Hem I and II/Hemostasis and Thrombosis Flashcards
What are the 4 general stages of hemostasis?
- Transient vasoconstriction
- Platelet adhesion to surface of disrupted vessel
- Platelet degranulation
- Platelet aggregation
When injury damages subendothelial tissue, what factor is released?
von Willebrand factor
Via which receptor does vWF contribute to platelet adhesion?
Gp1b to result in platelet adhesion
What two sources do vWF come from?
Weibel-Palade bodies of endothelial cells (vast majority) and some from alpha-granules of platelets
What is the disease which is a Gp1b deficiency? What is the result?
Bernard-Soulier disease; impaired platelet adhesion which leads to bleeding
What two factors are released by activated endothelial cells?
They synthesize tissue factor and secrete plasminogen activator inhibitor (PAI) which limits fibrinolysis
What are the following skin bleeding signs called:
1-2 mm
>3 mm
>1 cm
1-2 mm = petechiae (usually due to platelet deficiency or vit C deficiency; also sign of thrombocytopenia)
3-5 mm = purpura (also due to vasculitis or trauma)
>1 cm are ecchymoses (bruises)
What causes immune thrombocytopenic purpura (ITP)?
Autoimmune production of IgG against platelet antigens (e.g., GPIIb/IIIa)
In what organ does the events that eliminate platelets in immune thrombocytopenic purpura take place?
Most of the events take place in the spleen; the spleen will make the plasma cells that create the antibodies and they have macrophages that consume the antibody bound platelets
What are the two types of cytoplasmic granules that platelets have, and what do each contain?
Alpha granules: fibrinogen, factor V and VIII, vWF
Delta granules: ADP, ATP, calcium, serotonin, epinephrine
What would the PT/PTT values be for ITP?
Normal PT/PTT; it is a disorder of primary hemostasis and the coagulation cascade is unaffected.
What is microangiopathic hemolytic anemia?
Is the pathologic formation of platelet microthrombi in small vessels; the thrombi formation consumes platelets and shears RBCs resulting in hemolytic anemia with schistocytes
What two diseases is microangiopathic hemolytic anemia seen?
thrombocytopenic purpura and hemolytic uremic syndrome
What is the genetic cause of TTP?
Decreased ADAMTS13 which normally cleaves vWF Thus the resulting large multimers of vWF lead to platelet adhesion.
What is the cause of hemolytic uremic syndrome (HUS)?
Due to endothelial damage by drugs or via infection (esp. with undercooked beef)
What is the PT/PTT value for microangiopathic hemolytic anemia diseases?
Both are normal because this is a disease of primary hemostasis, not of coagulation cascade
What is the genetic defect in Glanzmann thromasthenia?
Due to a genetic GPIIb/IIIa deficiency; impairs platelet aggregation
What vasoconstrictor does aspirin block the synthesis of and where does this vasoconstrictor come from?
Aspirin blocks the synthesis of TXA2 from activated platelets. TXA2 is a prostaglandin made by COX enzymes which are inhibited by aspirin.
What role does ADP released from dense granules of platelets have?
It is a potent mediator of platelet aggregation
How are GIIb/IIIa receptors activated?
These receptors are expressed on activated platelets which bind fibrinogen and promotes platelet aggregation; this forms the platelet plug. Their exposure is promoted by ADP release from delta granules on other platelets
What is the overarching goal of secondary hemostasis and generally how is this accomplished?
Overall goal is to support the primary platelet plug. Accomplished via conversion of fibrinogen to fibrin which is cross linked.
How is fibrinogen converted to fibrin?
Via thrombin
What organ produces the factors of the coagulation cascade?
Liver
What activates the extrinsic pathway of the coagulation cascade?
Tissue thromboplastin
What activates the intrinsic pathway of the coagulation cascade?
Subendothelial collagen
The liver produces the factors of the coagulation cascade in an inactive form. What is required for their activation (3 things)?
- Exposure to activating substance (tissue thromboplastin or subendothelial collagen)
- Phospholipid surface of platelets
- Calcium (derived from platelet dense granules)
What factors make up the intrinsic pathway? What activates the intrinsic pathway?
Factor XII -> XI -> IX -> VIII -> X
Activated by subendothelial collagen
What factors make up the extrinsic pathway? What activates the extrinsic pathway?
Factor VII -> X
Activated by thromboplastin
What lab measure assesses the extrinsic pathway, and which lab measure assesses the intrinsic pathway?
Extrinsic pathway is assessed by prothrombin time (PT) while intrinsic pathway is assessed by partial thromboplastin time (PTT)
What factors make up the common pathway of the coagulation cascade?
X -> V -> II -> I (II = thrombin and I = fibrin; technically Ia is fibrin and is cleaved due to thrombin)
What factors are activated by thrombin?
Thrombin converts fibrinogen into fibrin which allows for clotting. Also activates factor XI, VIII and V. Also, XIII which cross links fibrin.
How does thrombin lead to platelet activation?
Via activation of protease-activated receptors (PARs)
How does thrombin mediate proinflammatory effects?
PARs are on immune cells in addition to being present on platelets and mediates these proinflammatory effects
What genetic defect is present in hemophilia A? What lab result (PT or PTT) would you expect to be abnormal?
Factor VIII deficiency. Part of the intrinsic pathway so PTT should be abnormal (is elevated) and PT normal.
What genetic defect is hemophilia B a result of?
Factor IX deficiency (also resembles hemophilia A because it is also part of the intrinsic pathway)
What causes coagulation factor inhibitor disease?
Is a result of an acquired antibody against a coagulation factor resulting in impaired factor function. mostly against factor VIII (thus resembles hemophilia A)
Which factors require vitamin K?
factors II, VII, IX, X and proteins C and S where gamma carboxylation is needed for functioning protein.
What is warfarin’s mechanism of action?
Inhibits vitamin K synthesis and thus
Is tissue plasminogen activator a coagulation promoter or inhibitor?
tPA inhibits coagulation via conversion of plasminogen to plasmin on endothelial cells which breaks clots.
What prevents the activity of plasmin?
alpha2-antiplasmin
How does liver failure lead to abnormal secondary hemostasis?
- Decreased production of the coagulation factors.
2. Decreased activation of vitamin K by epoxide reductase
What is the molecule that inactivates thrombin? What organ produces it?
Antithrombin III made by the liver and is activated by heparin-like molecules on endothelial cells.
What is the mechanism of action of heparin?
Is an anticoagulant that potentiates the antithrombin III activity
How does protein C inhibit clotting and what is its required cofactor (and what do both of these factors require)?
Protein C is made by the liver, requires cofactor of protein S and both protein C and S are vitamin K dependent. Inhibits clotting factors Va and VIIIa
