Clinical Presentation and Diagnosis

Clinical Presentation and Diagnosis

in Pulmonary Hypertension Due To Recurrent Pulmonary Thromboembolism

Numan EKİM MD.

Gazi University School of Medicine

Chest Diseases Department

Recurrent pulmonary thromboembolism

Epidemiology and risk factors -1 Venous thromboembolism (VTE) is a frequent, multicausal, and

potentially fatal disease

Despite adequate treatment, up to one quarter of patients with symptomatic deep vein thrombosis (DVT) and / or pulmonary embolism (PE) will experience recurrent venous thromboembolism (VTE) within the subsequent 5 years

Even after adequate anticoagulant therapy some 3-5 % of patients have reccurence of their VTE

Patients with thromboembolic events of unknown origin (idiopathic) have a more than two-fold higher rate of recurrent VTE in comparison to patients whose thrombosis is associated with acquired, transient risk factors Eichhinger S. et al.Circulation 2007

Prandoni P. et al. Ann Intern Med 2002

Lobo Jl et al.British J Haemat 2007

Trow TK, Mc Ardle JR. Clin Chest Med 2007


Epidemiology and risk factors - 2 Patients with continuous risk factors, such as cancer or the

antiphospholipid antibody syndrome, and those with idiopathic thrombosis have a two- to threefold increased risk for recurrence compared with patients who developed a thrombotic event in association with a transient risk factor

Risk of recurrence may be higher in the presence of residual venous thrombosis or elevation of D-dimer

The risk of recurrence depends on the number and severity of risk factors in an individual patient.

The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients

Paolo Prandoni, Franco Noventa, Angelo Ghirarduzzi, Vittorio Pengo, Enrico Bernardi,Raffaele Pesavento, Matteo Iotti, Daniela Tormene, Paolo Simioni, Antonio Pagnan

Haematologica 2007; 92:199-205

1626 consecutive patients who had discontinued anticoagulation after a first episode of clinically symptomatic proximal DVT and/or PE were followed up to a maximum of 10 years

All patients with clinically suspected reccurent VTE underwent objective tests to confirm or rule out the clinical suspicion

The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patientsPaolo Prandoni, Franco Noventa, Angelo Ghirarduzzi, Vittorio Pengo, Enrico Bernardi,Raffaele Pesavento, Matteo Iotti, Daniela Tormene, Paolo Simioni, Antonio Pagnan






The results of this study clearly show that after discontinuing anticoagulation the rate of recurrent VTE increases steadily over time, approaching 40% among all patients after 10 years

More than 10% of all recurrences were either documented fatal PE or sudden and otherwise inexplicable deaths, in which PE could not be ruled out

The results of this study fully confirm that patients who present with thrombotic episodes of unknown origin have a more than two-fold higher risk of recurrences than that observed in patients with temporary risk factors. Of interest, in the latter category of patients, those with associated medical diseases had the highest risk, while those with VTE triggered by recent trauma or surgery the lowest, and this is consistent with previous reports

Improving the long-term prognosis of patients with acute VTE still remains a challenging task.

In 301 consecutive patients with the first episode of acut PE, echocardiography was used to assess right ventricular dysfunction (RVD) on admission and before hospital discharge

Patients were followed up at 2,6, and 12 months and yearly thereafter. The primary endpoint was symptomatic,reccurent fatal or nonfatal VTE

According to the ECHO features on hospital admission and at discharge, patients were classified into 3 groups ;

1st. group- patients without RVD on admission,

2nd. group- patients with RVD regression at discharge, and

3rd. group - patients with RVD persistance at discharge

Association of Persistent Right Ventricular Dysfunction at Hospital Discharge After Acute Pulmonary Embolism With Recurrent Thromboembolic EventsStefano Grifoni, MD; Simone Vanni, MD; Simone Magazzini, MD; Iacopo Olivotto, MD; Alberto Conti, MD;Maurizio Zanobetti, MD; Gianluca Polidori, MD; Filippo Pieralli, MD; Nazerian Peiman, MD; Cecilia Becattini, MD; Giancarlo Agnelli, MD

Arch Intern Med 2006 ; 166 : 2151-2156


Arch Intern Med 2006 ; 166 : 2151-2156


Arch Intern Med 2006 ; 166 : 2151-2156 The results of the present study show that

persistence of RVD at hospital discharge is a frequent finding, occurring in approximately 20% of patients who present with a first episode of PE

RVD persistence is common at hospital discharge after the first episode of PE. Following discharge, RVD persistence is associated with an increased risk of recurrent VTE and death related to PE. Patients with RVD persistence should receive a strict surveillance for recurrences.

Extending anticoagulant therapy may be particularly useful for patients with RVD persistence and idiopathic PE presentation, both representing independent risk factors for VTE recurrence in the present study. I

Indeed, in these patients the estimated risk of recurrence was at least 5-fold higher than that of patients without the 2 combined risk factors.


Important risk factors of recurrence include ;

antithrombin deficiency, the lupus anticoagulant, High factor VIII, factor V Leiden and prothrombin G20210A mutation hyperhomocysteinemia, previous venous thrombosis, cancer, male sex. aging ( importance for VTE ? ) clinical presentation with primary PE the duration of anticoagulation following the initial thrombotic episode

Mortality Approximately 5% of patients with recurrence die of pulmonary embolism In

many patients with recurrent VTE,

Eichhinger S. et al.Circulation 2007Prandoni P. et al. Ann Intern Med 2002

Chronic thromboembolic pulmonary hypertension (CTEPH)

Definition Chronic thromboembolic pulmonary hypertension (CTEPH) is an

important cause of pulmonary hypertension that is commonly considered to be the consequence of acute pulmonary embolic disease.

Following an acute event, unresolved residual thrombus becomes organised and fibrosed, leading to ongoing obstruction to pulmonary blood flow.

Untreated, this leads to progressive pulmonary hypertension, right ventricular dysfunction and death

Suntharalingam J. et al. Thorax 2007

Trow TK, Mc Ardle JR. Clin Chest Med 2007

Progression of CTEPH Acute or recurrent PTE in pulmonary arteries

Organisation these thrombi

Occurence in situ thrombus due to slow blood flow in obstructed

pulmonary arteries

Occurence of arteritis in not obstructed small distal pulmonary

arteries(remodelling)

Increased PVR, pulmonary hypertension

CTEPH


Clinical presentation - 1

The diagnosis of CTEPH is usually not made until the degree of pulmonary hypertension is advanced

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)

Fedullo PF et al.N Engl J Med 2001


Clinical presentation - 2 Patients who have CTEPH typically complain of exertional

dyspnea and a gradual decrease in exercise tolerance over months to years

Diagnostic delay : Nonspesific nature of symptoms Absence a history of prior acute symptomatic venous

thromboembolism (DVT / PE)

The average delay from the onset of cardiopulmonary symptoms to establisment of the correct diagnosis can range from 2 to 3 years

Fedullo PF et al.Semin Resp Crit Care Med 2003Auger WR et al. Clin Chest Med 2007


Clinical presentation - 3Progressive dyspnea and exercise intolerance due to CTEPH are

often erroneously attributed to ; coronary artery disease cardiomyopathy congestive heart failure interstitial lung disease COPD (mild) asthma physical deconditioning psychogenic dyspnea

Prior to consideration of a pulmonary vascular problem as a basis for their complaints, many patients with CTEPH have undergone ;

left-sided cardiac catheterizations (one or more ) coronary angiograms lung biopsy. enrolling in an exercise program seeking psychiatric help.

Fedullo PF et al.N Engl J Med 2001Auger WR et al. Clin Chest Med 2007


Clinical presentation

Symptoms Progressive dyspnea Nonproductive cough (especially with exertion) Hemoptysis Palpitations A change voice quality or hoarseness Exertional chest pain Near-syncope or syncope Lower extremity edema

Fedullo PF et al.Semin Resp Crit Care Med 2003Auger WR et al. Clin Chest Med 2007


Clinical presentationPhysical examination - 1May be subtle early in the course of the illness.In time obvious findings develop, which may include :

Right ventricular lift Jugular venous distension Prominent A and V wave venous pulsations Fixed splitting of S2 with an accentuated pulmonic component A right ventricular S4 gallop A tricuspid regurgitation murmur Hepatomegaly Ascites Peripheral edema, which may be a result of either chronic lower

extremity venous outflow obstruction or right ventricular failure.



Clinical presentationPhysical examination - 2The presence of flow murmurs over the lung fields(30 percent of patients).

turbulent flow through partially obstructed or recanalized pulmonary arteries

high pitched and blowing in quality

heard over the lung fields rather than the precordium, accentuated during inspiration

frequently heard only during periods of breath-holding

they have not been described in primary pulmonary hypertension, which represents the most common competing diagnostic possibility



DiagnosisPulmonary function tests

Useful for excluding coexisting parenchymal lung disease or airflow obstruction

Often within normal limits

The majority of patients with CTEPH have a reduction in the single breath diffusing capacity for carbon monoxide (DLCO); a normal value, however, does not exclude the diagnosis

Approximately 20 percent of patients demonstrate a mild to moderate restrictive defect

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

Steenhuis KS. Et al. Eur Respir J 2000Auger WR et al. Clin Chest Med 2007


DiagnosisBlood gas analysis

Resting arterial PO2 may be within normal limits

Hypoxemia at rest implies very severe right ventricular disfunction or the presence of a right -to- left shunt, as through a patent foramen ovale

Majority of patients have a decline in the arterial PO2 with exercise

The alveolar-arterial oxygen gradient is typically widened

Dead space ventilation (VD/VT) is often increased at rest and worsens with exercise

Minute ventilation is typically elevated as a result of the increased dead space ventilation.

Fedullo PF et al. N Engl J Med 2001Auger WR et al. Clin Chest Med 2007


DiagnosisChest radiography

Often normal Enlargement of both 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 ( especially on the lateral film by encroachment on the normally empty retrosternal space)

Cardiomegaly



Diagnosis

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

Auger WR et al. Clin Chest Med 2007


Diagnosis

Echocardiography Enlargement and reduced systolic

function of the right ventricle are usually apparent,

Leftward septal displacement can impair left ventricular filling and performance

ECHO is useful for the excluding; Left ventricular dysfunction Valvular disease Cardiac malformations

Menzel T et al. Chest 2000Auger WR et al. Clin Chest Med 2007


DiagnosisRadioisotopic V / Q scanning – 1

In chronic thromboembolic disease, at least one (and more commonly, several) segmental or larger mismatched ventilation-perfusion defects are present but not spesific for this condition

In idiopathic pulmonary arterial hypertension (IPAH) , perfusion scans are either normal or exhibit a "mottled" appearance characterized by subsegmental defects

V- scannig of the lungs is almost always normal

Hasegawa I et al. AJR 2004Fedullo PF et al. N Engl J Med 2001

IN a case with CTEPH, 2008 Perfusion scan;Right lung ; 5 segmentary,3 subsegmentary, Left lung; 4 segmentary,2 subsegmentary perfusion defects


Diagnosis

Radioisotopic V / Q scanning – 2

Conditions indistinguishable from CTEPH in V/Q appearance :

Extrinsic vascular compression from mediastinal adenopathy or fibrosis Primary pulmonary vascular tumors ( ie. Angiosarcoma ) Pulmonary veno-occlusive disease Large-vessel pulmonary arteritis

Additional imaging studies are needed to define the vascular abnormality and establish the diagnosis

Hasegawa I et al. AJR 2004Fedullo PF et al. N Engl J Med 2001


DiagnosisComputed tomogaphy (CT)CT findings in CTEPH :

Right atrial and ventricular enlargement

Chronic thromboembolic material within dilated central pulmonary arteries

Central pulmonary artery enlargement

Variations in the size of lobar and segmental- level vessels

Mosaic perfusion of the lung parenchyma

Peripheral, scar- like densities in hypo-attenued lung regions

Presence of mediastinal collateral vessels arising from the systemic arterial circulation

Kronik tromboembolik pulmoner hipertansiyon

(KTEPH)

DiagnosisComputed tomogaphy (CT) - 2

CT imaging is also valuable in : Assesment of the lung

parenchyma in patients who have coexisting emphysematous or restrictive lung disease

Detection mediastinal pathology that might account for occlusion of the central pulmonary arteries


Diagnosis

Pulmonary angiography Pouch defects 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

Fedullo PF et al. N Engl J Med 2001


Diagnosis

Cardiac catheterization Defines the severity of the pulmonary

hypertension and degree of cardiac dysfunction

Biplane imaging provides optimal anatomical detail

When dilated and overlapping vessels are present, the lateral view provides more detailed images of lobar and segmental anatomy than those obtained with an anterior–posterior view alone

Fedullo PF et al. N Engl J Med 2001Auger WR et al. Clin Chest Med 2007


DiagnosisPulmonary angioscopy

A diagnostic fiberoptic device, was developed specifically for preoperativeevaluation.The angioscopic features of organized, chronic emboli :

Roughening or pitting of the intimal surface, Bands and webs traversing the vascular lumen, Pitted masses of chronic embolic material within the lumen, Partial recanalization. Intimal plaques are a nonspecific finding in pulmonary hypertension of any cause. Angioscopy is performed in approximately 30 percent of patients undergoing

evaluation for thromboendarterectomy,

Fedullo PF et al. N Engl J Med 2001

Conclusions

Up to one quarter of patients with acut VTE will experience recurrent venous thromboembolism (VTE) within the subsequent 5 years

Recurrent VTE is an important problem in patients with thromboembolic events of unknown origin (idiopathic) rather than in patients whose thrombosis is associated with acquired, transient risk factors

The patients, those with associated medical diseases had the highest risk, while those with VTE triggered by recent trauma or surgery the lowest

RVD persistence is associated with an increased risk of recurrent VTE and death related to PE. Patients with RVD persistence should receive a strict surveillance for recurrences.

Conclusions

Chronic thromboembolic pulmonary hypertension (CTEPH) is an important complication of acute VTE

The average delay from the onset of symptoms to establisment of the correct diagnosis can range from 2 to 3 years

ECO is an important laboratory method to determine the severity of the disease

V/Q sscannig gives considerable clues in the diagnosing of CTEPH

Right- heart catheterization should be considered in any patient with unexplained dyspnea and segmental or larger defects on V/Q perfusion scanning, especially if there is echocardiographic evidence of right atrial or right ventricular dysfunction

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Clinical Presentation and Diagnosis