decks)

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