Hypercoagulable States

Hypercoagulable States

Daniel A. Forman, DO

[email protected]

610 509 5067 April 26, 2014

•

Risk Factors for Venous Thromboembolism (VTE)

•

Hereditary thrombophilias

•

How long to treat

The hypercoagulable states

Ann Intern Med. 1985 Jun;102(6):814-28

• Patients are considered to have hypercoagulable states if they have laboratory abnormalities or clinical conditions that are

associated with an increased risk of thrombosis (prethrombotic

states) or if they have recurrent thrombosis without

recognizable predisposing factors (thrombosis-prone). These

disorders are generally inherited…..

• Secondary hypercoagulable states are generally acquired

disorders in patients with underlying systemic diseases or clinical

conditions known to be associated with an increased risk of thrombosis: for example, malignancy, pregnancy, use of oral contraceptives, myeloproliferative disorders…………

Venous Thrombo-Embolism (VTE)

•

Incidence

–

1 to 2 per 1,000

–

1 per 100 over 80

•

Deaths

Acquired Thrombophilia

Major Risk Factors

Acute Respiratory Failure

ICU Admission

Extensive trauma, LE fractures

Septicemia

Metastatic Cancer ± Chemotherapy

Pregnancy, PP

Age > 70

PHx of VTE

Acute CVA, Paralysis

Major Surgery

CHF

Acquired Thrombophilia

Minor Risk Factors

Obesity (BMI >28 or 30)

Nephrotic Syndrome

Acute Infection

Smoking (≥1 pack/day)

Central catheter

Varicose Veins

Estrogen, OC

(

CHF, Class I or II

FHx of VTE

Chronic Respiratory Disease

Long Travel

Acute Rheumatic Diseases

Age >40

Which of the following is not a

hereditary thrombophilia?

A. Protein C deficiency

B. Prothrombin gene mutation

C. Elevated factor VIII level

Inherited Thrombophilia

•

Factor V Leiden mutation

•

Prothrombin gene mutation

•

Protein S deficiency

•

Protein C deficiency

•

Antithrombin (AT) deficiency

•

Elevated Factor VIII level

•

Rare disorders

APC Resistance = Factor V Leiden

•

Factor Va propagates clot by ‘helping’ to

form thrombin

•

Activate Protein C inhibits this step

(anticoagulant)

•

Hereditary mutation in Factor V that causes

a resistance to inactivation by protein C

Factor V Leiden (FVL)

Heterozygous State (50% of thrombophilias):

Caucasians — 5.3 percent Hispanic Americans — 2.2 percent Native Americans — 1.2 percent African Americans — 1.2 percent Asian Americans — 0.45 percent

Condition Relative Risk Incidence % / year

Oral contraceptives (O.C.) 4 0.03

FVL (heterozygous) 7 0.06

OC plus FVL (heterozygous) 35 (16?) 0.29

Thrombotic risk during oral contraceptive use and pregnancy in women with factor V Leiden or prothrombin mutation: A rational approach to

contraception. Blood 2011 Aug 25; 118:2055.

Risk VTE:

OC

=

.19

FVL

=

.35

OC +FVL =

.49

FVL+Preg =

1.97

Hypothetical analysis by authors: If we withhold BCP to 100,000 woman we will see 336 VTE in condom users but on 6 in OC users.

Conclusion: Okay to use BCP in FVL and Prothrombin Gene Mutation

Prothrombin (Factor II) Gene

Mutation-G20210A

•

1-4% whites

•

Increased Prothrombin production

Protein C, Protein S, and

Anti-thrombin Deficiency

Type Antigen Activity

I Low Low

II Normal Low

• Autosomal Dominant

• Screen using activity assay • Falsely low activity in acute

clot, warfarin use

• High clinical penetrance

• Acquired deficiencies occur (ex. Liver Dz, NS)

Protein S Deficiency

•

Unlikely to be a risk factor of DVT

Pintao MC et al. Protein S levels and the risk of venous thrombosis: Results from the MEGA case-control study. Blood 2013 Oct 31; 122:3210.

Homocysteine and the MTHFR Gene

Elevated homocysteine levels are associated with increase risk of venous thrombosis (2.5-2.9X) and arterial vascular disease

RCTs of Vitamin supplementation to lower homocysteine has not proven to decrease risk of recurrent arterial or venous events ( 8 negative RCTs)

Do not screen for elevated homocysteine

levels or MTHFR

Thrombophilia, Clinical Factors, and Recurrent Venous Thrombotic Events

Leiden University Medical Center

Christiansen et al JAMA. 2005;293:2352-2361



474 patients followed

prospectively for 3 years



Clinical factors more

important than laboratory



Risk of clot higher

idiopathic clots, men, and

women using OC’s



Combined abnormalities

Work up for idiopathic DVT

• Don’t miss a malignancy (5-10%) • Think about venous obstruction

• Hospitalized Consider Heparin Induced Thrombocytopenia (HIT)

• Arterial clots too.

• Check CBC to exclude Polycythemia Vera and Essential Thrombocythemia

• Arterial clots too.

• Consider Paroxysmal Nocturnal Hemoglobinuria (PNH) if unusual location (hepatic, portal, or mesenteric vein)

Testing for Hypercoagulability:

• Consider only for unprovoked VTE in patients under 40 (50?).

• Testing for Antithrombin, Protein C, and Protein S deficiency reasonable if young and family history.

• Minimal value for testing for FVL & Prothrombin Mutation.

– Testing Family doesn’t make sense (financial implications) – These test don’t identify increased risk for recurrent clot

• Order testing for Anti-Phospholipid Antibody Syndrome (arterial clots too)

– Cardiolipin IgG or IgM

– B2- Glycoprotein 1 AB (IgG, IgM) – Lupus Anticoagulant

Thrombotic Risk Factors are additive



BLOOD CLOT



Surgery



Hospitalization



Infection/Inflammation



Increasing Age



Smoking



Obesity



Factor V Leiden

Phases of treatment of VTE

•

Initial phase (5-7 days)

•

Long term phase (7 days to 3 months)

–

Therapeutic anticoagulation reduces recurrence

and complications.

•

Extended phase (> 3 months) “prolonged prophylaxis”

– Reserved for high risk

– Not meant to be “life long” – No “bridging” if on warfarin

How Long to Treat?

• Idiopathic VTE may have a 50% risk of recurrence

• Patient counseling

− Provoked 10% risk 5 years − Unprovoked 30-40% 5 years

Risk Stratification for recurrence

Lower Risk

•

Women

•

Younger age

•

Distal DVT (HR 0.49)

•

Estrogen-related VTE

High Risk

•

Age (HR 1.17)

•

Male Sex (HR 1.56)

•

PE (HR 1.19)

•

Increased D-dimer (OR 2.36)

Predicting Risk of Recurrence-

Risk Assessment Model

 Prospective Cohort Study

 Followed 929 patients for 43 months

 Risk Recurrence = 25%

 Higher Risk- Male, Prox. Thrombosis,

PE, and elevated D-dimer

 Hereditary Thrombophilias not predictive

 Develop Nomogram

 5 year risk 5-30% depending on clinical

parameters

Circulation 2010; 121:1630-1636

Current CHEST Guidelines suggest

more extended

phase therapy

• In patients with an unprovoked DVT of the leg (isolated distal or

proximal), we recommend treatment with anticoagulation for at least 3 months over treatment of a shorter duration (Grade 1B). After 3 months of treatment, patients with unprovoked DVT of the leg should be

evaluated for the risk-benefit ratio of extended therapy.

• In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk, we suggest

extended anticoagulant therapy over 3 months of therapy (Grade

2B).

Clarification:

•

If a patient has a unprovoked PE, even if FVL is

determined upon a hypercoagulable workup,

the chart notation should read:

–

Unprovoked VTE (location, date)

•

We should avoid the inaccurate notation:

Extended therapy: What to do?

• Repeat the Ultrasound. • Check D-dimer?

• Does the patient have lymphedema or PTS?

• Does the patient have another indication for anticoagulation? • Did he present with a PE?

• Discuss risks : benefits and ask what patient prefers.

• If not bleeding, and no problems, why not take it a few months at a time. (indefinite duration)

Options for Extended Treatment

Next patient is a 42 year old female with multiple dvt’s, a second trimester

miscarriage, and laboratory confirmed Anti-phospholipid Antibody Syndrome (APAS). She has to leave work early for INR testing and it is causing conflict with her employer.

Her INR’s have been therapeutic for 6 months on 3 mg alternating with 4mg warfarin every other day. Which of the following is the best approach for this patient?

A. Change to dabigatran 150mg po bid.

B. Change to aspirin 81mg daily.

C. Change to enoxaparin 1.5 mg/kg/day.

D. Check the INR every 3 months.

Give your patient a break!

•

PRINT Study-

– Accepted by CHEST guidelines (2B).

– Not for Everyone (CHF, New Disease Development, etc).

You are treating a 55 y.o. black male presenting with an acute L. lower extremity DVT with IV Heparin, and warfarin that was started on his first hospital day. His dose of warfarin is 5 mg daily. His day 3 INR was 1.0. What

is the next best action?

A. Stop IV Heparin, start LMWH at therapeutic dosing.

Continue warfarin 5 mg daily.

B. Change to LMWH as above; but increase warfarin 10 mg

daily.

C. Continue IV Heparin. Continue warfarin 5 mg daily.

D. Continue IV Heparin. Increase warfarin 10 mg daily.

Newly diagnosed VTE disease case:

•

If the INR = 1.0 on Day 3 then double starting dose.

•

LMWH is better than UFH for VTE Disease!

–

No lab testing, Less risk HIT, more clot regression, lower

recurrence, lower bleeding, less deaths

–

One study reported 60% patient on UFH failed to achieve

adequate aPTT response in 24 hours.

–

ACCP 2B recommendation.

Arch Intern Med 1988; 148:1321 Chest 2012; 141: e495S

Ideal anticoagulant

•

Safe and effective

•

Rapid acting

•

Available p.o. and parenteral

•

Rapid elimination

•

Free of drug interactions

•

Predictable effect and wide therapeutic window

•

No need for monitoring

•

Minimal toxicity and side effects

Warfarin VS. Newer Rxs

Features Warfarin Newer Agents

Onset Slow (days) Rapid Dosing Variable Fixed Half life Long Short Food effects Yes No Drug Interactions Many Few

Monitoring Yes No

Antidote Yes No (but short ½ life)

Your patient is a 50 y.o. male who presented 6 months ago with syncope due to an idiopathic PE. He is afraid of dying and does not want to stop warfarin, but he is an international traveler and is concerned about work related travel

due to his INR testing. His INR’s have not been stable. He takes no other medications. What is the best option for this patient?

A. Stop warfarin and recommend aspirin.

B. Check INR every 3 months.

C. Change to LMWH.

Newer Anticoagulants FDA Approval

Drug Prophylaxis

(ortho) A. Fib ACUTE DVT Prolonged treatment

DVT/PE Dabigatran (Pradaxa)

x

x

x

x

x

x

x

x

x

Drug CYP 3A4 P-gp

Dabigatran

(Pradaxa) Yes

Rivaroxaban

(Xarelto) Yes Yes Apixaban

Dabigatran (Pradaxa)

•

Direct thrombin inhibitor

•

Renal excretion

•

VTE approval (bridging)

•

Not for use with mechanical

heart valves (increase CVA

and bleeding)

•

Slight increase for CAD

Circulation 2012; 125:669

Patient is a 57 y.o. male school teacher recently

diagnosed with AIDS while admitted for an acute

PE. Which of the following is correct?

A. HIV/AIDS is not a risk factor for VTE disease.

B. Intravenous unfractionated heparin is preferred in HIV

patients with acute VTE disease.

C. Rivaroxaban is contraindicated in patient on protease

inhibitor therapy due to CYP3A inhibition.

Rivaroxaban (Xarelto)

•

Once daily with food

for acute VTE x 3wk)

•

Avoid with medications that

affect both the P-gp and

Cytochrome P450 3A4.

Cyp3A4 inhibitors:

• (HIV protease inhibitors, ketoconazole, voriconazole)

CYP3A4 inducers:

• (Rifampin, carbamazepine, or phenytoin)

•

No need for overlapping

parenteral Tx

Rivaroxaban (Xarelto) vs. Warfarin for acute PE

• Symptomatic PE +/- DVT

• Excluded: Cr clearance < 30, Liver disease, SBP <110 or >180, drugs that affect CYP 3A4

• Average age 57

• 10% treated outpatient • 12% ICU

• Conclusion: Rivaroxaban is non-inferior with similar bleeding risk (less major

bleeding)

Apixaban (Eliquis)

Twice daily

Less bleeding

?

“AMPLIFY”

4.3% vs. 9.7%

AMPLIFY EXT for continued therapy after 6-12 months no

higher bleeding then placebo.

Risk of DVT 12 mo. 1.7% 2.5mg, 1.7% 5mg, and 8% placebo

Risk of Death 12mo 3.8%, 4.2%, 11.6%

Edoxaban

•

Once daily (60mg)

– 30mg/d. Cr.Cl 30-50 or weight less than

60kg.

•

Approx. 10% < 60 kg

•

Approx. 10% > 75 y.o.

•

More effective than

warfarin in patients with

high risk PE.

Bleeding Patients

• Supportive measures • Last dose?

• Renal or hepatic dysfunction? • Other anticoagulants?

• If PT normal, unlikely any effect of rivaroxaban.

• If PTT is normal, unlikely any effect of dabigatran.

“Oral Anticoagulants: The old and the new.” 2012; American Society of Hematology Webinar

Control of bleeding

Modality Dabigatran Rivaroxaban Apixaban

Charcoal X X X Hemodialysis X Prothrombin Complex Concentrates Kcentra

x

x

Future is here:

59 y.o. female with breast cancer.

Oct 24th_{, 2013 Hi Dr. Dan, I bet you thought I died or something. Just got back from the}

Italy trip on Monday night - had a wonderful time. Didn't think that I was going to be able to go. About a month ago, I had such bad chest pain that I thought I was having a heart attack - turned

out to be a blood clot on my lung. Was in the hospital for a week until they got my INR levels correct. Now I am on Warfarin.

Oct 25th_{, 2013 Dr. Dan , Just had a chemo. treatment today and they checked my pro-time}

levels - 3.9 - must have been all that wine I drank in Italy. Dr. Latif told me not to take my warfarin tonight and also tomorrow night, but I am to resume on Sunday, but only 5 mg. not the 7.5 mg.

1950’s- present

•

One week in the hospital

•

Numerous tests

•

Exposure to sick patients

•

Discharged on therapeutic

warfarin

•

Outpatient labs, risk of over

and under dosing.

•

Missed work, bills, etc.

“Future”

•

Start rivoroxaban BID for

three weeks then daily.

•

Discharge from the ED or

hospital the next day.

Conclusions:

1. Age is an important cause of hypercoagulability.

2. FVL and PG mutation are “wimpy” risk factors for

first VTE, and are not predictive of subsequent

clotting.

3. O.C.s are reasonable in known FVL.

4. Homocysteine and MTHFR: Just say “No.”

5. Having an unprovoked VTE is a major risk factor

for subsequent VTE.

6. Prolonged anticogulation can be carried out with