Venous Thromboembolism

2 Types of Venous Thromboembolism

* Pulmonary Embolism (PE)
* Deep Vein Thrombosis (DVT)

Venous Thromboembolism Homeostasis

Blood clot forms to prevent excessive bleeding

Venous Thromboembolism Homeostasis - Containment Mechanisms

Natural anticoagulants act to control/limit thrombin formation

Thrombosis

Blood clots block veins or arteries

Risk Factors

* Recent trauma
* Immobilization ≥3 days or surgery in the previous 4 weeks
* Major surgery
* Obesity
* Cancer
* Pregnant
* Replacement hormone therapy
* Smoking
* Burns
* After age 50
* Men > Women
* Ethnicity
* African Americans
* Caucasians
* Genetic Risk Factors
* Factor V Leiden
* Prothrombin 20210
* Antithrombin, Protein C, and Protein S deficiency

Virchow’s Triad

Thrombosis Formation

* Hypercoagulability
* Vascular damage
* Venous stasis

Virchow’s Triad - Hypercoagulability Risk Factors

* Genetic Disorders
* History of VTE
* Anti-phospholipid antibodies
* Pregnancy
* Estrogen
* Cancer
* Sepsis
* Smoking

Virchow’s Triad - Vascular Damage Risk Factors

* Trauma/surgery
* Chemical irritation
* Valve disease/replacement
* Atherosclerosis
* Spinal cord injury

Virchow’s Triad - Venous Stasis Risk Factors

* Immobility/Air travel
* Atrial Fibrillation/Stroke
* Left ventricular dysfunction
* Obesity
* Varicose Veins

Venous Thromboembolism Signs/Symptoms

* Respiratory symptoms
* Signs of massive Pulmonary Embolism (PE)
* __**Anxiety**__
* __**Asymptomatic**__
* Extremity symptoms
* Cardiac symptoms

Venous Thromboembolism Signs/Symptoms - Respiratory Symptoms

* Cough/rales
* Shortness of breath ( PO2)
* Tachypnea (>20 bpm)

Venous Thromboembolism Signs/Symptoms - Signs of Massive PE

* Lightheaded
* Cyanotic

Venous Thromboembolism Signs/Symptoms - Extremity Symptoms

* Pain in affected extremity
* Redness
* Swelling
* Warmth and tenderness

Venous Thromboembolism Signs/Symptoms - Cardiac Symptoms

* Chest pain
* Tachycardia (>100 bpm)
* Jugular venous distension
* Hemoptysis
* Diaphoresis (sweating)
* Palpitations

Pretest Probability of Deep Vein Thrombosis (Wells Criteria) - Clinical Features and Scoring

* Active cancer (treatment ongoing or within previous 6 months of palliative treatment) - Score 1
* Paralysis, paresis, or recent immobilization of the lower extremities - Score 1
* Recently bedridden for >3 days or major surgery within 4 weeks - Score 1
* Collateral superficial veins (not varicose) - Score 1
* Localized tenderness along the distribution of the deep venous system - Score 1
* Entire leg swollen - Score 1
* Calf swelling by >3 cm when compared with asymptomatic leg - Score 1
* Pitting edema (greater in the symptomatic leg) - Score 1

Pretest Probability of Deep Vein Thrombosis (Wells Criteria) - Score Interpretation

* DVT likely ≥ 2, DVT unlikely ≤ 1
* High probability ≥ 3
* Moderate probability 1-2
* Low probability ≤ 0

Pretest Probability of Pulmonary Embolism (Wells Criteria) - Clinical Features and Scoring

* Clinical signs and symptoms of DVT (leg swelling and pain with palpation of the deep veins) - Score 3.0
* Alternative diagnosis less likely than PE - Score 3.0
* Heart rate >100 bpm - Score 1.5
* Immobilization ≥3 days or surgery in the previous four week - Score 1.5
* Previous PE or DVT - Score 1.5
* Hemoptysis - Score 1.0
* Malignancy (receiving treatment or treated in past 6 months or palliative) - Score 1.0

Pretest Probability of Pulmonary Embolism (Wells Criteria) - Score Interpretation

PE likely > 4; PE unlikely ≤ 4.0

* High probability > 6
* Moderate probability 2-6
* Low probability < 2

Laboratory Tests

* D-dimer
* Arterial blood gases

Laboratory Tests: D-dimer

* Fibrin degradation product
* Sensitive but __NOT__ specific

Abnormal D-dimer Value

>500 ng/mL

D-dimer False Positives

* Recent surgery or trauma
* Pregnancy
* Increasing age
* Cancer
* Infection
* COVID

Laboratory Tests - Arterial Blood Gases

* pO2 and pCO2 decreased
* Not reliable diagnostic

Diagnostic Studies - Gold Standard for Pulmonary Embolism (PE)

* Pulmonary angiography (radiographic contrast)
* __**INVASIVE**__

Diagnostic Studies - Gold Standard for Deep Vein Thrombosis (DVT)

* Venogram (radiographic contrast)
* __**INVASIVE**__

Diagnostic Studies - Other Options

* Ultrasonography
* __**Most common for DVT (less invasive than Venogram)**__
* Computed tomography (CT) scan
* __**Most Common for PE (less invasive than pulmonary angiography)**__
* Echocardiogram (ECHO)
* Ventilation-perfusion (V/Q) lung scan
* Reserved for patient’s with an allergy to contrast or those with renal impairment

Pulmonary Embolism Classification

* Massive PE
* Submassive PE
* Low-Risk PE

Pulmonary Embolism Classification - Massive PE

Acute PE with sustained hypotension defined as:

* SBP

Massive PE are __**NOT**__ Due to

* Arrhythmias
* Hypovolemia
* Sepsis
* Left ventricular dysfunction

Pulmonary Embolism Classification - Submassive PE

Acute PE WITHOUT systemic hypotension BUT with either:

* __**Right Ventricular Dysfunction**__ (at least 1 of the following):
* Dilation or systolic dysfunction on echocardiography
* Dilation on Catscan
* Elevation of BNP (>90 pg/mL)
* Elevation of N-terminal pro-BNP ( > 500 pg/mg)
* Electrocardiographic changes
* __**Myocardial Necrosis**__ defined as:
* Elevation of troponin I (>0.4 ng/mL)
* Elevation of troponin T (>0.1 ng/mL)

Pulmonary Embolism Classification: Low-Risk PE

Acute PE and the __**ABSENCE**__ of clinical markers of adverse \n prognosis that define massive and submassive PE

Venous Thromboembolism - Goals of Therapy

* Prevent thrombus extension and embolization
* Reduce Recurrent risk
* 33% will have a recurrence within 10 years
* Prevent long-term complications
* Post thrombotic syndrome
* Chronic thromboembolic pulmonary hypertension
* Reduce the risk of bleeding

Provoked Venous Thromboembolism (VTE)

Identifiable transient medical or surgical risk factor

Provoked Venous Thromboembolism (VTE) Examples

* Surgery
* Hospital admission
* Immobility
* Pregnancy

Unprovoked Venous Thromboembolism (VTE)

No identifiable event or provoking risk factor

Hypercoagulable Disorders and Venous Thromboembolism

* Many patients with hypercoagulable disorders experience a first VTE only when experiencing a transient risk factor (surgery or long travel)
* Risk of recurrence therefore is concerning even when a transient event passes

Duration of Therapy: DVT/PE

Provoked/Non-Persistent vs Provoked Persistent

* Provoked/Non-Persistent: Condition that is not persistent and can be __**MODIFIED**__ (ex. surgery)
* Provoked Persistent: Has a condition that is persistent that is NOT going away/__**UNMODIFIABLE**__ (ex. Genetic factors)

Preferred Treatment Choice: DVT/PE

Preferred Extended Treatment Choice

* Reduced-dose apixaban or rivaroxaban is recommended over full-dose apixaban or rivaroxaban
* Apixaban 2.5 mg PO BID (__**NEVER DOSE REDUCE**__)
* Rivaroxaban 10 mg PO daily
* Alternatively, patients could continue their warfarin or other anticoagulants
* __Warfarin needs to be bridged with heparin__

Aspirin Role in VTE Therapy

* Those with __**unprovoked DVT or PE who are**__ __**stopping anticoagulant therapy**__ and __**do not have a**__ __**contraindication to aspirin,**__ recommend aspirin over no aspirin to prevent recurrent VTE
* Only for patients who refuse anticoagulants
* Extended ASA therapy reduced recurrent VTE by 1/3
* Anticoagulant > ASA at prevention of recurrent VTE

Treatment Management DVT/PE - Intravenous Anticoagulation

* Heparin
* Low-Molecular Weight Heparin
* Fondaparinux

Treatment Management DVT/PE - Oral Anticoagulation

* Warfarin (Coumadin ®)
* Apixaban (Eliquis®)
* Rivaroxaban (Xarelto®)
* Edoxaban (Savasya®)
* Dabigatran (Pradaxa®)

Heparin Target

* XIIa
* XIa
* Ixa
* VIIa
* Xa

Heparin Elimination

Dual mechanisms

Enoxaparin Target

Factor Xa and IIa

Enoxaparin Elimination

Extensively renal

Fondaparnox Target

Factor Xa

Fondaparnox Elimination

Urine (up to 77%)

Unfractionated Heparin MOA

Accelerates the activity of antithrombin III to inactive thrombin

Unfractionated Heparin Dosing

* For VTE: 80 unit/kg IV bolus x1 (maximum bolus dose = 10,000 units)
* Followed by initial infusion rate of 18 units/kg/hr

Unfractionated Heparin Monitoring

* Activated partial thromboplastin time (aPTT)
* Anti-factor Xa activity (anti-Xa level)
* Complete blood count (Hgb, Hct, Plts)

Unfractionated Heparin Side Effects

* Bleeding
* Thrombocytopenia
* Alopecia
* Osteoporosis

Unfractionated Heparin Contraindication

* Severe thrombocytopenia
* Heparin-induced thrombocytopenia (HIT)
* Uncontrolled active bleeding

Unfractionated Heparin Counseling Points

If Heparin-induced thrombocytopenia (HIT) develops → __**STOP ALL**__ heparin products

Low Molecular Weight Heparin (LMWH) MOA

Catalyzes the action of antithrombin, leading to inactivation of coagulation factor Xa and factor IIa

Low Molecular Weight Heparin (LMWH) Dosing - Enoxaparin (Lovenox)

* Preferred: 1 mg/kg sc every BID
* Alternative: 1.5 mg/kg sc daily

Low Molecular Weight Heparin (LMWH) Dosing - Dalteparin (Fragmin)

Active cancer: 200 units/kg sc daily

Low Molecular Weight Heparin (LMWH) Monitoring

* Complete blood count (Hgb, Hct, Ptts) and serum creatinine
* __**Routine monitoring with anti-Xa activity not recommended**__

Low Molecular Weight Heparin (LMWH) Side Effects

* Bleeding
* Thrombocytopenia
* Spinal hematoma
* Epidural intercranial hemorrhage
* Injection site reaction
* Osteoporosis/Ostropenia

Low Molecular Weight Heparin (LMWH) Contraindications

* Severe thrombocytopenia
* Active bleeding
* HIT
* Dialysis patients

Low Molecular Weight Heparin (LMWH) Counseling Points

CrCl < 30 ml/min, enoxaparin dose adjusted to 1 mg/kg sc daily

Low Molecular Weight Heparin (LMWH) Black Box Warning

Spinal or epidural hematomas

Low Molecular Weight Heparin (LMWH) Adminstration

* Wash & dry your hands thoroughly.
* Sit/lie in a comfortable position, so that you can see your stomach (or SQ site). Choose the area on the right or left side of your stomach, ≥ 2 inches from your belly button, where you will give yourself the shot. Do not use areas close to surgical sites or bandages. __**Be sure to change the site each day**__.
* Clean the chosen area to inject with an alcohol pad.
* Open the pack and remove the syringe. Pull the needle cap off.
* The syringe has a set dose of drug in it. __**Do not push**__ __**the air bubble out**__ from the syringe before you inject it.
* Hold the syringe, like a pencil, in your writing hand. With other hand, use your thumb & forefinger to pinch a fold of skin on the chosen area.
* Insert the entire needle straight (__**90 degrees**__) into the fold of your skin & slowly press the plunger down. Make sure the full dose of has been given.
* Pull the needle straight out, point it down & away from yourself & others, and push down on the plunger to activate needle shield.
* __**Throw away syringe in a “SHARPS” box**__

Enoxaparin Advantages

Enoxaparin Disadvantages

Unfractionated Heparin Advantages

Unfractionated Heparin Disadvantages

Fondaparinux MOA

Prevents thrombus generation and clot formation by indirectly inhibiting factor Xa activity

Fondaparinux Dosing - Weight Based

*

Fondaparinux Monitoring

* Complete blood count (Hgb, Hct, Ptts)
* Serum creatinine

Fondaparinux Side Effects

* Bleeding
* Spinal hematoma
* Epidural intercranial hemorrhage

Fondaparinux Contraindications

* Severe renal impairment
* Body weight

Fondaparinux Black Box Warning

Spinal or epidural hematomas

Heparin Reversal: Protamine

* IV Protamine (cationic) + Heparin (anionic) → Stable salt that results in loss of anticoagulation activity
* Neutralizes in 5 minutes

Protamine Heparin Reversal - Time Heparin Dose was Given

* Within 30- 60 minutes: 1 mg IV protamine for every 100 units of heparin (max = 50 mg)
* If > 60 minutes, need to decrease protamine dose
* May not be beneficial If heparin dose was given > 5-6 hours prior

Reversal of Parenteral Anticoagulant - Enoxaparin (Lovenox®)

Partial reversal with protamine, but degree unclear

* If dosed < 8 hours: 1 mg/ 1 mg enoxaparin
* If dosed >8 hours: 0.5 mg/1 mg enoxaparin

Reversal of Parenteral Anticoagulant - Fondaparinux (Arixtra®)

* Activated prothrombin complex concentrate (aPCC or FEIBA®)
* Limited data to support its use

Thrombolytics Data

Many Trials have shown patients with the highest risk of dying from PE and lowest risk of bleed obtain the __**greatest**__ benefit from thrombolytics

Thrombolytics Data - Pulomary Embolism Thrombolysis Trial

* Randomized 1006 patents with PE and RV dysfunction
* Tenecteplase: 30 mg to 50 mg
* Heparin

Pulomary Embolism Thrombolysis Trial - Primary Outcomes

* Efficacy: Composite of death from any cause or hemodynamic decompensation
* Safety: Major Bleed

Pulomary Embolism Thrombolysis Trial Results

__No convincing net benefit from thrombolytic therapy__

* Death or hemodynamic decompensation: 13 tenecteplase and 28 heparin (95% CI: 0.23 - 0.87)
* Major bleeding: 32 tenecteplase and 6 heparin (95% CI: 2.3-13.39)

Absolute Contraindication to Thrombolytics

* Previous intracranial bleed
* Structural intracranial disease
* Ischemic stroke (last 3 months)
* Active internal bleed
* Recent brain or spinal surgery/trauma
* Recent head trauma
* Bleeding diathesis

Relative Contraindication to Thrombolytics

* Severe HTN (>180/110)
* Recent bleeding (non-intracranial)
* Recent surgery/trauma
* Ischemic stroke (> 3 months)
* Current use of anticoagulation therapy
* Traumatic CPR
* Pericarditis
* Pregnancy
* Age > 75
* Low body weight < 60 kg

FDA Approved Thrombolytics for Massive PE

* Alteplase (Activase®)
* Tenecteplase (TNK) (__**not FDA approved for PE**__)
* __Due to bleeding risk__
* Streptokinase (not available in the US)
* Urokinase (not available in the US)

Alteplase (rt-PA) Total Dose

100 mg

Alteplase (rt-PA) PE Dosing

* 10 mg bolus
* Followed by 90 mg over 2 hours, administer through peripheral vein

Alteplase (rt-PA) Adverse Events

* Bleeding complications
* Intracranial hemorrhage

Key Concepts

* VTE are the LEADING CAUSE of PREVENTABLE death in the US
* Diagnostic Imaging is necessary to rule in or out a VTE event
* Thrombolytics are ONLY indicated in patients who are HYPOTENSIVE
* Parenteral anticoagulation is an appropriate therapy option in patients at risk of hemodynamic instability
* Anticoagulation is the mainstay of treatment and should be continues for at least 3 months

Heparin-Induced Thrombocytopenia (HIT)

Immune system causes your platelets to clot in the presence of heparin→ platelet levels dropping → Thrombosis

Heparin-Induced Thrombocytopenia (HIT) Types

* Type I: Heparin Associated Thrombocytopenia (HAT)
* Type II: Heparin-Induced Thrombocytopenia (HIT)

Heparin Associated Thrombocytopenia (HAT) - Immune Mediated

No

Heparin Associated Thrombocytopenia (HAT) - Onset

* Early
* < 4 days of therapy

Heparin Associated Thrombocytopenia (HAT) - Platelet Count

>100 k

Heparin Associated Thrombocytopenia (HAT) - Severity

Transient, mild

Heparin Associated Thrombocytopenia (HAT) -Complications

None usually

Type II Heparin-Induced Thrombocytopenia (HIT) - Immune Mediated

Yes

Type II Heparin-Induced Thrombocytopenia (HIT) - Onset

5-10 days after start of therapy (Earlier if recent exposure)

Type II Heparin-Induced Thrombocytopenia (HIT) - Platelet Count

50% decrease from baseline

Type II Heparin-Induced Thrombocytopenia (HIT) -Severity

Severe