Chapter 4: Hemostasis COPY

Question 1

What are the objectives of primary and secondary hemostasis?

Answer 1

• Primary hemostasis: forms a weak platelet plug and is mediated by interaction between platelets and the vessel wall
• Secondary hemostasis: stabilizes the platelet plug and is mediated by the coagulation cascade

Question 2

What are the steps of Primary Hemostasis?

Answer 2

1. Transient vasoconstriction of damaged vessel
   
   • mediated by reflex nueral stimulation and endothelial release from endothelial cells
2. Platelet adhesion to the surface of disrupted vessel
   
   • Exposed collagen allows WVF to bind
   • VWF acts as linker molecule allowing platelts to bind to it via GP1B
   • Most VWF comes from Weibel-Palade bodies of endothelial cell
3. Platelet Degranulation
   
   • Adhesion induces shape change in platelets and degranulation with release of multiple mediators
   • ADP and TXA2 call over platelets/promote platelet aggregation
     
     • ADP is released from platelet dense granules which promotes exposure of GPIIb/IIIa receptor on platelets
     • TXA2 is synthesized by platelet cyclooxygenease (COX)
4. Platelet Aggreggation
   
   • platelets aggregate at the site of injury via GPIIb/IIIa using fibrinogen as a linking molecule: results in formation of platelet plug
   • platelet plug is weak: coagulation cascade (secondary hemostasis) stabilizes it

Question 3

What are the clinical characteristics of disorders of primary hemostasis?

Answer 3

• Usually due to abnormalities of the platelets: divided into quantitative or qualitatitve disorders
• Clinical features include mucosal and skin bleeding
  
  • symptoms of mucosal bleeding include epistaxis (most common overall symptom), hemoptysis, GI bleeding, hematuria, and menorrhagia
  • Intracranial bleeding occurs with severe thrombocytopenia
  • Symptoms of skin bleeding: Petechiae, purpura, ecchymoses and easy bruising
    
    • petechiae are a sign of thrombocytopenia and are not usually seen with qualitative disorders

Question 4

What is Immune Thrombocytopenic Purpura (ITP)?

Answer 4

• Autoimmune production of IgG against platelet antigens (GPIIB/IIIa)
• Most common cause of thrombocytopenia in children and adults
• Autoantibodies are being made in the spleen, tagging the platelets and then the macrophages in the spleen are destroying the platelet

Question 5

What is the difference between the acute and chronic form in Immune Thrombocytopenic Purpura?

Answer 5

• Acute IPA
  
  • Arises in children weeks after a viral infection or an immunization
  • Self-limited and usually resolves within weeks of presentation
• Chronic IPA
  
  • Arises in adults, usually women of childbearing age
  • May be primary or secondary
  • May cause short lived thrombocytopenia in offspring since antiplatelet IgG can cross the placenta

Question 6

What are the lab findings associated with Immune Thrombocytopenic Purpura?

Answer 6

• Decreased platelet count
• Normal PT/PTT: coagulation factors are not affected
• Increase megakaryocytes on bone marrow biopsy
  
  • trying to produce more platelets

Question 7

Treatment for those with Immune Thrombocytopenic Purpura

Answer 7

• Initial treatment is corticosteriods
  
  • Children respond well
  • Adults may show early response but often relapse
• IVIG is used to raise platelet count in symptomatic bleeding but its effect is short lived
  
  • giving patient immunoglobulin so macrophages will eat that immunoglobulin instead of the immunoglobulin that is bound to the platelets
  • leaves platelets alone for a little
• Splenectomy elimates the primary source of antibody and the site of platelet destruction

Question 8

What is microangiopathic hemolytic anemia?

Answer 8

• Pathological formation of platelet microthrombi in small vessels
• Platelets are being used up forming inappropriate microthrombi in small vessels
• RBCs are sheared as they cross microthrombi, resulting in hemolytic anemia with schistocytes
• Seen in thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS)

Question 9

What is the cause of thrombotic thrombocytopenic purpura (TTP)?

Answer 9

• Platelets are forming inapproriate thrombi in small vessels b/c of a decrease in ADAMTS13
  
  • ADAMTS13 is an enzyme that normally cleaves vWF multimers into smaller monomers for degradation
  • Large, uncleaved multimers lead to abnormal platelet adhesion, resulting in microthrombi
• Decreased ADAMTS13 is usally due to an acquired autoantibody
• Most commonly seen in adult females

Question 10

What is the cause of Hemolytic Uremic Syndrome?

Answer 10

• Due to endothelial damage by drugs or infection
• RBC hemolysis occurs predominately in the kidneys causing kidney damage
• Classically seen in children with E. coli O157:H7
  
  • Produces E. coli verotoxin which damages endothelial cells causing microthrobi
  • Comes from exposure to undercooked meat

Question 11

What are the clinical findings in TTP and HUS?

Answer 11

• Skin and mucosal bleeding
  
  • getting platelt microthrombi which uses up platelets so have skin/mucosal bleeding b/c thrombocytopenic
• Microangiopathic hemolytic anemia
  
  • RBCs are sheered by microthrombi
• Fever
• Renal Insuffieciency (more common in HUS)
  
  • thrombi involve vessels of the kidney
• CNS abnormalities (more common in TTP)
  
  • thrombi inovlve vessels of the CNS

Question 12

What are the lab findings in TTP/HUS?

Answer 12

• Thrombocytopenia with increased bleeding time
• Normal PT/PTT (coagulation cascade is not activated)
• Anemia with schistocytes
• Increase in megakaryocytres on bone marrow biopsy

Question 13

What is the treatment for Microangiopathic hemolytic anemia?

Answer 13

• Plasmaphersis and corticosteroids
  
  • Remove autoantibody against ADAMTS13
  • More effective for TTP

Question 14

Bernard-Soulier Syndrome

Answer 14

• Qualititative Platelet disorder
• genetic GP1B deficiency
  
  • platelets can’t bind to vWF
• Platelets aggregate but don’t adhere
• Blood smear shows mild thrombocytopenia with enlarged platelets
  
  • platelets don’t live as long with GP1B deficiency
• Ristocetin test is abnormal b/c problem binding to vWF

Question 15

Glanzmann thrombasthenia

Answer 15

• qualitative platelet disorder
• Due to genetic GPIIb/IIIa deficiency
  
  • platelets can’t bind to each other
• Abnormal aggregation to ADP, collagen and epinephrine but normal ristocetin

Question 16

How does aspirin affect platelet aggregation?

Answer 16

• aspirin irreversibly inactivates cyclooxygenase
• TXA2 is synthesized by cyclooxygenase
  
  • responsible for calling in other platelets to aggregate at site of injury
  • less signal for platelet aggregation

Question 17

What happens during secondary hemostasis?

Answer 17

• Stabilizes the weak platelet plug via the coagulation cascade
• Coagulation cascade generates thrombin which converts fibrinogen in the platelet plug to fibrin
• Fibrin is then cross-linked, yielding a stable plate-fibrin thrombus

Question 18

What are the clinical findings typical for disorders of secondary hemostasis?

Answer 18

• Usually due to factor abnormalities
• Clinical features include deep tissue bleeding into muscles and joints (hemarthrosis) and rebleeding after surgical procedures

Question 19

Prothrombin time (PT) vs Partial thromboplastin time (PTT)

Answer 19

• PT: measures extrinsic factor (factor VII) and common factors (II, V, X and fibrinogen) pathways of the coagulation cascade
  
  • Coumadin
• PTT: measures intrinsic (XII, XI, IX, VIII) and common factors (II, V, X, fibrinogen) pathways of the coagulation cascade
  
  • Heparin

Question 20

Hemophilia A

Answer 20

• “Hemophilia Eight”
• Genetic Factor VIII deficiency
• X-linked recessive (predominately affects males)
  
  • Can arise from a new mutation (de novo) without any family history
• Presents with deep tissue, joint and postsurgical bleeding
  
  • BLEEDING INTO JOINTS AND SOFT TISSUE
    
    • Clinical severity depends on the degree of deficiency
• Lab findings include:
  
  • Increased PTT; normal PT
  • Decreased Factor VIII
  • Normal platelet count and bleeding time
• Treatment involves recombinant Factor VIII

Question 21

Hemophilia B (Christmas Disease)

Answer 21

• Clinically resembles Hemophilia A
• Genetic factor IX deficiency

Question 22

Coagulation Factor Inhibitor

Answer 22

• Acquired antibody against a coagulation factor resulting in impaired factor function
  
  • Anti-Factor VIII is the most common
  • Clinical and lab findings are similar to hemophilia A
  • PTT does not correct upon mixing normal plasma with patient’s plasma due to inhibitor
    
    • Mixing study: taking normal plasma and mixing it with the patient’s plasma
    • if the patient has hemophilia A, going to give enough Factor VIII to correct the PTT
    • if the patient has coagulation factor inhibitor, antibodies from patient’s plasma will destroy newly introduced Factor VIII

Question 23

Von Willebrand Disease

Answer 23

• Genetic vWF deficiency
  
  • Most common inherited coagulation disorder
• Most common type is autosomal dominant with decrease in vWF
• Presents with mild mucosal and skin bleeding
• Low vWF leads to problms with platelet adhesion
  
  • vWF stabilizes factor VIII
  • Factor VIII degrades without it
  • vWF won’t cause clinical secondary hemostasis issues
• Lab findings:
  
  • Increased bleeding time (bad platelet adhesion)
  • Increased PTT (Decreased Factor VIII half life)
  • Abnormal Ristocetin test
    
    • Ristocetin causes platelet aggregation but won’t work if you don’t have vWF
• Treatment is DDAVP which releases extra vWF stored in platelets

Question 24

Vitamin K Deficiency

Answer 24

• Disrupts function of multiple coagulation factors
• Vitamin K is activated by epoxide reductase in the liver
• Activated vitamin K gamma carboxlyates factors II, VII, IX, X and proteins C and S
• Deficiency occurs in:
  
  • Newborns: due to lack of GI colonization by bacteria that normally synthesize vitamin K
    
    • Give vitamin K injection for prophylaxis
  • Long term antibiotic therapy: disrupts vitamin K producing bacteria in the GI tract
  • Malabsorption: leads to deficiency of fat-soluble vitamins including vitamin K

Question 25

How does liver failure cause abnormal secondary hemostasis?

Answer 25

1. Not producing factors
2. Not getting secondarily activated b/c epoxide reductase can’t activate vitamin K: Factors II, VII, IX, X, Protein C, S

• Effects of liver failure on coagulation is followed using PT

Question 26

Heparin-Induced Thrombocytopenia

Answer 26

• Platelet destruction that arises secondary to heparin therapy
  
  • Heparin can form a complex on the surface of the platelets with PF4: develops IgG autoantibodies against it
• Fragments of destroyed platelets may activate remaining platelets, leading to thrombosis
• Don’t want to give these patients Coumadin b/c of fear of Coumadin skin necrosis

Question 27

What is Disseminated Intravascular Coagulation (DIC) and what lab findings are associated with it?

Answer 27

• Pathologic activation of the coagulation cascade
  
  • widespread microthrombi result in ischemia and infarct
  • Consuption of platelets and factors results in bleeding, especially from IV sites and mucosal surfaces
• Almost always secondary to another disease process
• Lab findings:
  
  • Decreased platelet count
  • Increased PT/PTT
  • Decreased fibrinogen
  • Microangiopathic hemolytic anemia: some of the thrombi might be partial and cause sheering of RBCs when they pass
  • Elevated fibrin split products, particularly D-diner
    
    • end goal of coagulation cascade is lyse the clot: product of lysing is D-dimer
    • Elevated D-dimer best screening test for DIC b/c tells you too much coagulation is going on
• Treatment involves addressing the underlying cause and transfusing blood products and cryoprecpitate (contains coagulation factors)

Question 28

What are some of the important secondary causes of DIC?

Answer 28

• Obstetric complications
  
  • tissue thromboplastin in the amniotic fluid activates coagulation
  • If fluid leaks into circulation, can activate coagulation cascade
• Sepsis
  
  • Endotoxins from the bacterial wall and cytokines induce endothelial cells to make tissue factor
• Adenocarcinoma
  
  • Mucin activates coagulation
• Acute Promyelocytic Leukemia
  
  • Primary granules activates coagulation
• Rattlesnake bite
  
  • Venom actiates coagulation

Question 29

Explain the purpose and process of normal fibronlysis

Answer 29

• Normal fibrinolysis removes thrombus after damaged vessel heals
  
  • Tissue plasminogen activator (tPA) converts plasminogen to plasmin
  • Plasmin cleaves fibrin and serum fibrinogen, destroys coagulation
  • alpha 2 antiplasmin inactivates plasmin

Question 30

What causes fibrinolysis disorders, what are the findings and how is it treated?

Answer 30

• Due to plasmin overactivity resulting in excessive cleavage of serum fibrinogen (destroying coagulation factors)
• Causes include:
  
  • Radical prostatectomy: release of urokinase activates plasmin
  • Cirrhosis of liver: reduced production of alpha 2-antiplasmin
• Presents with increased bleeding (resembles DIC)
• Lab findings:​
  
  • Increased PT/PTT: plasmin destroys coagulation factors
  • Increased bleeding time with normal platelet count:
    
    • Plasmin blocks platelet aggregation
  • Increased fibrinogen split products without D-Dimer products
    
    • No D-dimer b/c there was no thrombus to begin with
• Treatment is amniocaproic acid, which blocks activation of plasminogen

Question 31

Atypical HUS

Answer 31

• Associated with defects in complement Factor H, membrane cofactor protein (CD46) or factor I (fibrinogen)
• more similar to TTP
• Plasma exchange is the initial choice in treatment