Hemostasis, Thrombosis, Hemorrhage Flashcards
1
Q
Hemostasis
A
Interaction of endothelium, platelets, and coagulation cascade
- maintain blood in a fluid, clot-free state
- induce rapid and localized “hemostatic plug”
- anticoagulant activities occur to limit extend of the plug (fibrinolysis)
2
Q
Pathogenic hemostasis
A
Thromosis
- inappropriate activation of normal hemostatic processes
- formation of a clot in uninjured vasculature
- thrombotic occlusion of a vessel after relatively minor injury
3
Q
Sequence of events with vascular injury
A
- vasoconstriction
- primary hemostasis
- secondary hemostasis
- reorganization and formation of a permanent plug
4
Q
Vasoconstriction
A
Transient arteriolar vasoconstriction after initial endothelial injury that exposes collagen of the subendothelial matric (ECM)
- occurs due to local nerve reflex and release of endothelin by endothelial cells
- helps limit escape of RBCs and proteins from damaged areas
5
Q
Primary hemostasis
A
Platelets adhere to exposed ECM via von Willebrand factor –> platelets activate, change shape –> release of secretory granules –> form primary hemostatic plug
6
Q
Secretory granules
A
ADP and thromboxane A2
- cause vasoconstriction and promote further platelet aggregation
7
Q
vWF
A
Released immediately from adjacent endothelial cells
- aids platelet binding to collagen (procoagulant)
8
Q
Secondary hemostasis
A
Local activation of the coagulation cascade
- tissue factor (thromboplastin) secreted by adjacent endothelial cells
- thromboplastin initiates clotting cascade
= fibrin polymerization and cementing platelets into definitive secondary plug
9
Q
Thrombin
A
Makes fibrin
- made from fibrinogen (always found in blood)
- thrombin puts fibrinogen together = fibrin, nonsoluble, cements everything together
10
Q
Counter-regulatory mechanisms
A
Release of compounds that limit hemostatic process to the site of injury
- tissue type plasminogen activator (t-PA) = fibrinolytic
- thrombomodulin: interferes with the clotting cascade
11
Q
Thrombosis
A
Formation of a blood clot (hemostatic plug) due to either inappropriate activation of normal hemostasis or formation of a clot in a vessel after injury
- due to other abnormal process that block a vessel
12
Q
Fibrinolysis
A
Process of limiting the hemostatic process at the site of injury
- release of tissue plasminogen activator (t-PA) and thrombomodulin by adjacent endothelium
13
Q
What 2 properties does endothelium have?
A
- antithrombotic
- prothrombotic
14
Q
Antithrombotic properties
A
Acts as a barrier between blood and subendothelial collagen
- block platelet aggregation (antiplatelet)
- interfere with coagulation cascade by inactivating thrombin and factors Xa and IXa (anticoagulant)
- actively lyse clots (fibrinolytic)
15
Q
Prothrombotic properties
A
Injury or activation of endothelial cells can result in procoagulant phenotypes that augment local clot formation
16
Q
Normal endothelium
A
Prevents platelets and coagulation factors from meeting highly thrombogenic subendothelial ECM
- nonactive platelets do not adhere to uninjured endothelium
17
Q
Antiplatelet mechanisms of endothelium
A
Activated platelets are inhibited from adhering to surrounding uninjured endothelium by endothelial prostacyclin (PGI2) and NO –> potent vasodilators and inhibitors of platelet aggregation
- express ADPases –> ADP needed for platelet aggregation
18
Q
Anticoagulant mechanisms of endothelium
A
Heparin-like molecules (cofactors) from endothelium act indirectly with and inactivate several coagulation factors (thrombin, IXa, Xa, XIa, XIIa)
- thrombomodulin acts indirectly –> binds to thrombin and converts it from procoagulant to anticoagulant
- source for tissue factor pathway inhibitor: cell surface protein that complexes with and inhibits several proteins of the clotting cascade (VIIa and Xa)
19
Q
Fibrinolytic effects of endothelium
A
Endothelial cells synthesize tissue-type plasminogen activator (t-PA)
- promotes fibrinolytic activity
- clears fibrin deposits from endothelial surfaces
20
Q
Properties of platelets
A
Central role in normal hemostasis
- smallest components of mammalian blood (2-4 um)
- are NOT cells! membrane bound, no nucleus when unactivated
- originate from bone marrow megakaryocytes
- glycoprotein receptors (integrins) bind to exposed collagen –> vWF bridges integrins and exposed collagen (adhesion)
21
Q
What do platelets come in contact with after vascular injury?
A
- collagen
- proteoglycans
- fibronectin
- other adhesive glycoproteins
22
Q
What 3 reactions do platelets undergo after contact with ECM?
A
- adhesion and shape change
- secretion (release reaction)
- aggregation
23
Q
What 2 granules do platelets contain?
A
Alpha granules and dense bodies
24
Q
Alpha granules
A
Express adhesion molecule P-selectin
- contain fibrinogen, fibronectin, factor V, VIII, vWF, PDGF, TGF-B
25
Dense bodies
Delta granules
| - contain ADP, ATP, ionized Ca, histamine, serotonin, epinephrine
26
Properties of activated platelets
Activated platelets have spiny processes that protrude from cell membranes
27
Platelet activation process
Undergo change in shape --> secrete granule contents, express surface phospholipid complex --> aggregate (thromboxane A2) = reversible primary hemostatic plug via thrombin binding to surface receptors and binding fibrinogen to integrins on surface
Contract irreversibly to form secondary hemostatic plug --> thrombin converts fibrinogen to fibrin --> fibrin mortars in place
28
Thrombocytopenia
Lack of platelets
29
Secondary hemostasis
```
Blood clot (thrombus) forms thru the action of a cascade of proteolytic reactions involving 20 different substances
- most are liver-synthesized plasma glycoproteins
```
30
3rd step of hemostatic process
Cascade of enzymatic conversions that turn inactive proenzymes into activated enzymes
- culminates in formation of thrombin
- thrombin converts fibrinogen (soluble plasma protein) precursor into insoluble protein fibrin
31
Each reaction in the pathway results from the assembly of a complex composed of ___
- an enzyme: activated coagulation factor
- a substrate: proenzyme from of coagulation factor
- a cofactor: reaction accelerator
32
Components of coagulator cascade are assembled on _______
A phospholipid complex, held together by Ca ions
| - clotting remains localized to sites where assembly can occur (on surface of activated platelets or endothelium)
33
EDTA
Binds all Ca in the blood
| - enzymes in clotting cascade cannot stick together due to wrong charges (anticoagulant)
34
What are the clotting factors that require vitamin K as a cofactor?
10, 9, 7, 2
35
What 2 diagnostic tests are used to test the clotting cascade?
- PT: extrinsic pathway
| - PTT: intrinsic pathway
36
Intrinsic pathway
Initiated in vitro by activation of the Hageman factor (XII)
37
Extrinsic pathway
Initiated by tissue factor
| - cellular lipoprotein exposed at site of tissue injury
38
FDP
Fibrin degradation products
- diagnoses DIC, elevated levels measured as fibirn d-dimers
- fibrin split products that act as weak anticoagulants
- degrades fibrinogen
- any free plasmin in circulation is bound and neutralized by a-2-antiplasmin
39
DIC
Disseminated intravascular coagulopathy
- widespread clot formation
- seen clinically as a bleeding animal because all clot factors are used up
- diagnostically look for large numbers of FDP and no platelets
40
Plasminogen
Found in circulation, cleaved to plasmin by tissue plasminogen activator (t-PA)
- tissue type-PA is synthesized by endothelial cells --> active when attached to fibrin meshwork --> activity blocked by PA inhibitor (PAI)
- plasmin breaks down fibrin and interferes with polymerization
41
______ is an important process in the regulation of hemostasis
Fibrinolysis
| - FDP
42
Extravasation
Escape of blood from blood vessels
| - always antemortem!!
43
Does hemorrhage occur after death?
NO
44
Hemorrhage per rhexis
Rapid flow of blood through breaks in vessel wall
| - due to cut, rupture, etc
45
Hemorrhage per diapedesis
Oozing of blood thru holes in vessel wall
- vessel is intact morphologically, but RBCs are still leaking out
- due to severe passive congestion, shock, etc
46
Hematoma
Enclosed accumulation of blood in a tissue
- bulging, rounded area of hemorrhage
- can be insignificant (bruise) or cause death (intracranial hematoma)
47
Petechiae
1-2 mm hemorrhage in the skin, mucous membranes, or serosal surface of organ
- associated with locally increased intravascular pressure, thrombocytopenia, defective platelet function, clotting factor deficits
48
Ecchymoses
2 mm - 1 cm SQ hemorrhage
| - associated with same processes as petechiae, especially in trauma
49
Purpura
>1 cm hemorrhage in the skin, mucous membrane, or serosal surface
- associated with same as petechiation
- trauma, local vasculitis, increased vascular fragility
- petechia/ecchymoses become overlapped and get close together forming purpura
50
Suffusive
Hemorrhage along a natural plane (area of least resistance)
| - paintbrush hemorrhage
51
Hemorrhage
Large accumulation of blood in a body cavity
- hemothorax: blood in thorax
- hemopericardium: pericardial sac
- hemoperitoneum: peritoneal cavity
- hemarthrosis: joint or synovial cavity
52
Fate of hemorrhage
RBCs are phagocytized and enzymatically degraded
| - porphyrin release from hemoglobin produces color
53
What are the 3 colors of hemorrhage?
- hemoglobin: red/blue
- bilirubin: blue/green
- hemosiderin: gold/brown
54
Clot
Contracts which causes separation of serum from coagulum
55
Coagulum
Lysed and removed, if small
| - organized by connective tissue
56
Serum
Resorbed and removed
- form seroma: large area of fluid in a tissue
- seromas are great growth media for bacteria
57
Rate and amount
- >1/3 blood volume lost quickly: hypovolemic shock --> exsanguination
- <1/3 blood volume lost quickly: compensation and survival
- slow blood loss: compensatory changes
58
Hypovolemic shock
Hypoxic conditions occur due to loss of blood
- all capillary beds dilate to get blood = dilution of blood --> hypovolemic shock, blood is sequestered to capillary beds leading to widespread shock
59
What 3 areas will cause death from hemorrhage, even if blood loss is minimal?
Brain, pericardium (cardiac tamponade), lungs
60
How much blood can be lost for the animal to survive and compensate?
If lost slowly, an animal can lose as much as 1/2 blood volume over weeks/months and still be able to compensate
61
Methods of compensation
- RR increases to help oxygenate
- hematopoiesis in bone marrow
- extramedullary hematopoiesis
- limit exercise to keep O2 consumption low
- may die acutely if over exerted
62
Hematuria
Bloody urine
63
What are the 3 conditions that create thrombosis?
- endothelial injury
- abnormal blood flow
- hypercoagulability
64
Thrombosis
Pathological formation of a clot (thrombus) within the cardiovascular system
- leads to interference with blood flow (turbulence, stasis)
- result in infarction, passive congestion, or embolism
65
Infarction
Blockage of arterial supply due to thrombus
| - whatever is after the blockage will die
66
Embolism
Fragment of thrombus that breaks off and lodges somewhere distal
67
Causes of thrombosis
- change in blood flow (slow down)
- change in blood viscosity
- loss of vascular endothelial smoothness
- endothelial injury
- hyperactive states of platelets (parturition, sepsis, surgery, massive trauma)
- proteinuria (renal disease)
68
Endothelial injury
Endothelial cell damage and exposure of subendothelial collagen
- vasoconstriction follows --> platelet aggregation --> activation of clotting cascade
- platelet plug is formed, held together by polymerized fibrin
69
Turbulent blood flow
arterial and cardiac thrombosis via endothelial injury and countercurrent/local areas of stasis
70
Stasis
Major factor in venous thrombi
71
____ and _____ disrupt laminar flow and bring platelets into contact with endothelium
Stasis and turbulence
- prevents dilution of clotting factors by fresh flowing blood
- retards inflow of clotting factor inhibitors
72
Blood hypercoagulability
Least common cause of thrombosis
- humans: any alteration in coagulation pathways that predisposes to thrombosis
- commonly a secondary cause in all species
73
Primary hypercoagulability
Mutation in factor V gene
| - affects 2-15% of caucasian population as recurrent deep venous thrombosis
74
Secondary hypercoagulability
Acquired
- DIC
- disseminated cancers: release of procoagulant tumor products
- certain glomerular diseases (loss of anti-thrombin III)
75
Post-mortum clot
After death, blood clots in vessels and forms a mold in the shape of the vessel (or heart chamber)
- shiny, gelatinous
- fills entire chamber
- removes easily
- red, may be yellow plasma near surface and red at base
76
Thrombus characteristics
- rough surface and attached to vessel wall
- difficult to remove
- pale color due to protein and fibrin
- early thrombi may be red
77
Microscopic thrombus
- attached to wall
| - laminations: alternating pale layers of platelets admixed with fibrin and darker layers containing more RBCs
78
Venous thrombus
Occurs at sites with blood stasis, extending in the direction of blood flow (toward the heart)
79
Arterial thrombus
Begin at site of endothelial injury or turbulence (ex: vessel bifurcation)
- grow in retrograde direction from point of attachment
- ex: saddle thrombus in cat
80
Vegetative thrombus
Most common on mitral (left AV) valve
- tend to travel in general circulation (kidneys)
- occur on semilunar and right AV valves --> travel to lungs or general circulation
81
Verminous thrombus
Caused by parasites
82
Mural thrombus
Attached to the endocardium
83
Septic thrombus
Bacterial colonization of a thrombus
| - causes or is a result of bacteremia
84
What are the 4 outcomes of thrombosis?
- propagation
- embolization
- dissolution/resolution
- organization and recanalization
85
Propagation
Thrombus may accumulate more platelets and fibrin leading to vessel obstruction
86
Embolization
Thrombus may dislodge and travel to other sites, forming thromboemboli
87
Dissolution/resolution
Thrombi may be removed by fibrinolytic activity
| - drugs available for this
88
Organization and recanalization
May induce inflammation and fibrosis (organization), will eventually become recanalized
- possible formation of collateral circulation
89
Recanalization
Re-establish blood flow or be incorporated into a thickened vascular wall
- thrombus converted to fibrous connective tissue (scar tissue)
- may contract over time
