Thrombophilia

Courtney E. Gamston, PharmD

PGY-1 Ambulatory Care Resident
Pharmacy Health Services
Harrison School of Pharmacy
Health.howstuffworks.com

March 31, 2015

Outline
Objectives
Venous thromboembolism (VTE)
& Thrombophilia
Thrombophilia background
Types of Thrombophilia

Thrombophilia &
Pregnancy
Screening

Factor V Leiden

Controversy

Disorders of the Natural

Anticoagulants

Current
Recommendations

Protein C Deficiency
Protein S Deficiency
Antithrombin Deficiency
Prothrombin Mutation
Antiphospholipid Syndrome

Summary

Objectives
By the end of this class, the P3 student pharmacist should be able
to:
Define thrombophilia
Describe the general mechanisms of thrombophilia
Describe the general mechanism by which each thrombophilia
increases the risk of thrombosis
Recognize the risk of thrombosis with each discussed type of
thrombophilia
Discuss treatment of patients with thrombophilia
Recognize patients who should be screened for thrombophilia
Given a patient case, defend the decision to screen or not to
screen for thrombophilia

Venous thromboembolism
(VTE) & Thrombophilia
VTE Epidemiology
Affects ~500,000 Americans annually
30% die within one month of diagnosis
Percent that have sudden death as the 1st symptom =
25%
Percent that have long-term complications =
50%
Percent that have recurrence within 10 years 33%
=

Thrombophilia
Incidence of thrombophilia =5-8% US population
Percent of VTE patients with thrombophilia = Up 50%
to
35% with inherited thrombophilia

http://www.cdc.gov/ncbddd/dvt/data.html

Thrombophilia
History
Termed in 1965- Egeberg
Characterization in the 1980s and
1990s
Series of conditions that favor
thrombosis
Increased risk of thromboembolic
events
Inherited
Factor V Leiden (FVL)
Prothrombin G20210A mutation
Anticoagulant deficiency*
Increased clotting factors
VIII, IX, and/or XI
Others
J Pharm Pract
27.3 (2014): 227-33.
Reprod Sci 21.2 (2014): 167-82.
Clin Genet 81.1 (2012): 7-17.

Acquired
Antiphospholipid Antibodies
Others
Other hypercoaguable
conditions
Cancer
Liver failure
Nephrotic syndrome
Disseminated Intravascular
Coagulation (DIC)
Pregnancy

*Can be either inherited or acquired

Estrogen use

Inherited
Thrombophilias

Coagulation

https://www.boundless.com/physiology/textbooks/boundless-anatomy-and-physiology-textbook/blood-17/hemostasis-168/coagulation-839-3097/

Factor V Leiden
Background
Factor V binding to activated protein
C (APC) Inactivation via proteolysis
Cleavage site: Position 506 on
Factor V
Protein C resistance
Point mutation: glutamine substituted
for arginine
Unable to bind APC
Autosomal dominant
Factor V inactivation decreased ~10x
Clinical presentation
Venous thrombosis
Fetal loss
J Pharm Pract 27.3 (2014): 227-33.
Clin Genet 81.1 (2012): 7-17.

Other Causes of Protein C

resistance: Pregnancy,
Oral contraceptives,
Cancer, other Factor V
point mutations

Epidemiology
Most common inherited thrombophilia
Prevalence
General population: 5% Caucasians
VTE cases: 20%
40% in patients with risk factors for
an inherited thrombophilia
Risk
Heterozygous: 3-7x
~5% have VTE by age 65
Homozygous: 80x
Absolute Risk
Low : Higher in the context of other
risk factors

Protein C Deficiency
Background
Natural anticoagulant
Vitamin K-dependent
Inactivation of factors Va and VIIIa
Requires free Protein S

Types
Type I: Quantitative = Lowered levels
Type II: Qualitative = Normal levels with lowered activity

Epidemiology
Prevalence
General population = 0.14-1.5%
VTE Cases = 3-5%

www.mmj.dergisi.org

Risk: 4-15x

Clinical Presentation
Thrombosis
Homozygous: Neonata purpura fulminans or cerebral vein
thrombosis

Brit J Haem. 149 (2010): 209-220.

Clin Genet 81.1 (2012): 7-17.
J Pharm Pract 27.3 (2014): 227-33.

Protein S Deficiency
Background
Cofactor for activation of
Protein C
Synthesized in liver
Vitamin K-dependent
Circulates in both bound
and unbound forms
Epidemiology:
Prevalence
General population:
0.03-0.13%
VTE Cases: 1-4%
Risk: 1-10x
Brit J Haem. 149 (2010): 209-220.
Clin Genet 81.1 (2012): 7-17.
J Pharm Pract 27.3 (2014): 227-33.

3 Types
Type I: Lowered levels of
total and free protein
Type II: Normal free
levels with decreased
activity
Type III: Normal total
levels with lowered free
levels
Clinical Presentation
Comparable to Protein C
deficiency

https://www.boundless.com/physiology/textbooks/boundless-anatomy-and-physiology-textbook/blood-17/hemostasis-168/coagulation-839-3097/

Antithrombin (AT)
Deficiency
Background
Glycoprotein that binds heparin inactivation of IIa, Xa, IXa, XIa, XIIa
Most thrombogenic inherited thrombophilia

Epidemiology
Prevalence
General population: 0.1-0.2%
VTE cases: 1-2.5%
Risk: 5-50x

Types
Type I: Lowered levels and lowered activity
Type II: Normal levels with lowered activity
Type IIa: (reactive site?)
Type IIb: more common (heparin binding site?)
Brit J Haem. 149 (2010): 209-220.
Clin Genet 81.1 (2012): 7-17.
J Pharm Pract 27.3 (2014): 227-33.

https://www.boundless.com/physiology/textbooks/boundless-anatomy-and-physiology-textbook/blood-17/hemostasis-168/coagulation-839-3097/

A.K.A.
Prothrombin G20210A
Prothrombin Variant
Factor II Mutation

Prothrombin Mutation
Background
Factor II
Glycoprotein that is
cleaved to thrombin in the
common pathway
Cause
Point mutation in the 3
untranslated region of the
prothrombin gene
Increased prothrombin
levels Increased
thrombin
Increases circulating
prothrombin 150-200%
J Pharm Pract 27.3 (2014): 227-33.
Clin Genet 81.1 (2012): 7-17.

Epidemiology
2nd most common
heritable thrombophilia
Caucasians = 3%
African & Asian = 0.06%
Patients with VTE = 718%
Clinical presentation
Increased prothrombin
concentration
Venous thrombosis
Cerebral vascular
events at a young age

Inherited Thrombophilia
and Other Risk Factors
What weve learned:
Low incidence
Modest increase in risk of thrombosis

Inherited thrombophilias
are NOT mutually
exclusive!

Factors that increase the risk of thrombosis

Age 65
Family history
Cancer
Immobility
Hospitalization
Surgery
Obesity
Antiphospholipid antibodies
J Pharm Pract 27.3 (2014): 227-33.
Clin Genet 81.1 (2012): 7-17.

Trauma
Oral contraceptives
Hormone replacement therapy
Selective estrogen receptor
modulators
Travel
Central venous catheter

Treatment
VTE guidelines- What do they say about thrombophilia?
Acute VTE treatment not cause-specific
Studies evaluating prophylaxis and treatment of VTE do not
regularly screen for inherited thrombophilia
VTE treatment duration depends on bleeding risk versus
clotting risk
Case for extended therapy in thrombophilia- not evidence based
Evidence for extended therapy in unprovoked, proximal VTE

Acquired
Thrombophilia

Acquired Forms of
Thrombophilia
Protein C
Deficiency

Liver disease
Vitamin K
antagonists
Severe infection
Sepsis
Acute thrombosis
DIC
Autoimmune
syndromes

Protein S
Deficiency

Liver disease
Vitamin K
antagonists
Severe infection
Sepsis
Acute thrombosis
DIC
Autoimmune
syndromes
HIV
Nephrotic
syndrome
Pregnancy
Oral
contraceptives
HRT

Antithrombin
Deficiency

APC Deficiency

Pregnancy
Oral
contraceptives
HRT
Cancer
Antiphospholipid
antibodies

Cirrhosis of the
liver
Sepsis with DIC
Burn Injuries
Polytrauma
Hepatic
venoocclusive
disease
CABG
Large
hematomas
Metastatic
tumors

APC= activated protein C; DIC= disseminated intravascular coagulation; HRT= hormone replacement therapy
CABG= coronary artery bypass graft

Antiphospholipid Syndrome
Background
Autoimmune disorder
Associated with specific
HLA class alleles
Acquired after birth
Several different antibodies
Antiphospholipid antibodies
(aPL)
Bind anionic phospholipids
Several antibodies
Clinically relevant: anti2-glycoprotein-I, Lupus
anticoagulant (LA), antiCardiolipin antibody (aCL)
J Pharm Pract 27.3 (2014):234-242.
J Autoimmun 48-49 (2014): 20-5.

Mechanisms
Inhibition of fibrolytic system
Increased tissue factor (TF)
Activation of coagulation
Decreased anticoagulation
Activation of platelets,
monocytes, and endothelial
cells
Thrombocytopenia and
thrombosis
Increased GPIIb/IIIa expression
Increased endothelial cell
adhesion
Activation of complement
system

https://www.boundless.com/physiology/textbooks/boundless-anatomy-and-physiology-textbook/blood-17/hemostasis-168/coagulation-839-3097/

Antiphospholipid Syndrome
(APS)
Clinical Presentation
Recurrent thrombosis
Pregnancy morbidity
Thrombocytopenia
Hemolytic anemia
Skin ulcers
Nephropathy
Heart valve disease
Livedo reticularis
Neurological disorder
Catastrophic APS
Multiple thromboses leading
to multiple organ failure
J Pharm Pract 27.3 (2014):234-242.
J Autoimmun 48-49 (2014): 20-5.

Epidemiology
Prevalence: 1-5% have aPL
Accounts for up to 20% of
thromboembolism in young
adults
Risk of recurrence = up to
30%
Increased risk
Lupus Anticoagulant
Increases risk 15x
(pregnancy morbidity)
Anti-2-glycoprotein-I
Increases stroke risk 2x

Diagnosis
Positive diagnosis if 1 clinical AND 1 laboratory criteria are
met*
Clinical

Vascular thrombosis

Pregnancy morbidity

Laboratory**

Lupus anticoagulant in plasma

Anti-2-glycoprotein-I antibody in
serum or plasma of IgG and/or IgM
in medium or high titer

Anticardiolipin antibody in serum

or plasma of IgG and/or IgM in
medium or high titer

*Timing between clinical and laboratory criteria: >12 weeks and

<5years
**Must occur on 2 occasions 12 weeks apart

J Thromb Haemost 4.2 (2006): 295-306.

Treatment of APS
Standard thrombosis treatments
Low molecular weight heparins (LMWH)
Warfarin

Immunotherapy
Rebound effect
Antibodies return in 1-3 weeks after D/C
Increased thrombosis risk for 6 months

Risk factor avoidance

J Autoimmun 48-49 (2014): 20-5.

Lupus 20.2 (2011): 206-18.

Alternative Therapies
Hydroxychlorquine
Decreases platelet aggregation & arachadonic acid release
Prevents thromboembolic events in patients with lupus (SLE) aPL
Increases survival of and decreases irreversible organ damage in
patients with SLE
Low toxicity

Statins
Experimental models show statins reverse aPL activation of
endothelial cells
Pilot studies demonstrate lower levels of aPL markers and
thrombogenic mediators

Autoimmun Rev 12.7 (2013): 752-7.

APS Guidelines:
Primary Prophylaxis
aPL Carriers
Strict control of risk factors
(high risk profile) (Non-graded)
LMWH prophylaxis in high risk
circumstances (1C)
SLE patients with aPL
Primary prophylaxis with
hydroxychlorquine (1B) AND
low-dose ASA (2B)
aPL-positive without SLE
High risk aPL profile: Long-term ASA,
especially with other risk factors (2C)
Lupus 20.2 (2011): 206-18.

High Risk Profile

Lupus anticoagulant (LA)
Triple Positivity (LA + aCL +anti2-GPI)
Isolated, persistently (+) aCL
[med/high titers]
Low Risk Profile
Isolated, intermittently (+) aCL or
anti-2-GPI [low-med titers]

APS Guidelines:
Secondary Prophylaxis
Patients with aPL without APS
Same management as aPL-negative patients (1C)
APS with 1st venous thrombosis
Oral anticoagulation (INR 2.0-3.0) (1B)
APS with 1st arterial thrombosis
Warfarin therapy (INR >3.0) OR
Warfarin + antiaggregant-anticoagulant (INR 2.0-3.0)
(Ungraded)
Estimate bleeding risk before therapy initiation
Non-SLE with non-cardioembolic cerebral arterial
thrombosis: assess individually for use of antiplatelet
medications
Lupus 20.2 (2011): 206-18.

APS Guidelines
Treatment Duration
APS + thrombosis: Indefinite (1C)
Low-risk aPL profile with 1st VTE and a known
transient risk factor: 3-6 months (Ungraded)
Refractory/Difficult Cases
Patients with recurrent thrombosis, fluctuating
INR, major bleeding, high risk for major
bleeding: alternative therapies can be pursued
(Ungraded)
Long-term LMWH
Hydroxychlorquine
Statins

Lupus 20.2 (2011): 206-18.

Thrombophilia and Pregnancy

Guideline Recommendations (CHEST 2012)
Screening
Recurrent early pregnancy loss Screen for Antiphospholipid Antibodies
3+ miscarriages before 10 gestational weeks (1B)
History of pregnancy complications- Do not screen (2C)

Pharmacological Prophylaxis
Homozygous for FVL or Prothrombin 20210A with no VTE history
Positive family history- Antepartum & Postpartum (2B)
Negative family history- Postpartum only (2B)
All other thrombophilia AND positive family history with no VTE history
Postpartum only (2C)
Positive for APS with 3+ pregnancy losses
Antepartum (1B)

Chest 141.2 Suppl (2012): e691S-736S.

Thrombophilia and Pregnancy

Therapy
Timeline

Treatment

Positive FH

Antepartum
Postpartum

Prophylactic or intermediate
dose LMWH

Negative FH

Postpartum

Patient Characteristics
Homozygous for FVL
or Prothrombin
20210A

All other thrombophilia

AND positive family history

Prophylactic or intermediate
dose LMWH or warfarin

Postpartum

Antiphospholipid Syndrome

Chest 141.2 Suppl (2012): e691S-736S.

Antepartum

UFH: Prophylactic or
intermediate dose
LMWH: Prophylactic dose
+ ASA: 75-100mg/d

Who Should Be Screened?

General Population
Low incidence
Unclear clinical course with positive results
Possible false security with negative results

Patients with VTE

What effect do
screening results
have on treatment
and/or prophylaxis?

Factors suggesting inherited thrombophilia

Can screening results
VTE <50 years old
be utilized to
FH VTE
decrease the
Recurrent VTE
recurrence of
Idiopathic VTE
thrombosis?

J Pharm Pract 27.3 (2014): 227-33.

J Pharm Pract 27.3 (2014):253-259.

Risk factors for VTE

recurrence
Risk for recurrent thrombosis
Relationship to thrombophilia is unclear
Inconsistent predictors of recurrence
Negative D-Dimer 1 month after D/C VKA (RR
0.4)
Antiphospholipid antibody (RR 1.5)
Male gender (RR 1.6)
Asian ethnicity (RR 0.8)
Residual thrombosis in proximal veins (RR 1.5)

Chest 141.2 Suppl (2012): e419S-94S. Print.

Screening Guidelines
2005 Thrombophilia Screening Guidelines
Screen all 1st idiopathic VTE, VTE <50yo, Recurrent
VTE, or VTE <50yo in an unusual site
Screen asymptomatic 1st degree relatives of
patients with symptomatic VTE and known
thrombophilia

2013 Guideline update

Screen 1st time idiopathic VTE in patients <60yo
Screen any VTE <40yo
Screen asymptomatic 1st degree relatives of
patients with symptomatic VTE and known
thrombophilia

J Pharm Pract 27.3 (2014):253-259.

Considerations for
Screening
(*IF
Conducted)
Appropriate timing
Acute phase gives inaccurate and unreliable results
DO NOT test within 3 weeks of acute event
Transient suppression of natural anticoagulants
False positive for antithrombin deficiency while taking heparin
Withhold warfarin therapy for ~2 weeks before testing
False positive for Protein C and S deficiency
False negative for antithrombin deficiency
Best to test after 3 months of therapy
Confirm results with repeat testing

Genetic testing (DNA) unaffected by timing

Semin Thromb Hemost 2009;35:695-71

Haemophilia 2008;14:1229-39.
Br J Haematol 2001;114:512-28.
Am J Clin Pathol 2006;126:120-7.

Screening Guidelines
SCREEN

DO NOT SCREEN

H/O unprovoked VTE and considering to

D/C therapy

H/O unprovoked VTE with 1st degree

relative with H/O VTE and considering to

D/C therapy

Recurrent early pregnancy loss: Screen

for aPL
+
(3 miscarriages before 10 weeks/
gestation)

NICE clinical guideline; no. 144

Chest 141.2 Suppl (2012): e691S-736S.

Patients on anticoagulants
with plans to continue therapy
H/O provoked VTE
1st degree relative with H/O
VTE and thrombophilia

Summary
Thrombophilia has low prevalence in the general population, but accounts for up to
50% of VTE
Factor V Leiden is the most common inherited thrombophilia and causes Activated
Protein C resistance
Deficiencies in the natural anticoagulants are rare, yet raise the risk for lifetime VTE
Prothrombin mutation increases circulating levels of prothrombin causing a
concomitant increase in thrombin
Antiphospholipid syndrome is an auto-immune disorder that presents in a variety of
ways and can have a large impact on pregnancy
Guidelines recommend prophylactic therapy for specific patients with thrombophilia
during pregnancy
The choice to screen patients for thrombophilia should be based on the clinical
impact of a positive result

References
1. Armstrong, E.M., et al. Acquired thrombophilia. J Pharm Pract 27.3 (2014):234-242. Print
2. Baglin, T., et al. Clinical guidelines for testing for heritable thrombophilia. Brit J Haem. 149 (2010): 209220. Print.
3. Bates, S. M., et al. "VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy
and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical
Practice Guidelines." Chest 141.2 Suppl (2012): e691S-736S. Print.
4. Comarmond, C., and P. Cacoub. "Antiphospholipid syndrome: from pathogenesis to novel
immunomodulatory therapies." Autoimmun Rev 12.7 (2013): 752-7. Print.
5. Disorders, Division of Blood, and National Center on Birth Defects and Developmental Disabilities. "Deep
Vein Thrombosis (DVT)/Pulmonary Embolism (PE)- Blood Clot Forming in a Vein- Data & Statistics." Centers
for Disease Control and Prevention December 10, 2014. Web. February 2015.
6. Favaloro E, McDonald D, Lippi G. Laboratory investigation of thrombophilia: The good, the bad, and the ugly. Semin
Thromb Hemost 2009;35:695-710.
7. Gmez-Puerta, J. A., and R. Cervera. "Diagnosis and classification of the antiphospholipid syndrome." J
Autoimmun 48-49 (2014): 20-5. Print.
8. Hornsby, L.B, at al. Thrombophilia screening. J Pharm Pract 27.3 (2014):253-259. Print.
9. Kearon, C., et al. "Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of
Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines."
Chest 141.2 Suppl (2012): e419S-94S. Print.
10. MacCallum, P., L. Bowles, and D. Keeling. "Diagnosis and management of heritable thrombophilias." BMJ
349 (2014): g4387. Print.

References
11.
12.
13.

14.
15.
16.
17.

18.
19.
20.

Margeti, S. Laboratory iinvestigation of thrombophilia. J Medication Buichem 33.1 (2014):28-46.

Print.
Miyakis, S., et al. "International consensus statement on an update of the classification criteria for
definite antiphospholipid syndrome (APS)." J Thromb Haemost 4.2 (2006): 295-306. Print.
National Institute for Health and Clinical Excellence (NICE). Venous thromboembolic diseases: the
management of venous thromboembolic diseases and the role of thrombophilia testing. London (UK):
National Institute for Health and Clinical Excellence (NICE); 2012 Jun. 40 p. (NICE clinical guideline;
no. 144).
Pambaldi, M.P., F. Mecacci, S. Guaschino, and M.J. Paidas . "Inherited and acquired thrombophilias."
Reprod Sci 21.2 (2014): 167-82. Print.
Patnaik M, Moll S. Inherited antithrombin deficiency: a review. Haemophilia 2008;14:1229-39.
Phillippe, H. M., et al. "Inherited Thrombophilia." J Pharm Pract 27.3 (2014): 227-33. Print.
Ruz-Irastorza, G. et al. Evidence-based recommendations for the preventions and long-term
management of thrombosis in antiphospholipid antibody-positive patients: Report of a task force at
the 13th International Congress on antiphospholipid antibodies. Lupus 20.2 (2011):206-218. Print.
Somma J, Sussman I, Rand J. An evaluation of thrombophilia screening in an urban tertiary care medical center.
Am J Clin Pathol 2006;126:120-7.
Varga, E. A., and J. L. Kujovich. "Management of inherited thrombophilia: guide for genetics
professionals." Clin Genet 81.1 (2012): 7-17. Print.
Walker I, Greaves M, Preston F. Investigation and management of heritable thrombophilia. Br J Haematol
2001;114:512-28.