Hemostasis Flashcards

Plasmin
Terms Definitions
what does thrombin activates?
fibrin
Phospholipids
Prothrombotic, exposed with endothelial injury, negative charge provide surface for coagulation reactions.
hemophilia B
lack of factor 9
first step in hemostasis
vascular spasm
Thrombin
Potent platelet agonist generated during coagulation. Inc. platelet activation and aggregation. Converts fibrinogen to fibrin forming fibrin network that anchors & stabilizes platelet plug.
Dysfibrinogenemia
Autosomal dominant abnormal fibrinogen disorder, can cause coagulopathy.
Thrombomodulin
Binds thrombin forming complex activating protein C (natural anticoagulant protein). Limits intravascular spread of fibrin clot.
Antithrombin III
Natural anticoagulant protein inactivates thrombin, IXa, Xa, XIa. Accelerated by binding to heparin sulfate.
Hemostasis
Physiological process maintains fluid blood normally & forms local hemostatic plug when neccessary.
activation of prothrombin requires how many proteolytic cleavages?
two
What is ITP?
Idiopathic thrombocytopenic purpura (inherited platelet disorder); rare disorder that may be acute and half the cases occur with children; children resolve in 70% of cases while adults usually have a chronic course (make sure to look over the treatment of both acute and chronic)
two pathways of coagulation
intrinsic and extrinsic
What factor initiates the "contact pathway" of clotting?
FXIIa
von Willibrand factor
Prothrombotic released from endothelium, req. for platelet adhesion to subendothelial collagen. Binds glycoprotein Ib protein receptor on platelets. Forms bridge btwn platelet GPIb receptor and subendothelial collagen. The "glue".
Fibrinolytic system
Tissue plasminogen activator (tPA) released from damaged endothelial cells converts plaminogen to plasmin (active serine protease). tPA & plasminogen bind to fibrin facilitating plasmin generation and localized fibrinolysis. Regulated by plasminogen activator inhibitor.
Glycoprotein IIb/IIIa
Platelet membrane receptor for fibrinogen.
Hyperhomocysteinemia
Abnormally large amount of homocystein in blood leads to hypercoagulability. Can result from low folic acid, Vit B6, B12
Prostacyclin (PGI2)
Inhibits platelet adhesion and aggregation. Limits intravascular extension of platelet plug.
Endothelial prothromotic properties:
Subendothelial collagen, tissue factor, von Willebrand factor (vWF), phospholipids, plasminogen activator inhibitors (PAIs)
Factor XIIIa?
Transglutaminase activated by thrombin that stabilizes a clot by forming amide bonds btwn glutamine and lysine side chains in adjacent fibrin strands resulting in a fibrin clot that traps RBCs and platelets.
Name an example of an anti-protease?
anti-thrombin 3
Which system is this describing? fibrin forms sticky threads between platelets that are aggregated, a diffuse gel-like matrix serves as a scaffold for granulation and wound healing, plasminogen helps counter fibrin and tPA is released?
fibrinolytic system
Describe platelet aggregation.
platelets crosslink (GPIIb-IIIa binds fibrinogen) --> 1º hemostatic plug (reversible)
plug is loosely arranged & can only stop bleeding from small vessels
What is fibrinolysis?
breakdown of clots by plasmin
What are other inherited thrombocytopathies?
Basset Hound thrombasthenia
Glanzmann's thrombasthenia
Scott syndrome
hemostasis is the process of
stopping blood loss
degranulation releases the chemicals
serotonin (vasoconstrictor), ADP (platelet aggregation), and thromboxane A2)
Protein C system
Thrombin binding to thrombomodulin activates Protein C which inactivates cofactors Va & VIIIa limiting further thrombin generation.
Hemophilia A
Most common form of hemophilia, deficiency in FVIIa (cofactor).
Which factors contain carboxyglutamate?
thrombin, factor 7,9, and 10
Glutamate has a natural high affinity of?
calcium ions
What is fondaparinux?
a synthetic pentasacharide that mimics the active site of the smallest sequence capable of replicating heparin effects
Describe platelet shape change.
platelets swell & develop pseudopods
microtubules rearrange
platelets express PF3 (phospholipid): important for 2º hemostasis
Platelet Adhesion
vWF binds to exposed collagen and platelet surface receptor GPIb. Creates a monolayer over injured surface.
Tissue plasminogen activator (tPA)
Activates fibrinolysis by converting plasminogen to plasmin and limits fibrin clot size.
Platelet granules
alpha - vWF, fibrinogen, FV, platelet F4, fibronectin, platelet derived GF. dense - serotonin, ADP, ATP, Ca2+
Exposure of Phospholipid Surface
Activated platelets expose neg. charged phospholipids phosphatidylserine & phosphatidylinositol) binding clotting factors.
Platelet Storage & Release
Adhesion causes platelet activation and secretion of alpha and dense granules. ADP and other agonists activates nearby platelets. Arachidonic acid also released from cell membrane & converted to thromboxane A2 (TXA2) a potent agonist and vasoconstrictor activating platelets and potentiating aggregation.
what happens when fibrinogen is activated?
soft clot is formed
tissue factor binds to what factor in the initial stage of clotting?
factor 7
What are the types of hemophilia?
type a and b
what is the bond that keeps the prothrombin molecules together?
disulfide bond
Describe type 2 vWF disease
abnormal vWF produced, decreased activity
What are the main categories of thrombocytosis?
physiologic: common
reactive: common
myeloproliferative/neoplastic: rare
primary IMTP

a. pathogenesis
b. signalment
c. clinical signs
d. lab findings
e. dx
a. auto-Abs against platelets or megakaryocytes
b. dogs (occ. horses, cats), middle aged females
c. often no signs, even w/ severe dz: often present during crisis (severe hematuria, epistaxis, etc.)
d. low platelet count, usually < 50K, often < 10K, prolonged BMBT, ACT, +/- peripheral signs of platelet regeneration, +/- megakaryocytic hyperplasia
e. diagnosis of exclusion: R/O other causes of thrombocytopenia 1st, response to therapy (immuno-suppressive doses of steroids), additional tests (not specific for 1º IMTP)
Describe platelet secretion (release rxn).
release of granule contents
ADP released --> production & release of thromoboxane A2 (TXA2): most potent inducer of platelet aggregation & stimulator of release rxn
healing is stimulated by ____
PDGF, platelet derived growth factor
Tissue Factor Pathway Inhibitor
Plasma protease circulating and on endothelial surface. Inactivates the TF-FVIIa complex thereby blocking initiation of coagulation.
What is the aPPT assay?
Activated partial thromboplastin time used to detect coagulation disorders by adding kaolin (clay) that provides a surface for coag.
What are endothelial cell's antithrombotic properties?
Prostacyclin (PGI2), heparan sulfate, thrombomodulin, tissue plasminogen activator (tPA)
What are the two amino acids that transglutaminase cleave?
lysine and glutamine
What is characterized by type A hemophilia?
deficiency in factor 8
the peptides that are cleaved by thrombin contain many of these AA's
Aspartate, Glutamate, and sulfated-tyrosine
Which type of hemophilia can be treated?
type A (recombinant factor)
What are the acquired coagulation disorders?
liver disease, bile obstruction, non-tropical sprue, DIC and caused by meds
hemophilia B

a. cause
b. prevalence
c. inheritance pattern
d. clinical signs
e. lab results
a. factor IX deficiency
b. common in dogs & cats
c. X-linked recessive trait: all males effected, females must be homozygous to show signs
d. vary depending on degree of deficiency
-spontaneous bleeding w/ mechanical stress, hematomas, hemarthrosis, body cavity hemorrhage
e. ↑ APTT, ↑ ACT, ↓ factor IX assay
Which coag factors are considered cofactors/substrates?
↑ inflammation & accelerate cascade: fibrinogen (I), calcium (IV), V, VIII
gray top tube

a. contains
b. tests used for
a. diatomaceous earth: chemical activator of coagulation
b. ACT
What are the functions of thrombomodulin, protein C, & protein S?
thrombomodulin: binds to & inactivates thrombin

protein C: inhibits factors VIIIa, Va, promotes fibrinolysis

protein S: cofactor for protein C, inhibits factors Va, VIIIa, Xa
platelets

a. life span
b. responsive to...
c. regulated by...
d. 3 granule types
a. ~10 days
b. thrombopoietin, also erythropoietin, certain cytokines
c. circulating platelet mass (NOT platelet #)
d. α, dense body, lysosomal
What are the 3 main components of hemostasis?
vascular response
platelet response
coagulation response
What are some etiologies w/ concurrent secondary IM & non-immune mediated platelet destruction?
systemic autoimmune dz: IMHA
neoplasia
infectious agents: rickettsial, viral, vaccination w/ MLV
What additional lab tests are suggested to dx secondary IMTP or non-immune mediated platelet destruction?
CBC, blood film examination: inflammation, platelet regeneration, neoplasia, platelet destruction, etiologic agents, etc.
chemistry, U/A: underlying dz?
tick titers: Ehrlichia, RMSF, etc.
What tests evaluate the intrinsic & common pathways?
activated partial thromboplastin time (APTT)

activated clotting time (ACT)
Platelet plug formation
1. platelets react with ____
2. adhere to inner surface of ___ ___
3. contract and draw __ ___ together
4. release chemicals (_____)
collagen, blood vessel, vessel walls, degranulation
Hemophilia A is caused by what?
FVIII deficiency, 1:10,000 males. FVIIIa accelerates FIXa activation of FX which activates thrombin.
Factor V Leiden
Variant of normal FV which cannot be innactivated by Protein C causing hypercoagulability. Most common inherited hypercoagulable disorder. 3-8% general pop.. Single pt. mutation replaces arg w/ glut removing cleavage site for activated protein C so FVa can't be innactivated. Venous thromboembolism is primary clinical manifestation.
what is the mech of action of anti-thrombin 3?
binds and inactivates thrombin
Describe type 1 vWF disease
decreased amount of vWF, the vWF produced is normal, and all sizes are present
What is the primary drugs used to prevent deep venous thrombi?
Low molecular weight heparin
What maturation does the common pathway of the coagulation phase allow? (In a general sense)
Fibrin matures to a thrombus (including platelets)
What are the vitamin K dependent coag factors?
II, VII, IX, X
What does coag factor XIIa do besides its involvement in the coag cascade?
activates plasma kinin system
-converts prekallikrein to kallikrein
-kallikrein converts kininogen to kinins, can also activate XII & XI
-kinins important in inflammation: edema, vasodilation, ↑ capillary permeability, chemotaxis of WBCs
What are the functions of thrombin?
cleaves fibrinogen into soluble fibrin monomers

activates factors V, VIII, XIII

mature stable clot: fusion & contraction of platelet mass (viscous metamorphosis: irreversible)
How does the liver participate in hemostasis?
coag factor production, clotting inhibitor (AT-III) production, fibrinolytic agent (plasminogen) & inhibitor production, Kuppfer cells phagocytize FDPs & other byproducts
fulminant DIC

a. what is it?
b. clinical signs
c. lab data
a. consumption of factors exceeds production
b. end organ failure, coagulopathy
c. N to inc. PT/APTT, inc. FDPs/D-dimers, dec. platelets, N to inc. BMBT, dec. ATIII, N to dec. fibrinogen, schistocytes
When are individual coag factor assays used & what do they measure?
used to dx specific disorders

measures activity of factor in patient in relation to a normal control: reported as a percentage
What are the functions of vWF?
various forms (multimers): larger ones are more effective
released from damaged endothelial cells
facilitates platelet binding to exposed collagen via glycoprotein Ib receptor
circulates bound to coag factor VIII to protect it from premature degradation
What is the body's response to thrombocytopenia d/t decreased platelet production?
lack of peripheral regeneration, megakaryocytic HYPOplasia
von Willebrand's dz

a. cause
b. prevalance
c. breeds predisposed
d. clinical signs
e. dx
a. deficiency or abnormality of vWF
b. most common inherited thrombocytopathy in dogs (also cats, rabbits, horses, pigs)
c. Dobermans, Pembroke Welsh Corgis, Scotties, Aierdales, Shelties
d. vary w/ dz type: • mucosal hemorrhage, cutaneous bruising, prolonged bleeding, may be hard to distinguish from platelet dysfunction, petechiae usually NOT seen
e. BMBT: frequently prolonged, vWF antigen assay, protein electrophoresis, genetic testing
vascular spasm ____ the injured blood vessel via (3 things)
constrics (pain receptors, smooth muscle damage, serotonin (from platelets))
What's the "glue" for platelet aggregation?
Fibrinogen, it binds to activated GPIIb/IIIa receptors on platelets.
What is meant "intrinsic pathway"?
All the components needed to clot blood are intrinsic to the blood itself. The 8 things activated by thrombin.
what is the structure of factor 7?
TF inhibitory peptide, Ca2+ binding site, and a substrate binding pocket labeled the catalytic triad
Bleeding can be controlled be what means?
splints, pressure packs, ice, gelfoam with thrombin, oxycel, microfibrillar collagen, tranexamic acid
What are the four congenital platelet disorders?
1.) vWF disease 2.)storage pool disorder 3.) Glanzmans thrombasthenia 4.)Bernard-soulier 5.)ITP
If there is excessive bleeding after surgery and it is a vascular defect, is it an early or late problem?
Early; platelet phase and vascular defect are both early problems but a coagulation defect is a late problem
low grade (chronic) DIC

a. what is it?
b. clinical signs
c. lab data
a. low grade, compensated event: consumption matches production
b. organ dysfunction/failure 2º to thrombus formation & ischemia
c. N to dec. PT/APTT, inc. FDPs/D-dimers, N to dec. platelets w/ regeneration, N to inc. BMBT, N to inc. ATIII, N to inc. fibrinogen, few schistocytes
blue top tube

a. contains
b. tests used for
a. sodium citrate: chelates Ca
b. PT, APTT, factor analysis
What is the significance of a high MPV?
large platelets = regenerative response & young, active platelets
purple top tube

a. contains
b. tests used for
a. EDTA: chelates Ca
b. CBC, platelet count, blood smear
Give the signalment & expected clinical signs for the following less common inherited coag disorders:

a. fibrinogen deficiency
b. factor X deficiency
c. prekalikrein deficiency
a. Saanen goats, St. Bernards, Vislas: severe bleeding
b. blonde Cocker Spaniels: moderate to severe bleeding depending on degree of deficiency
c. Belgian & mini horses: no apparent symptoms
Extrinsic pathway caused by damaged ____ releases factor ___ leading to the final factor ____, which activates ___, ___, ___
tissues, 7, 10, prothrombin, thrombin, fibrin
What's the purpose of the coagulation cascade?
To turn soluble circulating fibrinogen into an insoluble fibrin clot. Thrombin (FIIa) cleaves 4 small peptides from center of fibrinogen molecule converting fibrinogen into fibrin monomers which spontaneously polymerize to form fibrin.
what is the function of the von Willebrand factor?
mediates binding of platelets to collagen during initial phase
When is endothelin released in normal hemostasis and what does it cause?
it is released directly after injuey and causes vasoconstriction
What are the screening tests for hemophilia?
aPTT --> abnormal and PT,BT & platelelt count are normal
Which types of vWF disease are autosomal dominant and which are autosomal recessive?
type 1&2 are autosomal dominant and type 3 is autosomal recessive
What 2 tests only evaluate the common pathway?
Russell Viper Venom test: rarely used
-venom, Ca, PF3 added to citrated plasma --> directly activates factor X

thrombin time (TT): rarely used
-tests fibrinogen quality & quantity
What will the following conditions do to reported platelet count & RBC count:

a. platelet clumping
b. small RBCs
c. large platelets
d. RBC fragments
a. dec. platelet count, normal RBC count
b. increased platelet count, decreased RBC count
c. decreased platelet count, increased RBC count
d. increased platelet count, decreased RBC count
3 reasons a clot remains confined to the site of vascular injury:
Platelets and binding factors only bind to injured endothelium, antithrombitic mechanisms limit clot to area of injury, blood flow to region dilutes and disperses activated clotting factors and platelets.
why should you monitor patients on vit K antagonist?
you wana make sure that carboxy protein production is still being formed.
T/F Gp2b/3a helps to adhere to vWF
F Gp1B helps adhere to vWF; Gp2b/3a helps to aggregate platelets by keeping fibrinogen between platelets for connection
Normal times for the following are what? 1.) platelet adhesion 2.) platelet aggregation 3.) platelet plug 4.) consolidation 5.) fibrin stabilization
1.)1-2 seconds 2.) 10 sec 3.) 1-3 minutes 4.) 3-5 minutes 5.) 5-10 minutes
With what liver lesions would you be most likely to see an acquired coagulopathy?

What lab data would you see?
acute massive hepatic necrosis or end stage liver dz

↑ PT, APTT, ↓ PIVKAs & individual factor assays, +/- ↑ FDPs, D-dimers, usually evidence of synthetic liver failure (↓ albumin, BUN, glucose, cholesterol)
How can you estimate platelet count on a blood smear?
evaluate 10 fields at 100x

1 platelet at 100x = 15-20K/µL blood

good to monitor hospitalized patient w/ IMTP: compare day to day counts
What are the different levels of hemophilia A?
> 25% --> no problem, 5-25% --> mild, 1-5% --> moderate, severe
T/F vWF stick to platelets, but not to damaged vessels?
F vWF stick to both platelets and damaged vessels
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