1. Pulmonary Embolism in the College Health Population
Vanessa Stoloff, MD
University of Pennsylvania
Student Health Services

2. This talk is entitled Pulmonary Embolism in the College Population
This talk is entitled Pulmonary Embolism in the College Population. I initially chose to talk about PE because it still is astonishing to me how relatively common this diagnosis can be – in a population where I never thought it would fall so high up on my differential list. I then realized that it would almost be impossible to talk about PE without talking about DVT. So I will define venous thromboembolism (VTE) as it is a blanket term for both – and branch out a bit and discuss each.

3. 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

4. Venous Thromboembolism - VTE
Types of VTE:
Deep Vein Thrombosis – DVT
Superficial Vein Thrombosis (SVT)
Pulmonary Embolism PE

5. Venous Thromboembolism - VTE
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
First described by Rudolf Virchow more than a century ago…
venous stasis
increased activation of clotting factors
and vessel wall damage
remain the fundamental basis for our understanding of thrombosis.

6. Venous ThromboembolisM
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
Coagulation (thrombogenesis) is the process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel. Disorders of coagulation can lead to an increased risk of bleeding (hemorrhage) or obstructive clotting (thrombosis).
intricate multi-factorial process
Platelets immediately form a plug at the site of injury; this is called primary hemostasis. Secondary hemostasis occurs simultaneously: Proteins in the blood plasma, called coagulation factors or clotting factors, respond in a complex cascade to form fibrin strands, which strengthen the platelet plug.

7. Venous Thromboembolism - VTE
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
Venous thromboembolism results from a combination of hereditary and acquired risk factors, also known as thrombophilia or hypercoagulable states.

8. 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
clotting or coagulation cascade
YouTube video:

9. 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 III deficiency
Dysfibrinogenemia
50-60% of inherited VTE cases

10. 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 III deficiency
Dysfibrinogenemia
Most of the remaining cases

11. Inherited Thrombophilia
Most of the remaining cases
Once found to have a VTE, and started on treatment, there may be limitations to the testing to see if one might have an inherited thrombophilia.

12. Risk Factors- Other Anatomic Risk Factors Not known to be inherited
Elevated clotting Factors
Not yet proven to be genetic – but are supposedly
Anatomic Risk Factors - Not known to be inherited
- Paget-Schroetter Syndrome (Underlying compressive anomaly at the thoracic outlet)
- May-Thurner Syndrome (Compression of left common iliac vein)
- Inferior Vena Cava Syndrome (Congenital venous malformations of the IVC)
Elevated clotting factors - Not yet proven to be genetic – but are supposedly
Associated with increased thrombotic risk
Factor VIII, IX, XI, thrombin-activatable fibrinolysis inhibitor (TAFI), Interleukin 8
ABO blood group
Non-O blood type
Other plasma components

13. Acquired Thrombophilia
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
Pretty long list of associations for thrombophilia – some stronger than others.
- Trauma (major trauma, minor injuries)
- Medications (OCPs, HRT, Tamoxifen, Bevacizumab (Avastin))
- Antiphospholipid antibody syndrome (associated with SLE and rheumatic disease)
- Myeloproliferative disorders (PV, essential throbocythemia)
- Renal disease (nephrotic syndrome, etc)
- Seasonal variation (highest during winter months)
- Cardiovascular risk factors (obesity, HTN, DM, smoking, hypercholesterolemia)
Other major medical illnesses

14. 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%+
11%

15. 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
Bringing it back to the college health population, we need to remember that our population is at risk!

16. CASE # 1

17. 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.

18. 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

19. 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
Low Wells score

21. 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 cases per 100,000
Most patients with acute PE have identifiable risk factors at time of presentation

22. 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

23. 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%)
Signs and Symptoms and signs of PE are highly variable and nonspecific

24. Pulmonary Embolism – Signs & Symptoms
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%)

25. Pulmonary Embolism – Signs & Symptoms
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

26. Diagnostic testing is necessary before confirming or excluding diagnosis of PE

27. 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
- many tools developed to try to help guide in the diagnosis of PE
- importance of using validated algorithms and various scoring systems – but they must stem from one’s initial clinical suspicion.
For DVT and PE, there are various scoring systems that are used to determine the a priori clinical probability of these diseases
a pri·o·ri  (ä pr-ôr, -r, pr-ôr, -r) adj. 1. Proceeding from a known or assumed cause to a necessarily related effect; deductive.
2. a. Derived by or designating the process of reasoning without reference to particular facts or experience.
b. Knowable without appeal to particular experience.
3. Made before or without examination; not supported by factual study.

28. 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
Class V
>125

29. 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
High risk
>1

30. 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
Heart Rate >100
+1.5
Immobilization at least 3 days or Surgery in the previous 4 weeks
Previously, objectively diagnosed PE or DVT?
Hemoptysis +1
Malignancy with treatment within 6 months or palliative
Patient has none of these
Wells criteria has been used extensively – probably the best known

31. 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

32. Revised Geneva Scoring System For PE
Age > 65 years 1
Previous DVT or PE 3
Surgery (gen anesthia) or fx (lower extremities) within 1 month 2
Active malignant condition
Unilateral lower limb pain
Hemoptysis
Heart rate bpm
Heart rate ≥ 95 bpm 5
Pain on LE deep venous palpation and unilateral edema 4
Much like the Wells criteria is the Geneva criteria, which depend on objective measures

33. Revised Geneva Scoring System For PE
Clinical Probability Assessment
Score
High
≥ 11
Intermediate
4 - 10
Low
0 - 3

34. 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
ge·stalt noun \gə-ˈstält, -ˈshtält, -ˈstȯlt, -ˈshtȯlt\
Definition of GESTALT:
a structure, configuration, or pattern of physical, biological, or psychological
phenomena so integrated as to constitute a functional unit with properties not
derivable by summation of its parts
Use of GESTALT. Collection of entities that creates a unified concept
Looking at something as a whole.

35. Just an example of one of the many algorithms to be found

36. Thankfully some are less complicated.

37. 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
importance of using clinical judgement and validated algorithms.
Diagnostic testing is necessary before confirming or excluding diagnosis of PE
Routine lab findings are usually non-specific.
- ABGs are generally NOT done in college health clinics, more used in EDs or other hospital settings
Not useful in diagnosis.
- Pulse Ox and Troponin – more used for prognosis – associated with adverse outcomes
- Many college health centers can perform EKGs, some even have their own radiology, however, these tests, too, are often of low yield.
- However - EKGs also can be used for prognosis (Atrial Atrial arrhythmias, RBBB, Inferior Q waves, Precordial T-wave inversion)
- CXR can show Atelectasis,Pleural effusion.

38. 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
- V/Q scan determines the vent/perfusion ratio
- Ultrasound – flawed in it’s use for PE. Sometimes used with serial exams – if anticoag is withheld.
- D-Dimer – we’ll talk more about it’s use
- Angiography – still considered the “gold standard” in diagnosis of acute PE
Inject contrast into a pulmonary artery branch after percutaneous catheterization (femoral vein)
Negative pulmonary angiogram excludes clinically relevant PE
Generally safe and well tolerated
Mortality < 2%, Morbidity ~5% but…(catheter, contrast rxn, arrhythmia, respiratory insuff)
- Spiral (helical) CT with intravenous contrast – CT Pulmonary Angiography (CT-PA)
Being used increasingly
Ability to detect alternative pulmonary abnormalities (that may otherwise explain patient’s symptoms)
- MR Angiography (MRA)
Not currently in favor as limited by respiratory and cardiac motion artifact
- Echocardiography
Only 30-40% of patients with PE will have Echo abnormalities suggestive of PE
Increased RV size
Decreased RV function
Tricuspid regurgitation

39. CASE # 2

40. 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.

41. 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

42. 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%

43. Case # 2- MD Wells Score = 0 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
HR >100
1.5
Immobilization 3 days/Surgery in 4 weeks
Previous PE or DVT
Hemoptysis 1
Malignancy within 6 mos
Patient has none
Wells Score = 0

44. Should I request a D-dimer???
PERC Rules actually say we “can” get a D-Dimer – because she is on hormones (OCPs)

45. 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
D-Dimer is a byproduct of thrombosis.
If present, there is likelihood of clot.

46. - + D-Dimer 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
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
Rapid D-dimer assays are available – not at our SHS – which can often limit it’s usefulness in our setting.
Other things that can elevate D-Dimer levels:
False positive readings can be due to various causes: liver disease, high Rheumatoid factor, inflammation, malignancy, trauma, pregnancy, recent surgery, advanced age, etc.

47. 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 /secure message: Hi Maria - I just left you a voice message... PLEASE contact me at 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....
Now what!?!

48. 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)

49. Case # 2- MD Why did I order the D-Dimer?
“PE, or Not PE?: That is the Question”
So, why did I order the D-dimer?
This presentation was initially named PE or Not PE: That is the question. Like Hamlet’s soliloquy… But it really is the question.
Did I only order it because her because mom wanted her to have a mono test – and since I was drawing blood…
Am I psychic? Was it a sixth sense? Or was I just using the force?
Isn’t that all part of clinical gestalt after all?
I would argue that: A little intuition + a lot of objectivity = proper diagnosis
And while I am as much a believer in evidence-based medicine, there is some merit to clinical experience and going a little bit with your gut.
There’s also a joke in my office as I tend to have more patients with the diagnosis of PE… is ending up in MY SCHEDULE an independent risk factor for PE? Or is it just that I/m looking for it more now?
Whatever it is…. it’s important to have PE on your Differential diagnosis list – even in a young, healthy college population!
a little intuition + a lot of objectivity = proper diagnosis

50. CASE #3

51. 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

52. Case # 3
Physical Exam:
Vitals: BP: 153/91 HR: 96 T: 98.9 Pox: 95-96%, HR:
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

53. 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.

54. Case # 3 ED evaluation Physical Exam:
Vital Signs: BP:142/70 HR: 122 T: 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

55. 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

56. 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
DVT of the lower extremity
Distal (confined to deep calf veins)
More associated with transient risk factors
Proximal (involves popliteal, femoral, iliac veins)
More associated with serious chronic disease
Higher risk of progression to PE
DVT of the upper extremity is less frequent
Increasing incidence (likely because of ↑ indwelling central venous catheters)

57. 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
Signs and Symptoms and signs of DVT are more specific than with PE
Pain or tenderness in one or both legs, which may occur only while standing or walking
Red or discolored skin in the affected leg
Warmth in the skin of the affected leg
Swelling in one or both legs

58. 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%

59. 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
Accurate diagnosis is essential - so take a detailed history
Remember to ask about:
recent potential precipitating conditions
Use of OCPs/medications
Past Medical History – prior VTE?, other illness
Family History of coagulopathies
Importance of OBJECTIVE diagnostic testing.

60. Wells’ criteria for Probability of DVT
Clinical Feature
Score
Active cancer +1
Paralysis, paresis, plaster (cast)
Bedridden >3 days OR major surgery w/in 4 weeks
Localized tenderness
Swelling of entire leg
Calf swelling > 3 cm
Unilateral Pitting edema
Previous documented DVT
Collateral superficial veins
Alternative diagnosis less likely -2
There’s even a Well’s score for DVT.
The most studied clinical prediction rule is the Wells score for DVT
Useful for differentiating low-probability patients (less than 10% prob DVT) from high-probability patients (> 65% prob DVT)

61. 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%)

62. More algorithms

63. 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)
D-Dimer – we spoke about. Same clot – same fibrin degradation products
Imaging
Contrast Venography (gold standard)
Invasive
Used when noninvasive testing is non-diagnostic or impossible to perform
Not for use in pregnancy
Compression Ultrasound with Doppler (real-time B-mode)
Non-invasive
Widely available
Been proved accurate for diagnosing acute, symptomatic, proximal DVT
Duplex (D/B mode) Ultrasound – combo to detect flow and brightness
Serial ultrasounds recommended for symptomatic patients with negative initial studies
Computed tomography (CT) – with contrast
With contrast
Quick (1-4 minute scan)
Not limited by casts, pain, open wounds, burns, obesity
Allows visualization of IVC, SVC, heart, contralateral limb (for comparison)
Magnetic resonance imaging (MRI)
Directly images thrombi and non-occlusive clots
Useful for visualization of both acute and chronic clots
Useful when clot is in pelvis, IVC, arms
Contrast nor radiation is required

64. If only it were this easy….
TREATMENT OPTIONS.
If only it were this easy….

65. Venous Thromboembolism - Treatment
Anticoagulant therapy
Thrombolysis
Inferior vena caval filters
Embolectomy

66. 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.
focus on anticoagulation - mainstay of therapy for both PE and DVT.

67. 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?

68. 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
Moderate risk 1
High risk 2+
Should one initiate anticoagulation? That’s more of a role for an Emergency provider.
However, it’s important to be aware of bleeding risk factors.
Most of our patients will have NONE. (Maybe alcohol abuse  risk of fall)

70. 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%)
If clinical suspicion is HIGH - when using validated prediction rule (ie. Wells criteria), empiric anticoagulation during diagnostic evaluation is recommended
If suspicion is MODERATE and the diagnostic evaluation is expected to take > 4 hours, empiric anticoagulation is also warranted.
Anticoagulation is NOT recommended empirically if suspicion is LOW.

71. ANticoagulation Warfarin Heparins

72. ANTICOAGULATION – Heparins
Unfractionated Heparin
Intravenous Unfractionated Heparin (IV UFH)
Subcutaneous Unfractionated Heparin (SC UFH)
Low Molecular Weight Heparin (LMWH)
Fondaparinux (Arixtra)
Unfractionated Heparin
Once was the preferred initial treatment (Many studies comparing UFH to no treatment)
But 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.

73. 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
Unfractionated Heparin -Many studies comparing UFH to no treatment
Shortest acting anticoagulant
Activity can be reversed by protamine sulfate if major bleeding occurs)
Intravenous Unfractionated Heparin (IV UFH) is still preferred agent if:
Persistent hypotension due to acute PE
Increased risk of bleeding
Thrombolysis is being considered
Severe renal insufficiency (CrCl < 30 ml/min)
Concerns about subcutaneous absorption
Morbid obesity, anasarca
Dosing: Weight based protocol
Goal is to achieve therapeutic aPTT within 24 hours
Starting bolus of 80 units/kg, followed by infusion at 18 units/kg/hour, Titrate infusion rate every 4-6 hours to goal aPTT
Therapeutic aPTT ranges and dose adjustments vary from institution to institution
Fixed Dosing - Bolus 5000 units followed by infusion
Monitoring- Using activated partial thromboplastin time (aPTT) to measure antithrombotic activity of heparin
In most institutions, therapeutic aPTT is times the control aPTT
Failing to achieve therapeutic aPTT in first 24 hours associated with higher rate of recurrent DVT or PE
aPTT does not always correlate with heparin levels
IV UFH Nomograms are often used.

74. 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
Enoxaparin 1mg/kg every 12 hours preferred for patients with cancer, extensive clot burden, actual body weight between kg, BMI bet

75. 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
Monitoring anti-Xa levels with use of LMWH may be warranted in special circumstances:
Obesity - Therapeutic anti-Xa levels found if actual body weight is up to 144 kg (enoxaparin)
Low body weight - < 45kg women, < 57kg men, might increase risk of bleeding
Periodic monitoring of anti-Xa activity is warranted
Renal insufficiency
No specific dose adjustment - mild to moderate renal insuff (CrCL ml/min)
Do not use LMWH if severe renal insufficiency CrCl < 30 ml/min
Pregnancy

76. 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 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
Fondaparinux
Similar effects on clinical outcomes: mortality, recurrent thromboembolism, major bleeding as does IV UFH
Advantages over IV UFH:
Once or twice daily administration
Fixed dosing (no adjustment)
Decreased likelihood of thrombocytopenia
Has no difference in clinical outcomes compared to patients on LMWH for DVT
Burdens and potential side effects are similar
Has not been directly compared to LMWH in patients with PE

77. 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

78. 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 ( ) for at least 24 hours
Its anticoagulant effect is not realized until the pre-existing factors are cleared from circulation (~ hours)
Intrinsic clotting pathway remains intact until ~ 5 days

79. 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

80. 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 ( )
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
MONITORING warfarin

81. ANTICOAGULATION – OTHER Anticoagulants
Rivaroxaban (Xarelto)
Oral Factor Xa inhibitor
Fixed dose
Does NOT require monitoring
Apixaban (Eliquis)
Dabigatrin (Pradaxa)
Dabigatrin (Pradaxa)
Not yet approved for use with PE or DVT
Rivaroxaban (Xarelto)
Oral Factor Xa inhibitor
Fixed dose
Does NOT require monitoring
Approved by FDA for acute PE
Should not be used if CrCL < 30 ml/min, significant hepatic impairment, or pregnancy
Apixaban (Eliquis)
orally active direct factor Xa inhibitor used for postoperative prophylaxis of VTE

82. 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
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
Not for fondaparinux – but 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
HIT is less common with use of LMWH compared to either IV UFH or SC UFH
Fondaparinux causes HIT infrequently (if at all)

83. ANTICOAGULATION – DURATION of Therapy
Risk for Recurrent VTE
Bleeding Risk
↑ if recurrent event
↓ If longer duration tx
↓ risk if provoked PE
↓surgical
↑ if longer term therapy
Low (0)
Moderate (1)
High (2+)
Longer term therapy reduces the risk of recurrent VTE, but increases the risk of bleeding
- look at the risk:benefit ratio.
- take into consideration patient preferences.
Take into account patient preferences:
monitoring, diet, restrictions to activity

84. 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
First episode of PE
Reversible or temporary risk factor (immobilization, surgery, trauma)-3 months of warfarin
Unprovoked - no identifiable risk factor- Anticoagulate for 3 months → reassess
Recurrent PE-Anticoagulate for 3 months → reassess
Special considerations :Cancer, Pregnancy
DVT: Mostly Outpatient
Unprovoked calf DVT or 1st VTE (provoked): 3 months
Proximal DVT or 1st unprovoked VTE: 3-6 months
Inpatient if: Massive DVT (eg. iliofemoral), w/ PE, Hi risk of bleed with anticoagulation, comorbid conditions
Most patients with DVT are treated for 3 months
After completing treatment for first unprovoked VTE event:
5 to 15 % risk of VTE recurrence within the first year following discontinuation of anticoagulation
VTE provoked by surgery 1% first year; 0.5% thereafter
VTE non-surgical 5%; 2.5%
Unprovoked VTE 10%; 5%
2nd unprovoked VTE 15%; 7.5%
Risk of recurrent VTE ~ 30-50% over next 5-10 years

85. ANTICOAGULATION – Treatment for DVT
Thrombolytic Therapy and Thrombectomy (percutaneous or surgical)
Inferior vena caval filter
Thrombolytic Therapy and Thrombectomy (percutaneous or surgical)
Controversial since most patients have an uncomplicated course with LMWH or UFH
Considered for pts with proximal occlusive DVT associated with significant swelling/symptoms.
Inferior vena caval filter
Acute VTE with absolute contraindication to anticoagulant therapy
Recent surgery
Active bleeding
Hemorrhagic stroke

86. Don’t forget your objective data, your algorithms, your scoring rules…
but sometimes you do also have to use the force.