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Heme/Onc Pathoma > Chapter 4: Hemostasis > Flashcards

Chapter 4: Hemostasis Flashcards

1
Q

What are the objectives of primary and secondary hemostasis?

A
  • 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
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2
Q

What are the steps of Primary Hemostasis?

A
  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
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3
Q

What are the clinical characteristics of disorders of primary hemostasis?

A
  • 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
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4
Q

What is Immune Thrombocytopenic Purpura (ITP)?

A
  • 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
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5
Q

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

A
  • 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
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6
Q

What are the lab findings associated with Immune Thrombocytopenic Purpura?

A
  • Decreased platelet count
  • Normal PT/PTT: coagulation factors are not affected
  • Increase megakaryocytes on bone marrow biopsy
    • trying to produce more platelets
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7
Q

Treatment for those with Immune Thrombocytopenic Purpura

A
  • 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
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8
Q

What is microangiopathic hemolytic anemia?

A
  • 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)
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9
Q

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

A
  • 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
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10
Q

What is the cause of Hemolytic Uremic Syndrome?

A
  • 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
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11
Q

What are the clinical findings in TTP and HUS?

A
  • 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
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12
Q

What are the lab findings in TTP/HUS?

A
  • Thrombocytopenia with increased bleeding time
  • Normal PT/PTT (coagulation cascade is not activated)
  • Anemia with schistocytes
  • Increase in megakaryocytres on bone marrow biopsy
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13
Q

What is the treatment for Microangiopathic hemolytic anemia?

A
  • Plasmaphersis and corticosteroids
    • Remove autoantibody against ADAMTS13
    • More effective for TTP
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14
Q

Bernard-Soulier Syndrome

A
  • 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
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15
Q

Glanzmann thrombasthenia

A
  • 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
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16
Q

How does aspirin affect platelet aggregation?

A
  • 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
17
Q

What happens during secondary hemostasis?

A
  • 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
18
Q

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

A
  • Usually due to factor abnormalities
  • Clinical features include deep tissue bleeding into muscles and joints (hemarthrosis) and rebleeding after surgical procedures
19
Q

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

A
  • 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
20
Q

Hemophilia A

A
  • “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
21
Q

Hemophilia B (Christmas Disease)

A
  • Clinically resembles Hemophilia A
  • Genetic factor IX deficiency
22
Q

Coagulation Factor Inhibitor

A
  • 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
23
Q

Von Willebrand Disease

A
  • 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
24
Q

Vitamin K Deficiency

A
  • 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
25
Q

How does liver failure cause abnormal secondary hemostasis?

A
  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
26
Q

Heparin-Induced Thrombocytopenia

A
  • 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
27
Q

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

A
  • 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)
28
Q

What are some of the important secondary causes of DIC?

A
  • 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
29
Q

Explain the purpose and process of normal fibronlysis

A
  • 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
30
Q

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

A
  • 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
31
Q

Atypical HUS

A
  • 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

Heme/Onc Pathoma (10 decks)

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