Pathoma - Hemostasis and Related Disorders

Question 1

What are the steps of primary hemostasis

Answer 1

(1) Transient vasoconstriction of damaged vessel; mediated by reflex neural stimulation and endothelin release
(2) Platelet adhesion; vWF (from Weibel-Palade bodies and alpha-granules of platelets) binds to exposed collagen; platelets bind vWF via GPIb
(3) Platelet degranulation; adhesion leads to platelet shape change which causes degranulation; ADP released from dense granules which promotes exposure of GP2b/3a receptor on platelets; TXA2 synthesized by platelet COX and released, which calls in other platelets
(4) Platelet aggregation; platelets bind to each other via GP2b3a using fibrinogen as a linking molecule

Question 2

What is the cause of Immune thrombocytopenic purpura (ITP)

Answer 2

Autoimmune production of IgG against platelet antigens (e.g. GP2a3b); spleen produces the antibody and also produces macrophages to consume the antibody-bound platelets

Question 3

What is microangiopathic hemolytic anemia and what are the 2 types

Answer 3

Pathologic formation of platelet microthrombi in small vessels which leads to shearing of RBCs

Seen in thrombotic thromocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS)

Question 4

What is the cause of thrombotic thrombocytopenic purpura (TTP)

Answer 4

Due to decreased ADAMTS13 (usually autoantibody against ADAMTS13)

ADAMTS13 is what degrades vWF, so if vWF cannot be degraded it accumulates and causes continued platelet adhesion

Question 5

What is the cause of hemolytic uremic syndrome (HUS)

Answer 5

Caused by endothelial damage due to drugs or infection; usually E. Coli O157:H7 verotoxin causing endothelial damage

Question 6

Genetic deficiency of GPIb is called ___?

Answer 6

Bernard-Soulier syndrome

Genetic GPIb deficiency - impaired platelet adhesion

Will show enlarged platelets on blood smear (“big suckers”) because bone marrow is producing immature platelets

Question 7

Genetic deficiency of GP2b3a is called ___?

Answer 7

Glanzmann thrombasthenia

Genetic GP2b3a deficiency - impaired platelet aggregation

Question 8

How does Aspirin affect platelet function

Answer 8

Aspirin inactivates COX, so TXA2 cannot be created. TXA2 is needed for platelet aggregation (it is released by platelets to call in other platelets)

Question 9

What are the coag factors involved in the extrinsic, intrinsic, and common pathways

Answer 9

Intrinsic pathway:
Subendothelial collagen - XII - XI - IX + VIII - X

Extrinsic pathway:
Tissue thromboplastin - VII - X

Common pathway:
X + V converts II (prothrombin) to IIa (thrombin)

Thrombin then converts fibronogen (I) to fibrin (Ia)

Fibrin + XIII leads to cross-linked fibrin clot

Question 10

Which pathways do PTT and PT measure

Answer 10

PTT - intrinsic pathway (more #s involved)

PT - extrinsic pathway

Question 11

What is the mechanism of action of Heparin and which lab value is used to measure its effects (PT or PTT)

Answer 11

Heparin binds to Anti-thrombin III, which is responsible for inactivating thrombin and coag factors

PTT

Question 12

What is the mechanism of action of Coumadin (aka Warfarin) and which lab value is used to measure its effects (PT or PTT)

Answer 12

Coumadin blocks epoxide reductase in the liver, which is responsible for activating Vitamin K, which is necessary for gamma-carboxylating of factors 2, 7, 9, 10, C, and S

Question 13

What is the deficiency in Hemophilia A

Answer 13

Factor VIII

Question 14

What is the deficiency in Hemophilia B (Christmas Disease)

Answer 14

Factor IX

Question 15

How do you differentiate between Hemophilia A and antibody against factor VIII

Answer 15

Hemophilia A will have a corrected PTT if patient’s plasma is mixed with normal plasma

Question 16

What is the cause of von Willebrand Disease and why is there an increased PTT

Answer 16

Genetic vWF deficiency

Will present will increased bleeding time but also increased PTT because vWF needed to stabilize factor VIII

Question 17

What is a ristocetin test and what does it test for

Answer 17

Ristocetin test: induces platelet aggregation by causing vWF to bind to platelet GP1b

Will be abnormal in von Willebrand Disease

Question 18

How do you treat von Willebrand Disease

Answer 18

Desmopressin causes release of vWF from Weibel Palade bodies

Question 19

How is Vitamin K activated and which factors does it gamma-carboxylate

Answer 19

Activated by epoxide reductase in the liver

Carboxylates factors 2, 7, 9, 10, C, and S

Question 20

What are causes of Vitamin K deficiency

Answer 20

Newborns (lack of GI bacterial colonization to synthesize Vitamin K; should give vitamin K injections at birth to prevent hemorrhagic disease of the newborn)

Long-term antibiotics (disrupts GI normal flora which synthesizes Vitamin K)

Malabsorption (ADEK are fat soluble vitamins)

Question 21

Describe the mechanism behind Heparin-induced thrombocytopenia

Answer 21

Heparin can form a complex with platelet factor 4 (a platelet surface molecule)
Body forms antibodies against this complex, and these antibodies activate remaining platelets, leading to thrombosis (opposite of what Heparin was supposed to do)

Question 22

Lab values of DIC

Answer 22

• Decreased platelet count
• Increased PT/PTT (due to coag factors being used up)
• Decreased fibronogen (consumed in clotting)
• Microangiopathic hemolytic anemia (microthrombi shearing RBCs)
• Elevated D-dimer (produced from splitting of fibrin)

Question 23

Describe fibrinolysis

Answer 23

Tissue plasminogen activator (tPA) converts plasminogen to plasmin

Actions of plasmin:

• Cleavage of fibrinogen and fibrin
• Destruction of coag factors
• Blockage of platelet aggregation

Plasmin is inactivated by alpha-2-antiplasmin

Question 24

Causes of plasmin overactivity

Answer 24

• Radical prostatectomy (release of urokinase activates plasmin)
• Cirrhosis of the liver (reduced production of alpha2-antiplasmin)

Question 25

How do you differentiate between DIC and disorders of fibrinolysis

Answer 25

Disorders of fibrinolysis will have a normal platelet count (plasmin blocks platelet aggregation) and will not have elevated D-dimer (there are no abnormal clots forming so plasmin will just be splitting fibrinogen - no D-dimer produced - and not fibrin)

Question 26

What is Virchow’s Triad

Answer 26

3 major risk factors for thrombosis:

(1) Disruption of blood flow
(2) Damage to endothelial cells
(3) Hypercoagulable state

Question 27

What are the substances produced by endothelial cells that prevent thrombosis

Answer 27

• Prostacyclin (prevents platelet aggregation)
• NO (vasodilation)
• Heparin-like molecules (augment antithrombin III)
• tissue plasminogen activator (tPA)
• thrombomodulin (redirects thrombin to activate Protein S and C)

Question 28

What does heparin-like molecule do?

Answer 28

Produced by endothelial cells

Augments antithrombin III (which inactivates thrombin and coag factors)

Question 29

What does thrombomodulin do?

Answer 29

Redirects thrombin to activate Protein S and Protein C

Question 30

What do Protein S and Protein C do?

Answer 30

Inactivate factors V and VIII

Question 31

How do vitamin B12 and folate deficiencies increase risk for thrombosis?

Answer 31

Methyl group is transferred from THF (tetra-hydrofolate) to B12 to homocysteine, resulting in methionine

If there is a B12 of folate deficiency, the methyl will never make it to homocysteine and there will be a buildup of homocysteine, which causes endothelial cell damage (one of Virchow’s triad) and increases the risk for thrombosis

Question 32

Besides B12 and folate deficiency, how can you get elevated homocysteine?

And what is the presentation of this disease?

Answer 32

Cystathionine beta synthase (CBS) deficiency

CBS converts homocysteine to cystathionine

This disease is characterized by vessel thrombosis, mental retardation, lens dislocation, and long slender fingers (Marfanoid habitus)

Question 33

What is the mechanism behind Warfarin skin necrosis and what deficiency increases the risk?

Answer 33

Warfarin (Coumadin) blocks epoxide reductase so that Vitamin K cannot be activated

This leads to a decrease in factors 2, 7, 9, 10, C and S; but C and S decrease first (shorter half-life), which can lead to increased risk for thrombosis, especially in the skin

So you should co-administer Heparin in the beginning, until the other factors (2, 7, 9, and 10) also decrease

Question 34

What is Factor V Leiden

Answer 34

Mutated form of factor V that lacks the cleavage site for protein C and S, leading to hypercoagulable state

Question 35

What is Prothrombin 20210A

Answer 35

Inherited point mutation in prothrombin that results in increased gene expression, resulting in increased risk fro thrombus formation

Question 36

What are the effects of ATIII deficiency on effects of Heparin?

Answer 36

Heparin works by binding and activating ATIII

So in the deficiency you need higher doses of Heparin in order to activate the remaining ATIII, and then you can start Coumadin