1. Pulmonary Thromboembolism
Prof. Sevda Özdoğan MD
Chest Diseases

2. Pathophysiology of Pulmonary Embolism
Virchow Triade
Venous stasis
Vascular endothelial (wall) damage
Hypercoagulation

3. Risk factors
The risk factors for VTE can be both genetic or acquired for a certain patient
Risk increase if age>40 (Comorbidity, stasis, hypercoagulability)

4. Acquired Risk Factors Risk Factor Hypercoagulability Stasis Trauma
Previous DVT, PE
Major surgery
Malignancy
Obesity
Fracture (Hip, leg)
Pregnancy MI
Congestive hearth failure
Stroke
Estrogen treatment
Immobilization
Burns

5. Genetic Risk factors Genetic Activated protein C (APC) resistance
Factor V Leiden mutation
Positive in 21% of VTE patients
Antithrombin III deficiency
Autosomal dominant
Risk of VTE x5
Protein C and S (cofactor) deficiency
Risk od VTE x6
Prothrombin G20210A
A single nucleotide change in prothrombin gene results in elevated prothrombin levels
Risk of DVT x5
Hyperhomocystinemia
Defects in enzymes of homocystein disposal
Risk of VTE x2
Antithrombin III is an important coagulation inhibitor, its deficiency is inherited in an autosomal dominant manner
Protein C and its cofactor Prot S deficiency is inherited in autosomal dominant manner, they inactivate the coagulation factors V and VII by activated protein C (APC)
Point mutation in factor V gene. Factor V can not be inactivated in APC resistance and the coagulation cascade continuies
The risk of surgery and trauma also depends on the age, site of surgery and the underlying condition of the patient

6. Genetic Increased Factor VIII RR for VTE x4.8 Blood group other than O
RR of DVT x2
Combination of the genetic risk factors

7. Clinical features and Diagnosis
Clinical suspicion***
Medical history:
To identify the patient at risk
Family history
Medical or acquired risk factors
Symptomatology:

8. Unexplained acute dyspnea Tachypnea Substernal chest discomfort
Pleuretic chest pain
Hemopthysis
Cyanosis
Shock / sencope
Asymptomatic
Physical findings: (nonspecific)
97%
Klinik bulgular embolinin büyüklüğüne, sayısına, lokalizasyonuna, infarktüs gelişip gelişmediğine, rezolüsyon hızına, ilk kezmi yoksa tekrarlayıcımı olduğuna ve hastanın kardiopulmoner rezervine bağlı olarak değişir.
Dispne, senkop, siyanoz hayatı tehdid eden ciddi bir emboli varlığının göstergesidir

9. Diagnostic approach Semptomatology and signs Chest radiology
Arterial blood gas analysis (ABG)
Electrocardiography
Standard laboratory tests
Echocardiography (Cardiac and venous doppler of the lower extremity)
D-Dimer
Spiral CT or Ventilation / perfusion scan
Pulmoner angiography (gold standard)

10. Chest Radiography
Negative chest radiogram is a common presentation so does’t exclude the diagnosis
80% Abnormal chest radiograph but nonspecific
Early:
Peripheral regional oligemia (Westermark’s sign) (7%)
A prominant pulmonary hilus with little tapering of vessels (Fleischner’s sign) (15%)
Later:
Peripheral wedge shaped densities (Hampton’s hump) (35%)
Plate like atelectasis
Diaphragmatic elevation (%24)
Pleural effusion (%48)
90% of the emboli are lodged in the lower lobe vessels so radiographic abnormalities are located on the lower portion of the chest radiogram

11. Linear atelectasis, pleural effusion
Pulmonary infarct
Linear atelectasis, pleural effusion

12. Frontal chest radiograph obtained from a patient with an acute pulmonary embolism. The left pulmonary artery is enlarged (small arrow), and a wedge-shaped peripheral opacity is present at the left costophrenic angle (large arrow)

13. ABG Analysis Hypoxemia, hypocapnia and respiratory alcalosis
PaO2 <%80
PaO2 may be normal in submassive embolism if no underlying pulmonary disease is present
(A-a)O2 gradient is increased in almost all the patients
Akut PE de hipoksemi alışıldık bir bulgu olmakla beraber bu bulgu bulunmayabilir. Örneğin 40 yaşın altında % 29 oranında PaO2 % 80 den yüksek olabilir

14. ECG Abnormalities of ECG are nonspecific Changes can be similar to MI
Acute right ventricular strain in massive embolism
Sinus tachicardia
Negative T wave and/or ST segment depression in leads V1-3
S1Q3T3 patern (Deep S wave in lead D1, deep Q wave in lead D3, inverted T waves in D3)
Right bundle branch block (complete or incomplete)
P-pulmonale
Changes can be similar to MI

15. Standard laboratory tests
Nonspecific changes
WBC can be slightly elevated
LDH, bilirubine can be slightly elevated
D-Dimer (fibrin degradation product) can be elevated
ELISA or Latex agglutination
Sensitivity % but specificity is low
<500 ng/ml PE can be excluded if there is also low clinical probability
Elisa is more sensitive but slow compared to Latex

16. ECHOCARDIOGRAPHY (Doppler)
Can be performed rapidly at the bedside
Features that suggest acute massive PE include
A dilated, hypokinetic right ventricle
With the absence of right ventricular hypertrophy
Distortion of the interventriculer septum toward the left ventricle
Tricuspit regurgitation the elevation of pulmonary artery pressure
Identified trombi in the central pulmonary arteries
Absence of significant pathologic left ventricular conditions
Akut pulmoner embolide ölüm nedeni sağ ventriküler yetersizlik. Sıklıkla masif pulmoner emboli RV yetmezliğine neden olmaktadır. Burada oldıkça büyük tek bir emboli söz konusu olabileceği gibi rekürrent PE de olabilir.
Nonspesik eko bulguları söz gelimi KOAH akut atakla karışabilir.

17. Spiral Computed Tomography Angiography (SCTA)
May demonstrate or exclude other abnormalities in the lung
Bolus contrast is used for the visualization of the pulmonary vasculature
Filling defects are diagnostic
Sensitivity and specificity is around 90% up to subsegmental defects
Bugün için altın standart olma yolunda

20. Partial filling defect in right middle lobe and lover lobe artery
Wedge shaped infiltration on the right upper lobe posterior segment

22. Ventilation-Perfusion Scintigraphy
Detection of the perfusion abnormalities subsequent to the embolic event
Classically to display that a segment distal to an obstructing embolus is not perfused but is still ventilated
99Tc is usually used for perfusion and 133Xe for ventilation scaning. The two studies are analysed together.
In clinical practice the results of V/Q scintigraphy are interpreted together with the clinical estimate of the likelihood of acute PE
A normal V/Q virtually excludes clinically relevant PE

23. Patient with multiple embolisms in both lungs: segmental mismatch defect in left lung was detected by both SPECT (A and B) and planar scintigraphy (C and D). Defects are marked by arrows in B and D. Subsegmental mismatch defects are present in right lung. CT angiography found thrombotic clots in branches of middle lobe artery and both lower lobe arteries

24. Pulmonary Angiography (gold standard)
Detects emboli in the subsegmental or even more peripheral arteries
Unfortunately it is invasive and there is lack of availability in an urgent investigation
Can be used if V/Q scan is nondiagnostic and the clinical probability is high
Mortality %0,5
Major complications %0,4

25. Suspected PE Treatment PE Treatment V-Q scan/ BT Nondiagnostic P.angio
Low clinical suspect
D dimer (-)
exclude
High clinical suspect
D dimer (+)
Treatment
V-Q scan/ BT
High probability/filling defect
Hipotension
Severe hypoxemia
Nondiagnostic
P.angio PE
Stabile clinical condition
PE (-)
No treatment
Klinik şüphe yüksekse ve kanama riski yoksa testler yapılırken antikoagülan tedavi başlanmalı
Bilateral lower extremity
(USG, IPG, CV, MRI)
Serial examination
Or angio
DVT (-) or
nondiag.
DVT (+)
Treatment
ATS
Clinical Practice Quideline-1999

26. Yüksek klinik olasılıkta ampirik antikoagülasyon hemen başlanıp tanısal tetkiklere devam edilir.

27. Deep Venous Thrombosis (DVT)
Compression ultrasound
Doppler ultrasonography
Venography (gold standard)

28. Treatment of PTE and DVT
Supportive treatment
Oxygen
Intravenous fluid
Vasopressor agents
Resuscitary measures depending on the clinical status of the patient
Anticoagulant therapy
Unfractionated heparin (UFH)
Low molecular weight heparin (LMWH)
Oral anticoagulants (Warfarin, rivaroxaban)
Thrombolytic treatment
Surgical treatment

29. UFH
Binds to AT-III
Anticoagulant factors are secreted from vascular endothelial cells
Inhibits platelet aggregation
Its effect is prophlactic for the recurrences, not thrombolytic

30. Administration of UFH APTT monitorisation should be performed
5000 UI bolus UI/24 hr. Or 1000 IU/hr continious iv infusion
aPTT check in 6 hours (x1,5-2,5), platelet count in 3-5 days
Probability of recurrent VTE 5.4% and major hemorrhagia 1.9%.

31. Body Weight-Based Dosing of Intravenous Heparin
Initial dosing: Loading 80 U/kg  18 U/kg/hr (APTT in 6 hrs)
APTT(s) Dose Change Additional Next APTT (h)
(x normal) (U/kg/h) Action
<35 (1.2 x) Rebolus 80 U/kg 6
( x) Rebolus 40 U/kg 6
( x) *
( x)
>90 (<3x) Stop infusion 1 h 6
* APTT check during first 24 hr, there after once a day

32. bed rest until heparin is therapeutic
elastic stockings until patient becomes ambulatory ( post-thrombotic syndrome)
Oral anticoagulant can be given as warfarin (Coumadin)5 mg/day on the first 24 hours, when prothrombin time (PT) becomes x2-2.5 (INR 2-2.5)heparin can be stopped
Antidode of UFH is protamine sulphate
Antidote of warfarin is Vitamin K

33. Complications and side effects of heparin
Hemorrhagia (major % 0.5-3, fatal %0-0,8)
Thrombocytopenia
(The risk is lover in LMWH but if the condition occurs due to autoantiplatelet antibodies it is a fatal complication. Heparin should be stopped and an alternative anticoagulant (Hirudin etc) should be given)
Osteopenia
Reversible condition and the risk is high in prolonged use of the drug
Alopecia
Cutaneous rush
Hypersensitivity reactions
Urticeria, konjonctivitis, rhinitis, asthma, angioneurotic edema
Trombosit sayısının bazal değerin yarısından aşağı düşmesi halidir. Heparin kesildikten 4-7 gün sonra normale döner. Geç dönemde gelişen daha ciddidir(immün tip) İmmün trombositopeni geliştiğinde yeni trombüslerin oluşma riski ortaya çıktığından heparin derhal kesilmelidir.

34. Contraindications for heparin
Active hemorrhagia
Recent cerebrovascular hemorrhagia
History of major hemorrhagia from gastrointestinal, genitourinary or respiratory system

35. LMWH
Weight adjusted fixed dose subcutaneous application is possible without laboratory monitoring
Safer and better biopharmacology
HIT, osteopenia complications are less
As plasma half life becomes longer in renal failure and morbid obesity anti Xa should be monitored in this group

36. Low-Molecular-Weight Heparin
Drug Treatment Dose
Ardeparin 130 anti-Xa U/kg bid (Normaiflo)
Dalteparin 120 anti-Xa U/kg bid (Fragmin, )
Enoxaparin mg/kg bid (Lovenox, Clexane) (1 mg  100 anti-Xa units)
Danaparoid (Orgaran)
Tinzaparin 175 IU/kg once a day
(Innohep)

37. Warfarin
Oral agent
Inhibits the synthesis of protrombin, Protein C, S,f II, VII, IX, X’un related to vitamin K
Plasma half life 42 hr
Monitorization PT(x2-3), INR(2-3)
5 mg/day is started in the first 24 hours of treatment

38. Rivaroxaban (New treatment)
Inhibitor of Factor Xa
Oral (Xarelto)
2x15 mg (3 weeks,) followed by 1x20 mg
Laboratory monitoring not needed
Plasma half life 5-9 hours
Dose should be reduced in renal failure
Side effects anemia, dizzinesss, vomiting, hemoragia

39. Dabigatran Trombin inhibitor Oral (Pradaxa) 2x150 mg
Laboratory monitoring not needed
Peak efficacy 1-4 hours after ingestion
Plasma half life hr but can be longer in renal failure, old age
No antidote!!
Can not be used in pregnancy,
Dyspepsia, hemoragia

40. Indications for thrombolytic treatment
Massive Pulmonary Embolism
Hypotension
Deep hypoksemia
Right ventricular disfunction/iskemia
Cardiovascular collaps
Thrombolytic treatment should be performed immediately
Can be performed in the first 14 days

41. Thrombolytics Drug Loading dose Infusion dose Treatment duration
Streptokynase IU
30 min
IU/hr
24 hours
Urokynase
4400 UI
10 min
4400UI/kg/hr
12 hours
rt-PA -
100 mg
2 hours
rt-PA is the treatment of choise

42. Complications Contraindications Hemorrhagia (intracranial 1-2%)
Fever, alergic reactions,nausea, vomiting, myalgia, headache
Contraindications
Cerebral surgery or hemorrhagic attack within the last 2 months
Active intracranial disease
Uncontrolled hypertension
Hemorrhagic diathesis
Infective endocarditis
Pregnancy
Hemorrhagic rethinopathy
Pericarditis
Aneurism

43. Treatment duration
Reversible risk factor, first event, age<60 : 3-6 months
Reversible risk factor, first event, age>60: 6-12 months
First event, unknown risk factor: 6-12 months
Recurrent event: >12months- life long
Irreversible risk factor, first event: >12 months- life long
Optimal tedavi süresi risk faktörünün sürekliliği yada reversbl olması yada risk faktörü bulunup bulunmaması ile ilşkilidir. Ayrıca proksimal venlerin trombozunda distal venlerin trombozuna oranla daha uzun süreli tedavi gerekebilir.
Warfarin dozu terapötik seviyeye (e az 2 gün) ulaşılıncaya kadar günlük daha sonra 2 hafta boyunca haftada 2-3 kez INR ile takip edilir.
Oral antikoagüaln tedavi en azından 3 ay devam etmelidir, idiopatik proksimal ve trombozunda yada tekrarlayan epizodların varlığında bu süre uzatılmalıdır. Tedavi esnasında INR nin 2-3 arasında olması daha yüksek INR değerleri kadar etkili fakat daha güvenlidir. İdeal olarak tedavinin sürdürülmesinde INR therapötik seviyesinin korunması gerekmektedir. Ancak bu bazı durumlarda güç olmaktadır.
Warfarin kulanımını takiben doza bağlı olarak 2-7 gün sonra antikoagülan etki ortaya çıkmaktadır. Bu nedenle en az 4 gün boyunca heparin ve warfarin birlikte kullanılmalıdır. Başlangıç dozu için 5 mg kullanıldığında genellikle 4-5 günde terapötik seviyeye ulaşıldığından daha yüksek başlangıç yükleme dozu gereksizdir. Özellikle yaşı hastalarda , karaciğer fonksiyon bozukluğu olanlarda ve kanama riskiyüksek olgularda yüksek doz warfarin başlanmamalıdır.

44. Vena Cava Filters If there is a contraindication for anticoagulation
If a complication due to anticoagulation occurs
Failure: new DVT or PE under treatment
Major or minor hemorragia
Trombocytopenia
Tissue necrosis
Drug reactions
For prophylaxsis
Thrombectomy, embolectomy are the other surgical options

45. Primary Prevention
Determined by the thrombotic risk of the clinical situation in conjunction with the patients profile of risk factors
Ortopedic surgery (post-traumatic)
ICU
Neurosurgery carry the highest risk

46. Prophylaxis LMWH or UFH can be used in low doses
LMWH’s can be used preoperatively safely
Prophylaxis should be continued up to 4 weeks after surgery (min days)
Rivaroxaban 1x10 mg, Dabigatran 1x220 mg can be used

47. Non medical Prophylaxis
Graduated compression stockings
İntermittent pneumatic compression
Foot impulse pumps
Early mobilization
Can be used for patients who have contraindications to anticoagulants.