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98 Cards in this Set

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What are the 3 main components of hemostasis?
vascular response
platelet response
coagulation response
What is primary hemostasis?
interaction of platelets & vessel wall --> formation of loosely arranged platelet plug
What factors contribute to thromboresistance in the vascular response of primary hemostasis?
normal intact endothelium discourages clotting
vasodilation: normal endothelium produces substances that promote vasodilation: prostacyclin (PGI2), nitrous oxide (NO)

anticoagulant
-thrombomodulin: endothelial cell mem protein that scavenges procoagulants (thrombin) & enhances activation of protein C: inhibits clotting by cleaving coag factors Va & VIIIa
-membrane assoc. heparin like molecules: co-factors for antithrombin III (inactives thrombin & factor Xa)

inhibition of platelet function
-laminar blood flow
-intact endothelium prevents platelets & coag factors from meeting thrombogenic subendothelium (exposed collage, vWF)
-NO & PGI2 produced by endothelial cells inhibit platelet aggregation

fibrinolytic
-endothelial cells produce tissue plasminogen activator (t-PA), promoting fibrinolytic activity to clear fibrin deposits
What prothrombotic activities are involved in the vascular response of primary hemostasis?
transient vasoconstriction: augmented by secretion of vasoactive substances (ex. endothelin)

endothelial cell activation: tissue factor production, release of vWF

exposure of subendothelial collagen: platelet binding, initiation of coag cascade
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
How do platelets contribute to formation of the primary hemostatic plug?
temporarily seals vascular defect
provides essential components for coagulation: granules, platelet factor 3 (PF3)
essential for clot retraction
What are the steps involved in the platelet response of primary hemostasis?
adhesion
shape change
secretion (release rxn)
recruitment
aggregation
What is secondary hemostasis?
formation of fibrin thru coag cascade
fibrin serves as seal to cement 1º platelet plug in place
results in 2º hemostatic plug: irreversible
What are the vitamin K dependent coag factors?
II, VII, IX, X
Which coag factors are involved in the intrinsic pathway?
XII, XI, IX, VIII
Describe platelet adhesion.
damaged endothelium --> exposed subendothelium
platelets bind to collagen & vWF
(vWF required for platelet adherence to collagen)
glycoprotein 1b receptor biding stimulates platelet activation
Describe platelet shape change.
platelets swell & develop pseudopods
microtubules rearrange
platelets express PF3 (phospholipid): important for 2º hemostasis
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
Describe platelet recruitment.
ADP & TXA2 recruit more platelets, stimulate platelet expression of GPIIb-IIIa receptors
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 initiates the intrinsic coag pathway?
exposure of subendothelial collagen or by HMWK, kallikrein
What is the tenase complex?
intrinsic pathway:

IXa, VIIIa, PF3, Ca2+
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 initiates the extrinsic coag pathway?
release of tissue factor from endothelial cells
What coag factors are involved in the extrinsic pathway?
tissue factor, VII
What is unique about coag factor VII?
activated by contact w/ tissue factor

shortest half life of all factors: in dz that affects multiple pathways, this is 1st place an effect is noticed
What is the prothrombinase complex?
common pathway
Xa, Va, PF3, Ca2+ --> converts prothrombin to thrombin --> --> formation of fibrin (cross linking) --> stable hemostatic plug
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)
What is fibrinolysis?
breakdown of clots by plasmin
Describe the effects of plasmin.
degrades fibrinogen, soluble & insoluble fibrin --> fibrin degradation products (FDPs)
-D-dimers: special type of FDP; cross-linked by factor XIIIa

formed by activation of plasminogen

normally confined to site of injury & kept in balance by inhibitors

proteolysis occurs in a systemic manner
What are the functions of antithrombin III (AT III)?
limit & localize thrombosis (clot formation)


activity markedly enhanced by heparin or heparin sulfate (endothelial cells)

inactivates factors XIIa, XIa, IXa, Xa, IIa (thrombin), kallikrein

loss (glomerular dz) or consumption --> thromboembolic dz
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
What are the clinical signs of disorders of primary hemostasis?
petechia, ecchymoses, mucous membrane bleeding, epistaxis, melena, hematochezia, retinal hemorrhage, bleeding from small vessels, spontaneous hemorrhage w/ < 20,000 platelets
What is the significance of a high MPV?
large platelets = regenerative response & young, active platelets
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
buccal mucosal bleeding time (BMBT)

a. purpose
b. affected by...
c. if prolonged suggests...
a. measures time to form primary hemostatic plug
b. platelet #, function, vascular integrity, vWD
c. thrombocytopathy or vWD
What is the purpose of the anti-platelet antibody assay?
used to diagnose IMTP: does not differentiate underlying cause

=fluorescent Ab that detects Ab bound to platelets in BM or blood
vWF assay

a. purpose
b. interpretation of results
c. other ways to measure vWF
a. measures plasma vWF levels (reported as % of normal)
b. < 50%: positive for vWD
50-70%: gray zone
> 70%: normal
c. protein electrophoresis: quantifies amount of vWF in blood & which sizes are decreased
DNA testing: genetic defect varies w/ breeds & type of dz (tests available for several breeds)
What are the main categories of thrombocytopenia?
spurious
increased destruction, loss, or consumption
decreased production
sequestration
What can cause "spurious" thrombocytopenia?
platelet clumping (“pseudothrombocytopenia”): may be d/t traumatic venipuncture

breeds that normally have lower counts
Cavalier King Charles Spaniel: has 2 types of platelets, 1 normal sized & 1 larger, which is often counted as an RBC
Greyhound, Shiba: normally mildly decreased platelet count
What is the body's response to thrombocytopenia d/t destruction, loss, or consumption?
↑ platelet production: large platelets on blood smear, ↑ MPV, megakaryocytic hyperplasia in BM
What is the cause of thrombocytopenia d/t loss?
massive hemorrhage (rarely < 50K)
What is the cause of thrombocytopenia d/t consumption?
DIC

results from widespread activation of coag system --> consumption of platelets & coag factors
relatively common in severely ill animals
What are causes of thrombocytopenia d/t increased destruction?
primary IMTP
secondary IMTP
non-immune mediated destruction
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)
secondary IMTP

a. pathogenesis
b. etiologies
a. non-self Ags absorbed onto platelets are targeted by Abs
b. infectious: rickettsial, viral, fungal, bacterial, parasitic
neoplasia
drug induced: sulfa drugs, methimazole
isoimmune: neonatal isoerythrolysis of foals
systemic immune mediated dz: SLE, IMHA
non-immune mediated platelet destruction

a. pathogenesis
b. etiologies
a. platelets targeted for destruction via non-immune mediated mechanisms
b. infectious: direct damage & lysis (viral, rickettsial)
mechanical destruction: DIC, vasculitis, microangiopathies
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 is the body's response to thrombocytopenia d/t decreased platelet production?
lack of peripheral regeneration, megakaryocytic HYPOplasia
thrombocytopenia d/t primary decreased platelet production

a. causes
b. CBC findings
c. prevalence
a. immune mediated destruction of platelet precursors, ineffective thrombopoiesis, thrombopoietin deficiency
b. ↓ platelets, normal WBCs, RBCs
c. rare
thrombocytopenia d/t secondary decreased platelet production

a. causes
b. CBC findings
a. BM hypoplasia/aplasia 2º to drug, toxin, viral dz, neoplasia (myelopthesis), myelofibrosis (ex. estrogen, griseofulvin, bracken fern, FeLV, FIV, parvovirus)
b. ↓ platelets, WBCs, RBCs
thrombocytopenia d/t sequestration

a. causes
b. CBC findings
a. usually 2º to splenic congestion or splenic dz
liver & lung may also sequester platelets
may occur w/ large tumors: esp. HSA
other: splenic torsion, pulmonary contusions, portal hypertension
b. mild to moderate thrombocytopenia, no peripheral regeneration, normal BM
What are the main categories of thrombocytosis?
physiologic: common
reactive: common
myeloproliferative/neoplastic: rare
physiologic thrombocytosis

a. definition
b. causes
c. expected platelet increase
a. transient mobilization from splenic & non-splenic pools
b. vigorous exercise, epinephrine (most common in excitable animals)
c. mild to moderate
reactive thrombocytosis

a. definition
b. causes
a. thrombocytosis 2º to ↑ EPO, TPO, or cytokines
b. inflammation or infection, iron deficiency anemia, Cushing’s, exogenous steroids, neoplasia, chronic hypoxia  ↑ EPO, post-splenectomy, Vincristine (used to tx refractory IMTP)
What are some causes of myeloproliferative/neoplastic thrombocytosis?
megakaryocytic leukemia, essential thrombocytopenia (platelets often > 1 million)
thrombocytopathy

a. definition
b. lab data
c. mechanisms
a. functional platelet defects
b. usually normal to slightly ↓ platelet counts w/ prolonged BMBT
c. failure to adhere, improper aggregation, lack of surface membrane factors to bind coag factors, storage pool defects (platelet granules)
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
What are the 3 types of von Willebrand's dz?
I: most common; bleeding is variable
-all multimers present, but in ↓ amounts

II: bleeding is more severe
-qualitative abnormalities w/ preferential ↓ in high molecular weight multimers

III: most severe; most don’t survive to adulthood
-almost complete absence of vWF w/ mildly ↓ coag factor VIII
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
Chediak-Higashi

a. signalment
b. defect
a. inherited in cats, cows
b. platelets lack dense bodies --> ↓ ADP, serotonin --> abnormal platelet aggregation
What are other inherited thrombocytopathies?
Basset Hound thrombasthenia
Glanzmann's thrombasthenia
Scott syndrome
How can the following cause acquired thrombocytopathies:

a. NSAIDs (esp. aspirin)?
b. uremia
c. hepatic dz
a. aspirin & other NSAIDs inhibit production of TXA2 --> ↓ platelet aggregation
aspirin: irreversible inhibition (for life of platelet)
other NSAIDs: reversible inhibition
b. metabolites impair platelet adhesion & aggregation, ↓ availability of platelet phospholipids
PLN --> loss of antithrombin III --> predisposed to clotting
c. ↓ clearance of FDPs: FDPs impair platelet function
↑ ammonia: nitrous oxide synthesis --> impaired platelet function
How can neoplasia cause acquired thrombocytopathies?
platelets may be consumed, destroyed, sequestered, or have ↓ production
hyperproteinemia (ex. multiple myeloma): coating of platelets with Ig
abnormalities in ADP aggregation & release
resulting DIC: coating platelets w/ FDPs
What are the clinical signs of disorders of secondary hemostasis?
hematomas, bleeding into body cavities, lameness, dyspnea, prolonged bleeding or re-bleeding from wounds
blue top tube

a. contains
b. tests used for
a. sodium citrate: chelates Ca
b. PT, APTT, factor analysis
purple top tube

a. contains
b. tests used for
a. EDTA: chelates Ca
b. CBC, platelet count, blood smear
gray top tube

a. contains
b. tests used for
a. diatomaceous earth: chemical activator of coagulation
b. ACT
What tests evaluate the intrinsic & common pathways?
activated partial thromboplastin time (APTT)

activated clotting time (ACT)
APTT

a. what it does
b. affected by platelet #?
c. sensitivity
a. measure time to form clot in seconds
b. no
c. factor activities must be < 30% of normal for prolongation
ACT

a. what it does
b. affected by platelet #?
c. sensitivity
a. similar to APTT but relies on presence of platelet phospholipid
b. yes: severe thrombocytopenia (< 10K) may prolong clotting
c. highly insensitive: clotting factors must be < 5% of normal for prolongation to occur
a. What test evaluates the extrinsic & common pathways?

b. what it does
c. affected by platelet #?
d. sensitivity
a. prothrombin time (PT)
b. measures time to form clot in seconds
c. no
d. factor activities must be < 20% of normal for prolongation: less sensitive than APTT
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 are causes of prolonged APTT?
hemophilia, factor XII deficiency, DIC, acquired vitamin K factor deficiency (rodenticide toxicosis, liver failure)
What are causes of shortened APTT?
hypercoaguable DIC, inflammation (↑ factors V & VIII)
What are causes of prolonged PT?
factor VII deficiency, DIC, vitamin K factor deficiency (rodenticide toxicosis, liver failure)
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 PIVKAs & what does an increase of PIVKAs indicate?
proteins induced by vitamin K antagonism (PIVKA)
deficiency or antagonism of vitamin K dependent factors --> ↑ precursors of those factors

↑ PIVKA: rodenticide toxicosis, liver dz, etc.
What tests are used to evaluate fibrinolysis?
fibrin degradation product (FDP) assay: detects fragments of soluble fibrin & fibrinogen
-sensitive, but not specific for clot formation

D-dimer assay: detects fragments of previously cross-linked fibrin
-more sensitive & specific than FDP assay

↑: accelerated fibrinolysis (DIC & thrombosis) or poor clearance of products d/t liver dz
hemophilia A

a. cause
b. prevalence
c. inheritance pattern
d. clinical signs
e. lab results
a. factor VIII deficiency
b. most common factor deficiency: dogs, cats, horses
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 VIII assay, normal vWF Ag
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
hemophilia C

a. cause
b. prevalence
c. inheritance pattern
d. clinical signs
e. lab results
a. factor XI deficiency
b. most common coagulopathy of cattle, esp. Holstein
rare in dogs: Springers, Great Pyrenes, Weimeraner, Kerry blue terrier
c. autosomal recessive
d. minimal bleeding until subjected to trauma or sx, spontaneous bleeding rare
e. ↑ APTT, +/- ↑ ACT, ↓ factor XI assay
factor XII deficiency

a. signalment
b. inheritance pattern
c. clinical signs
d. lab results
a. mixed breed cats (less common than hemophilias)
b. autosomal inheritance
c. mild to absent clinical signs
d. ↑ APTT, ↓ factor XII assay
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
vitamin K antagonism/deficiency

a. causes of antagonism
b. causes of deficiency
c. clinical signs
d. lab data
a. rodenticides (warfarin), moldy sweet clover (dicoumerol in cattle), severe liver dz (↓ activation of factors): inhibit conversion of inactive oxidized vitamin K to active reduced vitamin K
b. uncommon: ↓ production by microflora, severe GI dz, obstructive cholestasis, malnutrition: inhibits conversion of non viable factors to viable factors
c. weakness, pallor, dyspnea, hematuria, hematomas, body cavity hemorrhage, joint hemorrhage (varies w/ amt. of time since ingestion or lack of production)
d.early: ↑ PT (factor VII has shortest T1/2)
late: markedly ↑ APTT, PT, ↑ ACT, ↑ PIVKAs
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
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 neoplasia cause disorders of secondary hemostasis?
some tumors can initiate coagulation
mast cell tumors: release heparin, inhibit coagulation
some tumors secrete substances that trigger DIC
What is the definition of DIC?
= pathologic process in which both coagulation & fibrinolysis are inappropriately initiated in microvasculature, resulting in SYSTEMIC generation of thrombin & plasmin

ALWAYS 2º to another dz
What are the 2 main mechanisms that trigger DIC?
massive injury to vascular endothelium
-ex. pancreatitis, heat stroke, infectious agents that cause vasculitis (RMSF, Gram neg. bacteria, viral agents), severe metabolic acidosis, uremia, uncontrolled systemic immune mediated dz

release of substances that activate coag cascade
-tissue factor release: tumors, massive tissue trauma, burns, endotoxin
-other activating substances: snake venom, amniotic fluid, mucin secretions from adenocarcinoma
peracute DIC

a. what is it?
b. clinical signs
c. lab data
a. characterized by hypercoaguable state: coag cascade & platelets are activated
b. NOT evident: best time for clinical intervention, but hard to recognize
c. N to dec. PT/APTT, N. to inc. FDPs/D-dimers, mild dec. platelets, N to inc. BMBT
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
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
What are the 3 elements of Vichow's triad that can cause thrombosis?
endothelial injury (dominant influence: can lead to thrombosis by itself), alteration in normal blood flow (stasis, ↑ turbulence), hypercoagulability (lack of anticoagulants)
What are sequelae to thrombosis?
vessel obstruction, thromboembolic events/embolic showers, acute organ failure
How is thrombosis diagnosed?
difficult, few lab changes, often based on U/S & angiography

↓ AT-III, ↓ proteins C & S, ↑ FDPs, D-dimers, high levels of specific clotting factors
What are risk factors for thrombus development?
PLN, CV dz (saddle thrombi in cats), DIC, neoplasia that disrupts endothelium
Which coag factors are considered cofactors/substrates?
↑ inflammation & accelerate cascade: fibrinogen (I), calcium (IV), V, VIII
Which coag factors are the contact factors?
contact factors: XI, XII, XIII, prekallikrein, high molecular weight kininogen (HMWK)
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
What are some causes of increased FDPs?
acute decompensated DIC > compensated DIC
severe internal bleeding
severe thrombosis
severe liver dz (poor clearance of FDPs)
ddx for increased PT & APTT
DIC
vitamin K def/antag
advanced liver dz
common pathway factor deficiency (rare)