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PATHOPHYSIOLOGY OF THROMBOSIS “Virchow’s Triad”. Injury to blood vessels Trauma, atherosclerosis, surgery Stasis of blood Immobility, venous incompetence, heart failure Increased coagulability of blood - “thrombophilia” Various inherited and acquired conditions

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pathophysiology of thrombosis virchow s triad
PATHOPHYSIOLOGY OF THROMBOSIS“Virchow’s Triad”
  • Injury to blood vessels

Trauma, atherosclerosis, surgery

  • Stasis of blood

Immobility, venous incompetence, heart failure

  • Increased coagulability of blood - “thrombophilia”

Various inherited and acquired conditions

  • In general, vessel injury is the most important contributing factor to arterial thrombosis (heart attack, stroke) while stasis and increased coagulability are more important in venous thrombosis
inherited thrombophilia
INHERITED THROMBOPHILIA
  • Venous >> arterial thrombosis
  • Most venous thrombi in legs
    • Occasionally mesenteric, portal, cerebral,retinal veins
  • Prevalence of thrombosis varies between families
  • Thrombotic problems may begin in 20s and 30s – rarely in childhood
  • About half of thrombotic episodes occur in association with other identifiable risk factors (pregnancy, oral contraceptives, surgery, etc)
slide4

PULMONARY EMBOLISM

Arrow points to large clot in pulmonary artery

Clot dissolved after administration of fibrinolytic drug

slide5

THERE ARE MANY POTENTIAL GENETIC CAUSES OF THROMBOPHILIA

“If something can go wrong, it will”

(Murphy)

slide6

THERE ARE FIVE KNOWN CAUSES OF

INHERITED THROMBOPHILIA

Defects in physiologic anticoagulant pathways

  • Antithrombin deficiency
  • Protein C deficiency
  • Protein S deficiency
  • Factor V Leiden

Increased production of procoagulant

  • Prothrombin G20210A gene mutation
quantitative vs qualitative deficiency of clotting proteins
QUANTITATIVE VS QUALITATIVE DEFICIENCY OF CLOTTING PROTEINS
  • Quantitative deficiency: decreased protein production (gene deletion, nonsense mutation, etc)
    • Both antigen and activity low
    • “Type I” deficiency
  • Qualitative deficiency: normal protein production, decreased activity (missense mutation)
    • Antigen normal, activity low
    • “Type II” deficiency
antithrombin aka antithrombin iii
ANTITHROMBINAKA “ANTITHROMBIN III”
  • Serine protease inhibitor
  • Made in liver
  • 20 mg/dl plasma concentration
  • Inhibits thrombin, Xa, other clotting enzymes
  • Activity enhanced by heparin and heparin-like molecules on endothelium
antithrombin heparin
ANTITHROMBIN-HEPARIN

INHIBITORS OF MULTIPLE STEPS IN THE CLOTTING CASCADE

XIIa

Inhibits all serine protease clotting factors except VIIa

TF VII(a)

XIa

VIIIa IXa

Xa Va

ANTITHROMBIN

IIa

HEPARIN

inherited antithrombin deficiency
INHERITED ANTITHROMBIN DEFICIENCY
  • Prevalence: 0.2-0.4% of population; 2-5% of inherited thrombophilia
  • Dominant inheritance with variable penetrance
    • No homozygotes known (lethal?)
antithrombin assays
ANTITHROMBIN ASSAYS
  • Patient plasma + heparin + thrombin
    • Thrombin activity measured with chromogenic substrate
    • Measure decay of thrombin activity with time
  • Detects both quantitative and qualitative deficiency
  • Other serine protease inhibitors in plasma may contribute to measured activity causing decreased sensitivity
  • Alternative assay uses factor Xa rather than thrombin, greater specificity and sensitivity
the protein c system
THE PROTEIN C SYSTEM
  • PROTEIN C
    • Proenzyme precursor of serine protease
    • Made in liver, vitamin K-dependent
    • 0.4 mg/dl in blood
    • When activated by thrombin, degrades Va and VIIIa
  • PROTEIN S
    • No intrinsic enzymatic activity
    • Made in liver, endothelium, vitamin K-dependent
    • Bound/inactive and free/active forms in plasma
    • Cofactor for protein C
  • THROMBOMODULIN
    • Endothelial cell surface component
    • Binds thrombin
    • TM-bound thrombin activates protein C
the protein c system1
THE PROTEIN C SYSTEM

Vi

VIIIi

Va

VIIIa

APC

+

P S

IIa

P C

P C

IIa

IIa

TM

TM

E C

E C

protein c deficency
PROTEIN C DEFICENCY
  • Dominant form: 30-60% of normal protein C activity in blood
    • Found in about 5% of inherited thrombophilia
    • Both quantitative and qualitative deficiency can occur
  • Recessive form: < 10% of normal protein C activity
    • Parents (heterozygous) have about 50% of normal level, asymptomatic
    • Rare affected individuals (homozygous) have severe thrombotic tendency that may begin in infancy
  • Biologic basis for dominant vs recessive forms unknown
dominant inheritance of protein c deficiency
DOMINANT INHERITANCE OF PROTEIN C DEFICIENCY

32

30

24

22

19

30

26

21

22

18

17

13

8

Protein C

deficient

Protein C

normal

History of

thrombosis

slide20

PROTEIN C LEVELS DROP FASTER THAN LEVELS OF OTHER VITAMIN K-DEPENDENT PROTEINS DURING WARFARIN TREATMENT

Prothrombin

Protein C

slide21

WARFARIN-INDUCED SKIN NECROSIS IN A

PROTEIN C-DEFICIENT PATIENT

protein c assays
PROTEIN C ASSAYS
  • Immunologic
    • Detects only quantitative deficiency
  • Functional, chromogenic substrate
    • Snake venom enzyme activates protein C in test plasma
    • Activated protein C cleaves chromogenic substrate
    • Detects quantitative, most qualitative deficiency
  • Functional, clotting time-based
    • Detects any deficiency
    • Not useful in patients taking warfarin
protein s

Bound

(inactive)

Free

(active)

PROTEIN S

Crossed immunoelectrophoresis showing bound and free forms

protein s deficiency
PROTEIN S DEFICIENCY
  • Dominant inheritance, prevalence unknown

Found in about 5% of inherited thrombophilia

  • Three patterns of deficiency
    • Reduced (30-60%) total protein S antigen with proportionate reduction in free protein S
    • Reduced free protein S with normal total protein S antigen
    • Reduced protein S activity with normal total and free protein S antigen
protein s assays
PROTEIN S ASSAYS
  • Total protein S (immunologic)
    • Detects only type 1 deficiency
  • Free protein S (immunologic)
    • Detects type 1 and type 2 deficiency
  • Protein S activity
    • Theoretically should detect any deficiency
    • Some assays give false positive result in patients with activated protein C resistance due to factor V Leiden
protein c and s acquired deficiency states
PROTEIN C AND SAcquired deficiency states
  • Warfarin treatment
  • Vitamin K deficiency
  • Liver disease
  • Newborn
  • DIC (protein C)
  • Inflammation (free protein S)
  • Pregnancy (protein S)
  • Oral contraceptive use (protein S)
measuring protein c and s in warfarin treated patients
MEASURING PROTEIN C AND S IN WARFARIN-TREATED PATIENTS
  • Problem: warfarin causes decreased protein C and protein S level
  • Solution: compare levels of these proteins to another vitamin K-dependent protein (factor X)
  • Low ratio of protein C or S to factor X suggests underlying deficiency state
  • Requires steady state warfarin treatment (same dose for at least a week)
  • Only applicable to antigen measurements
factor v leiden
Factor V Leiden

Missense mutation changes amino acid 506 of factor V from arginine to glycine

Mutation is at preferred protein C cleavage site, slows inactivation of factor Va by protein C

Factor Va procoagulant activity not affected

Single mutation responsible for almost all cases

Very common (up to 5% of population heterozygous)

Accounts for up to 50% of inherited thrombophilia

slide29

Vi

VIIIi

Va

VIIIa

APC

+

P S

IIa

P C

P C

IIa

IIa

TM

TM

E C

E C

modified functional assay for fvl

MODIFIED FUNCTIONAL ASSAY FOR FVL

1.

Mix patient plasma with factor V deficient plasma (1:4)

2.

Plasma mixture

aPTT

3.

Mixture + APC

aPTT

aPTT with APC

aPTT without APC

APC ratio =

4.

dna testing for factor v leiden

NORMAL

HETEROZYGOUS

HOMOZYGOUS

DNA TESTING FOR FACTOR V LEIDEN

FVL DNA AMPLIFIED BY PCR, DIGESTED WITH RESTRICTION ENZYME

prothrombin g20210a gene mutation
PROTHROMBIN G20210A GENE MUTATION

Mutation in 3' untranslated (non-coding) part of prothrombin gene

No effect on prothrombin structure or function

Heterozygotes have 5-10% higher plasma levels of prothrombin

Heterozygotes have 2-3 fold risk of venous thromboembolism

Risk in homozygotes uncertain

About 1-2% of population heterozygous; 5-7% of young patients with DVT/PE

Diagnosis: DNA testing

inherited thrombophilia gene dose
INHERITED THROMBOPHILIA: GENE DOSE

Relative risk of thrombosis in heterozygous and homozygous factor V Leiden

Genotype

Relative Risk

Normal

1

Heterozygous

7

Homozygous

80

Rosendaal et al, Blood 1995;85:1504

inherited thrombophilia gene interactions
INHERITED THROMBOPHILIA: GENE INTERACTIONS

Co-inheritance of protein C deficiency and factor V Leiden within a family

Thrombosis present (%)

Thrombosis absent (%)

Gene Mutation

Protein C and Factor V

16 (73)

6 (27)

Protein C

5 (31)

11 (69)

Factor V

2 (13)

11 (87)

None

0

11 (100)

Koeleman et al, Blood 1994;84:1031

risk of venous thrombosis
RISK OF VENOUS THROMBOSIS

Factor V Leiden plus oral contraceptive

RELATIVE RISK OF THROMBOSIS

RISK FACTOR

Oral contraceptive

4

Factor V Leiden

8

Both

35

Vandenbroucke et al, Lancet 1994;344:1453

inherited thrombophilia is a risk factor not a disease
INHERITED THROMBOPHILIA IS A RISK FACTOR, NOT A DISEASE

Thrombophilia is a weak (not statistically significant) predictor of recurrence in patients with venous thrombosis

risk of venous thrombosis in affected vs unaffected relatives of thrombophilic patients

Unaffected (no defect)

PT

FVL, PT mutation:

Most carriers remain asymptomatic

FVL

PC, PS, AT deficiency:

Higher chance of thrombosis, but many carriers asymptomatic

PC

AT

PS

RISK OF VENOUS THROMBOSIS IN AFFECTED VS UNAFFECTED RELATIVES OF THROMBOPHILIC PATIENTS

Blood 2009;113:5314

testing for inherited thrombophilia

When is it indicated?

TESTING FOR INHERITED THROMBOPHILIA

Young patient

Family history

Thrombosis in absence of known risk factors

Warfarin-induced skin necrosis (protein C)

Neonatal purpura fulminans (protein C, S)

diagnosis of inherited thrombophilia

What's next?

DIAGNOSIS OF INHERITED THROMBOPHILIA

Rapid, cheap (?) screening for large numbers of mutations and polymorphisms using DNA chip technology

More accurate diagnosis of inherited antithrombin, protein C, protein S deficiency

Discovery of many new genetic conditions that affect thrombotic risk

More information than we know what to do with