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Pathogenesis and Clinical Management of Thrombotic Disease . Arterial Thrombosis. Abnormal Blood Flow. Abnormal Vessel Wall. Abnormal Blood. The Hypercoagulable State (thrombophilia ). Dr. Rudolph Virchow 1821-1902. Pathogenetic Associations and Hemostasis. Hemophilia

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Presentation Transcript
slide1

Pathogenesis

and

Clinical Management

of

Thrombotic Disease

slide3

Abnormal

Blood Flow

Abnormal

Vessel Wall

Abnormal

Blood

The Hypercoagulable State

(thrombophilia)

Dr. Rudolph Virchow

1821-1902

slide4

Pathogenetic Associations and Hemostasis

Hemophilia

Single Gene Mutation

Thrombosis

Multigenic +

Environmental Factors

Genetic diagnosis

available

Genetic pathogenesis

still under investigation

Genetic therapy

feasible

Far More

Complex

mechanisms of thrombosis
Mechanisms of Thrombosis

Clinical associations with thrombotic disease

Immobility

Obesity

Smoking

Cancer

Pregnancy

Estrogen therapy

types of thrombosis
Types of Thrombosis

Arterial: platelet-based (white) thrombus

Platelet-VWF interactions critical

Associated with end-stage atherosclerosis

Venous: Fibrin-based (red) thrombus

Coagulation factors critical

Venous stasis

slide7

Loss of Function Mutations

Natural Anticoagulant Proteins

Antithrombin

Protein C

Protein S

Rare - 0.02 – 0.2% of General Population

1-3% prevalence in Thrombosis Population

Stronger Risk Factors For VTE ~ 10 to 25-fold

slide8

Gain of Function Mutations

Pro-coagulant Proteins

Factor V Leiden

Prothrombin 20210 Mutation

Common - 2 – 10% in Western Populations

6% (prothrombin) to 20% (FV Leiden) in Thrombosis

Weaker Risk Factors For VTE 2 to 7-fold

slide9

Factor V Leiden

Factor Va

Arg 506

Arg 306

Arg 1765

Arginine

CGA

Glutamine

CAA

Factor Va resistant to APC cleavage

slide10

Leiden Study Group Data

Relative Risk for

Venous Thrombosis

Factor V Leiden Heterozygote x 7

Factor V Leiden Homozygote x 80

Oral Contraceptives x 3

Oral Contraceptives + Factor V Leiden x 35

slide11

Quantitative Traits

Homocysteine

FVIII

FIX

FXI

2 to 4-fold

increased

relative risk

Unknown

genetic

mechanisms

clinical case 1
CLINICAL CASE #1
  • 72 year old male seen in the ER
  • Three day history of swollen, painful right leg up to mid-thigh
  • Hypertension for 10 years. Treated with a diuretic
  • 10 pound weight loss over past four months
  • Smoked 20 cigarette/day for 50 years
slide13
Clinical Examination

Circumference of right leg 3 cm bigger than left at mid point of calf

Right leg warm, tender and erythematous

slide14
Differential Diagnosis

Venous thrombosis

Cellulitis

Knee pathology ie ruptured synovial cyst

Calf muscle strain

Calf muscle hematoma

slide15
Objective imaging test to confirm DVT

Invasive - radiocontrast venogram (gold standard)

Non-invasive

Doppler ultrasound studies

Less sensitive to thrombi distal to the popliteal vein

slide16
Flow of clinical management

Clinical history and examination

Imaging assessment

Day 1

Positive Test Begin treatment

Negative Test Need to retest

~25% of initial negatives will progress (ie extend proximal to the popliteal vein)

slide17
Reasons to Treat Venous Thromboembolic Disease

Threat of embolization

Much greater with large proximal vein thrombosis

slide19
Reasons to Treat Venous Thromboembolic Disease

Local Effects

Acute pain/swelling

Long-term: Post-phlebitic Limb

slide20
Treatment Options

Standard anticoagulant therapy

Thrombolytic therapy

Vena caval interruption

In >95% of cases

Standard anticoagulants

In 2008 - Low Mol Wt. Heparin

slide21
Relative or absolute contraindications to anticoagulant treatment

History of peptic ulcer disease

Recent surgery

slide22

Heparin

  • Highly sulphated glycosaminoglycan
  • Functions with Antithrombin as a cofactor
  • Unfractionated MW. 5-30,000 Daltons
  • Low Molecular Weight Heparins
    • MW 5,000
    • More predictable pharmacokinetics
    • Less cell binding, less protein binding
    • Laboratory monitoring not required
slide23

+ve

feedback

Heparin Action

through antithrombin

low molecular weight heparins
Low Molecular Weight Heparins

Several Types

eg. Tinzaparin (Innohep)

Daltaparin (Fragmin)

  • Dosage calculated by body weight
  • Q daily or Q12Hrly SC administration
  • No Laboratory monitoring necessary

Exceptions - children, obesity, renal failure

slide25

Oral Anticoagulants Coumadin/Warfarin

Vitamin K antagonists

Interfere with gamma carboxylation

Peak effect reached in ~4/5 days

Monitor with the PT (International Normalized Ratio - INR)

slide26

+ Protein C and Protein S

Procoagulant Vit K

dependent proteins

slide27

Start Coumadin

Daily INR

Days

1

2

3

4

5

6

7

Stop LMWH

When

INR>2

Begin therapy with

SC LMWH

Start of

Coumadin effect

anticoagulant complications
Anticoagulant Complications

Coumadin

Bleeding 2-5% per year

Embryopathy - skeletal abnormalities

Allergies - skin rashes

Low Molecular Weight Heparin

Bleeding 2-5% per year

Thrombocytopenia

Osteoporosis

slide29

Novel anticoagulant

Targets

Anti-Xa

Anti-IIa

slide30

New Anticoagulant Drugs

Possible standard therapy within 2-5 years

  • Anti-Xa Rivaroxaban

Synthetic pentasaccharide

  • Thrombin inhibitors

Lepirudin

Dabigatran

No laboratory monitoring required

No specific antidotes to treat bleeding

slide31

Unresolved Anticoagulant Issues

1. Optimal Duration of Treatment

3 months - several years

Optimal Intensity of Anticoagulation

Less Thromboembolic Recurrences

Less Bleeding Events

Target INR 2-3

heterozygosity for factor v leiden is associated with which one of the following
Heterozygosity for Factor V Leiden is associated with which one of the following?
  • An increased risk of arterial thrombosis.
  • A prevalence of 15% in Western populations.
  • Autosomal recessive inheritance.
  • An increased risk of venous thrombosis.
slide33

FV Leiden Heterozygosity

  • 5% in Western populations
  • Increased risk for venous thrombosis (~7-fold)
  • Autosomal co-dominant inheritance
  • risk with homozygous FV Leiden 70-fold
heparin treatment is not associated with which one of the following
Heparin treatment is NOT associated with which one of the following?
  • Inhibition of FIXa.
  • Prolongation of the thrombin clotting time.
  • Inhibition of FVIIIa.
  • Prolongation of the aPTT.
slide35

+ve

feedback

Heparin Action

through antithrombin

coumadin anticoagulation is associated with which one of the following
Coumadin anticoagulation is associated with which one of the following?
  • Prolongation of the thrombin clotting time.
  • Laboratory test abnormalities consistent with vitamin K deficiency.
  • A low plasma FXI level.
  • Inability to correct the PT with a 50:50 mix.
antithrombin deficiency is not associated with which one of the following
Antithrombin deficiency is NOT associated with which one of the following?
  • Increased risk of venous thrombosis.
  • Autosomal dominant inheritance.
  • Resistance to heparin therapy.
  • Increased levels of FX.
slide39

+ve

feedback

Heparin Action

through antithrombin