Dr.Ashraf Abdelfatah Deyab
Assistant Professor of Pathology
Faculty of Medicine
Almajma’ah University

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Pulmonary vascular disease-introduction
In the human body, there are two types of circulation that enable distribution of blood throughout the body:
I. SYSTEMIC CIRCULATION . pumps oxygenated blood from the left side of the heart to all parts of the body.
II. PULMONARY CIRCULATION: pumps deoxygenated blood from the right side of the heart into the lungs to obtain oxygen .

Pathology of pulmonary vascular disease
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Damage to the vessels wall.
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Obstruction.
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Variation in intra-vascular pressure.

Pathology of pulmonary vascular disease
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Damage to the vessels wall:
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- Arteritis with ischaemia and local necrosis
( Wegener's granulomatosis, Churg-Strauss syndrome)
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- Good pasture's syndrome (with circulating antiglomerular basement membrane antibody).
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Obstruction: Thrombo-embolism.
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Variation in intra-vsacular pressure:
Arterial or venous hypertension.

Goals
Pathology of Pulmonary Vascular Diseases
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To discuss the etiology, morphological features and clinical consequences of pulmonary embolism (PE)
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To describe the pathogenesis, morphology and clinical features of pulmonary hypertension (PH).

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Etiology, morphological features and clinical consequences.

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P. Embolism: caused by Blood clots , that
BREAK & TRAVEL to occlude the pulmonary arteries& branches (ONE OR MORE).
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P. Embolism: define as complications of othe r
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Rare- emboli from other source can block arteries , such as tumors, air bubbles, amniotic fluid, or fat.

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HOW COMMON

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650,000 cases in the US each year.
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150,000 – 200,000 US deaths each year
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Most common preventable cause of hosp death
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Thrombo-embolism is the commonest among pulmonary vascular lesion.
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Autopsy reports suggest it is commonly
“ missed ” diagnosed

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Most emboli are thrombotic, originating in veins , typical sites are the deep pelvic veins or the deep veins of the calf e.g
popliteal vein (>95%).
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Large-vessel in situ thromboses are rare and develop only in the presence of pulmonary hypertension, pulmonary atherosclerosis, and heart failure.

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Thrombotic
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Non-thrombotic : Fat, Air, Tumor ,
Amniotic fluid, IV Drug abusers.

PE Predisposing\Risk factors:
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All predisposing factors to DVT:
Virchows Triad: “ Rudolph Virchow”
 Alterations in blood flow (stasis).
 Injury to endothelium.(irritation, trauma )
 Thrombophilia.
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Cardiac disease , Congestive heart failure,
Atrial fibrillation, MI, HTN (DM, CHL).
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Immobilization, recent\ prolonged postoperative recovery phase

Surgery on the legs, hips, abdomen.
Severe trauma : fractures and burns.
women who use oral contraceptives rich in estrogen.
Disseminated cancer.
- Hypercoagulable states, inherited (AT III def., protein C, S deficiency) or acquired (e.g. obesity, pregnancy, DIC,)

PE - Pathophysiologic response
The Pathophysiologic response& clinical effect depends on:
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(1) The size & site of occluded emboli.
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(2) The numbers of emboli.
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(3) The overall status of CVS.
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(4) Volume of lung tissue deprived of blood.

Emboli result in two main pathophysiologic
“effects” consequences:
1) Respiratory compromise due to the nonperfused tissue. ( Infracted area )
2) Hemodynamic compromise due to increased resistance to pulmonary blood flow by the embolic obstruction.

Pulmonary Embolism OUTCOME .

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1) Occlusion of a major vessels leads to:
I. Sudden DEATH .
II. Increase pulmonary pressure, decrease in cardiac output , then Right sided heart failure.

2) Occlusion of a smaller vessel :
INo effect if the bronchial circulation is good.
II - If there is impaired circulation infarction.
occurs.
III. If small and multiple lead to pulmonary HT

OUTCOME of pulmonary thrombo-embolism.
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PE outcome conclusion:
1) Sudden death (if massive).
2) Pulmonary infarction (if small).
3) Pulmonary hypertension (if small and multiple).

Morphology of pulmonary embolism.

► may lodge in various sites in the pulmonary arterial tree.
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1) Large emboli lodge the in the main pulmonary artery or its major branches or at the bifurcation as a saddle embolus ( sudden death).

Pulmonary Arteries:
Here is a "saddle embolus" that bridges across the pulmonary artery from the heart as it divides into right and left main pulmonary arteries.

PE morphology based on site and size
2) Small emboli cause hemorrhage or infarction at the periphery,
Occlusion of a lobar or segmental artery , causes chest pain and may lead to distal lung infarction .

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Thromboemboli in patient who is immobilized.
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? Differentials diagnoses?

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Postmortem assessment of PE/’
How to differentiate between thromboemboli AND post-mortem clot ?
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Thrombus\clot can be distinguished from a post-mortem clot by the presence of the lines of Zahn in the thrombus.

A closer view of a thromboembolus filling a main pulmonary artery reveals a layered appearance ,

This is the microscopic appearance of a pulmonary thromboembolus
There are interdigitating areas of pale pink and red that form the "lines of Zahn" characteristic for a thrombus

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Morphology of lung infarction:
- Wedge-shaped , with their base at the pleural surface & the apex pointing to the hilus of the lung.
- usually > 3\4 affects the lower lobes .
- > 1\2 are multiple lesion occurs.
- vary in site, size& shape .
- Pulmonary infarcts are typically hemorrhagic and appear as raised red areas in early stages.

Pulmonary infarction wedge-shaped and based on the pleura surface & the apex pointing to the hilus

Multiple small pulmonary thromboembolihemorrhagic infracted areas.

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The pulmonary infarct:
Microscopic :
1) Ischemic necrosis of the lung substance within the area of hemorrhages , affecting the alveolar walls, bronchioles, and vessels.
2) Cellular events with Hemosiderin deposits
3) Infected embolus , reveals intense neutrophilic inflammatory reaction referred as septic infarcts= abscesses .

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The pulmonary infarct:
Microscopic:
4) Fibrous replacement – converts into a contracted scar.

PE morphology- based on emboli source
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Fat embolism
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Air embolism
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Amniotic fluid emboli
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Tumor emboli

PE morphology- based on emboli source
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Fat embolism: result from fractures of bones containing fatty marrow, or from massive injury to subcutaneous fat .
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Air embolism: occur occasionally during childbirth or with abortion

PE morphology- based on emboli source
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Amniotic fluid emboli: occur during delivery or abortion .
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Tumor emboli: very common; this is an important mechanism in the development of metastases.

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Clinical course:
- 60-80% are clinically silent .
- 5% sudden death (large emboli).
- in less than 3% of cases recurrent pulmonary infarcts , result in pulmonary hypertension and right sided heart failure.

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Common symptoms& signs
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The Classic Triad : (sudden unexplained
Pleuritic chest pain, Hemoptysis ,
Dyspnea ,)
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Tachypnea .
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Fibrinous pleuritis may produce a pleural friction rub.

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Three Clinical Presentations
 Pulmonary Infarction
 Submassive Embolism
 Massive Embolism
47

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Resolved after management by fibrinolysis.
with Recurrence rate 3%
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Unresolved, multiple small emboli over the course of time may lead to pulmonary hypertension , pulmonary vascular sclerosis, and chronic cor pulmonale.
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Death (if massive) by blockage of BV or by acute right heart failure (acute cor Pulmonale)

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PE can be difficult to diagnose.
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Over diagnosis - under diagnosis
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No easy solution.
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Prevention of pulmonary embolism constitutes a major clinical problem.
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Laboratory investigations:
D-dimer blood test.
Fibrin split product,
Circulating half-life of 4-6 hours.

2)Radiological assessment:
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Spiral computed tomographic angiography.
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Pulmonary angiography.
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Lung scan.
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MRI
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Duplex ultrasonography- DVT

PULMONARY HYPERTENSION (PH)

PULMONARY HYPERTENSION (PH)
Goals
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To describe the pathogenesis, morphology and clinical features of pulmonary hypertension (PH).

Pulmonary hypertension - PH
Introduction
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The pulmonary circulation is normally one of low resistance.
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Pulmonary BP is normally only about one eighth = (1\8) of systemic BP .
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Pulmonary hypertension (PH) defined when mean pulmonary artery pressure reaches one fourth= (1\4) of systemic levels or greater than BP> 25 mm Hg at rest & greater > 30 mm Hg during exercise.

Pulmonary hypertension - PH
Introduction
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The pulmonary arteries pressure usually wrote as a single figure (average)
Pulmonary artery pressure ( abbreviated to mPAP) .

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Pulmonary hypertension - PH
500 to 600 cases diagnosed annually.
- Occur in men, women and children of all ages,
However most common in women (20-40ys).
- Rare in children but sometimes seen in infants born with heart defect

The pressure within the pulmonary arterial system may be increased for two reasons:
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1) Increased blood flow
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2) Increased resistance within the pulmonary circulation.

PULMONARY HYPERTENSION (PH)etiology

Pulmonary hypertension – PH
(Etiology)
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Can be classified into three main
causes:
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1Secondary pulmonary hypertension.
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2- Primary pulmonary hypertension.
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3- Idiopathic.

I)
Pulmonary hypertension – PH
(Etiology)
Secondary pulmonary hypertension :
• Secondary to another medical problem e.g:
• Diseases that impedes flow of blood through
Lungs or
• Diseases that affect the oxygen levels (periods of low oxygen) in blood.
• Examples: COPD, Scleroderma, pulmonary fibrosis, lung diseases such as asbestosis

Pulmonary hypertension – PH
(Etiology)
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Secondary pulmonary hypertension main causes :
1) Cardiac diseases \causes.
2) Recurrent thrombo-embolism .
3) Inflammatory vascular disease.
4) Connective tissue disease
5) Lung diseases

Pulmonary hypertension – PH
(Etiology)
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Secondary pulmonary hypertension :
1) Cardiac diseases :
Congenital or acquired heart disease :
MI- increase left atrial pressure.
- Left to right shunts e.g. septal defects.
Mechanical obstruction e.g. atrial myxoma and mitral stenosis.

Pulmonary hypertension – PH
(Etiology)
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Secondary pulmonary hypertension :
2) Recurrent thromboemboli: reduced vascular bed- increase vascular resistant.
3) Inflammatory vascular diseases :
scleroderma,other CT diseases & vasculitis .
4) Connective tissue diseases: inflammation, intimal fibrosis , medial hypertrophy

5) Lung diseases :
- Chronic obstructive or interstitial lung diseases: hypoxia, alveolar and vascular bed damage- increase resistance- increase
PH.
- Pneumoconiosis e.g. asbestosis & silicosis.
Extra-pulmonary restrictive causes e.g.
(
Abnormal pulmonary function, obstructive sleep apnea, obesity hypoventilation syndrome).

2- Primary pulmonary hypertension
(Familial)
Rare, autosomal dominant.
- Mutations in bone morphogenic protein receptor 2 signalling pathway (BMPR2).
No underlying cause for the high BP in lungs
- Most-likely due to spasm of the muscle layer in pulmonary arteries, patients are rather sensitive any vasoconstrictors elements.

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3) Idiopathic PH:
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Sporadic, requires exclusion of other known causes.
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Usually women 20-40 years old, some time children.

Abnormally high BP in pulmonary vessels arteries
Increased pressure damages large and small pulmonary arteries
Blood vessel walls thicken
Cannot transfer oxygen and carbon dioxide normally
Levels of oxygen in blood fall
Constriction of pulmonary arteries
Further increase in pressure in pulmonary circulation

Pulmonary Hypertension right side of heart must work harder push blood through pulmonary arteries to lungs cor pulmonale right ventricle thickens and enlarges
Heart Failure
In some people, the bone marrow will produce more red blood cells to compensate for less of oxygen in blood leading
Polycythemia
Extra RBCs cause the blood to become thicker and stickier, further increasing the load on the heart
Pulmonary Embolism

PULMONARY HYPERTENSION (PH)
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PH resulting directly from another medical problem
(Secondary PH), include :
1) Chronic obstructive or interstitial lung disease (
Hypoxic vasculopathy)
2) Pulmonary veno-occlusive disease leads to chronic venous congestion with interstitial fibrosis.
3) Venous congestion and pulmonary oedema.
4) Left heart failure.
(Congestive vasculopathy)
5) Recurrent pulmonary embolic disease. (
Postthrombotic vasculopathy).
6) Right-to-left shunt (Congenital atrial septal defect).
plexogenic art.

The pathogenesis pulmonary hypertension

PH- Pathogenesis
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I. Molecular basis (Mutation).
(Primary PH).
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II. Shear and mechanical injury
(Secondary PH)
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III. Pulmonary vasoconstriction
(Secondary PH)
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IV. Idiopathic

PH pathogenesis- Primary PH
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I. Molecular basis (Mutation):
(Familial or primary PH) is caused by mutations in the bone morphogenetic protein receptor type 2 (BMPR2) signaling (with existence and support of modifier genes and/or environmental triggers).

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BMPR2 is a cell surface protein belonging to the TGF-β receptor
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BMPR2 specific effects in vascular smooth muscle cells causes inhibition of proliferation & favors apoptosis.
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BMPR2 Mutation lead to increased smooth muscle survival and proliferation may be expected.
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BMPR2 plays it’s effect by support of gene modifier& environmental trigger.

PH- Pathogenesis-Primary PH
(cont.) Molecular basis (Mutation)
( Primary PH) : lead to:
1) Pulmonary vascular thickening& occlusion : proliferation of endothelial, smooth muscle, and intimal cells accompanied by concentric laminar intimal fibrosis.
Note: The gene mutation supported by existence of
(modifier gene elements) e.g. that control vascular tone, including endothelin, prostacyclin synthetase, and angiotensin converting enzymes.

(II) Increased shear and mechanical injury
(Secondary PH) produced endothelial cell dysfunction e.g.: :
Leftto-right shunts (Mechanical).
- Thromboembolism, injury mediated by biochemical injury produced by fibrin.

Pulmonary Hypertension
1 .
Pulmonary Arterial
Hypertension 3.
Chronic
Hypoxemia
2. Left Heart
Disease
.
4
4.
Thromboembolic 5. Miscelaneous
-Sarcoid, fibrosing mediastinitis

III) Pulmonary vasoconstriction:
1) Decreased elaboration of prostacyclin& nitric oxide-and increased release of endothelin- this lead to activate platelet
Aggregation& adhesion
2) Endothelial activation , makes endothelial cells thrombogenic and promotes the persistence of fibrin.

PH pathogenesis-Secondary PH
3) Production and release of growth factors and cytokines induce the migration and replication of vascular smooth muscle cells and elaboration of extracellular matrix.
4) Vasospastic component, after ingestion of certain plants or medicines .

Pulmonary hypertension- morphology

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Medial hypertrophy = muscular thickness of muscular and elastic arteries.
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Atheromas, Atheromatous deposits of pulmonary artery, branches.
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Initimal fibrosis= narrowing of the lumen
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Organizing or recanalized thrombi , with coexistence of diffuse pulmonary
fibrosis this favors recurrence.

Pulmonary hypertension, reveal atheroma formation, usually limited to large vessels

Small peripheral pulmonary artery thromboembolus &their direct role in PH

Vascular changes in pulmonary hypertension
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Initimal fibrosis= narrowing.
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Marked medial hyperatrophy
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Alveolar haemorrhages

- Plexiform lesion caused by:
- Longstanding severe primary PH and idiopathic& CHD with left-to-right shift .
- Characterized by multi-channeled outpouching of the arterial wall due to reparative lesions in areas of fibrinoid necrosis.

Vascular changes in pulmonary hypertension
Plexiform lesionin small arteries multichannel
Associated with advanced pulmonary hypertension:
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Idiopathic& primary PH+
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Congenital heart disease with left-to-right shunts.

Plexiform lesion- Pulmonary hypertension

Coexistence morphological features:
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Diffuse pulmonary fibrosis , or severe emphysema and chronic bronchitis .
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Dilated vessels and arteritis may also be present.
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Extensive occlusion of the veins by fibrous tissue.

PH Clinical features
Signs & symptoms
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Like other forms of HTN are subtle in the early stages.
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Sign& symptoms are hidden by underlying diseases, and varying from pt. to pt.
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Initial Symptoms : dyspnea, fatigue, chest angina-like pain, cough, fail to put on weight like a normal child with slowed growth (in child)
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Overtime Severe respiratory distress , cyanosis , and right ventricular hypertrophy.

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Diagnosis :
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Proper medical work-up& correlation, ruleout others, Echo, lung FT, Lung scan, ect..
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PH outcome:
Death from decompensated cor pulmonale, often with superimposed thromboembolism and pneumonia, usually ensues within 2 to
5 years in 80% of patients.