Hemostasis

Question 1

What cell types are involved in primary hemostasis? secondary hemostasis?

Answer 1

primary - platelets

secondary - coagulation cascade

Question 2

What is the process of hemostasis?

Answer 2

repair of an injured blood vessel that involves a formation of a clot at the site of injury

Question 3

what are the steps in primary hemostasis?

Answer 3

reflexive, transient vasoconstriction. Von Willebrand factor (vWF) binds to the exposed sub endothelial collagen. Via receptor GpIb, platelets bind to vWF. Platelets release the contents of their granules. ADP from the granules upregulate the GpIIb/IIIa receptor that allows platelets to cross-link and thromboxane A2 promotes platelet aggregation. Platelets aggregate using fibrinogen as a linker molecule and form a weak plug

Question 4

what are the qualitative disorders of platelets? what are the quantitative disorders of platelets?

Answer 4

qualitative - Bernard Soulier syndrome, Glanzmann thrombasthenia, uremia, aspirin
quantitative - Immune thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome

Question 5

What are the major symptoms of a platelet disorder? What are doctors most worried about?

Answer 5

mucosal bleeding - epistaxis, hemoptysis, hematuria, GI bleeding, menorrhagia. Most concerned about an intracranial bleed.
skin bleeding - petechiae, purpura, ecchymoses

Question 6

What is the pathogenesis of ITP (immune thrombocytopenic purpura)? What are the main differences in the acute versus chronic forms?

Answer 6

Autoantibodies (IgGs) against platelets are made by plasma cells in the spleen and the antibody bound platelets are destroyed by splenic macrophages, leading to thrombocytopenia.
The acute form usually occurs in children after a viral infection or immunization
The chronic form usually occurs in adults, especially in patients with SLE

Question 7

What is microangiopathic hemolytic uremia? How do thrombotic thrombocytopenic purpura and hemolytic uremic syndrome lead to it?

Answer 7

MHU = platelets form microthrombi over a large area, leading to thrombocytopenia. RBCs get sheared and burst as they cross the micro thrombi leading to anemia and schistocytes.
TTP and HUS cause microthrombi formation.
In TTP, a defective ADAMTS13 enzyme results in improper structure of vWF and thus abnormal platelet adhesion and microthrombi.
In HUS, drugs or infection (usually E. coli O157:H7) damages endothelial cells leading to the formation of microthrombi.

Question 8

What is the pathogenesis of Bernard-Soulier syndrome?

Answer 8

genetic deficiency in the GpIb receptor leading to impaired platelet adhesion
Blood smear shows mild thrombocytopenia and enlarged platelets (more immature)

Question 9

what is the pathogenesis of Glanzmann thrombasthenia?

Answer 9

genetic deficiency in the GpIIb/IIIa receptor leading to impaired platelet aggregation.

Question 10

What effect does aspirin have on platelets?

Answer 10

Aspirin inhibits cyclooxygenase so the platelets can’t make thromboxane A2 leading to impaired platelet aggregation.

Question 11

What effect does uremia have on platelets?

Answer 11

Impairs platelet adhesion and aggregation

Question 12

How does secondary hemostasis strengthen the weak platelet plug formed in primary hemostasis?

Answer 12

The coagulation cascade forms thrombin which converts fibrinogen (which is linking the platelets together) into fibrin. Fibrin is then cross-linked, making the clot much more stable.

Question 13

What factors are involved in the extrinsic pathway of the coagulation cascade? intrinsic pathway of the coagulation cascade?

Answer 13

extrinsic: tissue thromboplastin -> factor VII -> factor X -> factor V -> factor II -> factor I
intrinsic: sub endothelial collagen -> factor XII -> factor XI -> factor IX -> factor VIII -> factor X -> factor V -> factor II -> factor I

Question 14

prothrombin time measures which coagulation pathway? partial thromboplastin time measures which coagulation pathway?

Answer 14

PT - extrinsic pathway

PTT - intrinsic pathway

Question 15

What is the difference between hemophilia A and hemophilia B? What would be expected for the bleeding time, platelet count, PT and PTT?

Answer 15

Hemophilia A - deficiency in factor VIII
Hemophilia B - deficiency in factor IX
Elevated PTT, normal PT, normal platelet count, normal bleeding time

Question 16

What is the pathogenesis of Von Willebrand’s disease? What would be expected for the bleeding time, platelet count, PT and PTT? What is the treatment for this disease?

Answer 16

Von Willebrand’s disease is a genetic deficiency or defective vWF that impairs platelet adhesion. Elevated bleeding time, elevated PTT (vWF stabilizes FVIII so in this disease there will be decreased levels of FVIII), normal PT, normal platelet count. Treatment is desmopressin which causes endothelial cells to release vWF from the Weibel-Palade bodies

Question 17

How does vitamin K deficiency lead to a disorder of hemostasis?

Answer 17

Vitamin K, activated by epoxide reductase in the liver, carboxylates/activates factors II, VII, IX, X, protein C and protein S. Without carboxylation, these factors cannot function.

Question 18

What is the pathogenesis of DIC (disseminated intravascular coagulation)? What is the best screening test for DIC?

Answer 18

pathologic activation of the coagulation cascade consumes platelets and coagulation factors in microthrombi which can lead to ischemia and infarction and thrombocytopenia and low levels of coagulation factors. D-dimer is the best screening test for DIC. D-dimer is formed by the splitting of cross-linked fibrin

Question 19

How is the thrombus removed after the damaged vessel heals?

Answer 19

Through the process of fibrinolysis: tissue plasminogen activator (tPA) converts plasminogen to plasmin. Plasmin cleaves fibrin cross-links and destroys any remaining fibrinogen or coagulation factors.

Question 20

What are the two features of a thrombus that distinguishes it from a post-mortem clot?

Answer 20

lines of Zahn and attachment to the vessel wall

Question 21

What are the three major risk factors for thrombosis?

Answer 21

stasis/turbulent blood flow, endothelial damage and hyper coagulable state (Virchow triad)

Question 22

How do endothelial cells normally protect against thrombosis?

Answer 22

1. Block exposure to subendothelial collagen and tissue factor
2. produce prostacyclin I2 and NO which cause vasodilation and inhibit platelet aggregation
3. secrete heparin-like molecules which stimulates antithrombin III
4. secretes tissue plasminogen activator (tPA)
5. secrete thrombomodulin which redirects thrombin to activate protein C instead of fibrinogen. Protein C inactivates factors V and VIII

Question 23

What are the main causes of endothelial damage, increasing risk of thrombus formation?

Answer 23

atherosclerosis, vasculitis, elevated homocysteine. High levels of homocysteine can come from a vitamin B12 or folate deficiency a genetic deficiency in the enzyme cystathionine beta synthase

Question 24

What can induce a hyper coagulable state?

Answer 24

Protein C or S deficiency - protein C and S inactivate factors V and VIII
Factor V Leiden - a mutated form of factor V that lacks the cleavage site used by protein C and S
Mutated prothrombin - prothrombin 20210A results in increased gene expression
Antithrombin III deficiency
oral contraceptives - estrogen increases production of coagulation factors

Question 25

What types of emboli are there?

Answer 25

thromboembolus
fat embolus - associated with bone breaks
gas embolus - decompression sickness
amniotic fluid embolus