Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

General Pathology > hemostasis > Flashcards

hemostasis Flashcards

1
Q

what are the 3 layers of blood vessels?

A

– Intima lined by endothelium – single layer of endothelial cells, rests on membrane of elastin and collagen
– Media – smooth muscle and collagen
– Adventitia – collagen and fibroblasts

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

what is the tunica intima?

A

The innermost layer of an artery or vein. Consists of a layer of endothelial cells supported by an elastic lamina.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

what is the function of tunica intima?

A
  • -Diffusion barrier
  • -Selective permeability
  • -Extracellular matrix (ECM) synthesis
  • -Regulation of:
    1) Adhesion (e.g., leukocyte extravasation)
    2) Coagulation
    3) Vessel width
    4) Angiogenesis (via VEGF)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

the tunic media is composed of…

A

smooth muscle cells
Regulates lumen width and therefore vascular resistance (in line with the Poiseuille equation)
Produces ECM and elastic fibers for the internal elastic lamina

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

describe the tunica adventitia

A

connective tissue
Regulates lumen width and therefore vascular resistance (in line with the Poiseuille equation)
Produces ECM and elastic fibers for the internal elastic lamina

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

list eh content of platelet alfa and dense granules

A
  • Alpha Granules: Factor V, vWF, fibrinogen, growth factors,P-selectin
  • Dense Granules: ADP,ATP, calcium ions, histamine, serotonin
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

what is the hemostasis?

A

The physiological process by which bleeding is stopped. Includes blood vessel constriction, formation of a platelet plug, and blood coagulation through the formation of a fibrin clot.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

what are the 3 factors involved in hemostasis?

A

• Blood vessel wall, platelets, coagulation factors

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

what is the role of blood vessels in hemostasis?

A
  • Once activated, the endothelium expresses adhesion molecules (selectins) and von Willebrand factor (vWF)
  • Undisturbed endothelium express NO and prostacyclin (PGI2)which cause vasodilatation and inhibit platelet aggregation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

activation of endothelial cells leads to?

A
  • -initiation: endothelial injury results in transient vasoconstriction. → exposure of subendothelial collagen → von Willebrand factor (vWF), which is a glycoprotein synthesized and stored in Weibel-Palade bodies of endothelial cells and α-granules of platelets, binds the exposed collagen
  • -Adhesion (hemostasis): vWF and platelet GpIb receptors mediate the adhesion of platelets to the injured endothelium by forming pseudopodia; phospholipid is expressed on cellular membranes.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

what factors of uninjured endothelium prevents hemostasis?

A

NO and prostacyclin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

what are the 3 main phases of hemostasis?

A
  • Vasoconstriction
  • Platelet plug formation
  • Blood coagulation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

what factors contribute to vasoconstriction due to endothelial injury

A
  • -Endothelial damage – vascular spasm
  • -Endothelin released from endothelial cells – vasoconstriction
  • -Thromboxane A2 released by platelets is a potent vasoconstrictor
  • -Serotonin released by activated platelets
  • -Adrenal glands release adrenaline– systemic vasoconstriction
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

what is the endothelin?

A

A peptide that plays a major role in vascular homeostasis by causing vasoconstriction and raising blood pressure. Three isoforms of endothelin (ET) are known: ET-1, ET-2, and ET-3.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

what is the bosentan?

A

A competitive antagonist of endothelin-1 at the endothelin receptor that decreases pulmonary vascular resistance. Commonly used for treatment of pulmonary arterial hypertension.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

what are the steps of vasoconstriction secondary to vascular injury?

A

A. Vascular injury triggers transient vasoconstriction through local neurohumoral factors
B. Platelets adhere to exposed ECM via vWF and are activated, undergoing a shape change and granule release. Released ADP and TXA2 lead to further platelet aggregation to form the primary hemostatic plug
C. Local activation of the coagulation cascade (involving tissue factor and platelet phospholipids) result in fibrin polymerization “cementing” platelets into a definitive secondary hemostatic plug.
D. Counter-regulatory mechanisms (release of t-PA and thrombomodulin) limit the hemostatic process to the site of injury.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

describe the activation and aggregation of platelets

A
  • -activation: release of adenine diphosphate (ADP), thromboxane, calcium, and platelet activating factor (PAF), which assist in platelet aggregation, vasoconstriction and degranulation
  • -Aggregation (hemostasis): mediated by GpIIb/IIIa-receptor and fibrinogen → formation of a white thrombus composed of platelets and fibrin
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

thrombotic plaques developed during platelet aggregation are stable and permanent. True/False

A

False

This plug is temporary, unstable, and easily dislodged.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

what is primary hemostasis?

A
  • involves platelet and vWF predominantly
  • goal? rapid cessation of bleeding
  • Vessel injury results in collagen (subendothelial) exposure and release of vasoconstrictors. Blood flow is slowed and platelets come into contact with damaged vessel wall.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

what are the 3 A’s of primary hemostasis?

A

1)Adhesion: platelets adhere to subendothelium via vWF(platelets have GP1b receptor that bind to vWF)
Platelet-collagen binding
2)Activation: Platelets contain protease activated receptors (PARS) that are activated via thrombin (a protease). This
results in change in shape of platelets, causing an intracellular signaling cascade, releasing intracellular calcium. This causes activated phospholipase A2 to release thromboxane A2.
TXA2 is a vasoconstrictor and causes platelet aggregation.
TXA2 reason there is a primary hemostatic plug
ADP is also released during platelet activation causing platelet aggregation
3)Aggregation: more platelets are recruited forming a localized hemostatic plug
(Platelets bind together via GPIIb/IIIa receptor and fibrinogen)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

what is the vWF?

A

circulating glycoprotein that is involved in the process of coagulation. It is produced in megakaryocytes, as well as in the endothelium and subendothelial connective tissue of blood vessels and stored in the Weibel-Palade bodies of endothelial cells and α-granules of platelets. vWF binds to free collagen, factor VIII, and the GP1b surface receptor of platelets. vWF mediates adhesion between platelets and the adhesion of platelets to exposed collagen fibrils of damaged blood vessels. It also prevents the breakdown of factor VIII.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

what is the G1pb

A

A glycoprotein that forms part of the receptor for von Willebrand factor on the endothelial lining. Mediates platelet adhesion. Deficiency of GpIb causes Bernard-Soulier syndrome.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

what is the platelet activation

A

release of adenine diphosphate (ADP), thromboxane, calcium, and platelet activating factor (PAF), which assist in platelet aggregation, vasoconstriction and degranulation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

what is the most important mediator of a primary hemostatic plug

A

TXA2
An arachidonic acid derivative and potent platelet aggregator and vasoconstrictor. Inhibition of thromboxane A2 synthesis in thrombocytes is responsible for aspirin’s antiplatelet effect.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

platelet aggregation is mediated by?

A

mediated by GpIIb/IIIa-receptor and fibrinogen → formation of a white thrombus composed of platelets and fibrin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

what is G1pb s GPIIb/3a?

A
  • adhesion vs aggregation

- platelet-endothelium vs platelet-platelet

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

what is the secondary hemostasis?

A

Platelet clot is reinforced by production of a fibrin clot, either by intrinsic or extrinsic pathway.
it is the coagulation cascade

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

what is the intrinsic pathway of hemostasis?

A

A part of the coagulation cascade that is initiated when collagen is exposed. Primarily consists of factors VIII, IX, XI, and XII. Activated mainly by thrombin. Impairment of this pathway results in bleeding disorders (e.g., hemophilia A and B).
Hemostasis and bleeding disorders

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

what is the extrinsic pathway of secondary hemostasis

A

A part of the coagulation cascade that is activated by injury to the endothelium. Consists of tissue factor (factor III) and factor VII. Impairment of this pathway results in bleeding disorders (e.g., factor VII deficiency).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

what is the most important factor of the extrinsic pathway?

A

VII

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

which factor initiates the intrinsic pathway?

A

XII

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

what are the steps of the extrinsic pathway?

A

or (factor III), which is present under the endothelium on fibroblasts, binds to and thus activates factor VII
Factor VIIa and tissue factor form a complex (TF-FVIIa)* that activates factor X and factor IX.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
33
Q

what are the steps of the intrinsic pathway?

A

Thrombin activates factors XI and factor VIII.
Factor XIa activates factor IX
Factors VIIIa and IXa form a complex* that activates factor X.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
34
Q

what is the role of factor VIII?

A

it is bound to vWF and is released during primary hemostasis. Activated by thrombin and acitvates factor X

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
35
Q

what is the tissue factor?

A

A protein that is found in the cytoplasm of vascular endothelial cells, on the surface of fibroblasts in the subendothelium of blood vessels, and within leukocytes. Tissue factor is involved in the extrinsic pathway of the coagulation cascade. Damage to blood vessels results in the release of tissue factor, which binds to circulating factor VII and allows its activation. The complex of activated factor VII (VIIa) and tissue factor can then activate factor X of the common pathway in the coagulation cascade.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
36
Q

what is the role of factor XII

A

Factor XII is a coagulation cascade factor that activates the kallikrein system and leads to the production of bradykinin. Can be activated by bacterial endotoxins.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
37
Q

what are the steps of common pathway of hemostasis?

A
  • -Factor Xa and factor Va form a complex* that cleaves prothrombin to thrombin (= factor II).
  • -Thrombin cleaves fibrinogen (factor I) into insoluble fibrin (factor Ia) monomers.
  • -Cross links of the fibrin network are stabilized by factor XIIIa → formation of a fibrin network → fibrin closely binds to the platelet plug, forming a stable fibrin clot (secondary or red thrombus)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
38
Q

factor V is activated by…

A

thrombin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
39
Q

Crosslinks of the fibrin network are stabilized by factor

A

XIIIa

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
40
Q

what electrolyte is a must for coagulation cascade?

A

The coagulation cascade requires the presence of calcium ions (factor IV)!

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
41
Q

what are the factors of the extrinsic pathway?

A

A helpful way of remembering the coagulation factors of the extrinsic pathway is 3 + 7 = 10. Factor III and factor VII form a complex to activate factor X of the common pathway.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
42
Q

what are the factors of the common pathway?

A

A helpful way of remembering the coagulation factors of the common pathway is 1 x 2 x 5 = 10. Factors Xa and Va form a complex that cleaves prothrombin (II) to thrombin (IIa). Factor IIa then cleaves fibrinogen (I) into insoluble fibrin monomers (Ia).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
43
Q

anticoagulation is mediated by what factors?

A

a. thrombomodulin
binds to thrombin and converts it from a procoagulant into an anti-coagulant via its ability to activate protein C.
Protein C inhibits clotting by inactivating factors Va and VIIIa. Protein S (cofactor for protein C)
b. tissue pathway factor inhibitor
Directly inhibits tissue factor-factor VIIa and factor Xa activities.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
44
Q

what factors are inhibited by protein C?

A

forms the activated protein C complex together with its cofactor protein S (APC complex) → inhibition of factors Va and VIIIa → inhibition of coagulation cascade
Produced in the liver; synthesis requires vitamin K
Shorter half-life than the other coagulation factors dependent on vitamin K
Clinical relevance: APC resistance; treatment with vitamin K antagonists

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
45
Q

what is the antithrombin III

A

One of the most important physiological inhibitors of hemostasis. Degrades thrombin and other coagulation factors (factor IXa and Xa) and activates tissue plasminogen activator (tPA).
Clinical relevance: The efficacy of antithrombin may be affected by various factors (it is increased by unfractionated heparin and decreased in states of impaired hepatic and kidney function.)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
46
Q

what is the tPA

A

A serine protease found on endothelial cells of the blood vessels. Catalyzes the conversion of plasminogen to plasmin, which is the main enzyme responsible for clot breakdown. Recombinant tissue plasminogen activators (e.g., alteplase, reteplase, tenecteplase) are used as thrombolytics in patients with acute coronary syndrome, pulmonary embolism, or ischemic stroke.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
47
Q

what are the steps of fibrinolysis?

A

–Tissue injury → release of factor XII , urokinase and tissue plasminogen activator (tPA)
→ Breakdown of plasminogen, leading to the formation of active plasmin → breakdown of fibrin by activated plasmin
→ Release of degradation products, including D-dimers
–Regulation of fibrinolysis: tPA activity is reduced if tPA binds to plasminogen activator inhibitor (PAI).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
48
Q

what is the D-dimer

A

fibrin degradation product released when plasmin cleaves crosslinked fibrin. Increased serum concentrations of D-dimer indicate recent intravascular coagulation and/or fibrinolysis (e.g., from deep vein thrombosis, pulmonary embolism, disseminated intravascular coagulation).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
49
Q

what are the fibrinolytic effects?

A

Once healing is initiated, clot dissolution via action of fibrinolytic system.
Endothelial cells synthesize tissue type plasminogen activator (t-Pa).
• It cleaves plasminogen to form plasmin. Plasmin then cleaves fibrin to degrade thrombi.
• Plasmin lyses clot form fibrinogen degradation products (such as D-dimer)
• tPA is inhibited by Plasminogen Activator Inhibitor

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
50
Q

what is the thrombomodulin

A

Thrombomodulin functions as a cofactor in the thrombin-induced activation of protein C in the anticoagulant pathway by forming a 1:1 stoichiometric complex with thrombin. This raises the speed of protein C activation thousandfold.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
51
Q

what is the Hageman factor?

A

factor XII

activated by negatively charged surfaces (glass)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
52
Q

what factor activates plasmin?

A

XII

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
53
Q

deficiency of factor XI results in?

A

hemophilia C

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
54
Q

deficiency of factor IX cause what type of hemophilia

A

hemophilia B

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
55
Q

Hemophilia A is caused by a deficiency of what factor?

A

factor A

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
56
Q

how intrinsic vs extrinsic pathways are activated?

A

The intrinsic pathway is activated by exposing factor XII to thrombogenic surfaces whereas extrinsic pathway requires exogenous trigger (provided originally by tissue extracts).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
57
Q

what is the initiation of the coagulation cascade?

A
  • Initiation – TF (thromboplastin) + Factor VII
  • VIIa – high affinity bind with TF
  • Results in activation of IX and X
  • Xa with its cofactor Va generates a small burst of thrombin
  • Not sufficient to generate large amounts of fibrin
  • Thrombin back-activates to amplify process
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
58
Q

what is the amplification of the coagulation cascade?

A
  • Thrombin burst back-activates FV, FVIII, FXI
  • FXIa activates FIX
  • FIXa complexes with FVIII (Haemophilia A)
  • FIXa-FVIIIa – tenase(intrinsic) complex
  • Tenase complex further activates FX
  • FXa complexes with FVa – Prothrombinase complex
  • Explosive generation of thrombin leading to clot formation
  • These reactions occur on a phospholipid bearing surface – cell membrane
  • In general reactions take place on the surface of activated platelets
  • The product of one reaction becomes the enzyme in the next reaction
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
59
Q

what is the tenase?

A

In coagulation, the procoagulant protein factor X can be activated into factor Xa two ways; extrinsically or intrinsically.
The activating complexes are called tenase.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
60
Q

what are the components of extrinsic vs intrinsic tenase complex?

A

Extrinsic tenase complex is made up of tissue factor, factor VII, and Ca2+ as an activating ion.
Intrinsic tenase complex contains the active factor IX (IXa), its cofactor factor VIII (VIIIa)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
61
Q

describe the extrinsic pathway

A
  1. activated in the case of tissue injury
  2. is only factor seven (VII) which gets activated by tissue factor
  3. Tissue factor then that activates factor 10
  4. Factor 10 activates factor 5
  5. Factor 5 activates factor 2 which is prothrombin(the inactive name of thrombin is prothrombin).
  6. Factor 2a then activates factor 1 which is fibrin (the inactive name of fibrin is fibrinogen).

    So both pathways aim to eventually activate factor 10 which then activates 5, 2, and 1 to form fibrin at the end
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
62
Q

describe the intrinsic pathway

A
  1. Factor 12 activates factor 11.
  2. Factor 11 activates factor 9.
  3. Factor 9 then form an active complex with factor 8 called the tenase complex.
  4. That complex activates factor 10.
  5. Factor 10 activates factor 5.
  6. Factor 5 activates factor 2 which is thrombin(the inactive name of thrombin is prothrombin).
  7. Factor 2 then activates factor 1 which is fibrin (the inactive name of fibrinogin is prothrombin).
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
63
Q

both the extrinsic and intrinsic pathways eventually aim to activate what factor?

A

both pathways aim to eventually activate factor 10 which then activates 5, 2, and 1 to form fibrin at the end

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
64
Q

what lab tests are used to evaluate coagulation pathway

A
  • Prothrombin Time (PT)
  • Activated Partial Thromboplastin Time (APTT)
  • Fibrinogen
  • D-Dimer
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
65
Q

what is the Prothrombin time?

A

An assay that evaluates the extrinsic and common pathways of the coagulation cascade (measures activity of factors I, II, V, VII, and X). Used to evaluate coagulation disorders and to monitor the effect of warfarin. The normal range is 11–15 seconds.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
66
Q

prothrombin time is used to evaluate what pathways?

A
  • It is used to monitor the functioning of the extrinsic and the common pathways.
  • Sample collected + citrate added (anticoagulant) - centrifuge to separate platelet-poor plasma
  • Add Ca2+, phospholipid + thromboplastin + measure time to form fibrin clot (in secs) at 37°C
  • Normal PT is 12-15 seconds.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
67
Q

what are the ingredients used in prothrombin time?

A

Ca2+, phospholipid + thromboplastin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
68
Q

what factors are evaluated by PT

A

I, II, V, VII, and X

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
69
Q

what are the factors that prolong PT

A 
Liver disease
Vitamin K deficiency
Warfarin
Rivaroxaban*
Low Fibrinogen
70
Q

why vit K deficiency results in prolonged PT

A

vit K is important for synthesis of factors X, IX, VII, II (1972), so as you see severe deficienc of vit K will prolong also PTT because factors invloved in common pathway are also affected (factor VII has the shortest half-life so affected first)

71
Q

why warfarin prolong PT?

A

A vitamin K antagonist that inhibits hepatic epoxide reductase, thereby blocking synthesis (recycling) of the active, reduced form of vit. K. Without reduced vit. K, γ-carboxylation of glutamate residues cannot occur, which reduces the production of active coagulation factors II, VII, IX, and X, as well as anticoagulatory proteins C and S. Typically administered in patients with artificial heart valves, increased risk of deep vein thrombosis and pulmonary embolism, and/or valvular A-fib.

72
Q

what is the aPTT

A

An assay that evaluates the intrinsic and common pathways of the coagulation cascade (measures activity of factors XII, XI, X, IX, VIII, V, II, and I). Used to evaluate coagulation disorders and to monitor the effect of heparin. Normal range is 25–40 seconds.

73
Q

what factors are evaluated by aPTT

A

Fibrinogen, II, V, VIII, IX, X, XI, XII

74
Q

what pathways are evaluated by aPTT?

A

Activated partial thromboplastin time (aPTT)
• It is used to monitor the functioning of the intrinsic and the common coagulation pathways.
• Normal aPTT is 24-38 seconds.
• Platelet poor plasma at 37°C
• Coagulation activated by kaolin calcium added  time taken for clot to form is recorded

75
Q

what are the reasons for aPTT prolongation

A

VWF deficiency
Liver Disease
Low Fibrinogen
Lupus Anticoagulant

76
Q

why vWF prolong aPTT if it is involved in platelet adhesion?

A

because VWF carries factor VIII in blood!!!!!!!!!!!! exam question

77
Q

what is the thrombin time?

A

–Measures the time it takes for fibrin polymers to form after adding thrombin
–Only common pathway
Fibrinogen
–Formation of fibrin polymers

78
Q

TTI is dependent on?

A

adequate fibrinogen levels.

79
Q

TT is used for?

A

Detect fibrinogen deficiency

Monitoring of heparin therapy and fibrinolytic therapy (alternative for aPTT)

80
Q

what is the D-dimer

A

Fibrin degradation products (FDPs)= D-dimer
• They are used to assess the fibrinolytic activity and they are increased in disseminated
intravascular coagulation (DIC), indicating fibrinolysis.
Thrombin converts fibrinogen to fibrin. Fibrin monomers polymerize. Factor XIII forms a fibrin clot by linking 2 D-domains. Plasmin cleaves fibrin to produce D-dimers.
• Useful test in excluding venous thrombosis- high negative predictive value
NB: does not have a high positive predictive value (can be elevated for many reasons such as inflammatory disorder as well as thrombosis)
• The normal value increases with age

81
Q

DD has a high positive predictive value. True/False

A

False
Useful test in excluding venous thrombosis- high negative predictive value
NB: does not have a high positive predictive value (can be elevated for many reasons such as inflammatory disorder as well as thrombosis)

82
Q

why fibrinogen levels are decreased in DIC?

A

DIC, also called consuption couagulopathy, it is consumpted by fibrin cloths

83
Q

what is the rivaroXaban?

A

An orally administered anticoagulant that directly and selectively inhibits factor Xa.
it is used to treat deep vein thrombosis and pulmonary emboli and prevent blood clots in atrial fibrillation and following hip or knee surgery.

84
Q

what is the Weibel Palade body?

A

A storage granule found in endothelial cells. Contains von Willebrand factor and selectins (e.g., P-selectin).

85
Q

VWF is stored in?

A

platelet alpha-granules and Weibel Palade bodies

86
Q

vWF binds to?

A
  • Contains binding sites for fibrinogen (factor I), collagen and platelets (GP1b)
  • After vascular injury vWF binds to the exposed collagen – become unwound exposing more binding sites and binds fibrinogen and platelets
87
Q

what is the most common bleeding disorder?

A

VWD

88
Q

how VWD is inherited?

A

Autosomal Dominant

89
Q

what manifestations commonly lead to the diagnosis of VWD in a woman?

A

menstrual bleeding or peripartum bleeding

90
Q

what are the features of vWD?

A
  • -Mostly asymptomatic
  • -Symptomatic patients:
    1) Ecchymosis (esp. mucosal hemorrhages) → from the reduced half-life of factor VIII
    2) Petechial hemorrhages in severe cases → caused by impaired platelet aggregation
    3) Other symptoms include epistaxis, gingival bleeding, menorrhagia, GI bleeding, and excessive bleeding during surgical procedures.
91
Q

How vWD is diagnosed?

A

1) Prolonged bleeding time and sometimes prolonged activated partial thromboplastin time (aPTT)
2) ↓ Factor VIII levels
3) vWF-specific measurements
- –Quantitative assessment by vWF antigen assay: ↓ factor levels
- –Qualitative assessment by a collagen or glycoprotein Ib binding assay, or a ristocetin cofactor activity assay
- Ristocetin normally activates vWF to bind to glycoprotein Ib
- Failure of aggregation with a ristocetin assay or a ristocetin cofactor level < 30 IU/dL is considered definitive for vWD

92
Q

what is the ristocetin test?

A

An antibiotic used for platelet aggregation tests. Activates von Willebrand factor to bind glycoprotein Ib, thereby inducing platelet aggregation. Failure of aggregation occurs in conditions such as von Willebrand disease and Bernard-Soulier syndrome.

93
Q

how vWD is treated?

A
  • -Recombinant von Willebrand factor (rVWF) concentrate
  • -Desmopressin: Stimulates vWF release from endothelial cells.
  • -Other treatment options: factor VIII concentrates ; oral contraceptives in cases with menorrhagia; antifibrinolytic drugs (i.e., aminocaproic acid, tranexamic acid)
  • -Avoid aspirin, NSAIDS, and intramuscular injections
94
Q

what are the types of vWD?

A
  • Type 1- partial deficiency (Autosomal dominant)
  • Type 2- variety of defects in multimers – qualitative defect
  • Type 3 – virtually absent vWF (mimics haemophila A, autosomal recessive)
95
Q

Desmopressin is helpful in all types of vWD. True/False

A

False
It is of no use in complete vWF deficiency (type 3) because it only causes the release of stored vWF. It may be used in type 1 and in some patients with type 2.

96
Q

how Hemophilia A and B are inherited

A

X-linked recessive so mainly boys are affected

97
Q

how the severity of hemophilia A is classified?

A

is based on Factor VIII level
• <1% severe
• 1-5% moderate
• 6-50% mild

98
Q

what is the Christmas disease?

A

Hemophilia B

99
Q

do female carriers have bleeding manifestations?

A

no or mild symptoms (due to skewed X-inactiation)

100
Q

define hemophilia A

A

An X-linked recessive disease that results in the deficiency of factor VIII. Most often presents in boys with recurrent episodes of epistaxis, bruising, and/or hemarthrosis. Lab studies show normal platelet counts, BT, PT, but prolonged aPTT.

101
Q

what factor is deficient in Hemophilia A?

A
  • Factor VIII is made predominantly in the liver
  • Circulates bound to vWF – inactive in this form
  • Tissue injury occurs – then dissociates from VWF and becomes active – FVIIIa
  • FVIII interacts with Factor FIX
  • Dysfunctional Factor VIII or reduced amount of FVIII
  • Factor VIII gene Xq28
102
Q

factor VIII is synthesized in…

A

liver

103
Q

factor VIII bound to vWF is active or inactive

A

inactive

104
Q

what mutations are responsible for hemophilia A

A

1) The severe variant of hemophilia A is caused due to an inversion of the intron 22 sequence involving the X chromosome that completely abolishes the synthesis of factor VIII (50% of severe Haemophilia A cases). Other mutations include deletions and point mutations.
2) A rarer mechanism for Factor VIII deficiency is the development of antibodies (inhibitors) to Factor VIII – accelerates clearance of Factor VIII from circulation.

105
Q

what are the clinical features of Hemophilia A

A

1) Spontaneous or delayed onset bleeding (joints, muscular and soft tissue, mucosa) in response to different degrees of trauma
- -Repeated hemarthrosis → joint destruction
2) Further sites/symptoms of hemorrhage:
- -CNS (e.g., headache, neck stiffness)
- -Gastrointestinal tract (e.g., melena, hematemesis)
- -Genitourinary system (e.g., hematuria)
- -Oral mucosa bleeding, epistaxis, excessive bleeding following small procedures (e.g., dentist procedures)
- -Female carriers may show mild symptoms.

106
Q

what are the laboratory findings in hemophilia A?

A

1) Screening
- -Prothrombin time: normal
- -Platelet count: normal
- -Activated partial thromboplastin time (aPTT): usually prolonged
2) If aPTT prolonged → mixing study
3) If mixing study is positive (or if patient/family history are strongly positive) → quantitative assessment of factor activity levels

107
Q

what is the mixing study?

A

First, measure the aPTT of the patient’s blood. Then, mix the patient’s plasma with external plasma that is known to contain sufficient clotting factors and measure the resulting aPTT. If the patient suffers from hemophilia, the aPTT will be corrected in the sample with the external plasma.

108
Q

how Hemophilia A is treated?

A

1) Substitution of clotting factors
- -Mild or moderate hemophilia: when needed (e.g., trauma or surgery)
- -Severe hemophilia: prophylactic (additional substitution may be needed in, e.g., trauma)
2) Desmopressin
- -Indication: mild hemophilia A
- -Synthetic analog of vasopressin
3) Antifibrinolytic therapy (e.g., ε-Aminocaproic acid, tranexamic acid): used in addition to factor substitution (e.g., if surgery is performed in the oral cavity)

109
Q

what os the CI for antifibrinolytic therapy in bleeding disorders?

A

Antifibrinolytic therapy is contraindicated in patients with hematuria (usually macroscopic) due to the formation of blood clots in the urinary tract.

110
Q

if patient with Hemophilia develops antibodies to factor VIII, what factor should be replaced?

A

VIIa,

to bypass factor VIII activation of X

111
Q

what medications should be avoided in patients with Hemophilia A?

A

aspirin, NSAIDs, clopidogrel,

112
Q

what is tranexamic acid?

A

A synthetic lysine analog and inhibitor of plasminogen with antifibrinolytic action. Indicated in the treatment of excessive blood loss from major trauma, menorrhagia, acute AUB, postpartum bleeding, surgery, dental procedures, and epistaxis. Side effects include changes in color vision, thromboembolic events, and anaphylaxis.
• Very cheap and useful medication
• Given IV or PO
• Lysine analog
• Binds to lysine receptors on plasminogen
• Reduces conversion of plasminogen to plasmin
• Reduces degradation of fibrin
• Reduces mortality if given <3 hours of major trauma
• NB – relatively contraindicated in haematuria or prior thrombosis

113
Q

what is the reason for inadequate hemostasis in the case of thrombocytopenia?

A

there is an ability to form an adequate platelet plug

114
Q

define thrombocytopenia

A

Thrombocytopenia is defined as counts < 100,00 uL, but spontaneous bleeding does not occur until platelet numbers < 20,000 uL. Counts between 20,000-50,000 uL can exacerbate posttraumatic haemorrhage.
Most spontaneous bleeds involve small vessels of the skin and mucous membranes.

115
Q

what are the causes of thrombocytopenia?

A
  • -decreased productiondue to ineffective megakaryopoiesis (eg. HIV, myelodysplastic syndromes) or to generalised bone marrow disease that compromises megakaryocyte number (aplastic anaemia, disseminated cancer so secondary to cancer).
  • decreased survival due to increased consumption(DIC), or to immune-mediated platelet destruction (immune complex deposition on platelets).
  • sequestration in red pulp of enlarged spleen
  • dilution due to massive transfusions
116
Q

at what platelet count bleeding usually occurs?

A

count is <30 x 109/L
• Spontaneous bleeding rare unless platelet count <1010/L
• Other factors may alter this: Aspirin, Anticoagulants, NSAIDs, Trauma, Renal Failure, Liver Failure

117
Q

what is the ITP?

A
  • an immune-mediated attack (usually IgG antiplatelet antibodies) against platelets leading to decreased platelets (thrombocytopenia).
    This results in petechiae, purpura (bruises), and a bleedingdiathesis (e.g., hematomas).
  • classically presents with a petechial rash – often lower limbs – or with mucocutaneous bleeding
118
Q

what are the causes of ITP?

A
  • -Primary (acute) ITP: inciting factors such as viral infection that causes an autoimmune reaction. It resolves over weeks with little or no intervention
  • -Secondary ITP: associated with lymphoma, leukemia, SLE, HIV, HCV. Usually seen in women in their childbearing years and can be the first manifestation of systemic lupus erythematosus (SLE).
119
Q

what is the pathophysiology of ITP?

A

antiplatelet antibodies against platelet antigens such as GPIIb-IIIa and GPIb-IX (type II hypersensitivity reaction). The antibodies are made in the spleen, and the platelets are destroyed peripherally in the spleen by macrophages.

120
Q

what are the lab findings in ITP?

A

Lab studies usually show decreased platelet count and prolonged bleeding time but normal prothrombin time and partial thromboplastin time. Peripheral bloodsmear shows thrombocytopenia with enlarged immature platelets (megathrombocytes).
Bone marrow biopsy shows increased numbers of megakaryocytes with immature forms.

121
Q

in ITP PT and PTT are prolonged. True/False

A

False

Only BT as it does not involve coagulation cascade

122
Q

what is the treatment of ITP?

A

Treatment is corticosteroids, which decrease antibody production; immunoglobulintherapy, which floods Fc receptors on splenic macrophages; and/or splenectomy,

123
Q

what infections should be screened in case of secondary ITP?

A

HIV and HCV

124
Q

what is the etiology of ITP?

A
  • F>M
  • Onset in adulthood - 30s-40s
  • Incidence 1/10,000
  • Isolated thrombocytopenia in a well patient
  • Normal Hb and WCC count
  • Asymptomatic apart from bleeding symptoms
  • May arise secondary to infection (HIV), Drugs (quinine), coexisting autoimmune disease (SLE), lymphoma, immunodeficiency syndromes (CVID)
  • Bone marrow morphology is normal or may show increased megakaryocytes
  • Autoimmune disorder – antiplatelet antibodies are present in most cases
  • Treatment not indicated unless platelets <20-30*9/L
125
Q

what can cause ITP?

A

quinine

126
Q

which monoclonal antibody can be used in the treatment of severe or refractory ITP

A

Rituximab-kills B cells–no antibody production against platelets
• Treated with immunosuppression
• Steroids
• Intravenous immunoglobulin
• Rituximab
• Splenectomy results in longterm remission in about 60-70% of cases

127
Q

what are the medications that can cause bleeding?

A

• Aspirin
• Clopidogrel
• Warfarin
• DOACs
1. Anti-X agents – apixaban, rivaroxaban, edoxaban
2. Direct-thrombin inhibitors - dabigtran

128
Q

what is the clopidogrel?

A

A P2Y12 receptor antagonist that blocks platelet aggregation. It is used in the treatment of acute coronary syndrome and peripheral arterial disease as well as in the prevention of ischemic stroke (ADP usually binds to P2Y12 receptors, leading to activation of Gp IIb/IIIa receptors and subsequent platelet aggregation.)

129
Q

what are the uses of oral anticoagulants?

A
  • Primary treatment of venous thrombosis
  • Prevention of stroke and systemic thrombo-embolism
  • 70% - Atrial Fibrillation
  • 20% treatment of and prevention of recurrence of venous thrombosis
  • 10% other – valvular heart disease/replacement, peripheral vascular disease
130
Q

what is the risk of bleeding with oral anticoagulants?

A
  • Major Bleeding – approx 2% of patients/yr– hospitalisation for transfusion, procedure or >2g drop in Hb
  • Minor bleeding – e.g. epistaxis – 10-15% per year
  • Highest mortality – ICH (Intracranial Haemorrhage) – 50% - approx.. 10-20% of all major bleeds
  • Latest data suggests lower ICH rate with newer OACs (DOACs) over warfarin
  • Possible increased risk of GI bleeding with DOACs
131
Q

in contrast to warfarin, newer oral anticoagulants have increased risk of bleeding from where?

A

GIT

132
Q

what are the4 anti-Xa agents

A
  • ApiXaban, RivaroXaban, EdoXaban (all contain Xa in the name!!)
  • Oral – Apixaban BD, others OD
  • Short half-lives – 12-14 hours
  • Renal route of excretion – therefore caution and dose adjustment in renal impairment
  • Concentration affected by CYP inhibitors/inducers
  • Rivaroxaban prolongs PT
  • Routine monitoring not available
133
Q

what is the disadvantage of newer oral anticoagulants?

A

in cases of overdose, there is no antidote

134
Q

do newer anticoagulants require lab parameter monitoring?

A

NO (vs heparin or warfarin)
studies have demonstrated a correlation between the levels of rivaroxaban and PT through inhibition of factor Xa, but not to the same extent as warfarin.

135
Q

what medications affect anti-Xa concentrations in blood?

A 
The most common form of drug interaction results from the induction of the cytochrome P450 enzyme system. 
CYP induction increases the rate of metabolism of the substrate, while CYP inhibition decreases it
Common CYP inducers are
--prednisolone
--Carbamazepine
--Rifampicin
--St. John's Wort
--Griseofulvin
--Isoniasid
--antiepileptic drugs
136
Q

what are the direct thrombin inhibitors?

A
  • Dabigatran
  • Oral agent - BD dosing
  • Renal excretion – needs dose adjustment/caution in renal impairment
  • Prolongs Thrombin Time
  • Variably prolongs APTT but not PT
137
Q

does dabigatran prolong PT?

A

no,

prolong aPTT

138
Q

what is the warfarin?

A
  • Vitamin K antagonist (coumarins)
  • Warfarin inhibits Vitamin K epoxide reductase(VKORC) – required to form active Vitamin K
  • Prevents gamma-carboxylation of glutamic acid residues of Factors II, VII, IX, X
  • Also inhibits production of anticoagulant proteins – proteins C and S
  • Long-half life – 2-3 days
  • Takes 4-5 days to reach therapeutic level – oral – OD
  • Dose adjusted according to a blood test called INR – International Normalised Ratio
  • NB – Teratogenic – absolutely contraindicated in the first trimester
139
Q

what is the absolute contraindication of warfarin?

A

pregnancy

140
Q

how does warfarin work?

A

Inhibit hepatic vitamin K epoxide reductase → ↓ hepatic synthesis (recycling) of the active, reduced form of vitamin K → ↓ γ-carboxylation of glutamate residues on coagulation factors II, VII, IX, and X

141
Q

what factors are affected by warfarin?

A

X, IX, VII, II (1972)

142
Q

does warfarin inhibit anticoagulant factors also?

A

yes

Also inhibits production of anticoagulant proteins – proteins C and S

143
Q

warfarin has a short half-life. True/False

A

False
Long-half life – 2-3 days
• Takes 4-5 days to reach therapeutic level – oral – OD

144
Q

what lab parameter is used to monitor warfarin?

A

INR

145
Q

`what is the antidote in case of warfarin overdose

A 
vit K (takes days for effect)
PCC (prothrombin con=mplex concentrate) forimmediate reveral of bleeding
146
Q

what is the antidote for dabigatran?

A

Idarucizumab

A monoclonal antibody that is used to reverse the effects of the anticoagulant dabigatran.

147
Q

what are the antidotes for anti-Xa oral anticoagulants

A

tranexamic acid, PCC and andexanet

148
Q

what is the andexanet?

A

A modified, inactive form of human factor Xa that binds to factor Xa inhibitors, such as rivaroxaban and apixaban, to reverse their anticoagulant effects (e.g., in patients who have life-threatening or uncontrolled bleeding). Also inhibits tissue factor pathway inhibitor to increase thrombin generation.

149
Q

what is the DIC

A

A condition characterized by systemic activation of the clotting cascade, platelet consumption, and subsequent exhaustion of clotting factors that leads to widespread thrombosis and hemorrhage. Often associated with trauma, shock, and sepsis.

150
Q

DIC is always a secondary condition. True/False

A

True
It is a secondary complication in a variety of diseases. It is triggered by two main mechanisms:
1. Release of tissue factor or thromboplastic substances into circulation
2. Wide-spread endothelial injury

151
Q

what are the thermoplastic substances that trigger DIC?

A

Thromboplastic substances can be derived from: placenta/amniotic fluid/ damaged tissue following trauma, burns, surgery.

152
Q

how sepsis leads to DIC?

A

In sepsis, bacterial endotoxins activate monocytes to release TNF-a – activation of clotting system and inhibition of coagulation control.

153
Q

how endothelial injury cause DIC?

A

Endothelial injury initiates DIC by causing tissue release factor from endothelial cells, promoting platelet aggregation and activating intrinsic coagulation pathway by exposing subendothelial connective tissue.

154
Q

what leukemia can result in DIC?

A

Acute Promyelcytic Leukemia due to release of procoagulant activity from leukemic cells

155
Q

how snakebite causes DIC?

A

Venom may contain thrombogenic enzymes that promote the formation of a fibrin clot, which in turn activates plasmin and results in consumptive coagulopathy.

156
Q

• DIC is evidence for the simultaneous presence of:

A

– Thrombin(procoagulation)

– plasmin(fibrinolysis)

157
Q

what are the presentations of DIC?

A

– an acute hemorrhagic disorder
– an indolent, subacute thrombotic disorder
• Not a primary diagnosis
• Secondary phenomenon
The clinical features of DIC may appear acutely (e.g., following trauma, sepsis), or may appear subacutely (e.g., DIC following malignancy)!

158
Q

what are the characteristic lab findings of DIC?

A

1) Thrombocytopenia → ↑ bleeding time
2) ↑ Markers of fibrin breakdown (D-dimer, or FDP)
3) ↑ PT and APTT
4) ↓ Fibrinogen levels
5) ↓ Antithrombin
6) ↓ Hematocrit
7) Schistocytes (In the case of DIC, schistocytes (fragmented erythrocytes) are seen in association with microangiopathic hemolytic anemia.)

159
Q

what is the venous thrombosis?

A

Thrombus formation and subsequent inflammatory response in a superficial or deep vein.

  1. Superficial thrombophlebitis
  2. Deep vein thrombosis
  3. Pulmonary embolism
    - Deep vein thrombosis is the commonest cause of pulmonary thromboembolism.
    - The thrombi propagate in direction of blood flow (more common in lower extremity).
160
Q

what is Virchow’s triad?

A
  1. Endothelial damage (changes in vessel wall)
    - exposes endothelium to promote hemostasis
  2. Venous stasis (reduced/altered blood flow)
    - immobilization (post-MI, CHF, stroke, post-operative) inhibits clearance and dilution of coagulation factors
  3. Hypercoagulability (alterations in blood constituents- prothrombotic changes)
161
Q

venous thrombosis can be inherited. True/False

A

True

- inherited or acquired (age/surgery/trauma/neoplasms) or idiopathic

162
Q

what is the mortality of PE (pulmonary embolism?)

A
  • DVT: PE – 2:1

* PE fatal in approximately 5-10% of cases within 1 month of diagnosis and DVT 2.5-5%

163
Q

what are the clinical features of DVT and PE

A
  • DVT – pain, swelling, erythema,+ Homan sign

* PE – shortness of breath, chest pain, tachycardia, tachypnoea, haemoptysis

164
Q

what are the causes of venous stasis?

A

Immobility
travel
trauma
surgery

165
Q

what are the prothrombotic states

A 
Cancer
age
pregnancy and OCPs
genetic thrombophilia
APS
trauma
myelophroliferative disorders
166
Q

what is the Well’s score of DVT?

A

A scoring system used to estimate the risk of deep vein thrombosis (DVT). Includes medical history (presence of active cancer, history of previous DVT), history of immobilization (paralysis or recent immobilization of a lower extremity, recent history of major surgery of remaining bedridden), and clinical symptoms (localized tenderness along the deep venous system, leg swelling, asymmetrical calf swelling, unilateral pitting edema, and presence of collateral, non-varicose superficial veins).

167
Q

what are the hereditary thrombophilias?

A

The hereditary thrombophilias are a group of inherited conditions that predispose to thrombosis. Examples are protein C, protein S, and antithrombin resistance or deficiency

168
Q

what is the thrombophilia?

A

An inherited or acquired state in which an individual is predisposed to forming blood clots. This most often manifests as recurrent deep vein thromboses or pulmonary emboli. Etiologies include conditions of inherited thrombophilia (e.g., factor V Leiden mutation), malignancy, pregnancy and the puerperium, various drugs (e.g., oral contraceptives, tamoxifen), and immobilization.

169
Q

what are the common hereditary causes of thrombophilia?

A
  • -Factor V Leiden (most common genetic cause of –hypercoagulability in the white populations)
  • -Protein C deficiency
  • -Protein S deficiency
  • -Antithrombin III deficiency
  • -Prothrombin G20210A mutation
170
Q

what are the common acquired causes of thrombophilia?

A
  • -Pregnancy
  • -Advanced age
  • -Smoking
  • -Obesity
  • -Surgery
  • -Immobilization
  • -Trauma
  • -Malignancy (especially adenocarcinoma)
  • -Antiphospholipid syndrome
  • -Nephrotic syndrome
  • -Oral contraceptive pills (OCPs)/hormone replacement therapy (HRT)
  • -Systemic lupus erythematosus (SLE)
  • -Heparin-induced thrombocytopenia
171
Q

how venous thromboembolism is managed?

A

1) reduce risk factors (smoking, OCPs)
2) anticoagulation
- -heparin+warfarin
- -new anticoagulants (anti-Xa or thrombin inhibotors)
- -3-6 months if provoked

General Pathology (9 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions