Bleeding Disorders Pt. II & Hypercoagulable States

Question 1

What factors are deficient in hemophilia?

Answer 1

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

Question 2

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

Answer 2

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

Question 3

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

Answer 3

• 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

Question 4

What are the functions of vWF?

Answer 4

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

Question 5

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

Answer 5

• 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

Question 6

How would a vitamin K deficiency affect PT and PTT?

Answer 6

• ↑ PTT
• ↑↑ PT

Question 7

Liver disease:

• Deficient coagulation factors:
• What causes the thrombocytopenia?

Answer 7

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

Question 8

How would liver disease affect the PT and PTT?

Answer 8

• ↑ PTT
• ↑↑ PT

Question 9

What is Virchow’s Triad?

Answer 9

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

Lead to thrombosis

Question 10

Coagulation Control Mechanisms:

• Blood flow:
• Natural anticoagulant processing:

Answer 10

• 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

Question 11

What is the function of antithrombin?

Answer 11

Inhibits serine proteases ⇒ mainly 10a, 2a

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

Question 12

Describe the Protein C system:

Answer 12

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

Question 13

Primary Hypercoagulable States

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

Answer 13

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

Question 14

AT, Protein C & Protein S deficiencies:

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

Answer 14

• 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

Question 15

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

Answer 15

• 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

Question 16

Factor 5^Leiden is a ______ thrombotic risk factor

Answer 16

Factor 5^Leiden is a venous thrombotic risk factor

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

Question 17

Describe prothrombin gene variation:

Answer 17

• 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 5^Leiden
    • Much weaker risk factor than deficiency of AT, Protein C or Protein S

Question 18

Antiphospholipid Antibody Syndrome:

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

Answer 18

• 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

Question 19

Antiphospholipid Antibody:

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

Answer 19

• 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

Question 20

“Lupus-like” anticoagulant

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

Hint: What is seen from these assays?

Answer 20

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

Question 21

Site of Thrombosis: Arterial or Venous?

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

Answer 21

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

Question 22

Acquired predisposition to thrombosis:

Answer 22

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

Question 23

Secondary Hypercoagulable States:

• Disease-Related factors:
• Circumstantial factors:

Answer 23

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

Question 24

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

Answer 24

• 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

Question 25

What syndromes are associated with DIC (by mechanism)?

Answer 25

* **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

Question 26

What kind of disease is DIC? * Describe the manifestations:

Answer 26

**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**

Question 27

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

Answer 27

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

Question 28

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

Answer 28

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

Question 29

How is DIC diagnosed?

Answer 29

* 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)

Question 30

What are the consequences of DIC?

Answer 30

**Microcirculatory failure** ⇒ **multiorgan dysfunction**

Question 31

How is **DIC treated**?

Answer 31

* **Treat the triggering condition!** * _Restore tissue perfusion & acid/base balance_ * **Replacement therapy for bleeding**

Question 32

**Lab findings for the differential diagnosis for DIC:** 1. DIC 2. Liver failure 3. Vitamin K deficiency 4. "Lupus" anticoagulant

Answer 32