Vanessa Stoloff, MD University of Pennsylvania Student Health Services PULMONARY EMBOLISM IN THE...

Vanessa Stoloff, MDUniversity of Pennsylvania

Student Health Services

PULMONARY EMBOLISM IN THE COLLEGE HEALTH POPULATION

INTRODUCTION• What is venous thromboembolism?

• Venous thromboembolism (VTE) refers to a blood clot occurring inside a blood vessel

• VTE is a relatively common diagnosis

• Each year two million cases of deep vein thrombosis (DVT) are diagnosed in the United States

• Another 600,000 patients are diagnosed with pulmonary embolism (PE) yearly

• DVT and PE can result in significant morbidity and mortality

• PE is a difficult diagnosis that may be missed because of non-specific clinical presentation

• However, early diagnosis is fundamental since early treatment is highly effective

• Along with clinical suspicion comes the importance of using validated algorithms + objective testing

VENOUS THROMBOEMBOLISM - VTE

• Types of VTE:

• Deep Vein Thrombosis – DVT

• Superficial Vein Thrombosis (SVT)

• Pulmonary Embolism PE


• Pathogenesis

• Virchow’s Triad – 3 primary influences that predispose to thrombus formation:

• Alterations in blood flow (ie. stasis)

• Alterations in the constituents of the blood (ie, inherited or acquired hypercoagulable state)

• Vascular endothelial damage

• Compression, immobility, ↑blood viscosity → stasis

• Clot formation develops (and if endothelial damage) → activation of platelets and coagulation cascade

• RBCs and fibrin accumulate and clot increases with ↑ risk of dislodgement

• Thrombogenesis - the process by which blood forms clots

• Hemostasis – cessation of bleeding

• Primary hemostasis

• Platelets immediately form a plug at the site of injury

• Secondary hemostasis (occurs simultaneously)

• Coagulation factors respond in a complex cascade to form fibrin strands

VENOUS THROMBOEMBOLISM


• In over 80% of patients with VTE – risk factor for thrombosis can be identified

• Can often be more than one risk factor

• More commonly, 3+ risk factors (in one study 56%)

• Causes of venous thrombosis

• Inherited (Hereditary)

• Acquired

INHERITED THROMBOPHILIA• Genetic tendency to venous thromboembolism

• Most frequent genetic causes

• Factor V Leiden mutation (most common)

• Prothrombin gene mutation

• Protein S deficiency

• Protein C deficiency

• Antithrombin deficiency

• Dysfibrinogenemia

HTTP://WWW.MED.ILLINOIS.EDU/HEMATOLOGY/PTCLOTINFO.HTM







• Antithrombin III deficiency


50-60% of inherited VTE cases







• Antithrombin III deficiency


Most of the remaining cases

INHERITED THROMBOPHILIA

Most of the remaining cases

RISK FACTORS- OTHER

• Anatomic Risk Factors

• Not known to be inherited

• Elevated clotting Factors

• Not yet proven to be genetic – but are supposedly

• Central venous catheter

• Chronic liver disease

• Hyperviscosity

• Hyperhomocysteinemia

• Seasonal variation

• Cardiovascular risk factors Age

• Air pollution

• Microalbuminuria

• Heparin-induced thrombocytopenia

• Inflammatory bowel disease

• Trauma

• Prior thrombotic event

• Intravenous drug use

• Pregnancy

• Medications

• Immobilization

• Heart failure

• Antiphospholipid antibody syndrome

• Myeloproliferative disorders

• Renal disease

ACQUIRED THROMBOPHILIA

ACQUIRED THROMBOPHILIA• Many patients have more than one risk factor.

• Six most prevalent pre-existing medical characteristics:

• Hospitalization in the past 3 months

• Surgery in the past 3 months

• > 48 hours of immobility in past month

• Malignancy in the past 3 months

• Infection in the past 3 months

• Current hospitalization

Risk Factors %

≥ 3 53%

1-2 36%+

0 11%

ACQUIRED THROMBOPHILIA - SHS

• Major trauma/ Minor injuries

• Surgery (orthopedic)

• Medications (OCPs)

• Immobilization (prolonged sitting, extended travel)

• Pregnancy

• Prior thromboembolic event

• Intravenous drug use

• Genetic predisposition

CASE # 1

CASE # 1 - JW

• JW - 25 yo female – graduate school of Nursing

• CC: L sided shoulder pain

• HPI: Healthy 25 yo female developed L sided shoulder pain x 3 days. Pain progressed down into her L chest. Pain described as a “pulled muscle”. Exacerbation with deep inspiration. Ran 11 miles and felt like she was unable to take a deep breath. While getting ready for her birthday dinner, friend told her she sounded more winded. She realized there was something wrong. Called on call provider after hours.

• Pain started near her left shoulder and migrated to under her left breast. Pain worse w/ cough, deep inspiration. Pt denied associated fever/chills, no cough. She had a "bad cold" 10 days prior - with clear rhinorrhea. Denies trauma to chest wall.

• Meds: Yasmin-28

• After much discussion, she was sent to Emergency Dept. for further evaluation.

CASE # 1 - JW

• ED evaluation

• Additional History: No leg pain or swelling. No weakness/numbness. No prolonged immobilization or recent travel. No history of DVT. Pain 8/10.

• Physical Exam:

• VS: BP: 151/74 HR: 90 T: 99.0F RR: 16

• Gen: 25 yo female tearful and concerned, but in no acute respiratory distress

• Lungs: CTAB, no wheezes, some discomfort with deep inspiration

• + Left CVA tenderness

• LE: pulses 2+, no calf swelling/warmth/ttp

CASE # 1 - JW

• ED Evaluation• Pulse Ox: 95%-100%• CXR: No active disease seen in the chest, no fractured ribs• Labs:

• CBC, Chem-7 - normal• D-dimer: Not done

• EKG: NSR, no acute ST changes• Spiral CT: Bilateral segmental pulmonary emboli, occlusive on the left and non-

occlusive on the right. Left anterior basilar pulmonary infarct. Small left pleural effusion with bibasilar atelectasis.

• Admitted for anticoagulation and pain control

WWW.MEDICAL-ARTIST.COM

PULMONARY EMBOLISM - PE

• PE is an obstruction of the pulmonary artery (or one of it’s branches) by material:

• Thrombus, tumor, air, fat

• PE can be classified as

• acute or chronic

• massive or sub-massive

• Acute PE is a common and often fatal disease

• Untreated PE is associated with ~ 30% mortality rate

• Mortality can be reduced by prompt diagnosis and therapy

• More than half of all PE are probably undiagnosed

• In an older study of >42 million deaths over 20 years, 1.5% were diagnosed with PE (now considered an underestimate)

• Since CT Pulmonary angiogram (CT-PA) incidence has increased from 62.1 to 112.3 cases per 100,000

• Most patients with acute PE have identifiable risk factors at time of presentation

PULMONARY EMBOLISM - PATHOPHYSIOLOGY

• Most PE arise from thrombi in the deep venous system

• Iliofemoral veins are source of most clinically recognized PE

• May originate from right heart, or pelvic, renal, or upper extr veins

• Thrombi travel to lung and may lodge at bifuraction (saddle)

• Smaller thrombi can continue past main pulmonary artery

and lobar branches

• More likely to produce pleuritic chest pain

• Can initiate an inflammatory response

• Lower lobes involved in majority of cases

• Most PEs are multiple

WWW.VASCULARWEB.ORG

PULMONARY EMBOLISM – SIGNS & SYMPTOMS

• Most Common Symptoms

• Dyspnea at rest or with exertion (78%)

• Pleuritic pain (44%)

• Cough (34%)

• > 2-pillow orthopnea (28%)

• Calf or thigh pain (44%)

• Calf or thigh swelling (41%)

• Wheezing (21%)


• Most Common Signs

• Tachypnea (54%)

• Tachycardia (24%)

• Rales (18%)

• Decreased breath sounds (17%)

• Accentuated pulmonic component of 2nd heart sound (15%)

• Jugular venous distension (14%)


• Highly variable and nonspecific

• Frequency similar among patients with and without PE

• PE is frequently asymptomatic

• Clinical impression alone has a sensitivity and specificity of 85% and 51%

• Not helpful diagnostically

Diagnostic testing is necessary before confirming or excluding diagnosis of PE

PULMONARY EMBOLISM - PE

• Importance of using validated algorithms and various scoring systems

• Help to determine the a priori clinical probability of PE and DVT

• Pulmonary Embolism Severity Index (PESI)

• Simplified PESI

• Wells Criteria

• Modified Wells Criteria

• Pulmonary Embolism Rule-Out Criteria (PERC)

• Geneva Scoring System

PULMONARY EMBOLISM SEVERITY INDEX (PESI)

• Pulmonary Embolism Severity Index (PESI)

• 10 variables + Patient Age = PESI score

• Male sex (+10 points)

• Hx of Cancer (+30)

• Heart failure (+10)

• Chronic lung disease (+10)

• Pulse ≥ 110 bpm (+20)

• Systolic BP < 100 mmHg (+30)

• Respiratory rate ≥ 30 breaths/min (+20)

• Temperature < 36 degrees C˚

• Altered mental status (+60)

• Arterial oxygen saturation < 90 (+20)

• Difficult to apply in a busy clinical setting

Risk Class for Mortality

Points

Class I < 66

Class II 66-85

Class III 86-105

Class IV 106-125

Class V >125

PULMONARY EMBOLISM SEVERITY INDEX (PESI)

• Simplified PESI

• Assigns one point for each of several variables

• Age >80

• History of cancer

• Chronic cardiopulmonary disease

• Hear rate ≥ 110 bpm

• Systolic BP < 100 mmHg

• Arterial oxyhemoglobin saturation < 90%

• Seems to have a prognostic accuracy similar to the original PESI

Risk Class for Mortality

Points

Low risk 0

High risk >1

WELLS’ CRITERIA FOR PROBABILITY OF PE

Wells’ Criteria for Pulmonary Embolism

Clinical Signs and Symptoms of DVT +3

PE is #1 diagnosis, or equally likely +3

Heart Rate >100 +1.5

Immobilization at least 3 days or Surgery in the previous 4 weeks +1.5

Previously, objectively diagnosed PE or DVT? +1.5

Hemoptysis +1

Malignancy with treatment within 6 months or palliative +1

Patient has none of these 0

WELLS’ CRITERIA FOR PROBABILITY OF PE

Clinical Probability Assessment Score

High > 6.0

Moderate 2.0 to 6.0

Low < 2.0

Modified Clinical Probability Assessment

Score

PE likely > 4.0

PE unlikely ≤ 4.0

REVISED GENEVA SCORING SYSTEM FOR PE

Geneva Scoring

Age > 65 years 1

Previous DVT or PE 3

Surgery (gen anesthia) or fx (lower extremities) within 1 month 2

Active malignant condition 2

Unilateral lower limb pain 3

Hemoptysis 2

Heart rate 75-94 bpm 3

Heart rate ≥ 95 bpm 5

Pain on LE deep venous palpation and unilateral edema 4

REVISED GENEVA SCORING SYSTEM FOR PE

Clinical Probability Assessment Score

High ≥ 11

Intermediate 4 - 10

Low 0 - 3

PULMONARY EMBOLISM RULE-OUT CRITERIA - PERC• PERC (Pulmonary Embolism Rule-out Criteria) rule can significantly decrease work-up for pulmonary embolism

• Created for use by Emergency Medicine Clinicians

• To apply this rule, the clinician must first use clinical gestalt to classify the patient as low risk

• Eight clinical criteria (+ history, physical and VS) used to help decision making:

• Age < 50 years

• Pulse < 100 bpm

• SaO2 > 94%

• No unilateral leg swelling

• No hemoptysis

• No recent trauma or surgery

• No prior PE or DVT

• No hormone use

• If all criteria are present and pre-test probability is ≤15%, then there is less than a 2% risk that a patient has a PE, no further work-up is needed

HTTP://ANNALS.ORG/

WWW.AAFP.ORG

PULMONARY EMBOLISM – OBJECTIVE TESTING

• Importance of using validated algorithms + objective testing

• Routine lab findings are usually nonspecific (↑WBCs, ↑ESR, ↑LDH, ↑AST)

• Arterial blood gas (ABG) (hypoxemia, hypocapnia, resp alk)

• Pulse oximetry (<95% ↑ risk of complications)

• Brain natriuretic peptide (BNP) (↑BNP, but insensitive and nonspecific)

• Troponin I and T (↑ 30-50% with moderate to severe PE)

• Electrocardiography (Non-specific ST-segment,T-wave changes)

• Chest radiography

PULMONARY EMBOLISM – TESTING

• Ventilation/Perfusion (V/Q) Scan

• Lower extremity ultrasound

• D-dimer – (measurable degradation product of cross-linked fibrin)

• Angiography

• “gold standard” in diagnosis of acute PE

• Spiral (helical) CT with intravenous contrast – CT Pulmonary Angiography (CT-PA)

• Ability to detect alternative pulmonary abnormalities

• MR Angiography (MRA)

• Echocardiography

CASE # 2

CASE # 2- MD

• MD - 21 yo female

• CC: difficulty breathing while working out

• HPI: 21 yo female recently in Emergency Dept (2 weeks prior) for “severe allergic reaction” -- diagnosed as urticaria (unknown cause). Treated with prednisone and antihistamines, discharged. No breathing concerns at that time (no wheezing, SOB). She had a “super bad cold” at that time, felt she might have been having some SOB after running.

• Now her complaint is that her SOB is still present. Now describes her condition as “feeling OK while running – up to a point”. She will develop a burning sensation in her lungs with running -- “not in a good way”. Her parents encouraged her to go to SHS so that she could have “blood work” and a “mono test”. She is already scheduled to see Allergy.

CASE # 2- MD

• PMHx: unremarkable

• healthy 21 yo female

• No history of asthma

• May have slight seasonal allergies (doesn’t use meds)

• FHx: non-contributory

• SHx: non-smoker

• non-drinker

• senior - studying business and Chinese

• Runner - has run in marathons before, training for 10K run next month

• Meds: OCPs

CASE # 2- MD

• Physical Exam:

• Vital Signs: BP: 121/72 HR: 67 T: 97.8 RR: 14

• GEN: well-developed, well-nourished, speaking in full sentences with no effort

• HEENT: unremarkable

• Lungs: CTAB, no wheezing, no pleurisy

• Heart: RRR, no murmurs

• Ext: WNL, no calf pain or edema, Neg Homans

• Peak Flows: 450 → 440 → 440

• Pox: 95-96%

CASE # 2- MD

• Impression:

• 21 year old otherwise healthy female

• Dyspnea on exertion

• Decreased Pulse Ox

• Oral contraceptives

• Work up:

• CXR

• CBC, TSH, Mono screen (parent’s request)

• D-Dimer?

• Rx: Albuterol MDI

• Disposition: Stable. Since evening appt. was discharged to home. Advised to get CXR in AM. Will contact in AM with results. Trial of bronchodilator.

Wells Criteria for PE Score

Clinical Signs and Symptoms for DVT 3

PE is most likely diagnosis 3

HR >100 1.5

Immobilization 3 days/Surgery in 4 weeks 1.5

Previous PE or DVT 1.5

Hemoptysis 1

Malignancy within 6 mos 1

Patient has none 0

Wells Score = 0

WWW.LIFEINTHEFASTLANE.COM

D-DIMER• D-dimers are a fibrin degradation product

• Elevated if increased plasmin-activated fibrinolysis during thrombosis

• D-dimer testing is of clinical use when there is a suspicion of DVT or PE

• If low or moderate probability of DVT, a D-dimer level might be obtained, which excludes a diagnosis if results are normal

• When individuals are at a high-probability of having DVT, diagnostic imaging is preferred to a D-dimer test

• D-dimer < 500 ng/ml (<0.50 mcg/ml) is sufficient to exclude PE in patients with a low or moderate pretest probability of PE

• Hospitalized patients often have elevated levels for multiple reasons

• ↑ levels require further investigation with diagnostic imaging

• Poor specificity and positive predictive value

• Normal in only 40-68% patients without PE

• Clinically useful when there is a suspicion of DVT or PE

• Variety of different assays (rapid tests)

• Good sensitivity and negative predictive value

• Abnormal in 95% of all patients with PE

D-DIMER

CASE # 2- MD

• Results: (seen the next day)

• CBC: WBC: 9.6, Hgb/Hct: 13.8/40.6, TSH: 1.94, Mono spot negative – all WNL

• D-Dimer – 4.38 mcg/ml FEU (<0.50)

• Now what!?: Unable to reach patient via telephone.

• Left email/secure message: Hi Maria - I just left you a voice message... PLEASE contact me at 215-746-1048 as soon as you get these results. I am concerned about your D-Dimer level (the one we discussed yesterday at length). It is elevated which increases my suspicion for a possible clot in your lungs. I have already contacted the ED at HUP and they are expecting you. PLEASE head over to HUP ED now at 34th & Spruce. Call me on the way....

CASE # 2- MD

• Thankfully, she got my messages and contacted SHS. She was promptly sent to the ED.

• ED Evaluation:

• CC: “I was seen yesterday at SHS. I have a low pulse ox and + D-dimer”

• Exam: VSS, exam WNL

• Pulse Ox: 95%

• CXR: No active disease

• EKG: NSR at 74 bpm

• CT: Large pulmonary emboli most of both lower lobe pulmonary arteries with the right embolus extending from the upper to the lower lobe and occluding most of the upper lobe and middle lobe pulmonary arteries.

• Admitted for anticoagulation (given SC dalteparin)

CASE # 2- MD

• Why did I order the D-Dimer?• “PE, or Not PE?: That is the Question”

a little intuition + a lot of objectivity = proper diagnosis

CASE #3

CASE # 3• BS - 28 yo male

• CC: Heart racing, SOB with movement, a bit dizzy

• HPI: Healthy 28 yo male s/p recent arthroscopic ACL repair 5 days prior. Complicated post-op course with pneumonitis/pneumonia for which he was admitted for IV antibiotics. Was discharged to home following day.

• Developed fever and some chest tightness along with SOB 1 day ago.

• Tmax: yesterday 101.7

• Meds: Albuterol MDI, Hydromorphone

CASE # 3• Physical Exam:

• Vitals: BP: 153/91 HR: 96 T: 98.9 Pox: 95-96%, HR: 112-116

• Well appearing, NAD

• Lungs: CTAB

• L knee in immobilizer

• Impression: Post-op (Orthopedic procedure), Tachycardic secondary to pain? vs infection? vs PE?

• Wells criteria: Moderate probability (Post-op + immobilized, ?sign of DVT)

• Sent to Emergency Dept for further evaluation

• needs repeat CXR

• ?CT

• ?IV ABX

CASE # 3• ED evaluation

• History: Sent to ED for “fever/cough/tachycardia since operation 5 days ago”.

• At ED, denies CP/SOB, No N/V. +Mild left knee pain, unchanged since operation

• Post-op history: Patient was observed to have fever in PACU and was treated for pneumonitis (? aspiration during intubation) vs. malignant hyperthermia (patient has family member with history of MH). Patient was observed in SICU overnight and discharged home on azithromycin.

CASE # 3• ED evaluation

• Physical Exam:

• Vital Signs: BP:142/70 HR: 122 T: 100.0 F RR: 18

• GEN: well-developed, well-nourished, in mild distress

• Lungs: CTAB, unlabored respirations with no accessory muscle use

• Heart: regular, tachycardic, no murmurs, no JVD

• Ext: left knee with +swelling, no warmth/erythema, appropriately tender, suture line c/d/i, +slight LE edema to calf

CASE # 3• ED Evaluation

• Pulse Ox: 98%

• CXR: Interval resolution of previously noted right upper and lower lobe alveolar opacities.

• Ultrasound: Vascular studies reveal probable calf vein thrombus

• Labs:

• CBC, Chem-7 – normal, WBC: 7.2

• D-dimer: Not done

• EKG: Not done

• Spiral CT: Multiple bilateral pulmonary emboli as described, more extensive on the left. Enlarged main pulmonary artery to 3.4 cm, findings suggest right heart strain.

• Admitted for anticoagulation and pain control

DEEP VEIN THROMBOSIS - DVT

• DVT of the lower extremity

• Distal (deep calf veins)

• Proximal (involves popliteal, femoral, iliac veins)

• Mortality rate of proximal DVT >> distal DVT

• Over 90% of acute PE are due to emboli emanating from the proximal veins

• Actual physical signs of DVT can be quite unreliable

• Not necessarily a correlation between the location of symptoms and site of thrombosis

• DVT of the upper extremity is less frequent

• Increasing incidence

WWW.DVTPUMPS.COM

DEEP VEIN THROMBOSIS – SIGNS & SYMPTOMS

• Most Common Signs and Symptoms

• Pain or tenderness

• Erythema or discoloration

• Warmth

• Swelling

• Larger leg circumference in affected leg

• Homan’s sign – increased resistance to dorsiflexion of the foot +/- pain

• Visible surface veins

• Leg fatigue

DEEP VEIN THROMBOSIS – DVT OF LOWER EXTREMITY

• Differential Diagnosis

• Muscle strains, pulls, tears, and twists – 40%

• Leg swelling in paralyzed limb – 9%

• Lymphangitis – 7%

• Venous insufficiency – 7%

• Popliteal cysts (Baker’s cyst) – 5%

• Cellulitis – 3%

• Knee abnormality – 2%

• Compartment syndrome – 1%

• Unknown – 26%

DEEP VEIN THROMBOSIS– SIGNS & SYMPTOMS

• Only a minority of patients suspected of having DVT on clinical grounds actually has DVT

• Accurate diagnosis is essential

• High potential risks with diagnosis

• Untreated proximal DVT → can lead to fatal PE

• Anticoagulating patient without DVT → can lead to serious bleeding

• Importance of using validated algorithms + objective testing along with clinical suspicion

WELLS’ CRITERIA FOR PROBABILITY OF DVT

Clinical Feature Score

Active cancer +1

Paralysis, paresis, plaster (cast) +1

Bedridden >3 days OR major surgery w/in 4 weeks

+1

Localized tenderness +1

Swelling of entire leg +1

Calf swelling > 3 cm +1

Unilateral Pitting edema +1

Previous documented DVT +1

Collateral superficial veins +1

Alternative diagnosis less likely -2

WELLS’ CRITERIA FOR PROBABILITY OF DVT

• Interpretation

• Score of 0 = low probability of DVT (less than 10%)

• Score of 1 or 2 = moderate probability of DVT

• Score of 3 or more = high probability of DVT (more than 65%)

WWW.TCD.IE

DEEP VEIN THROMBOSIS – OBJECTIVE TESTING

• D-Dimer

• Imaging

• Contrast Venography (gold standard)

• Compression Ultrasound with Doppler (real-time B-mode)

• Widely available

• Been proved accurate for diagnosing acute, symptomatic, proximal DVT

• Computed tomography (CT) – with contrast

• Magnetic resonance imaging (MRI)

If only it were this easy….

VENOUS THROMBOEMBOLISM - TREATMENT

• Anticoagulant therapy

• Thrombolysis

• Inferior vena caval filters

• Embolectomy

VENOUS THROMBOEMBOLISM - TREATMENT

• Anticoagulation is the main therapy for acute PE and DVT

• Goal is to decrease mortality by preventing recurrent VTE

• Parenteral anticoagulant therapy should be initiated in all patients whom acute PE has been confirmed

• Efficacy of parenteral anticoagulant therapy depends upon achieving a therapeutic level within the first 24 hours of treatment.

• LMWH and fondaparinux are the preferred anticoagulants for initial therapy in most cases of acute PE as they confer superior or equivalent outcomes, are more convenient, and are associated with less thrombocytopenia.

ANTICOAGULATION – TREATMENT OF PE

• Common questions asked by clinicians:

• Should I initiate anticoagulant therapy?

• Which anticoagulant should I initiate?

• What is the appropriate dose?

• How should I monitor treatment?

• What is the clinical evidence supporting its use?

• What are the common complications?

• For how long should I treat?

ANTICOAGULATION – DECISION TO ANTICOAGULATE

• Bleeding Risk Factors

• Age >65 years

• Previous bleeding

• Thrombocytopenia

• Antiplatelet therapy

• Poor anticoagulant control

• Recent surgery

• Frequent falls

• Reduced functional capacity

• Previous stroke

• Diabetes

• Anemia

• Cancer

• Renal failure

• Liver failure

• Alcohol abuse

Risk Class for Bleeding

Points

Low risk 0

Moderate risk 1

High risk 2+

ANTICOAGULATION – INITIATION

•

• If clinical suspicion is HIGH - empiric anticoagulation is recommended

• If suspicion is MODERATE and the diagnostic evaluation is > 4 hours, anticoagulate

• Anticoagulation is NOT recommended empirically if suspicion is LOW.

Risk of recurrent PE without optimal anticoagulation (25%)

Risk of major bleed with anticoagulant therapy (3%)

ANTICOAGULATION

HTTP://WWW.MED.ILLINOIS.EDU/HEMATOLOGY/MEDICATIONS.HTM

Warfarin

Heparins

ANTICOAGULATION – HEPARINS

• Unfractionated Heparin

• Intravenous Unfractionated Heparin (IV UFH)

• Subcutaneous Unfractionated Heparin (SC UFH)

• Low Molecular Weight Heparin (LMWH)

• Fondaparinux (Arixtra)

ANTICOAGULATION – UNFRACTIONATED HEPARIN (UFH)

• Once was the preferred initial treatment

• Shortest acting anticoagulant

• Activity can be reversed by protamine sulfate (if major bleeding occurs)

• Intravenous Unfractionated Heparin (IV UFH) is still preferred in certain situations

• Dosing (Weight-based or Fixed)

• Monitoring - activated partial thromboplastin time (aPTT)

• SC not often used as LMWH, Fondaparinux are more convenient

HTTP://LIFEINTHEFASTLANE.COM/BOOK/CRITICAL-CARE-DRUGS/HEPARIN/

ANTICOAGULATION – LOW MOLECULAR WEIGHT HEPARIN

• Low Molecular Weight Heparin (LMWH)

• Recommended for most hemodynamically stable patients with acute PE rather than IV UFH or SC UFH.

• Anti-Xa activity

• Formulations and Dosing

• Enoxaparin (Lovenox) – administered subcutaneously 1mg/kg every 12 hours OR 1.5mg/kg daily

• Dalteparin – subcutaneous 200 IU/kg once daily

• Nadroparin – subcutaneously 171 IUs/kg once daily

• Tinzaparin – subcutaneously 175 IUs/kg once daily

ANTICOAGULATION – LOW MOLECULAR WEIGHT HEPARIN

• LMWH advantages (numerous trials)

• Lower mortality

• Fewer recurrent thromboembolic events

• Less major bleeding

• Monitoring anti-Xa levels is not necessary for most patients*

• Greater bioavailability

• More predictable pharmacokinetics

• Once or twice daily administration

• Fixed dosing (without adjustment)

• Decreased likelihood of thrombocytopenia

ANTICOAGULATION – FONDAPARINUX

• Fondaparinux (Arixtra)

• Synthetic Factor Xa Inhibitor – catalyzes factor Xa inactivation by antithrombin without inhibiting thrombin

• Dosing: subcutaneous administration once daily

• 5 mg for patients < 50 kg

• 7.5 mg for patients 50-100 kg

• 10 mg for patients >100 kg

• Contraindicated in patients with severe renal insufficiency (CrCl<30ml/min)

• Routine monitoring of anti-Xa levels is not necessary

ANTICOAGULATION – WARFARIN

• Oral anticoagulants are most often used for long-term anticoagulation

• Most oral anticoagulants are Vitamin K antagonists

• Suppresses production of Vitamin K-dependent clotting factors (II, VII, IX, and X)

• Warfarin (Coumadin) is the most common and best studied

• Warfarin is highly effective for preventing recurrent VTE

ANTICOAGULATION – WARFARIN INITIATION

• Warfarin can be initiated on the same day or after heparin or fondaprinux is begun

• Warfarin should NOT be initiated prior to heparin or fondaparinux

• Warfarin alone is associated with 3x increase in recurrent PE or DVT

• Warfarin should be overlapped with heparin or fondaparinux for a minimum of 5 days until the International Normalized Ratio (INR) has been within the therapeutic range (2.0-3.0) for at least 24 hours

• Its anticoagulant effect is not realized until the pre-existing factors are cleared from circulation (~ 36-72 hours)

• Intrinsic clotting pathway remains intact until ~ 5 days

ANTICOAGULATION – WARFARIN

• Dosing:

• Administer Warfarin with initial dose of not more than 5mg per day for first 2 days

• Use smaller doses in elderly patients

• Adjust the daily dose according to the INR

• Rate at which individuals metabolize warfarin varies greatly

• Required dose can be impacted by multiple variables:

• Age

• Concomitant medications

• Diet

ANTICOAGULATION – WARFARIN MONITORING

• International Normalized Ratio (INR) is test most used to measure effects of warfarin

• Target INR for acute PE and DVT is 2.5 (2.0-3.0)

• INR < 2.0 associated with increased likelihood of recurrent PE or DVT

• INR monitored daily at first → once every few days until stable dose is achieved → once every 4 weeks

• Use of Warfarin Nomogram

HTTP://WWW.AAFP.ORG/AFP/2005/0215/P763.HTML

ANTICOAGULATION – OTHER ANTICOAGULANTS

• Rivaroxaban (Xarelto)

• Oral Factor Xa inhibitor

• Fixed dose

• Does NOT require monitoring

• Apixaban (Eliquis)

• Dabigatrin (Pradaxa)

ANTICOAGULATION – COMPLICATIONS

• Bleeding

• Major bleeding: Intracranial hemorrhage, Retroperitoneal hemorrhage, Bleeding that leads to death, hospitalization, or transfusion

• Frequency of major bleeding is proportional to number of risk factors

• LMWH appears to have a lower major bleeding rate than IV UFH

• Protamine sulfate can be used to reduce clinical bleeding by neutralizing antithrombin activity (LMWH, IV UFH, SC UFH)

• For fondaparinux – recombinant factor VIIa may be effective

• Vitamin K and fresh frozen plasma (FFP) can be used to reverse oral vitamin K antagonists

• Thrombocytopenia

• Heparin-induced thrombocytopenia (HIT) is a complication of heparin therapy

• ↑ if longer term therapy

• Low (0)

• Moderate (1)

• High (2+)

• ↑ if recurrent event

• ↓ If longer duration tx

• ↓ risk if provoked PE

• ↓surgical

ANTICOAGULATION – DURATION OF THERAPY

Risk for Recurrent VTE Bleeding Risk

Take into account patient preferences: monitoring, diet, restrictions to activity

ANTICOAGULATION – DURATION OF THERAPY

• At least 3 months for most patients with a first episode VTE

• Vitamin K antagonists are preferred over LMWH for long term therapy of PE

• PE treatment can be for as little as 3 months, sometimes indefinitely

• Inpatient → outpatient

• Reversible or temporary risk factor (immobilization, surgery, trauma) → 3 months

• Unprovoked → 3 months → reassess

• Recurrent PE → 3 months → reassess

• Most patients with DVT are treated for 3 months

• Mostly Outpatient

• Unprovoked calf DVT or 1st VTE (provoked): 3 months

• Proximal DVT or 1st unprovoked VTE: 3-6 months

• Special considerations

ANTICOAGULATION – TREATMENT FOR DVT

• Thrombolytic Therapy and Thrombectomy (percutaneous or surgical)

• Inferior vena caval filter

Vanessa Stoloff, MD University of Pennsylvania Student Health Services PULMONARY EMBOLISM IN THE...

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