Coagulation and Fibrinolysis Flashcards
1
Q
“stoppage of blood flow”
A
Hemostasis
2
Q
hemostasis involves what
A
blood vessels, platelets, coagulation mechanisms, fibrinolysis and tissue repair
3
Q
Purpose of hemostasis
A
• Ensure that coagulation mechanisms are: ® Activated upon injury/Not necessarily activated
• Restore tissue blood flow after repair of injury (fibrinolysis)
• Simply put, the purpose of hemostasis is to stop bleeding.
® Continuous bleeding will mean low amount of circulating blood in the body which can lead to hypovolemic shock and eventually death
4
Q
Balance of hemostasis includes
A
Balance between coagulation and fibrinolysis, with platelets at the fulcrum
5
Q
An imbalance towards fibrinolysis means
A
Bleeding disorders
6
Q
Three hemostatic components
A
Extravascular (Surrounding tissue outside the blood vessel)
Intravascular (everything in the vessels, most importantly the platelets and procoagulants; Involved in coagulation (clotting/thrombus formation) and fibrinolysis (clot dissolution))
Vascular (vessels through which the blood flows)
7
Q
[Three hemostatic components]
• Provides back pressure on the injured vessel via swelling and trapping of escaped blood.
• Increased tissue pressure tends to collapse venules and capillaries.
A
Extravascular component
8
Q
Factors affecting ability to aid hemostasis
A
• Bulk or amount of supporting tissue
§ muscular back pressures in thigh vs scalp
• Type of tissue
§ Skeletal muscles= more absorbent > LCT
• Tone of the tissue
§ Elasticity decreases with age, making older people more prone to bleeding
9
Q
The role played by the vascular components involve:
A
- Size
- Amount of smooth muscle within their walls
- Integrity of the endothelial cell lining
10
Q
Part of blood vessel which control for blood flow rate and pressure via constriction and dilatation of blood vessels
A
Smooth muscles
11
Q
Part of blood vessels whose secretions contribute to normal blood flow and prevent abnormal formation of clots
A
Endothelial and subendothelial cells
12
Q
Part of blood vessels which are anti-thrombotic; does not activate platelets or promote coagulation.
A
Intact endothelial linings
13
Q
Sequelae of vessel injury
A
- Vasoconstriction due to neurogenic response
- Exposure of collagen to the protein von Willebrand factor due to endothelial lining breakage
- Platelets adhere to von Willebrand Factor to form a thrombus.
- Collagen exposure activates the intrinsic coagulation pathway (contact phase of coagulation)
- Release of tissue thromboplastin from an injured vessel promotes the extrinsic coagulation pathway
14
Q
[hemostatic mechanisms]
response of the coagulation processes
A
Secondary hemostasis
15
Q
[hemostatic mechanisms]
vascular and platelet response to injury
A
Primary Hemostasis
16
Q
Basic Sequence of Events after Vessel Injury
A
- Vasoconstriction
- Platelet adhesion
• Adhesion to exposed subendothelial connective tissue - Platelet aggregation
• Interaction and adhesion of platelets to one another to form initial plug at injury - Fibrin-platelet plug formation
• Coagulation factors interact on platelet surface to produce fibrin
• Fibrin-platelet plug then forms at the site of vessel injury - Fibrin stabilization
• Fibrin clot must be stabilized by coagulation factor XIII
17
Q
Events involved in primary hemostasis
A
Vasoconstriction Platelet response (adhesion and aggregation)
18
Q
What controls and enhances vasoconstriction in primary hemostasis?
A
- Controlled by vessel smooth muscle
* Enhanced by chemicals secreted by platelets
19
Q
What happens during platelet response in primary hemostasis?
A
- When there is an injury, the endothelial surface is exposed
- Platelets become exposed to collagen
- The platelets become “activated”
- Contents of cytoplasmic granules of platelets are released
20
Q
What are the contents of cytoplasmic granules released during platelet response?
A
- Adenosine diphosphate (ADP) (Accelerates platelet aggregation or activation)
- Thromboxane (TXA2) (Vasoconstriction and Increases the ADP release from platelets)
21
Q
Secondary hemostasis is also known as
A
Coagulation cascade
22
Q
Three main steps involved in coagulation cascade wherein weak plugs are stabilized and reinforced
A
- Formation of prothrombin activator
- Conversion of prothrombin into thrombin
- Conversion of fibrinogen to fibrin
23
Q
Sources of all coagulation factors
A
Liver
24
Q
[Coagulation Factors (Procoagulants in the Plasma)]
Factor V
A
Proaccelerin
25
[Coagulation Factors (Procoagulants in the Plasma)]
| Factor XI
Plasma Thromboplastin Antecedent
26
[Coagulation Factors (Procoagulants in the Plasma)]
| Factor I
Fibrinogen
27
[Coagulation Factors (Procoagulants in the Plasma)]
| Factor IV
Calcium
28
[Coagulation Factors (Procoagulants in the Plasma)]
| Factor HMWK
High molecular weight kininogen
29
[Coagulation Factors (Procoagulants in the Plasma)]
| Factor VIII:C
Antihemophilic factor
30
[Coagulation Factors (Procoagulants in the Plasma)]
| Factor II
Prothrombin
31
[Coagulation Factors (Procoagulants in the Plasma)]
| Factor VII
Proconvertin
32
[Coagulation Factors (Procoagulants in the Plasma)]
| Factor III
Tissue factor
33
[Coagulation Factors (Procoagulants in the Plasma)]
| Factor IX
Plasma Thromboplastin Component
34
[Coagulation Factors (Procoagulants in the Plasma)]
| Factor X
Stuart-Prower Factor Liver
35
[Coagulation Factors (Procoagulants in the Plasma)]
| Factor XII
Hageman Factor
36
[Coagulation Factors (Procoagulants in the Plasma)]
| Factor XIII
Fibrin Stabilizing Factor Liver
37
Coagulation factors involved in Vit.k-dependent group
Factors II, VII, IX, X (1972)
38
This coagulation group is considered as having the highest molecular weight, are most labile and consumed in coagulation. They are also the only group that acts as substrates for the fibrinolytic enzyme plasmin
Fibrinogen Group (Factors I, V, VIII, XIII)
39
Steps involved in coagulation mechanism
Activation of clotting factors > Requires a phospholipid surface > Vitamin-K dependent factors (II, VII, IX, X) > Formation of reaction complex ® Labile factors: V and VIII
40
In requiring a phospholipid surface in coagulation mechanism, what are extrinsic and intrinsic to the blood?
* extrinsic:Tissue factor (TF)
| * intrinsic: Activated platelet (platelet factor III phospholipid) to blood
41
Labile factors involved in forming a reaction complex in coagulation mechanism
Factor V and VIII
42
What happens after the tissue becomes injured in extrinsic pathway?
Extrinsic pathway (see picture)
2. The injured tissue releases tissue thromboplastin (tissue factor) 3. This activates factor VII to become factor VIIa (serine protease)
4. In the presence of factor VIIa, Ca2+, and platelet phospholipid (PL), factor X is activated to become factor Xa to be used in the common pathway
43
What happens during intrinsic pathway?
1. The tissue is injured and becomes exposed to the subendothelial basement membrane and collagen (The contact group (prekallikrein, HMWK, XII, XI) adsorbs to the collagen)
2. This converts factor XII to factor XIIa
3. In the presence of factor XIIa, HMWK, and prekallikrein, factor XI is activated to factor XIa (prekallikrein is also converted to kallikrein)
4. In the presence of factor XIa and Ca2+, factor IX is activated to factor IXa
5. In the presence of thrombin, factor VIII is activated to factor VIIIa
6. In the presence of factor VIIIa, factor IXa, platelet phospholipids and Ca2+, factor X is converted to factor Xa to be used in the common pathway
44
[Common pathway]
| Where do the two pathways meet?
at the point wherein both produce factor Xa
45
[Common pathway]
| What happens after intrinsic and extrinsic pathway meet?
2. In the presence of factor Xa, factor Va, Ca2+, and plasma phospholipids, prothrombin (factor II) is converted to thrombin (factor IIa)
3. In the presence of thrombin, fibrinogen (factor I) is converted to fibrin (factor Ia)
4. This creates the fibrin clot, which is stabilized by factor XIII
46
the system whereby the temporary fibrin clot is systematically and gradually dissolved as the vessel heals in order to restore normal blood flow
Fibrinolysis
47
During fibrinolysis, what does the injured vessel release?
tissue plasminogen activator (converts plasminogen to plasmin)
48
[Fibrinolysis]
| What happens to plasmin after being converted from plasminogen?
The plasmin gets trapped in the clot which is eventually slowly dissolved
49
[Fibrinolysis]
| Why is clot dissolving slow in fibrinolysis?
It is slow because of the fibrin stabilization exerted by factor XIII
50
[Fibrinolysis]
| What are produced when the clot is dissolved?
fibrin degradation/split products (FDP or FSP)
51
[Fibrinolysis]
| What neutralizes inhibitors to fibrinolysis?
Protein C and Protein S
52
Summary of steps in blood clotting
| See picture and physiologic response to vessel damage
(1) Injured tissue and platelets release clotting factors (prothrombin activator and calcium ions)
(2) prothrombin activator converts prothrombin to thrombin
(3) thrombin splits fibrinogen to form fibrin
(4) fibrin fibers form a mesh over wound, trapping red blood cells and platelets
(5) bleeding stops
(6) cloth hardens and becomes smaller
(7) new cells grow to repair wound site
(8) enzyme plasmin is released to dissolve clot
53
The smallest microscopically visible element in the peripheral blood smear and are small fragments of the megakaryocyte cytoplasm
Platelets
54
Size, shape snd life span of platelets
* Size (diameter): 2 to 4 μm
* Shape: discoid
* Life span: 9 to 10 days
55
What do platelets do?
* Adhere to injured vessels
* Aggregate at the site of injury
* Promote coagulation on their phospholipid surface
* Release biochemicals important to hemostasis
* Induce clot retraction (smaller clots) (tremendous consumption of energy and observed in vitro after a few hours)
56
Where do platelets store biochemical substances secreted?
Surface membrane and within cytoplasmic granules called dense granules and alpha granules
57
When is calcium required?
During clot retraction
58
What does In vitro phenomenon of clot retraction indicate?
It is subjectively indicative of normal platelet function
59
What are stabilized during clot retraction?
platelet-platelet and platelet-fibrin attachments
60
These provide the pulling forces in clot retraction
The pulling forces are provided by contractile platelet elements in a process similar to muscle tissue contraction
61
Some hypotheses on why clot retraction happens
Participation in the vascular constrictive response to injury
Stabilization of the fibrin clot network
Debulking of the clot to help reestablish blood flow
62
Steps involved in clot formation
1. A break in the endothelial cell wall results in bleeding from the site.
2. Smooth muscle cells contract, pinching off the blood vessel and reducing blood flow.
3. Platelets come together (aggregation) to form a platelet plug which serves as a temporary seal.
4. The coagulation cascade (thrombin converting soluble fibrinogen wc) forms a fibrin network to secure the clot in place.
63
Basis of classifying coagulation disorders
Classification depends on involvement of platelets, clotting factors and/or presence of inhibiting factors (such as FDP)
64
Treatment for coagulation disorders usually involve
* Transfusion of platelets and/or clotting factors (ex. XIII, IX)
* Pharmacologic agents affecting platelet function (DDAVP, antiplatelet drugs), Clotting factors (vit. K, coumadin, heparin) and Inhibitors (antifibrinolytics, protamine, fibrinolytics)
65
A hereditary platelet disorder which is the most common congenital bleeding disorder whose symptoms include easy bruising, excessive bleeding and frequent nosebleeds
Von Willebrand Disease (vWD)
*w/ quantitative or qualitative abnormality of vWF
66
Type of vWF disease which involves qualitative alterations in the vWF structure & function
Type 2
| * There is enough production of vWF but they are defective
67
most common form of vWF disease which is autosomal dominant and involves partial quantitative deficiency of vWF (low production) and mucocutaneous bleeding
Type 1
| *need for Hematology consult prior to surgery and involves prolonged bleeding time, normal platelet
68
An autosomal recessive disease, least common and most severe of vWF disease types wherein there is a complete absence of vWF in plasma or storage organelle
Type 3
69
Possible causes of acquired vWF disease
* Lymphoproliferative disease
* Autoimmune disease
* Cardiac/valvular disease
* Hypothyroidism
* Tumors
* Medications (valproic acid)
70
a hereditary factor deficiency that involves x-linked recessive conditions and whose type depends on which factor is deficient (Type A, B and C)
Hemophilia
71
Factor deficient in type A hemophilia
Factor VIII C (Classic Hemophilia; mild, moderate, severe where CNS bleeds)
72
Factor deficient in type B hemophilia
Factor IX (Christmas disease)
73
Factor deficient in type C hemophilia
Factor XII
74
Symptoms of hemophilia include
* Unexplained bruising or bleeding in young males, usually around one year of age
* Joint & muscle bleeding leads to arthropathy
75
screening test for hemophilia
prolonged PTT
76
treatment for hemophilia
factor replacement
| rFVIIa
77
origin of factor VIII
extrahepatic
78
two components with separate genetic control of factor VIII
* VIII R: Ag (VIII antigen + vWF)
| * VIII: C (COAGULANT activity)
79
vWF mediates what
adhesion of platelets to surface collagen and is also a carrier of VIII :C
80
defect of vW disease
primary homeostasis defect
| hemophilia A
81
vWD type 1
both F VIII: C and VIII: vWF decrease
82
vWD type 2
normal VIII: C and VIII: vWF decreased
83
hemophilia A
decreased FVIII: C
84
Acquired platelet disorders
Thrombocytopenia (platelets <150,000/mm3)
Idiopathic Thrombocytopenic Purpura (children; diagnosis of exclusion)
Platelet Dysfunction
85
causes of thrombocytopenia
* Inadequate production by bone marrow
* Splenic sequestration
* Consumption coagulopathy
* Dilutional thrombocytopenia
* Immunogenic destruction
86
indications of ITP
* Petechia: < 20,000 x 109 L platelets
| * Bleeding: < 10,000 x 109 L platelets
87
Causes of platelet dysfunction
* Myeloproliferative and myelodysplastic syndromes
* Renal failure
* Liver disease
* Drugs: Non-Steroidal Anti-inflammatory Drug (NSAIDS), ASA (Acetyl Salicilic Acid – aspirin)
* DIC
88
liver disease in platelet dysfunction involves problems in?
- Problems in synthesis of coagulation factors (except VIII), anticoagulants, ATIII (antithrombin), protein C and S, plasminogen
- Problems in clearance of activated clotting factors, tissue plasminogen activator (tPA), FDPs
89
Widespread activation of the clotting cascade which results in the formation of blood clots in the small blood vessels throughout the body compromising tissue blood flow leading to multiple organ damage
Disseminated Intravascular Coagulopathy or Consumptive Coagulopathy (DIC)
*As the coagulation process consumes clotting factors
and platelets, normal clotting is disrupted and severe bleeding can occur from various sites.
*comorbidity with critical illness
90
What are the signs of DIC?
o Prolongation of the prothrombin time (PT) and the activated partial thromboplastin time (aPTT)
o A low fibrinogen level is more consistent with the consumptive process of DIC.
o A rapidly declining platelet count
o High levels of fibrin degradation products, including D-dimer
o The peripheral blood smear may show fragmented red blood cells (known as schistocytes)
91
this is a test of extrinsic pathway activity
Prothrombin time
*measures vit K-dependent factors activity
92
normal values of PT
12-14 seconds
| > : Prolonged PT (measure of coagulation abnormality)
93
This standardizes PT reporting
International Normalized Ratio
*normal values: 0.8-1.2 seconds
> : prolonged INR (measure of coagulation abnormality in extrinsic pathway)
94
PT is most sensitive to what
alteration in F-VII levels
95
antithrombotic activity in PT is shown by
reduction of F-II and F-X activity (after several days)
96
What drug does PT monitors response to?
warfarin (anticoagulant drug) therapy
97
a test for intrinsic and common pathways
Activated Partial Prothrombin Time (aPTT)
| *Dependent on activity of all coagulation factors except VII and XIII
98
normal values for aPTT
25-35 seconds
99
aPTT monitors response to?
heparin (anticoagulant drug) treatment & screen for hemophilia
100
This monitors heparin anticoagulation in the operating room (cardiac and vascular surgeries)
• Normal values: 90-120 seconds
Activated Clotting Time
101
This is an indirect test for coagulation proteins which monitors hirudin, bivalirudin, LMWH function
Thrombin Clotting time
Principle: Addition of thrombin to plasma
• Bypasses all coagulation reactions except polymerization of
fibrinogen to fibrin
(Not influenced by deficiencies of the other coagulation factors)
102
Prolonged TCT is found in
presence of dysfibrinogenemia, hypofibrinogenemia, fibrin splits products, immunologic antithrombin, presence of abnormal globulin, heparin, thrombin inhibitors
103
Results of TCT
* Prolonged clotting time reflects abnormalities in the conversion of fibrinogen to fibrin
* Plasma + excessive amount of thrombin
* INR & PT may be normal or elevated
104
OTHER TESTS FOR COAGULATION AND FIBRINOLYSIS
* Tissue Thromboplasmin Inhibition Test
* One–Stage Clotting Assays
* Reptilase Time
* Modified Thrombin Clotting Time Assay
105
Common tests to evaluate platelet function
```
• Estimates from Peripheral Blood Films
• Manual Platelet Count (uses EDTA)
• Bleeding Time
Others:
• Automated Platelet Counts
• Glass Bead Retention Test
• Platelet Adhesiveness in vivo
```
106
Ratio of RBC:platelet in normal PBS
10-40 RBC per platelet
| OIO: 3-10 platelets for 100 RBCs
107
dilution of blood in manual platelet count
1:100 or 1:200 dilution of blood, applied to Neubauer hemocytometer
108
diluent used in manual platelet count which employs a buffer which is a citrateformaldehyde
with brilliant cresyl blue which stain the platelet,
while diluent fixes and preserves RBC and platelets
Rees-Ecker diluent
109
Description of platelets in manual platelet count
• Platelets are seen as highly refractile bodies which are 1/10 the size of RBC that surround them.
• May be counted at the 1/5mm2 or 1mm2 in the center of the
chamber
110
This test for evaluating platelet function is conprehensive for platelet action in vivo
Bleeding time
* time it takes for a standard wound to stop bleeding
* normal values: 2-9 minutes
111
What does bleeding time results suggest??
* Abnormalities of platelet number and functions
* Plasma VIII: vWF deficiencies
* Abnormalities of vessel composition that interfere with platelet function
112
Disadvantages of bleeding time
• Not specific indicator of platelet function
• Not very reliable
• Very operator-dependent (subjective)
• Variable from each institution
• Not done anymore because injury is induced to the patient
• No evidence as a predictor of risk of hemorrhage or as useful indicator of efficacy of antiplatelet therapy
• Insensitive to mild platelet defects
• Other factors to consider: degree of venostasis, depth and
direction of incision
113
(see reasons to perform blood clotting tests)
(see reasons to perform blood clotting tests)
