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DVT PULMO. EMBOLISM PULMO. HYPERTENSION Dra.

Deduyo

Signs and Symptoms suggestive of Deep Vein Thrombosis in 160 consecutive


ACUTE DEEP VEIN THROMBOSIS patients with negative venograms
Take Off Case No. of
57 year old male Signs and Symptoms %
patients
pain, erythema and swelling in his right leg for two days Pain, tenderness and swelling 94 59
he denies any trauma, fever, or dyspnea
Pain and tenderness only 35 22
Physical Examination Swelling only 18 11
tenderness in his right popliteal fossa Tenderness and swelling 13 8
pitting edema in his right leg Other clinical findings:
his calf circumference, measured 10 cm below the tibial tuberosity in
Edema 38
both legs, is 3 cm greater in the right leg.
Homans sign 35
EPIDEMIOLOGY OF DVT Cord 8
Site
VTE
Calf only 90 56
Is a general term for DVT and PE
US Figures: 1, 2 Calf and thigh 56 35
1 per 1000 individuals Thigh only 14 9
40% DVT *sx usually unilateral
60% PE Hull RD et al. Clinical Validility of a negative venogram in patients
Acute PEs cause 25,000 deaths per year Clinically suspected venous thrombosis, Circulation 64:622, 1981
Untreated proximal DVT is associated with 30-50% for PE, and 12%
mortality rate DVT- Clinical Presentation
Classically= calf pain, tenderness, swelling, redness and Homans sign
PHIL Data: 3 Overall sens/spec= 3-91%
Incidence of DVT in ICU patients is 20.7% Unreliable for diagnostic decisions
Up to 50% have none of these
ETIOLOGY AND PATHOGENESIS
Well developed and tested in clinical prediction model for DVT in 1997
VIRCHOWS TRIAD
Wells PS, Anderson DR, Bormanis J, et al. Value of assessment of pretest
probability of deep vein thrombosis in clinical management. Lancet 1997; 350
(9094): 1795-8

Clinical Prediction Rules: Wells Clinical Criteria

Table 1: Clinical Model for Predicting the Pretest Probability of Deep Vein
Thrombosis
Clinical Characteristic Score
Active Cancer (patient receiving treatment for cancer within the 1
previous 6 mos or currently receiving palliative treatment
Paralysis, Paresis or recent plaster immobilization of the lower 1
extremities

Recently bedridden for 3 days or more or major surgery within the 1


previous 12 week requiring general or regional anesthesia
Localized tenderness along the distribution of the deep venous 1
system
Entire leg swollen 1
CLINICAL FEATURES AND CLINICAL DIAGNOSIS Calf swelling at least 3 cm larger than that on the asymptomatic side
(measured 10cm below tibial tuberosity) 1
The alternate diagnosis in 87 consecutive patients with clinically suspected
Pitting edema confined to the symptomatic leg 1
venous thrombosis and negative venograms
Diagnosis No. of Patients Collateral superficial veins (non varicose) 1
Previously documented deep vein thrombosis 1
Muscle strain 21
Alternative diagnosis atleast as likely as deep vein thrombosis -2
Direct twisting injury to leg 9 A score of two or higher indicates that the probability of deep vein
Leg swelling in paralyzed leg 8 thrombosis is likely; a score of less than two indicates that the
Venous reflux 6 probability of deep vein thrombosis is unlikely. A patient with
symptoms in both legs, the more symptomatic leg is used.
Lymphangitis, lymphatic obstruction 6
Muscle tear 5
Bakers cyst 4
Cellulitis 3
Internal abnormality of knee 2
Unknown 23
Total 87
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DVT PULMO. EMBOLISM PULMO. HYPERTENSION Dra. Deduyo

CLINICAL ESTIMATE OF THE PROBABILITY OF DEEP VEIN THROMBOSIS (DVT)

Wells Clinical Score Interpretation 1997


Total Points Probability of DVT

<0 low
1 or 2 intermediate
>3 high

Wells Clinical Score Interpretation 2003


<2 unlikely
>2 likely

VENOGRAPHY
Considered the diagnostic standard for lower extremity DVT
Infrequently used today due to its numerous disadvantages
Its use is limited to situations of diagnostic uncertainty

VENOUS DUPLEX SCAN


Accuracy for the diagnosis of DVT in the iliofemoral and popliteal DVT D-DIMER
areas: Fibrin degradation product elevated in active thrombosis
Sensitivity and specificity: >90% (approaches 100% in some series) Quantitative test with high specificity and low sensitivity
thigh If the result is >2000, higher sensitivity
Leg sensitivity and specificity is <(80%) Negative test can help exclude VTE
Its easier to dx if its in the thigh because the veins are larger Preferred test
Quantitative Rapid ELISA sensitivity 96/95% for DVT/PE

Other methods include latex agglutination and RBC agglutination


(SimpliRED)

N: Artery non compressible Patients who are in hypercoagulable state lifetime treatment
Vein compressible New guideline: start warfarin at day 1, you need to overlap LMWH,
DVT: thrombus inside the vein makes it non compressible fondaparinux because it takes 3 days before warfarin starts to work
Duplex ultrasound: Old guidelines: start warfarin at day 3
Vein is vasodilated thrombus is hypoechoic acute dvt
Vein is no longer dilated and thrombus is hyperechoic chronic dvt

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DVT PULMO. EMBOLISM PULMO. HYPERTENSION Dra. Deduyo

In patients who are considered clinically unlikely to have deep vein


thrombosis and who have a negative D-Dimer test, the diagnosis of
deep vein thrombosis can safely be excluded without the need for
further diagnostic testing.

TREATMENT OF DEEP VEIN THROMBOSIS


Objectives:
Prevent pulmonary embolism
Prevent extension of thrombus
Control symptoms
Limiting post thrombotic syndrome development

TREATMENT RECOMMENDATIONS FOR DEEP VENOUS THROMBOSIS


CHEST
th
Antithrombotic Therapy for Venous Thromboembolic Disease: American College of Chest Physicians Evidenced Based Clinical Practice Guidelines( 8 Edition)

Current Approach To Grades of Recommendations


Grade of Clarity of Risk/ Methodological Strength of Supporting Evidence Implications
Recommendation Benefit
RCTs without important limitations Strong recommendation: can apply to most patients in
1A Clear
most circumstances without reservations
No RCTs but strong RCT result can be unequivocally Strong recommendation: can apply to most patients in
1C+ Clear extrapolated or overwhelming evidence from most circumstances
observational studies
RCTs with important limitations (inconsistent results Strong recommendation: likely to apply to most
1B Clear
and methodological flaws) patients
Observational studies Intermediate strength recommendation: may change
1C Clear
when stronger evidence is available
RCts without important limitations Intermediate strength recommendation: best action
2A Unclear may differ depending on circumstances or patients or
societal values
No RCTs but strong Rct result can be unequivocally Weak recommendation: best action may differ
2C+ Unclear extrapolated or overwhelming evidence from depending on circumstances or patients or societal
observational studies values
RCTs with important limitations (inconsistent results Weak recommendation: alternative approaches likely
2B Unclear and methodological flaws) to be better for some patients under some
circumstances.
Observational studies Weak recommendations: other alternatives maybe
2C Unclear
reasonable

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DVT PULMO. EMBOLISM PULMO. HYPERTENSION Dra. Deduyo

ACC/AHA Classification of Recommendations and Level of Evidence

In patients with Acute DVT start VKA together with LMWH, UFH or
SUMMARY OF RECOMMENDATIONS Fondaparinux on the first treatment day (Grade 1A)
Therapeutic level of warfarin: 2-3
ACCP: Initial Anticoagulation of Acute DVT of the Leg Subtherapeutic level <2
For Patients with objectively confirmed DVT: At risk of bleeding if its >3
SC LMWL (Grade A1) Very high risk of bleeding >4
IV UFH (Grade A1)
Monitored SC UFH (Grade A1) IV UFH for the Initial Treatment of DVT
Fixed-Dose SCUFH (Grade A1) Initial IV Bolus (80 U/kg or 5000 U) by continuous infusion (initially
SC Fondaparinux (Grade A1) 18U/kg/h or 1300 U/h) with APTT monitoring (Grade 1C)

ACC/AHA: Initial Anticoagulation of patients with IFDVT SC UFH Compared with IV Heparin for the Initial Treatment of DVT
1.) In the absence of suspected or proven heparin induced Initial Dose of 17,500 U or 250 U/kg BID, APTT measured 6h after
thrombocytopenia injection (Grade 1C)
Intravenous UFH (Class A1)
UFH by Subcutaneous Injection (Class 1B) If Fixed-Dose, Unmonitored SC UFH is chosen:
LMWH (Class 1A) Initial Dose of 333 U/kg followed by 250 U/kg BID (Grade 1C)
Fondaparinux (Class 1A)
LMWH for the INITIAL treatment of DVT
2.) Patients with IFDVT iliofemoral DVT who have suspected or proven -LMWH SC once or twice daily, as an outpatient if possible
Heparin-Induced Thrombocytopenia should received a direct thrombin (Grade 1C) or as an inpatient if necessary (Grade 1A), rather than
inhibitor. treatment with IV UFH
(eg. Argatroban, Lepirudin, Class 1B) -In patients with acute DVT and severe renal failure, suggest UFH
over LMWH ( Grade 2c)
ACCP: Initial Anticoagulation of Acute DVT of the Leg
For patients with a high clinical suspicion of DVT start Anticoagulants DOSE CALCULATION
while awaiting the outcome of diagnostic tests (Grade 1C) Enoxaparin twice daily at 1 mg/kg or once daily at 1.5 mg/kg,
You need the base time, protime/prothrombin time before you can start Dalteparin once daily at 200 IU/kg or twice daily at 100 IU/kg, or
this. Tinzaparin once daily at 175 anti Xa IU/kg
Protime and prothrombin time is used to know if you are in the UFH monitor every 6 hours (PTT)
therapeutic level o The target should be 1.5 times the normal
In patients with Acute DVT start with LMWH, UFH or Fondaparinux for o If the target is reached, maintain the patient on that dose
atleast 5 days and until the INR is >2.0 for 24h (Grade 1C) of UFH
LMH more convenient
o You dont have to monitor every 6 hours

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DVT PULMO. EMBOLISM PULMO. HYPERTENSION Dra. Deduyo

FONDAPARINUX for the INITIAL treatment of DVT Grade 2 pressure 20-30mmHg


-Fondaparinux by SC injection once daily Grade 3 pressure 30-40mmHg
o 5mg for patient weighing 50 kg Bandages
o 7.5 mg for patients weighing 50 to 100 kg o Compression will eventually disappear
o 10 mg for patients weighing 100 kg o Amount of compression is difficult to duplicate everyday
Fondaparinux vs LMWH Graduated compression stockings
o Less bleeding Highest compression is at the level of the ankle and gradually decreasing at the
Fondaparinux is also used for acute coronary syndrome (2.5mg) level of the calf and weakest pressure at the thigh to promote blood flow. If the
pressure is equal, it will induce ischemia
DURATION OF ANTICOAGULANT THERAPY
FIRST EPISODE:
-with tramsient (reversible) risk factor Comparison of ACCP and ACC/AHA Recommendations on Certain Aspects of
-unprovoked DVT DVT Management

DURATION OF THERAPY Treatment ACCP 8th 2008 ACC/AHA 2011


-3 mos. VKA (Grade 1A) (IFDVT)
-at least 3 mos. (Grade 1A) Catheter Directed
o First unprovoked proximal DVT with no risk of bleeding Thrombolysis Grade 2B Class 1C
and for whom good anticoagulant monitoring is
Balloon angioplasty/Stenting
achievable, long term treatment is recommended
(after CDT) Grade 2C Class 2a/bC
(Grade 1A)
o After 3 months of anticoagulant therapy, all patients
with unprovoked DVT should be evaluated for the risk- Systemic thrombolysis Grade 2C Class 3A
benefit ratio of long term therapy (Grade 1C) Operative venous
o First isolated unprovoked distal DVT 3 months of thrombectomy Grade 2B Class 2aB
anticoagulant therapy is sufficient rather than indefinite
therapy (Grade 2B) Percutaneous venous
thrombectomy Grade 2C -
o Second episode unprovoked DVT longter/lifetime
treatment Vena cava filter Against it (IA) Class IIIB
VCF as substitute because of
INTENSITY OF ANTICOAGULANT EFFECT Grade 1C Class IB
bleeding
INR of 2.5(ideal) (range: 2.0 to 3.0) for all treatment durations
(Grade 1A) Anticoagulation after IVC filter
With unprovoked DVT who have a strong preference for less placement Grade 1C Class IB
frequent INR testing to monitor their therapy, after first 3 months Early ambulation Grade 1A
of conventional-intensity anticoagulation (INR range: 2.0 to 3.0),
low intensity therapy (Range: 1.5 to 1.9) is recommended with Elastic Stockings Grade 1A
less frequent INR monitoring over stopping treatment (Grade 1A) Pentoxyphilline, MPFF,
Grade 2B Class IB
Asians needs a lower anticoagulant dosage compared to the Sulodexide in venous ulcers
westerns
Monitor if using warfarin RETURNING TO OUR PATIENT
o Monitor 3 days after you start anticoagulation
o Warfarin is affected by food with increased amounts of 57-year-old male
vitamin k such as green leafy vegetables Pain, erythema, and swelling in his right leg for two days
o Depending on the initial result, you can repeat it after 3 He denies any trauma, fever, or dyspnea
days or 1 week. If stable, repeat it after a month or in 1-2 Physical examination:
months Tenderness in the right popliteal fossa
Pitting edema of the right leg
FOR PATIENTS WITH DVT AND CANCER His calf circumference, measured 10 cm below the tibial tuberosity
LMWH for the first 3 to 6 months of long-term anticoagulant in both legs, is 3 cm greater in the right leg
therapy (Grade 1A)
For these patients, subsequent anticoagulant therapy with VKA or Wells Score 3 Likely for Acute Deep venous Thrombosis
LMWH is recommended indefinetely or until the cancer is
resolved (Grade 1C) D-Dimer for VTE Exclusion: accuracy of assays: meta-analysis
DVT (49 studies) PE (31 studies)
IMMOBILIZATION FOR THE TREATMENT OF ACUTE DVT Se Se
early ambulation is recommended if feasible (Grade 1A) use Sp(%) LR(neg)(*) Sp(%) LR(neg)(*)
(%) (%)
compressive stocings (compression <20 mmHg) Elisa
96 44 0.10 97 41 0.07
(VIDAS@)
ELASTIC STOCKINGS AND COMPRESSION BANDAGES TO PREVENT PTS
Elisa
For symptomatic proximal DVT, elastic compression stockings 95 40 0.12 96 51 0.08
(microplate)
with an ankle gradient pressure of 30 to 40 mm Hg if feasible
Elisa
(Grade 1A) 92 43 0.20 92 55 0.16
(membrane)
Compression therapy, which may include use of bandages acutely,
Latex (auto) 86 61 0.23 89 47 0.23
should be started as soon as feasible after starting anticoagulant
therapy and should be continued for a minimum of 2 years, and SimpliRED@ 86 67 0.20 83 64 0.27
longer if patients have symptoms of PTS Latex
Contraindication for compressive stockings: 79 66 0.32 80 56 0.36
(manual)
o Peripheral arterial disease
Grade 1 pressure <20mmHg (*) Negative likelihood ratio = false negatives/true negatives = (1-se)/sp
o White stockings or anti embolic stockings

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DVT PULMO. EMBOLISM PULMO. HYPERTENSION Dra. Deduyo

High sensitivity at the expense of lower specificity Potential difficulties/limitations with the new oral agents
Best safety by VIDAS These drugs behave like circulating anticoagulants and cannot be reversed
o Highest sensitivity; lowest LR(neg) with blood products
Bleeding has been an issue with these new drugs
Characteristics of new oral anticoagulants FDA looking into post-market reports of serious bleeding events with
Dabigatran Rivaroxaban Apixaban Dabigatran
Mechanism of Direct
Direct FXa
Direct Reports of fatal bleeding events in Japan using Dabigatran
action Thrombin FXa
inhibitor Postoperative bleeding a concern in some patients
inhibitor inhibitor
Oral Systemic thrombolytic therapy for acute DVT(2C)
6.5% 80% ~50%
bioavailability higher risk for bleeding
Route of to reduce acute symptoms and post thrombotic morbidity
administration Oral Oral Oral

Dosing Systemic thrombolytic therapy for acute DVT(2C)


OD or BID OD or BID BID
Vena caval filters for initial treatment of DVT (1A)
Pro-drug Yes No No o If an anticoagulant is not possible due to risk of bleeding
Food effect No No No o Insert to prevent PE
o Anticoagulant therapy if the risk of bleeding resolves
Renal o Remove IVC filter from time to time bc it can promote
85% 36% ~27%
Clearance thrombus formation
Mean o Use SVC filter if upper ex DVT
14-17 h
Half0Life 7-11 h ~12 h More expensive
(patients)
(T1/2) Happens in hypercoagulable states
Tmax 0.5-2 h 2-4 h 3h
Drug P-gp CYP 3A4 CYP 3A4 Percutaneous venous thrombectomy
interactions inhibitors and P-gp and P-gp o Px should not be treated with this alone
P-gp inhibitors inhibitors
inducers CYP 3A4 CYP 3A4 Operative venous thrombectomy
Amiodarone inducers inducers o For selected patients with acute iliofemoral DVT symptoms
in <7D with good functional status and life expectancy of
ADVANTAGES WITH THE NEW AGENTS >1yr
o For acute bleeding
Half life (9-17 hrs): OD/BID dosing for prophylaxis
o Catheter selective thrombolysis
Post operative initiation for prophylaxis If patient does not have a high risk of bleeding
Fixed oral doses for both indications (no weight adjustment) More preferable than operative venous
Routine monitoring not needed thrombectomy
Eg. If DVT is at the level of the iliofemoral vein
Few interactions with other medications/food
upto the IVC, you can directly inject
Potentially better compliance for extended prophylaxis and treatment than thrombolytics in the iliofemoral vein distal to the
with injections level of the thrombus
Potential difficulties/limitations with the new oral agents there is a chance of promoting PE needs a
Half life (9-17 hrs): requires adequate compliance for VTE treatment device to catch the thrombus (IVC filter)
How to revert or measure the anticoagulant effect?
Immediate post-op use (nausea/vomiting) for prophylaxis
Lower compliance with prescription with unmonitored pills than with
parenterals
Are these agents really cost effective in routine clinical practice?

Novel Oral Anticoagulants (NOAS)


Potential successors for warfarin
Less bleeding but does not have an antidote if you bleed
Dabigatran
o Direct thrombin inhibitor
o 1st indication if the prevention of stroe in an atrial
fibrillation patient
o 2nd indication for DVT and PE
o Give 2x/D (effectivity: 12 hours)
Rivaroxaban
o Direct factor Xa inhibitor
o 1x/D for DVT and PE (24 hour effectivity)
Apixaban
o Direct factor Xa inhibitor
o Newest, 2x/D
Edoxaban
o Japanese drug
Apixaban and edoxaban approved for the prevention of stroke
atrial fibrillation patients

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DVT PULMO. EMBOLISM PULMO. HYPERTENSION Dra. Deduyo

PULMONARY EMBOLISM
EPIDEMIOLOGY
300,000 hospitalizations and 100,000-200,000 deaths/year
Case fatality of 15% (not changed in last decade)
Majority of emboli from deep veins of the lower extremity
Majority of deaths in undiagnosed
PE risk with proximal LE DVT = 50%
Upper extremity venous thrombosis (rare)
o PE risk = 12-17%
70% PE deaths not diagnosed prior to death
A lot will survive the 1st episode of PE *437/930 pts with neg D-dimer and low pres-test prob 1 PE in flu; NPV=99.5%
2nd episode - fatal Ann Int Med 2001; 135:98

Evaluation : CXR, labs, EKG, Thoracentesis


not really helpful

DIFFERENTIAL DIAGNOSIS
(PULMONARY)
Pneumonia VENTILATION PERFUSION SCAN (VQ SCAN)
COPD/Asthma Look for VQ mismatches (ventilated but non-perfused areas of lung)
Pneumothorax Risk of PE (% probability)
Pleurisy o Normal 0%
o Low <10%
TB
o Intermediate 20-30%
Cancer o High 90%
40-50% suspected PEs will have non-diagnostic VQ and normal LE
(CARDIAC) evaluation (US/IPG)
Myocardial N: homogenously hyperechoic
Infarction
Pericarditis SPIRAL CT
CHF Radiology 1996; 201:467-70
Tamponade VQ vs. spiral CT in 149 patients
PAgram done if VQ indeterminate
Effective in detecting up to segmental level PE
Sensitivity 82% & 94%
Specificity 93% & 96%

VENOGRAPHY OR NON-INVASIVE STUDY OF THE LOWER EXTREMITY


(MUSCULOSKELETAL) Same positive findings as for DVT
Costochondritis Positive LE DVT in a suspicious patient is usually adequate for
Rib Fracture diagnosis
Myositis
Trigger Point Pain

(OTHER)
Herpes Zoster
Sepsis
Radiation of abdominal pain

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DVT PULMO. EMBOLISM PULMO. HYPERTENSION Dra. Deduyo

PULMONARY ANGIOGRAPHY
Gold standard equivalent of
venography
Death rate 2-5/1000
Not widely available
Consider use if:
o Low prob VQ in
suspicious patient
o Consideration for use of
thrombolytics
o Contraindication to
anticoagulants
Both diagnostic and
therapeutic

***thrombosed Pulmonary V. You can


see lysis of the PE

MR ANGIOGRAPHY
TREATMENT OPTIONS
PAgram vs MRA
Anticoagulation
with Gadolinium
Thrombolytics
Three sets of
readings
ANTICOAGULATION
Sensitivities 100, Prevent further embolization
87, & 75%
IV Heparin for 5 days
Specificities 95, o Or LMWH
100, & 95% Coumadin starting as early as day 1 Heparin with 4 day overlap
Segmental or o Duration same as for DVT
larger vessels Use NOAS: dabigartan/rivaroxiban
Consider using in Be careful if px is >75yo w/ inc. Cr
patients with CKD Pregnant with DVT
bc you wont be Use LMWH 1-1.5mg/kg 1/D (enoxapharin)
using any dye Discontinue LMWH prior to delivery, continue after 12 hours of
delivery
Source: Ebel MH
THROMBOLYSIS BENEFITS
Accelerated clot lysis and tissue perfusion
Decreased mortality
Reversal of right heart failure
Decrease recurrence
Decrease Pulmonary HTN
Catheter directed thrombolytics using angiogram much better outcome than
maximum medical treatment

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PROGNOSIS POST THROMBOTIC SYNDROME


If untreated survival is 70% (death secondary recurrent PE) (POST PHLEBITIC SYNDROME)
Treated survival = 92%
DEFINITION
Majority of deaths occur before therapy initiated or : condition
Incompetent lower extremity venous valves result in ambulatory
recognized
venous hypertension
Patient always complains about leg pain, heaviness especially with
PREVENTION
prolonged sitting or standing. (same sx as venous insufficiency)
Same as for DVT
You will develop venous HPN because the venous pressure in your
Identify high risk patients and institute recommended protocols lower extremities is neutral when lying down.
Venous pressure increases by 50% while seated and increases by 100%
while standing up.
When you walk, venous pressure will go down.

FINDINGS
Edema
Soft tissue fibrosis
Ulceration
Pain
MANAGEMENT
Compression
stockings (20-30
mmHg class 2)
Surgical (goal is ulcer healing and decreased pain)
WHAT TO DO WITH THE IDIOPATHIC DVT? (RISK OF CANCER OR o Perforator Interruption
HYPERCOAGULABLE STATE) Pneumatic compression ankle to thigh
New laparoscopic technique
HYPERCOAGULABLE W/U o Valve Repair
Age < 40 Symptom relief 65%
Thrombus in unusual locations Ulcer healing approx 65% (@ 5 yrs)
Upper extremity, neck, anterior abd wall, eye, CNS Major treatment is prevention of DVT
Recurrent thrombotic events without incident causation More aggressive treatment of DVT Thrombolytics
Recurrent thrombotic events when on anticoagulants in therapeutic
CONCLUSION
range
Thromboembolism is a common primary care problem
Thrombotic events in absence of underlying illness or medication
Clinical suspicion is still quite important
Family history of thrombotic events or hypercoagulability
Careful use of diagnostic exams
Bilateral symmetric thrombotic events (bilateral DVT)
Use LMWH
HYPERCOAGULABLE LABS Survey for Hypercoagulability
CBC, PT, PTT
ANA
Protein C & S
APC resistance (Factor V Leiden mutation) PULMONARY HYPERTENSION
Antiphospholipid antibody
Antithrombin III Hemodynamic and pathophysiological condition defined as an increase in
MPAP of > 25mmHg at rest as assessed by right heart catherization
Fibrinogen & plasminogen
Prothrombin 2010A Mutation
An increase of exercise mPAP >30mmHg
RISK OF CANCER?
Increased risk of discovering cancer in the <60 age group Ernst von Romberg (1981) case report of pulmonary vascular sclerosis
2/3 adenocarcinoma
Abel Ayerza
o GI 25%
1901- unpublished lecture describing pulmonary artery and right heart disease
o Urogenital F=12%; M=16%
1913- Dr. F.C. Arrillaga attributed the disease to syphilis
o Hematologic 10%
o Highest risk in first 6 months Oscar Brenner
o H&P, CBC, ESR, Chem 20, PSA, GUIAC 1940- first detailed pathologic characterization from 100 autopsy reports at
o NEJM 1998; 338:1169 MGH in the disease in arterioles
15,348 DVT & 11,305 PE
1737 cancer (est. 1372) Paul Wood
1951- clinical cardiologist, elucidated pathophysiology and clinical
characteristics of pulmonary hypertension (PH)

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David Dresdale
1951- first reported hemodynamic variables in cases of pulmonary
hypertension without evident etiology and coined the name primary
pulmonary hypertension

Questions to address
How does derrangement of normal pysiology explain the symptoms
and clinical worsening in PAH?
What do we know regarding the histopathology and pathogenic
mediators of PAH?
What is the WHO classification for PAH based on this underlying
pathophysiology?
How do we differentiate PH from PAH?
What is an evidence-based approach in the diagnosis of PAH?

The Problem

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Pulmonary HPN
Not readily diagnosed due to lack of awareness
1995 and beyond awareness and research of pulmonary HPN has
increased
Before 1995 they are only using Ca channel blockers as treatment
1st drug for pulmonary hpn came out at 1995
Pulmonary artery changes in vessel wall progression to
Pulmonary HPN
o Asymptomatic compensated
o Symptomatic decompensated
o Declining compensation
In pulmonary HPN, there is increase in arterial pressure and pulmonary
vascular resistance
Cardiac output has a concominant decrease

WHO functional Classes of PAH


Pulmonary Arterial hypertension Class I patient with (PAH)but without resulting irritation of physical activity.
Is a syndrome resulting from restricted flow through the pulmonary Ordinary physical activity does not cause undue dyspnea, chest pain, or near
arterial circulation resulting in increased pulmonary vascular resistance and syncope
ultimately in right heart failure.
Class II patients with (PAH) resulting in slight limitation of physical activity.
Use of Right Heart Catheterization They are comfortable at rest. Ordinary physical activity causes undue dyspnea
PAH: mPAP25mmHg plus PCWP15mmHg or fatigue, chest pain, or near syncope
In previous guidelines, PVR>3 wood units was included in the definition of
PAH. Class III patients with (PAH) resulting in marked irritation of physical activity.
They are comfortable at rest. Less than ordinary activity causes undue dyspnea
Clinical Classification of PH (Dana Point 2009) or fatigue, chest pain, or near syncope
1) PAH (Our Focus)
- Idiopathic PAH Class IV patients with (PAH) with inability to carry out any physical activity
- Heritable without symptoms. These patients manifests signs of right- heart failure.
- Drug and toxin induced Dyspnea and/or fatigue (including near syncope) may even be present at rest.
- Persistent PH of newborn Discomfort is increased by any physical activity.
- Associated with:
o CTD
o HIV infection What is the difference between PH and PAH?
o Portal Hypertension
o CHD
o Schistosomiasis
o Chronic hemolytic anemia

1) PVOD and PCH

2) PH owing to left Heart Disease


- Systolic dysfunction
- Diastolic dysfunction
- Valvular disease

3) PH owing to lung disease and/or hypoxia


- COPD
- ILD
- Other pulmonary diseases with mixed restrictive and obstructive
pattern sleep-disordered breathing
- Alveolar hypoventilationdisorders
- Chronic exposure to high altitude
- Developmental abnormalities

4) CTEPH chronic thromboembolic pulmonary hpn

5) PH with unclear Multifactorial Mechanisms


- Hematologic disorders/splenectomy
- Systemic disorders
- Metabolic disorders

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DVT PULMO. EMBOLISM PULMO. HYPERTENSION Dra. Deduyo

Who is at high risk for development of PAH? Possible


- Cocaine
Who develops risk for PAH? - Phenylpropanolamine
- St. Johns Wort
- Chemotherapeutic agents
- SSRI

Unlikely
- Oral contraceptives
- Estrogen
- Cigarette smoking

OTHER RISK FACTORS OF PAH

Human Immunodeficiency Virus Infection (HIV) Infection


Estimated prevalence of PAH in HIV is 0.5%
Cases of PAH are declining; however, overall prevalence is similar to
periods before HAART
Treatment with HAART does not appear to prevent the development
of PAH

Schistosomiasis Infection
Estimated prevalence of PAH in schistosomiasisis
o Probably the leading cause of PAH worldwide
Endemic in developing tropical countries, affecting million people
Parasite not found in United States

Hemolytic Anemia
Estimated prevalence of PAH in hemolytic anemia is inconsistent
o Varies among studies from 2% (in SCD) to 68% (in
thalassemia)

Portal Hypertension
Prevalence varies with patient population and method used to
diagnose PAH
o Range from 0.78% in autopsy study of patients with
cirrhosis to as much as 12% in patients being evaluated for
orthotopic liver transplants assessed on 2-diomensional
echocardiography

How do we get an Accurate Diagnosis of PAH?

ADDITIONAL RISK FACTORS FOR DRUGS AND TOXINS ASSOCIATED WITH PAH
Definite
- Aminorex
- Fenfluramine
1990s for losing weight
- Dexfenfluramine
- Toxic rapeseed oil

Likely
- Amphetamines
- L-tryptophan
- Methamphetamines

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Et factum est ut amicis transcribit durum simul in unum! 2014 -2015
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DVT PULMO. EMBOLISM PULMO. HYPERTENSION Dra. Deduyo

SYMPTOMS AT TIME OF DIAGNOSIS OF PAH


1. dsypnea 93% (most common, same in CHF and PE)
2. fatigue 73%
3. chest pain 47%
4. near syncope 41%
5. syncope 36%
6. leg edema 37%
7. palpitations 33%

COMMON SIGNS OF PAH


1. accentuation of P2 93%
2. tricuspid regurgitation 40%
3. right-sided s4 38%
4. peripheral edema 32%
5. right sided s3 23%
6. cyanosis 20%
7. pulmonic insufficiency 13%

PAH prognosis is poor. The later the functional class, the poorer the prognosis

From a diagnostic standpoint, how do we differentiate PH from PAH?

Normal sinus rhythm, complete RBBB (Tall R), Biatrial enlargement (seen in
patients with COPD + PAH)

Non-specific
Is Echo a useful screening tool for PAH?

Page 13 of 17
Et factum est ut amicis transcribit durum simul in unum! 2014 -2015
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DVT PULMO. EMBOLISM PULMO. HYPERTENSION Dra. Deduyo

What is the most appropriate test to conduct to Rule Out CTEPH?

RVH or RA Enlargement in PAH (not LVH)


If a px has right heart enlargement and you are suspicious that this may have
pulmonary HPN do RH catherization immediately

Echocardiographic Features of PAH


2-D echo
- Normal LA, LV size, small LV (<3.5 cm)
- No LVH
- Normal to high EF
THE IMPORTANCE OF PULMONARY FUNCTION TESTING IN PAH
- RV apex sharing
- Septal flattening (systole>diastole) Important in assessing for presence of obstruction or restriction
- Pericardial effusion
DLco
Doppler Important as it relates to scleroderma patients
- Variable PASP Among patients with systemic sclerosis (n=33), DLco correlates
- No MR inversely (r=0.60) with invasively measured
- Stage 1 diastolic dysfunction (E<A)
sPA
These patients should have annual PFTs in addiction their annual
echocardiogram
Echocardiographic Features of PH
2-D echo Right Heart Catheterization
- Dilated LV and/or LA= LVH Required to confirm diagnosis, calculate resistance, and guide therapy
- Variable EF for PAH
- RV:LV ratio <1.0
Exudates other etiologies of PH
- LV remains round in short axis
Intracardiac or extracardiac shunts
Doppler
Left heart disease
- Variable PASP
- 2+ MR Measures degree of right-heart dysfunction
- E>A (pseudonormal or restrictive) Right atrial pressure
Cardiac output

Page 14 of 17
Et factum est ut amicis transcribit durum simul in unum! 2014 -2015
medicine vade
DVT PULMO. EMBOLISM PULMO. HYPERTENSION Dra. Deduyo

Essential Components of Invasive Hemodynamic


Assessment
Oxygen saturations (SVC, IVC, RV, PA, SA)
RAP
RV pressure
PAP, systolic, diastolic, mean
PCWP, LA pressure, or LVEDP
CO/CI
PVR
Systemic blood pressure
HR
Response to acute vasodilator

Your role in the Screening and diagnosis of PAH

Summary
Have a high index of suspicion for the disease in high-risk patient populations

CASE IN POINT

Will the hemodynamics found on repeat RHC match the Echo-Doppler (and
clinical) findings under review?
RV dysfunction
o TAPSE 1.6
Grade 1 diastolic Dysfuntion
o E to A reversal

What is the most appropriate next step?


A. Initiate aggressive diuresis
B. Continue medical therapy for severe pulmonary venous hypertension
C. Request hemodynamic tracings for review, consider repeating Right
(Animation) Rheumatology appointment heart catheterization
Physical exam and preliminary PFTs. A low DLco (55% predicted) was D. Repeat right heart catheterization with acute vasodilator challenge to
also noted. Pt denies PND and orthopnea. Pt referred to a test reversibility of pulmonary venous hypertension
pulmonologist for further w/u of suspected PAH.

(Animation) Appointment with pulmonologist


Ordered new set of PFTs and an Echo. Following review of rheum and
pulmo reports, VS referred to cardiologist for complete cardiac w/u.
FC II

(Animation) Appointment with cardiologist #1


W/u included ECG< CXR< repeat Echo and RHC. PVH diagnosed.

Case in Point
VS was immediately started on evidence-based treatment to stabilize
and improve heart function
After 2 weeks on medical therapy, VS continued experiencing dyspnea
on exertions well as intermittent episodes of exertional presyncope

(Animation) Return to pulmonologist, symptoms worse


Physical exam: HR 88, BP 130/90, RR 12, SpO2 91% Room Air 85%
with exertion; WHO FC III
Echo: Normal Left heart structure and function. Mild to moderate RV
dilation, moderate RV dysfunction, moderate septal bowing, E/A 0.8
Review of hemodynamics: performed 2 weeks prior

Page 15 of 17
Et factum est ut amicis transcribit durum simul in unum! 2014 -2015
medicine vade
DVT PULMO. EMBOLISM PULMO. HYPERTENSION Dra. Deduyo

Understand the screening and diagnostic progression for PAH


- History and physical examination, ECG, and
CXRechocardiographyRHC

Be aware of the strengths and limitations of echocardiography as a screening


tool

Be able to accurately interprets results from RHC

RHC is the gold standard for assessment of hemodynamics in PAH

PAH Treatment Goals


Functional class improvement
Improve exercise capacity
Improve hemodynamics
Delay of clinical worsening
Improved quality of life
Improved survival

Evidence based Therapies for PAH


Prostacyclin derivatives
- Inhaled
- Subcutaneous/IV

Endothelin Receptor Antagonists


- Oral

Phosphodiesterase Type-5 inhibitors


- Oral
- IV

Benefits of a Multidisciplinary Approach


All physicians are important in the screening of PAH patients
o This includes pulmonologists, cardiologists and
rheumatologists who frequently see patients at high risk for
PAH
A coordinated and collaborative diagnostic process:
o Reduces confusion
o Helps optimize the overall PAH screening, diagnostic
How can we optimize the cooperation amongst specialties in the treatment and follow-up plan
management of a PAH patient?
Pulmonologist
Cardiologist
Rheumatologist

Page 16 of 17
Et factum est ut amicis transcribit durum simul in unum! 2014 -2015
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DVT PULMO. EMBOLISM PULMO. HYPERTENSION Dra. Deduyo

Conclusion

PH and PAH share many overlapping features


The Echo-doppler exam is an essential part of the initial workup for screening
a patient with PH
- RHC is the gold standard for assessment of hemodynamics in PAH

A multidisciplinary approach is a critical period of the diagnostic evaluation


and differentiation of PH and PAH

Future Directions in PAH


- New diagnostic /prognostic tools
o Imaging (MR), biomarkers

- Long term event-driven trials

- Combination therapy

- Emerging therapies:
o Guanylate cyclase stimulator
o Kinase inhibitors
o Elastase inhibitors
o Surviving inhibitors
o NO coupling agents
o Prostacyclin receptor agonists
o Metabolic modulators
o Statins
o Anti-inflammatory/immunomodulatory agents
<
- Endothelial cell replacement:
o Stem/progenitor cells

LOVE

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