Bleeding Disorders Pt. II & Hypercoagulable States Flashcards Preview

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Flashcards in Bleeding Disorders Pt. II & Hypercoagulable States Deck (32):
1

What factors are deficient in hemophilia?

  • Hemophilia A ⇒ factor 8 
  • Hemophilia B ⇒ factor 9
  • Hemophilia C ⇒ factor 11

2

  • What is the inheritance for Hemophilia A and B?
  • What are the hallmark clinical findings?

  • X-linked inheritance (for F-8 and F-9)
  • Hallmark: hemarthrosis & deep muscle bleeds
    • Other sites:
      • 30% bleed at circumcision
      • Easy bruising is common

3

  • What is found on lab evaluation for Hemophilia A and B?
  • What symptoms are associated with low factor 8 or 9?

  • Prolonged PTT (corrects on 1:1 mix)
  • Normal PT, TT, fibrinogen, PFA-100
  • Low factor 8 or 9 (Symptoms correlate with level)
    • Severe (<1%) ⇒ Spontaneous bleed episodes
    • Moderate (1-5%) ⇒ Bleed with mild trauma
    • Mild (>5%) ⇒ Bleed with major trauma

4

What are the functions of vWF?

  • Support platelet adhesion
  • Serve as carrier for Factor 8
    • Thus: abnormalites of vWF may lead to F-8 deficiency

5

  • What are the vitamin K dependent factors?
  • What are problems that can cause vitamin K deficiency?

  • Vitamin K dependent factors:
    • Factors 2, 7, 9, & 10, Protein C & S
  • Problems causing vitamin K deficiency
    • Drugs:
      1. Oral anticoagulant (warfarin) inhibit liver enzymes
      2. Antibiotics: Decrease bowel flora (less vitamin K synthesis)
    • Malabsorption or dietary deficiency
    • Liver disease
    • Newborns

6

How would a vitamin K deficiency affect PT and PTT?

  • ↑ PTT
  • ↑↑ PT

7

Liver disease:

  • Deficient coagulation factors:
  • What causes the thrombocytopenia?

Rebalancing of homeostasis

  • Deficiency of multiple coagulation factors:
    • Procoagulants: Factors 2, 7, 9, & 10, and also 5
    • Anticoagulants: Antithrombin, Protein C, Protein S
  • Thrombocytopenia:
    • Hypersplenism
    • Decreased thrombopoietin production

8

How would liver disease affect the PT and PTT?

  • ↑ PTT
  • ↑↑ PT

9

What is Virchow's Triad?

  1. Endothelial injury
  2. Hypercoagulability
  3. Abnormal blood flow

Lead to thrombosis

10

Coagulation Control Mechanisms:

  • Blood flow:
  • Natural anticoagulant processing:

  • Blood Flow:
    • washes away activated factors
  • Natural anticoagulant processing:
    • TFPI: stops initiation (inactivates F-7, F-10)
    • Antithrombin inactivates enzymes:
      • F-2a, F-10a
    • Protein C system digests cofactors:
      •  F-5 and F-8

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11

What is the function of antithrombin?

Inhibits serine proteases ⇒ mainly 10a, 2a

  • Also 7a, 9a, 11a and 12a to a lesser degree

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12

Describe the Protein C system:

Thrombin binds to thrombomodulin ⇒ activates Protein C ⇒ Protein C degrades factors (5a and 8a)

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13

Primary Hypercoagulable States

  • Associated with ....
  • What are the accepted conditions?

Associated with Venous Thromboembolism

  • Accepted conditions:
    • Deficiency of control proteins
      • Antithrombin, Protein C or Protein S.
    • Subtle changes causing control mechanisms
      • Factor V Leiden (Resistance to aPC)
    • Increased coagulation factor levels
      • Prothrombin gene variation G20210A

14

AT, Protein C & Protein S deficiencies:

  • What % of familial thrombosis
  • When do risks begin to pick up?
  • What tests should be ordered?

  • Account for 5-15% of familial thrombosis
  • Risk picks up after puberty:
    • 2-4% develop thrombosis per year
    • 30% - 60% of clots are “provoked”
      • Clots often occur with “acquired” risk events
    • Family studies: ~70% with clot by age 50
  • Tests to order:
    1. Functional AT, PC or PS assay
    2. Protein S free antigen

15

  • What two tests can be done if there is suspicion for Protein C resistance?
    • What will be found in each test?

  • PTT based assay:
    • Failure of PTT to prolong in response to addition of activated protein C
  • Protein & Sequencing studies revealed genetic defect of factor V:
    • Factor V Leiden: Arg 506 replaced with Gln
      • Delayed inactivation of F-5a by aPC
      • Procoagulant activity of F-5 is normal

16

Factor 5Leiden is a ______ thrombotic risk factor

Factor 5Leiden is a venous thrombotic risk factor

  • This is 10 times more frequent than deficiency of AT-III, Protein C or Protein S
  • Heterozygous Factor 5Leiden is a much weaker risk factor than deficiency of AT, Protein C or Protein S

17

Describe prothrombin gene variation:

  • G20210A in 3’untranslated region of RNA
    • stabalizes the mRNA ⇒ more F-2 produced?
  • Associated with venous events (DVT/PE)
  • Mechanism: ? Elevated F-2 levels
  • In normal population carrier rate is 1 - 2%.
    • This is more frequent than deficiency of AT-III, Protein C or Protein S
      • Risk of VTE with heterozygous Factor 2 gene variation is similar to that of het Factor 5Leiden
      • Much weaker risk factor than deficiency of AT, Protein C or Protein S

18

Antiphospholipid Antibody Syndrome:

  • Clinical Symptoms:
  • Lab signs:
    • What shows evidence for a antiphospholipid antibody?

  • Clinical symptoms:
    • Venous and/or arterial thrombosis
    • Recurrent fetal wastage
  • Lab signs:
    • evidence of antiphospholipid antibody
      • “Lupus-like” anticoagulant
      • Positive antiphospholipid serology
    • May have thrombocytopenia

19

Antiphospholipid Antibody:

  • What are the two types of antiphospholipid antibodies?
  • How can the following be determined from assays:
    • Inhibitor:
    • Phospholipid dependence:

  • Two types:
    1. Anti-cardiolipin, anti ß2GP1
    2. “Lupus” anticoagulant
  • Inhibits phospholipid dependant in-vitro coagulation assays
    • Inhibitor: Failure of clot time to correct on 1:1 mix
    • Phospholipid dependence: clot time corrects with high PL

20

“Lupus-like” anticoagulant

  • Inhibitor of phospholipid dependent in-vitro assays of coagulation:

Hint: What is seen from these assays?

 

  1. Prolonged PL-dependent clot time
    • dRVVT (dilute Russell Viper venom time) or PTT
  2. Failure of correction on 1:1 mix study
  3. Correction occurs in lipid rich assay
  • ​Factor 8 inhibitors or factor 2 deficiency should be considered if patient has bleeding

21

Site of Thrombosis: Arterial or Venous?

  1. APCR/Factor 5Leiden  
  2. Prothrombin Gene 
  3. Antithrombin 
  4. Protein C/S  
  5. Homocysteine 
  6. APLA syndrome 

  1. APCR/Factor 5LeidenVenous 
  2. Prothrombin Gene ⇒ Venous
  3. Antithrombin ⇒ Venous
  4. Protein C/S ⇒ Venous 
  5. Homocysteine ⇒ Arterial and Venous 
  6. APLA syndrome ⇒ Arterial and Venous

22

Acquired predisposition to thrombosis:

  1. Obstruction to flow:
    • Pregnancy, Prior deep vein thrombosis, etc
  2. Activation of hemostatic mechanism:
    • Sepsis, Neoplasm, Foreign body, etc
  3. Damaged endothelium:
    • Inflammation, Athlerosclerosis, trauma, etc

23

Secondary Hypercoagulable States:

  • Disease-Related factors:
  • Circumstantial factors:

  • Disease-Related factors:
    • Post-operative state
    • Neoplasm or Chemo
  • Circumstantial factors:
    • Immobilization

24

  • What is Disseminated Intravascular Coagulation (DIC)?  
  • What is the pathophysiology?

  • Widespread activation of thrombin and plasmin mechanisms:
    • Overwhelmed control mechanisms
  • Consumption of participants in hemostasis
    • Platelets
    • Coagulation proteins:
      • Fibrinogen, Prothrombin, Factor 5, Factor 8
    • Control proteins:
      • Antithrombin, Protein C, Protein S, Plasminogen
  • May present as bleeding or thrombosis

25

What syndromes are associated with DIC (by mechanism)?

  • Introduction of extrinsic clot promoting material
    • malignancy (APL), amniotic fluid, fat embolism, etc.
  • Intravascular elaboration of procoagulants
    • acute hemolytic process
    • heparin associated thrombocyotpenia (HIT)
  • Vascular injury
    • bacterial viral sepsis, hypotension

26

What kind of disease is DIC?

  • Describe the manifestations:

DIC is NOT a disease!

  • DIC is a manifestation of another disease:
    • It may reflect the severity of that disease
  • Usually disease is blatantly obvious
    • Burns, trauma, sepsis, cancer, etc.
  • Occasionally manifestations of DIC stimulate a search for the underlying disease
    • Purpura Fulminans may be the presenting symptoms of:
      • Meningococcal sepsis
      • Severe protein C deficiency in a newborn

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27

What are the clinical presentations of DIC that we have to know?

  1. Bleeding from venipunctures and other sites
  2. Purpura Fulminans

28

  • What factors are affected in DIC?
  • How does DIC affect PT and PTT?

  • Affected factors:
    • ​Factors 2, 5, 7, 8, 10 and 13
  • ↑ PT and ↑PTT

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29

How is DIC diagnosed?

  • Based largely on clinical suspicion and appropriate clinical setting
  • Lab studies are supportive, but usually not diagnostic:
    • PT/PTT are usually prolonged (~50-75% of cases)
    • Fibrinogen usually reduced
    • Platelets usually reduced (< 30 K in ~ 80-90% of cases)
    • D-dimer elevated in 99% of cases (sensitive, but less specific)

30

What are the consequences of DIC? 

Microcirculatory failuremultiorgan dysfunction

31

How is DIC treated?

  • Treat the triggering condition!
  • Restore tissue perfusion & acid/base balance
  • Replacement therapy for bleeding

32

Lab findings for the differential diagnosis for DIC:

  1. DIC
  2. Liver failure
  3. Vitamin K deficiency
  4. "Lupus" anticoagulant

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