Pathos Chapter 4 Flashcards
Hemostasis occurs in what two stages?
primary and secondary
What does primary hemostasis involve?
forms a weak platelet plug and is mediated by interaction between platelets and the vessel wall
What does secondary hemostasis involve?
stabilizes the platelet plug and is mediated by the coagulation cascade
What is the first step of primary hemostasis?
Transient vasoconstriction of the damaged vessel that is mediated by reflex neural stimulation and endothelin release from endothelial cells
What is the second step of primary hemostasis?
Platelet adhesion to the surface of disrupted vessel via vMF binding to exposed sub endothelial collagen and GPIb on platelet surface.
vMF comes from Weibel-Palade bodies of endothelial cells and a-granules of platelets when activated
What is the third step of primary hemostasis?
Platelet degranulation caused by adhesion that induces shape change in the platelets and release of the contents of alpha and dense granules
What are the contents of dense granules of platelets?
ADP which promotes exposure of GPIIb/IIIA receptor on platelets and calcium which is needed for the coagulation cascade
What is the fourth step of primary hemostasis?
Platelet aggregation at the site of the injury via GPIIb/IIIa using fibrinogen (from plasma) as a linking molecules; results in formation of a weak platelet plug that is stabilized in secondary hemostasis
What is the normal platelet count in blood?
150-400 K/ul; less than 50 K/ul leads to symptoms
What is a normal bleeding time for cutaneous cuts?
2-7 minutes
What is Bernard-Soulier syndrome?
genetic deficiency of GPIb on platelets
What is Glanzmann thrombasthenia?
genetic deficiency of GPIIn/IIIa impairing platelet aggregation
What is the main purpose of secondary hemostasis?
Stabilizing the weak platelet plug formed during primary hemostasis
How does secondary hemostasis make a clot stronger?
The coagulation cascade generates thrombin, which converts fibrinogen in the platelet plug to fibrin. The fibrin is then cross-linked to form a stable thrombus
Coagulation cascade factors are made where?
the liver in inactive states
What things are needed to activate the coagulation cascade?
intrinsic- subendothelial collagen activates factor XII
extrinsic- tissue thromboplastin activates factor VII
phospholipid surface of platelets
calcium from dense granules of platelets
What is PT?
prothrombin time- measures extrinsic (factor VII) and common (factors II, V, X, and fibrinogen) pathways
What is PPT?
partial thromboplastin time- measures intrinsic (factors XII, XI, IX, and VIII) and common (factors II, V, X, and fibrinogen) pathways
What is hemophilia A caused by?
genetic factor VIII deficiency
What is the MOI of hemophilia A?
X-linked; more common in men
can arise simplex
When should hemophilia a be suspected?
Pt experiences deep tissue, joint, and post surgical bleeding
How does Hemophilia A affect PT and PTT? Other lab findings?
PT- normal
PTT- elevated
VIII- low
normal platelet count and bleeding time
What is hemophilia B caused by?
aka Christmas disease
genetic factor IX deficiency
Clinical finding of Hemophilia B?
same as hemophilia A (PT normal, PTT elevated, normal platelet and bleeding time), but IX is low instead of VIII
What is Von Willebrand disease caused by?
genetic vMF deficiency- most common inherited genetic disorder
MOI of Von Willebrand disease?
AD
Clinical finding of Von Willebrand disease?
mild mucosal and skin bleeding
low vMF
increased bleeding time and elevated PTT
decreased VIII half-life (vMF stabilizes it usually) however, no deep tissue, joint, and post surgical bleeding seen n hemophilia A
Abnormal ristocetin test- ristocetin induces platelet agglutination by causing vMF to bind to GPIb; lack of vMF= impaired agglutination= abnormal test
How do you treat Von Willebrand disease?
desmopressin (ADH analog) which increases vMF release from Weibel-Palade bodies on endothelial cells
How does vitamin K deficiency impair coagulation?
Vitamin K is needed for gram carboxylation of factor II, VII, IX
What might cause vitamin K deficiency?
Newborns can be deficient of the normal flora of the GI that synthesize vitamin K (vitamin K is given prophylactically to all newborns at birth to prevent hemorrhagic disease)
Long-term antibiotic therapy disrupts vitamin-K producing bacteria in the GI tract
Malabsorption leads to deficiency of fat-soluble vitamins, including vitamin K
What does tissue plasminogen activator do?
tPA converts plasminogen to plasmin, which is responsible for cleaving fibrin and serum fibrinogen, destroying coagulation factors and blocking platelet aggregation
What inactivates plasmin?
a2-antiplasmin
What could decrease the levels of a2-antiplasmin in the body?
cirrhosis of the liver
What prevents the activation of plasminogen (e.g. for treatment in cirrhosis)?
aminocaproic acid
What are the three major risk factors for thrombosis?
disruption in blood flow
endothelial cell damage
hyper coagulable state (Virchow triad)
Why does disruption in blood flow increase the risk of thrombosis?
blood flow is normally continuous and laminar, keeping platelets and factors dispersed and inactivated. Turbulent flow and stasis disrupts this
Why does endothelial cell damage increase the risk of thrombosis?
exposes the sub endothelial collagen and underlying tissue factor and prevents the formation of PGI2 and NO from healthy endothelial cells that cause vasodilation and prevent platelet aggregation
prevents healthy endothelial cells from producing heparin-like molecules (augment antithrombin III which inactivates thrombin and other factors)
prevents healthy endothelial cells from producing tPA from converting plasminogen to plasmin
prevents healthy endothelial cells from producing thrombomodulin which redirects thrombin to activate protein C, which inactivates factors V and VIII
What are some common causes of endothelial cell damage?
atherosclerosis, vasculitis, and high levels of homocysteine
What would cause an increase in levels of homocysteine?
vitamin B12 and folate deficiency
Mechanism:
i. folic acid circulates as methyl-THF in the serum
ii. Methyl is transferred to cobalamin (vitamin B12), allowing THF to participate in the synthesis of DNA precursors
iii. Cobalamin transfers methyl to homocysteine resulting in methionine
iv. Lack of vitamin B12 or folate lead to decreased conversion of homocysteine to methionine resulting in buildup of homocysteine
or Cystathionine beta synthase (CBS) deficiency- with homocysteinuria
i. CBS converts homocystine to cystathionine
ii. characterized by vessel thrombosis, mental retardation, lens dislocation, and long slender fingers
What causes hypercoagulable state?
i. due to excessive procoagulant proteins or defective anticoagulant proteins; may be inherited or acquired
classic presentation is recurrent DVTs or DVT at a young age
ii. Protein C or S deficiency (AD)
iii. Factor V Leiden
iv. Prothrombin 20210A
vi. ATIII deficiency
vii. Oral contraceptives
How does protein C or S deficiency cause a hypercoagulable state?
protein C and S normally inactivate factors V and VIII
this causes increased risk for warfarin skin necrosis
-the initial stage of warfarin therapy results in a temporary deficiency of proteins C and S (due to shorter half life) relative to factors II, VII, IX, and X
How does Factor V Leiden cause a hypercoagulable state?
mutated form of factor V that lacks the cleavage site for deactivation by proteins C and S
How does Prothrombin 20210A cause a hypercoagulable state?
an inherited point mutation in prothrombin that results in increased gene expression, increasing risk of thrombus formation
How does ATIII deficiency cause a hypercoagulable state?
decreases the protective effect of heparin-like molecules produced by the endothelium, increasing the risk for thrombosis
heparin-like molecules normally activate ATIII, which inactivates thrombin and coagulation factors
How do oral contraceptives cause a hypercoagulable state?
estrogen indues increased production of coagulation factors
