Download Normal Hemostasis

Hemostasis and Thrombosis
Vic Vernenkar, D.O.
St. Barnabas Hospital
Dept. of Surgery
Normal Hemostasis
• A well regulated process
• Maintains blood in a fluid, clot free
state in normal vessels
• Induces the rapid formation of a
localized hemostatic plug at the site of
vascular injury
Thrombosis
• Pathological state
• Inappropriate activation of the normal
hemostatic process
– within the non-interrupted vascular
system.
• Thrombus (blood clots) formation
– Blocks blood flow to vital areas
Normal sequence of Hemostasis
(4 steps)
• 1. Arteriolar vasoconstriction (transient)
– Reflex neurogenic mechanisms
– Bleeding would resume after vasoconstriction if
it weren’t for the activation of platelets or
coagulation systems
• 2. Exposure of subendothelial ECM when
there is endothelial injury
– ECM, especially collagen, is highly
thrombogenic
– Platelets adhere and become activated
• Change in shape
• Release of secretory products
– Aggregation of platelets forms hemostatic
plug
– This is primary hemostasis
First two steps
of normal
hemostasis
Normal hemostasis continued
• 3. Tissue factor released at the site of
injury (by endothelial cells)
– Works with secreted platelet factors
– Activates coagulation cascade
• A series of proteins where thrombin is
activated
• Induces further platelet recruitment and
granule release
– Ends in fibrin deposition
– Called secondary hemostasis
Normal hemostasis continued
• 4. Formation of permanent plug
– Prevents further hemorrhage
– Polymerized fibrin and platelet
aggregation
– Counter regulatory mechanisms (t-PA)
limit the plug to the site of the injury
Steps 3 and 4
The Main Players in Hemostasis
• Endothelial cells
• Platelets
• Coagulation cascade
Endothelial Cells
• Produce vWF (vonWillebrand factor)
– A product of normal endothelium
– found in the plasma
– essential for platelet binding to collagen and other
surfaces
• Secrete Tissue factor
– induced by cytokines (TNF, IL-1)
– activates the extrinsic clotting pathway
Endothelial Cells have
Prothrombotic Effect
• Via vWF and tissue
factor
• factors that depress
fibrinolysis
• factors needed for the
clot are not destroyed
before clot forms
Collagen is highly
thrombogenic
For hemostasis
For inflammation
For wound healing
Endothelial cells have Anti-thrombotic
properties, too
• Antiplatelet effects
– Intact cells are barrier to
subendothelial ECM
– PGI-2 and NO prevent
platelets from adhering
• Fibrinolytic properties
– Tissue type plasminogen
activator (t-PA)
• promotes activity to clear
fibrin deposits from
endothelial surfaces
• Anticoagulant
properties
– Membrane associated
molecules
• Heparin like
molecules and
thrombomodulin
– Inactivate thrombin
and several
coagulation factors
Factors that favor or inhibit
thrombosis
SOooo…..
• Endothelial cells modulate the balance of
hemostasis
• Endothelial injury is the dominant influence
that leads to thrombosis
Platelets
• Express glycoprotein receptors on
membranes. Gp Ib,IIb/IIIa
• Have three types of granules
– Alpha granules
• Fibrinogen, fibronectin, factor V and VIII,
PDGF, TGFb
– Dense bodies or delta granules
• ATP/ADP, ionized calcium, histamine,
serotonin, epinephrine
– Lysosomal granules
Platelets
Hyalomere and granulomere
Platelets continued
• Upon encountering the ECM, platelets
undergo three general reactions:
1. Adhesion and shape change
mediated by vWF and glycoprotein Ib
2. Secretion (release reaction)
– calcium required in coagulation cascade
– ADP as mediator of platelet aggregation
– Surface expression of phospholipid complex
• Binding site for calcium ions and coagulation
factors
Platelets continued
• 3. Aggregation
– ADP and TXA2 (vasoconstrictor thromboxane A2)
are the stimuli for the formation of the primary
hemostatic plug
• Aspirin inhibits synthesis of TXA2
– Fused mass of platelets
• Created by coagulation cascade that produces
thrombin
• Thrombin also converts fibrinogen to fibrin cementing
platelets in place
Thrombocytopenia
• Spontaneous bleeding, prolonged bleeding
time
• Lowered platelet count
– Uremia, too much aspirin and rare genetic
disorders
– Various marrow failure or injury
• Aplastic anemia, leukemia
– Sometimes immunologically mediated
– Destruction of platelets by prosthetic heart valves
• Bleeding into CNS a concern
• Common hematologic manifestation of AIDS
Coagulation Cascade
• A series of conversions of
inactive proenzymes to
activated enzymes,
– culminating in the formation of
thrombin
• Thrombin then coverts the
soluble plasma protein
fibrinogen to insoluble
fibrous protein fibrin
Two pathways of
coagulation
cascade
• Intrinsic
– Surface contact
• Extrinsic
– Tissue injury
Coagulation cascade
Hemophilia A (classic)
is due to reduced
amount or reduced
activity of Factor VIII
Hemophilia B (Christmas
Disease) results from
Deficiency of factor IX
Heparin is a cofactor that
Allows antithrombin III to
Inactivate thrombin and
Factor Xa
Thrombomodulin binds
To thrombin, making it
An anticoagulant which
Then activates antiCoagulant protein C.
Protein C cleave factors
Va and VIIIa
Control of cascade to prevent
clotting elsewhere
• Antithrombins
• Plasminogen– activated by heparin like
plasmin system
molecules on endothelial
cells
• Clinical administration of
heparin minimizes thrombosis
• Proteins C and S
– Vitamin K dependent
– Inactivate cofactors Va
and VIIIa
– Breaks down fibrin
and inhibits its
polymerization
– Products of split fibrin
are anticoagulants
Conditions Causing
Bleeding
• Incomplete hemostasis is most
common cause of bleeding.
• Vitamin K deficiency
– severe coagulation defect
– Required for synthesis of prothrombin
and factors VII, IX and X
• Parenchymal diseases of the liver
– Liver synthesizes several coagulation
factors
Hereditary deficiencies
• Hemophilia A--factor
VIII deficiency
– Sex-linked recessive
– 30% due to new mutations
and don’t have family link
– Hemarthroses common
(spontaneous bleeding in
joints)
– Infuse patient with factor
VIII from human blood or
cryoprecipitate.
– Need 100% levels preop,
keep at 30% postop.
• Hemophilia B--factor IX
deficiency
– Clinically indistinguishable
from Hemophilia A
– Sex-linked recessive
– Need 50% preoperatively
– Prolonged PTT, normal PT
TX: Factor IX or FFP
Von Willebrand’s Disease
Von Willebrand’s
Disease- Most common
•
•
•
•
•
congenital bleeding
disorder.
Types I, II, and III.
PT normal PTT normal or
elevated
Prolonged bleeding time
Type I most common
(70%) with mild sx.
Type III causes most
bleeding
• Type I and IIIreduced quantity of
vWF
• TX: Cryo, DDAVP
• Type II- defect in vWF
molecule, enough of it
but doesn’t work well.
TX: Cryo
Platelet Disorders
• Acquired-H2
blockers, heparin.
• Bernard-Soulier, a
Gp1b receptor
deficiency (can’t bind
to each other)
• Uremia-Inhibits
Gp1b, vWF. TX:
dialysis, DDAVP,
cryo, plts.
• Ticlopidine- decreases
ADP in platelets, prevents
exposure of Gp1b/IIIa
receptors.
• Dipyramidoledecreases ADP induced
plt aggregation.
• Plavix-ADP receptor
antagonist.
• Pentoxifyllin- inhibits
plt aggregation
Platelet Disorders
• Heparin induced
thrombocytopenia
(HIT)
• Antiplatelet antibodies
results in platelet
destruction.
• Also causes aggregation
and thrombosis.
• Low doses of heparin.
• LMWH may have less
risk.
• DIC
• Decreased plts,
prolonged PT, PTT.
• Low fibrinogen, high
fibrin split products,
high D-dimers
• Often initiated by
tissue factor.
• Treat underlying cause
Thrombi
• Platelet aggregates
• Fibrin
• Trapped erythrocytes
and leucocytes
– Not part of this
hemostatic process
• This is a deep vein
thrombosis
– Postoperative patients
confined to bed
Thrombotic cycle and influences
Endothelial injury is dominant
influence
• Heart and arterial circulation
• Hypercholesteremia, cigarette smoke
products
• Radiation, bacterial endotoxins
• Results in exposure of subendothelial
collagen, adherence of platelets, release of
tissue factor and local depletion of
prostacyclin (antithrombin)
Alterations in normal blood flow
• Turbulence
– injures endothelium
– Atherosclerotic plaques
• Stasis
– Can create venous thrombi
– Aneurysms cause local stasis
– Deformed cells of Sickle cell anemia cause
vascular occlusions
Stasis and Turbulence
• Disrupt laminar flow (cells in middle)
• Bring platelets into contact with
endothelium
• Prevent dilution of activated clotting
factors by fresh-flowing blood
• Retard inflow of clotting factor
inhibitors
Hypercoagulability
• Leiden Factor- 30% spontaneous venous
thrombosis.
• Most common congenital disorder.
• Resistance to Protein C, defect on factor V
• TX: heparin, warfarin.
• Protein C, S deficiency-5% venous
thromboses. TX: heparin, warfarin.
Hypercoagulability
• Antithrombin III deficiency- 2-3%
thrombosis. Heparin doesn’t work. Can
develop after previous heparin exposure.
• TX: ATIII concentrate, FFP(highest conc)
followed by heparin.
• Polycythemia- defect in platelet function,
usually thrombotic, but can bleed. Keep
HCT<48, PLTS<400 before SX. TX: ASA.
Hypercoagulability
• Lupus Anticoagulant- antiphospholipid
antibodies. Not all patients have SLE. A
procoagulant (prolonged PTT but
hypercoagulable).
• Diagnose by seeing prolonged PTT, false
positive RPR test for syphilis.
• TX: heparin, warfarin.
Hypercoagulability
• Cardiopulmonary Bypass- factor XII
activated, results in hypercoagulable state.
TX: heparin, warfarin.
• Warfarin induced skin necrosis- Occurs
when coumadin started before heparin. Due
to a decrease in protein S,C making patient
transiently hypercoagulable. Patients with
Protien C deficiency highly susceptible.
Hypercoagulability
• May be genetic or
acquired
• Genetic mutations in
the factor V gene
– Mutant factor V is
resistant to
anticoagulant effect of
activated protein C
• Smoking, obesity and
age
• Late pregnancy and
postpartum
– amniotic fluid infusion
into circulation
• Disseminated cancers
– tumors release
procoagulants
• Advanced age, bed
rest and
immobilization
Hematologic Drugs
• Warfarin- prevents Vit K dependent
decarboxylation of glutamic residues on Vit
K dependent factors.
• Dextran- inhibits platelets and coagulation
factors.
• Sequential compression devices-improve
venous return but also induce fibrinolysis
with compression (release of tPA).
Hematologic Drugs
• Heparin- activates antithrombin III.
• Reversed with protamine (1-1.5 protamine
per 100u of heparin).
• Half-life 60-90 min.
• Long term heparin use causes osteoporosis,
alopecia. Does not cross BBB.
• Protamine side-effects are hypotension,
bradycardia, decreased heart function.
Hematologic Drugs
• Hirudin- leeches, thrombin inhibitor.
• Ancrod- Malayan pit viper venom, stimulates
tPA release.
• Amicar-antifibrinolytic, procoagulant, inhibits
plasmin. Used in DIC, persistent bleeding
following CABG, thrombolytic overdoses.
• Streptokinase, tPA-need to follow fibrinogen
levels, levels<100 associated with severe bleeding.
Fate of thrombus
• Propagation
– Accumulate more
platelets and fibrin and
obstruct a critical
vessel
• Embolization
– Dislodge thrombi and
transported to other
sites in vasculature
Fate of thrombus,
continued
• Dissolution/resolution
– Removed by
fibrinolytic activity
• Organization
– Induce inflammation
and fibrosis and may
reopen and allow blood
flow
Fates continued
• Recanalization
– Openings and even
blood vessels created
in thrombus