Hemostasis and Related Disorders

Question 1

Hemostasis (and its two stages)

Answer 1

formation of a <b>thrombus</b>/clot in response to BV wall damage

Primary: <b>weak platelet plug</b>
Secondary: <b>coagulation cascade stabilizes plug</b>

Question 2

4 stages of Primary Hemostasis

Answer 2

1. <b>VASOCONSTRICTION</b>: reflex neural stimulation & endothelin
2. <b>platelet ADHESION</b>: Weibel Palade bodies & platelet a-granules–> vWF–> binds exposed collagen–> platelets bind vWF using GPIb receptor
3. <b>platelet DEGRANULATION</b>: adhesion causes release of–> ADP (released from granules; promotes GPIIb/IIIa) & TXA2 (made by platelet COX)
4. <b>platelet AGGREGATION</b>: platelet plug from aggregation via GPIIb/IIIa using fibrinogen as a linking molecule

Question 3

What are the sources of vWF?

Answer 3

1. Weibel Palade bodies of endothelial cells

2. platelet a-granules

Question 4

Secondary Hemostasis (and how its factors are activated)

Answer 4

coagulation cascade stabilizes platelet plug
*generation of thrombin–> converts fibrinogen to <b>fibrin (cross-linked)</b>

-factors are produced by liver and activated by: <b>exposure to an activating substance, phospholipid surface of platelets & calcium</b>

Question 5

Overview of Primary Hemostasis Disorders and Secondary Hemostasis Disorders

Answer 5

<b>Primary Hemostasis Disorders</b> (ITP, TTP and HUS causing Microthrombic Hemolytic Anemia, 4 Qualitative Platelet disorders)

• Cause: usually due to abnormalities in platelets (quantitative or qualitative)
• Clinical Features: <b>mucosal</b> (epistaxis, hemoptysis, GI bleeding, hematuria, menorrhagia, intracranial bleeding) <b>and skin bleeding</b> (petechiae, purpura, ecchymoses, easy bruising)

<b>Secondary Hemostasis Disorders</b> (Hemophila A & B, Coagulation Factor Inhibitor, von Willebrand Disease, VitK deficiency)

• Cause: -<b>factor abnormalities</b>
• Clinical Features: <b>deep</b> tissue bleeding into muscles and joints & rebleeding after surgical procedures

Question 6

Petechiae is a sign of:

Answer 6

Quantitative disorder of primary hemostasis (i.e. thrombocytopenia)

Question 7

What do blood smears & bone marrow biopsies assess?

Answer 7

Blood smears: #/size of platelets

Bone marrow biopsies: megakaryocytes

Question 8

Immune Thrombocytopenic Purpura (ITP)–> cause, forms, labs, treatment

Answer 8

-most common cause of thrombocytopenia in which there is an autoimmune production of <b>IgG, via spleen plasma cells, against platelet antigens</b>

• <b>Acute</b>: self-limited after viral infection in children
• <b>Chronic</b>: primary (unknown etiology) or secondary (underlying issue) in women of child-bearing age (can cross placenta)
• <b>low platelets, normal PT/PTT), high megakaryocytes</b>
• Treatment: corticosteroids (adults- relapse), IVIG (short-lived effect) & <b>splenectomy</b> (removed primary source of Ab and site of platelet destruction)

Question 9

Microangiopathic Hemolytic Anemia–> causes, labs, treatment

Answer 9

• seen in <b>TTP</b> (Thrombotic Thrombocytopenic Purpura) and <b>HUS</b> (Hemolytic Uremic Syndrome) causing formation of platelet microthrombi that shears RBCs
• TTP–> acquired autoantibody resulting in <b>decreased ADAMTS13</b> which normally cleaves vWF causing renal insufficiency
• HUS–> <b>endothelial damage</b> from drugs or infection (E coli O157:H7 verotoxin) affecting ADAMTS13 causing CNS abnormalities
• <b>thrombocytopenia, increased bleeding time, normal PT/PTT, anemia, high megakaryocytes</b>
• Treatment: plasmapheresis (removed autoantibodies) and corticosteroids (decreases autoantibody production)

Question 10

4 Qualitative Platelet Disorders

Answer 10

1. <b>Bernard-Soulier Syndrome</b>: no adhesion from GPIb deficiency (thrombocytopenia & enlarged/immature platelets)
2. <b>Glanzmann Thrombasthenia</b>: impaired platelet aggregation from GPIIb/IIIa deficiency
3. <b>Aspirin</b>: irreversibly inactivates COX (lack of TXA2) impairing aggregation
4. <b>Uremia</b>: disrupts function impairing adhesion & aggregation

Question 11

Extrinsic and Intrinsic Pathways to activate factors of Secondary Hemostasis

Answer 11

Extrinsic: <b>factor VII (7)</b> activated by tissue thromboplastin; measured by Prothrombin time (PT)

Intrinsic: <b>factors XII (12), XI (11), IX (9), VIII (8)</b> activated by subendothelial collagen; measured by Partial thromboplastin time (PTT)

Question 12

Hemophilia A–> cause, symptoms and labs

Answer 12

• X-linked or de novo mutation causing factor VIII (8) deficiency
• secondary hemostasis causing deep tissue, joint & postsurgical bleeding

-<b>labs: high PTT, low FVIII, normal PT, platelet count and bleeding time</b>

Question 13

Hemophilia B–> cause

Answer 13

-factor IX (9) deficiency

Question 14

Coagulation Factor Inhibitor–> cause and labs

Answer 14

• <b>acquired antibody</b> against a coagulation factor (usually VIII)
• similar labs to Hemophila A: high PTT, low FVIII, normal PT, platelet count and bleeding time

**<b>PTT canNOT be corrected due to tremendous amount of antibody against factor VIII</b>

Question 15

Von Willebrane Disease–> cause, symptoms, labs, treatment

Answer 15

• vWF deficiency impairing platelet adhesion (usually autosomal dominant)
• causes: mucosal and skin bleeding
• <b>labs: high bleeding time, high PTT (since vWF usually stablizes it), abnormal ristocetin test, normal PT</b>
• treatment: <b>desmopressin</b>–> increases vWF release from Weibel Palade bodies of endothelial cells

Question 16

RIstocetin

Answer 16

used to detect for von Willebrand disease

<b>-causes vWF to bind GPIb inducing platelet agglutination</b>
-abnormal if there is a lack of vWF since agglutination will be impaired

Question 17

Vitamin K’s role and deficiency

Answer 17

Vit K enters through gut–> activation in liver by <b>epoxide reductase–> y carboxylation of factors II, VII, IX, X (2, 7, 9, 10)</b> which is required for factor function

-deficiency occurs in: newborns, long-term antibiotic therapy & malabsorption

Question 18

other causes of abnormal Secondary Hemostasis

Answer 18

• <b>liver failure</b>: decreased production of coagulation factors and decreased activation of vitamin K by epoxide reductase
• <b>large volume transfusion<b>: dilutes coagulation factors (relative deficiency)</b></b>

Question 19

Heparin-Induced Thrombocytopenia–> cause and what it potentially can lead to

Answer 19

• platelet destruction after Heparin forms <b>PF4 and IgG Ab</b>
• fragments of destroyed platelets may <b>activate remaining platelets, leading to thrombosis</b>

Question 20

Disseminated Intravascular Coagulation (DIC)–> causes, labs, treatment

Answer 20

• pathologic <b>activation of the coagulation cascade</b> causing widespread microthrombi & bleeding from consumption of platelets and factors
• secondary to another disease: <b>obstetric complications</b> (tissue thromboplastin in amniotic fluid), <b>sepsis</b> (endotoxins induce endothelial cells to make tissue factor), <b>adenocarcinoma</b> (mucin), <b>APL</b> (primary granules), <b>rattlesnake bite</b> (venom)
• <b>labs: low platelet count & fibrinogen, high PT/PTT & D-dimer, microangiopathic hemolytic anemia</b>
• treatment: transfusing blood products and cryoprecipitate

Question 21

D-dimer

Answer 21

• best screening test for DIC
• derived from <b>splitting of cross-linked fibrin thrombi</b>

<i>fibrinolysis disorders: increased fibrogen split products without D-dimer since there are no fibrin thrombi</i>

Question 22

Fibrinolysis

Answer 22

-removal of thrombus

**<b>tPA converts plasminogen to plasmin (cleaves fibrin & fibrinogen, destroys coagulation factors and blocks platelet aggregation preventing formation of new clots</b>)

**plasmin is inactivated by a2-antiplasmin to prevent bleeding out

Question 23

Disorders of Fibrinolysis–> definition, causes, labs, treatment

Answer 23

-plasmin overactivity leading to increased bleeding (resembles DIC)

• <b>Radical Prostatectomy</b> (plasmin is activated by urokinase)
• <b>Cirrhosis</b> (reduced production of a2-antiplasmin)

<b>labs: high PT/PTT, bleeding time & fibrinogen split products (without D-dimer), normal platelet count</b>

-treatment: amincaproic acid (blocks plasminogen activation)</b>

Question 24

thrombosis–> characterization and risk factors

Answer 24

-blood clot characterized by <b>lines of Zahn (platelets/fibrin and RBCs), & attachment to vessel wall</b>

• risk factors:
  1. <b>blood flow disruption</b>
  2. <b>endothelial cell damage</b>
  3. <b>hypercoaguable state</b>

Question 25

Blood flow disruption (risk factor for thrombosis)

Answer 25

• continuous & laminar–> stasis & turbulence

- from immobilization, cardiac wall dysfunction, aneurysm

Question 26

Endothelial cell damage (risk factor for thrombosis)

Answer 26

• from atherosclerosis, vasculitis, high levels of homocysteine
• <b>vitamin B and folate deficiency</b>: mildly elevated homocysteine levels (methyl is donated from THF–> cobalamin/VB12–> homocysteine which becomes methionine
• <b>cystathionine beta synthase deficiency</b>: CBS normally converts homocysteine to cystathionine thus a deficiency results in buildup

Question 27

How do endothelial cells normally prevent formation of thrombosis?

Answer 27

• <b>blocking subendothelial collagen exposure</b>
• producing <b>PGI2 and NO</b> (vasodilation & inhibition of platelet aggregation)
• <b>heparin-like molecule secretion</b> (augments antithrombin III–> inactivates thrombin & coagulation factors)
• <b>tPA secretion</b> (converts plasminogen to plasmin cleaving fibrin, destroys coagulation factors and blocks platelet aggregation)
• <b>thrombomodulin</b> (redirects thrombin to activate protein C–> inactivates factors V and VIII)

Question 28

Hypercoaguable state (risk factor for thrombosis)

Answer 28

• excessive procuagulant proteins or defective antiboagulant proteins (inherited or acquired)
• <b>Protein C or S deficiency</b> decreases negative feedback since normally inactive factors V & VIII; increased risk for warfarin skin necrosis
• <b>Factor V Leiden</b>: mutated factor V that lacks cleavage side for deactivation by proteins C & S (inherited)
• <b>Prothrombin 20210A</b>: mutation in prothrombin–> increased expression–> more thrombin–> thrombus formation (inherited)
• <b>ATIII deficiency</b>: decreases protective effect of heparin-like molecules produced by endothelium which normally activate ATIII; PTT does not risk with standard heparin dosing
• <b>Oral Contraceptives</b>: estrogen increases coagulation factors