Chronic Thrombo Embolic Pulmonary Hypertension.pptx

CTEPH

1. CHRONIC PULMONARY THROMBOEMBOLISM PATHOPHYSIOLOGY AND MANAGEMENT

2. DEFINITION CTEPH is defined as pre-capillary Pulmonary Hypertension as assessed by right heart catheterization (mean PAP ≥ 25 mmHg, PAWP ≤ 15 mmHg) in the presence of multiple chronic/organized occlusive thrombi/emboli in the elastic pulmonary arteries (main, lobar, segmental, subsegmental) after at least three months of effective anticoagulation.

3. CTEPH is defined as pre-capillary Pulmonary Hypertension as assessed by right heart catheterization (mean PAP ≥ 25 mmHg, PCWP ≤ 15 mmHg) in the presence of multiple chronic/organized occlusive thrombi/emboli in the elastic pulmonary arteries (main, lobar, segmental, subsegmental) after at least three months of effective anticoagulation.

4. CTEPH is defined as pre-capillary Pulmonary Hypertension as assessed by right heart catheterization (mean PAP ≥ 25 mmHg, PCWP ≤ 15 mmHg) in the presence of multiple chronic/organized occlusive thrombi/emboli in the elastic pulmonary arteries ( main, lobar, segmental, subsegmental ) after at least three months of effective anticoagulation.

5. CLINICAL CLASSIFICATION OF PULMONARY HYPERTENSION

6. NATURAL HISTORY OF CTEPH Honeymoon period after acute PE Usually present in their 40s Later presents with dyspnea , hypoxemia & RV dysfunction Death usually due to RV failure

7. INCIDENCE 0.5% to 3.8% -Acute PE Upto 10% -Recurrent PE.

8. CHRONIC PULMONARY THROMBOEMBOLISM PATHOPHYSIOLOGY

9. CHRONIC PULMONARY THROMBOEMBOLISM PATHOPHYSIOLOGY CTEPH can develop several months or years after an acute PE (which may be silent), despite continuing anticoagulation, and in the absence of new symptoms or any new acute event.

10. THROMBUS NONRESOLUTION IN CTEPH In acute PE, the fresh clots are red, easily detached from the pulmonary artery wall and consist mainly of red cells and platelets in a fibrin mesh. In CTEPH, the chronic clots are yellow, highly adherent to the pulmonary vascular wall, and contain collagen, elastin, inflammatory cells, re-canalised vessels and more rarely, calcification. Organisation and fibrosis of this residual thrombotic material impairs blood flow, and ultimately leads to the development of CTEPH.

11. CLINICAL CONDITIONS PREDISPOSING TO CTEPH VTE (Large pulmonary emboli = higher risk of CTEPH) Recurrent Pulmonary Emboli. Insufficient Anticoagulation. Autoimmune and Haematological Disorders. Hypercoagulability Malignancy Nonmalignant thrombophilia Pregnancy Postpartum status. Long-distance travel. Recent surgery. Recent trauma (especially the lower extremities and pelvis)

12. Cancer Various Mechanisms cause increased risk of thromboembolic events resulting from activation of the fibrinolytic and coagulation systems acute-phase reactions, inflammation and cytokine production.

13. Inflammation and infection Patients with chronic thromboembolic pulmonary hypertension (CTEPH) have elevated levels of C-reactive protein (CRP) and tumor necrosis factor- α, which are reduced after pulmonary endarterectomy (PEA), and chronic infection with Staphylococcus aureus is common in CTEPH patients.

14. Biological and genetic risk factors for thrombus nonresolution Patients with thrombus nonresolution could have a hypercoagulability state. There is no evidence to suggest that deficiencies in Protein C, Protein S, Antithrombin, or mutations of Factor V and II are more prevalent in patients with Chronic Thromboembolic Pulmonary Hypertension (CTEPH) compared to healthy control populations.

15. Biological and genetic risk factors for thrombus nonresolution – adamts 13 ADAMTS13 A Disintegrin And Metalloproteinase With Thrombospondin Type 1 Motif, Member 13, von Willebrand factor-cleaving protease. Regulates the size of von Willebrand factor and plays a fundamental role in haemostasis . Severe deficiency of ADAMTS13 causes thrombotic thrombocytopenic purpura. Patients with DVT showed relatively lower plasma levels of ADAMTS13 activity.

16. Blood groups The ABO locus is a susceptibility locus for VTE and non-O carriers have a higher risk for VTE than O carriers

17. Fibrinogen and fibrinolytic abnormalities in CTEPH Patients with CTEPH appear to have a high prevalence of abnormal fibrinogen molecules in the blood such as fibrinogen Aα-Thr312Ala . This mutation leads to a modified fibrin structure in clots, including increased cross-linking of α-chains The common feature are that they are able to resist physiological thrombolysis, and thus affect thrombus resolution

18. Platelet function in CTEPH Conditions such as thyroid hormone replacement therapy and splenectomy are risk factors for CTEPH. Patients with CTEPH have a higher mean platelet volume, increased spontaneous platelet aggregation and decreased platelet aggregation in response to agonists.

19. Small-vessel disease in CTEPH There is evidence that in addition to mechanical obstruction of proximal arteries, some patients develop severe pulmonary microvasculopathy (small-vessel disease), first described by Moser and Bloor. Moser KM, Bloor CM. Pulmonary vascular lesions occurring in patients with chronic major vessel thromboembolic pulmonary hypertension. Chest. 1993 Mar;103(3):685-92. doi : 10.1378/chest.103.3.685. PMID: 8449052.

20. This vascular remodelling affects the wall of distal muscular pulmonary arteries (0.1−0.5 mm in diameter), and may even reach arterioles and venules of <0.1 mm in diameter. Redistribution of the pulmonary flow in nonoccluded pulmonary arteries are exposed to high pressure and shear stress, leading to endothelial dysfunction, a progressive increase in PVR and ultimately to symptomatic CTEPH.

21. RV dysfunction and failure in CTEPH Chronic increase in RV afterload and wall stress RV is not capable of sustaining long-term pressure overload, which increases further during physical activity. Continuously increasing burden on the RV, leads to its maladaptive remodelling . Eccentric hypertrophy, RV dilatation, reduced RV contractile force, diastolic dysfunction and myocardial fibrosis.

22. CHRONIC PULMONARY THROMBOEMBOLISM management

23. Diagnostic approach

24. CLINICAL PRESENTATION. Cardinal Symptom : Dyspnea on progressively minor exertion. Mainly linked to right ventricle (RV) dysfunction. A patient may carry on relatively normal activities following a pulmonary embolic event, whether clinically apparent or occult, even when extensive pulmonary vascular occlusion has occurred (asymptomatic – honeymoon period)

25. Central, peripheral, or mixed cyanosis Accentuated pulmonary component of second heart sound RV third heart sound Systolic murmur of tricuspid regurgitation Diastolic murmur of pulmonary regurgitation Signs of pulmonary hypertension

26. Distended and pulsating jugular veins Abdominal distension Hepatomegaly Ascites Peripheral oedema Signs of RV backward failure

27. Peripheral cyanosis (blue lips and tips) Dizziness Pallor Cool extremities Prolonged capillary refill Signs of RV forward failure

28. Investigations : Chest radiography Enlargement of main pulmonary arteries or asymmetry in the size of the central pulmonary arteries Areas of hypoperfusion or hyperperfusion . Evidence of old pleural disease, unilaterally or bilaterally Right atrial or right ventricular enlargement, based on the outline of the right cardiac border. Cardiomegally .

29. Electrocardiography (ECG) Right axis deviation Right ventricular hypertrophy Right atrial enlargement Right bundle – branch block ST segment displacement T- wave inversions in anterior precordial and inferior limb leads. ECG = Predictive Value. Normal ECG + Normal Biomarkers = Low Likelihood for PH.

30. Useful for excluding coexisting parenchymal lung disease or airflow obstruction A mild obstructive defect may be present as a result of mucosal hyperemia, which is related to development of a large bronchial arterial collateral circulation. Resting arterial PO2 may be within normal limits. Hypoxemia at rest implies very severe right ventricular dysfunction or the presence of a right -to- left shunt. Majority of patients have a decline in the arterial PO2 with exercise. Pulmonary function tests and arterial blood gases

31. PH leads to RV pressure overload and dysfunction, which can be detected by echocardiography. Enlargement and reduced systolic function of the right ventricle are usually apparent ECHO is useful for excluding; Left ventricular dysfunction Valvular disease Cardiac malformations echocardiography

32. A ventilation/perfusion (V/Q) lung scan (planar or SPECT) is recommended in the diagnostic work-up of patients with suspected or newly diagnosed PH, to rule out or detect signs of CTEPH. In the absence of parenchymal lung disease, a normal perfusion scan excludes CTEPH with a negative predicted value of 98%. Non-matched perfusion defects similar to those seen in CTEPH may be present in 7–10% of patients with PAH. Ventilation/perfusion lung scan

33. 23 year old female with h/o sob and dvt .

34. 54 year old female with dyspnea and dec. o2 saturation.

35. Computed tomogaphy (CT) Right atrial and ventricular enlargement Chronic thromboembolic material within dilated central pulmonary arteries Central pulmonary artery enlargement ( PA-to-aorta ratio >0.9) Variations in the size of lobar and segmental level vessels Presence of mediastinal collateral vessels arising from the systemic arterial circulation. Combination of three parameters (PA diameter ≥30 mm, RVOT wall thickness ≥6 mm, and septal deviation ≥140° [or RV:LV ratio ≥1]) is highly predictive of PH.

36. Computed tomography pulmonary angiography Direct or indirect signs of CTEPH, such as filling defects (including thrombus adhering to the vascular wall), webs or bands in the PAs, PA retraction/dilatation, mosaic perfusion, and enlarged bronchial arteries. To detect other cardiovascular abnormalities, including intracardiac shunts, abnormal pulmonary venous return, patent ductus arteriosus, and PAVMs.

37. M R Angiography Limited sensitivity No extra advantage over CTA

38. Digital subtraction angiography Pulmonary artery webs or bands Intimal irregularities Abrupt narrowing of the major pulmonary arteries Obstruction of lobar or segmental vessels at their point of origin, with complete absence of blood flow to pulmonary segments normally perfused by those vessels. Measuring pulmonary arterial haemodynamics during right heart catheterisation .

39. Cardiac catheterization Right heart catheterization is the gold standard for diagnosing and classifying PH. The guidelines recommend a complete haemodynamic evaluation by right heart catheterisation including cardiac output because PVR is important to assess prognosis and the risks associated with PEA. In addition to diagnosing and classifying PH, clinical indications include haemodynamic assessment of heart or Lung Transplant candidates.

40. Therapeutic modalities

41. Treatment of choice for patients with accessible PA lesions. Surgical pulmonary endarterectomy.

42. University of California San Diego chronic thromboembolism (CT) surgical classification

43. Surgical pulmonary endarterectomy. Type I disease (15%) Refers to the situation in which major vessel clot is present and readily visible on the opening of the pulmonary arteries. All central thrombotic material has to be completely removed before the endarterectomy.

44. In Type II disease (approximately 50% of cases no major vessel thrombus can be appreciated. In these cases only thickened intima can be seen, occasionally with webs, and the endarterectomy plane is raised in the main, lobar, or segmental vessels. Surgical pulmonary endarterectomy.

45. Type III disease (approximately 30% of cases) presents the most challenging surgical situation. The disease is very distal and confined to the segmental and subsegmental branches. No occlusion of vessels can be seen initially. The endarterectomy plane must be carefully raised in each segmental and subsegmental branch. Surgical pulmonary endarterectomy.

46. Type IV disease does not represent primary thromboembolic pulmonary hypertension and is inoperable. In this entity there is intrinsic small vessel disease, although secondary thrombus may occur as a result of stasis. Surgical pulmonary endarterectomy.

47. Riociguat – for inoperable CTEPH / recurrent PH after PEA. After 16 weeks of therapy, improved 6MWD and reduced PVR by 31% compared with placebo, and is approved for this indication. Treprostinil s.c. showed improved 6MWD at week 24 in patients with inoperable CTEPH or those with persistent/recurrent PH after PEA and is approved for this indication. Macitentan 10 mg improved PVR and 6MWD vs. placebo at 16 and 24 weeks, respectively. Other medical therapies—PDE5is (e.g. sildenafil) and ERAs (e.g. bosentan )—have been used off-label, as their efficacy in inoperable CTEPH has not been proven by RCTs or registry data. However, oral combination therapy, including PDE5is and ERAs, is common practice in patients with CTEPH with severe haemodynamic compromise. Medical therapy Ghofrani HA, D'Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, Mayer E, Simonneau G, Wilkins MR, Fritsch A, Neuser D. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. New England Journal of Medicine. 2013 Jul 25;369(4):319-29. Sadushi-Kolici R, Jansa P, Kopec G, Torbicki A, Skoro-Sajer N, Campean IA, Halank M, Simkova I, Karlocai K, Steringer-Mascherbauer R, Samarzija M. Subcutaneous treprostinil for the treatment of severe non-operable chronic thromboembolic pulmonary hypertension (CTREPH): a double-blind, phase 3, randomised controlled trial. The lancet respiratory medicine. 2019 Mar 1;7(3):239-48. Ghofrani HA, Simonneau G, D'Armini AM, Fedullo P, Howard LS, Jaïs X, Jenkins DP, Jing ZC, Madani MM, Martin N, Mayer E. Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension (MERIT-1): results from the multicentre, phase 2, randomised, double-blind, placebo-controlled study. The Lancet Respiratory Medicine. 2017 Oct 1;5(10):785-94.

48. Balloon pulmonary angioplasty is an established treatment for selected patients with inoperable CTEPH or persistent/ recurrent PH after PEA, improving haemodynamics (PVR decrease 49–66%), right heart function, and exercise capacity. A staged interventional procedure with a limited number of dilated PA segments per session is preferred. Procedural and post-interventional complications include vascular injury due to wire perforation, and lung injury with haemoptysis and/or hypoxia. Interventional treatment

49. Patients should be regularly followed-up, including invasive assessment with RHC 3–6 months after intervention, allowing for consideration of a multimodal treatment approach. After successful treatment, yearly non-invasive followup , including echocardiography and an evaluation of exercise capacity, is indicated because recurrent PH has been described Most experts accept achieving a good functional class (WHO-FC I–II) and/or normalization or near normalization of haemodynamics at rest, obtained at RHC 3–6months post-procedure (PEA or last BPA), and improvement in quality of life. followup

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