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Mahmoud MassalhaPathology – Sheet #1429/10/2013

Today we'll discuss a new topic regarding blood vessels, which can be

affected by different conditions and diseases.

-Diseases that affect vessels can be reflected on different tissues. The vessels can have different diseases depending on their size and type-whether they are veins, Arteries or lymphatics-.Very important condition that affects the blood cells is the sclerosis of blood vessels and this is known as arteriosclerosis. Arteriosclerosis: simply and literally means "hardening of the arteries".Sclerosis histologically means hardening of the tissue and arteriosclerosis is the hardening of the blood vessels.However,blood vessels normally should have some degree of flexibility and elasticity,in order to interact with the cardiac output and that's why they should interact with the pulse as well.-blood vessels adapt to the volume of the blood which is ejected from the heart itself-.So if blood vessels weren't elastic enough they couldn't act properly and this clinically results in many complications. Normal Blood Vessel consists of : Endothelium rests on a layer of elastic tissue called Internal Elastic Lamina that gives elasticity and can also increase the caliber then goes back to its normal size.Definitely muscular arteries have got smooth muscle layer.In the outer surface there is also an External Elastic Lamina and the most outer layer is the Adventitia.As you notice in the following picture there is an actual artery and vein.Veins are thinner and more dilated,however,we can see internal elastic lamina and we can do special stain to demonstrate this elastic lamina,this is important because the interruption and fragmentation of the elastic lamina means that there is an injury of the vessel,particularly, the epithelium.However,it's important to have this normal structure in order to have normal blood vessels.Otherwise,hardening any part of the this blood vessel, particularly, Media and Intima, means that the blood vessel now is hard and cannot expand with ejection causing the sclerosis. Note: When we mention sclerosis, it means that the predominance of the extracellular matrix over the cellular components of the fibrous tissue

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becomes hard, whereas this fibrous tissue or collagen doesn’t have this elasticity feature, which is exerted by the elastic tissue causing hardening.

When blood vessels get to be thickened there could be three subtypes of sclerosis.

Sclerosis 1)Arteriosclerosis 2)Mönckeberg Medial Calcific Sclerosis 3)Atherosclerosis

1)Arteriosclerosis: Usually affects small arteries and arterioles. It's commonly seen in patients with hypertension and diabetes mellitus. Moreover, some organs may be affected by this process due to the effect on small arteries, such as Kidneys which considered as the commonest organ to be affected by this type.

2)Mönckeberg Medial Calcific Sclerosis :

"Medial":This means that the sclerosis or affection of the blood vessel wall by calcific deposits is on the muscular wal l"Media" ,and this is not clinically significant because this calcification doesn’t affect the lumen of blood.

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Whereas, in the proper Arteriosclerosis the thickening of the wall results in obstruction of the lumina- there might be a complete obstruction – and that's why they've clinical consequence . But here in the Monckeberg medial clacific sclerosis calcification occurs in the media without an actual affection or thickness of the wall. So, Lumen would still be opened and there is no problem. This manifestation occurs with age and that's why usually affects the elderly people -older than age of 50-.This is related to the Calcium deposition which is evident and reasonable by radiology. We can observe some calcification in the patients' X-ray indicating a

multiple blood vessels are being involved.

3)Atherosclerosis : Most important form and is associated with a clinical consequence. It means "Hardening of the blood vessels due to a change ". The affected blood vessels lose their normal wall, their elasticity and normal consistency. Usually those blood vessels are hard in palpation. This hardening is associated with narrowing of the lumen and that's why it is clinically significant.Note: Atherosclerosis affects blood vessels rather "focally" not involving the whole circumference of the blood vessel wall. That's why the site of deposition and accumulation of the material will form a mass that protrudes into the lumen and this is called Atheroma .So Atheroma or Atherosclerotic plaques are a deposition and narrowing of the

lumina that has occurred.

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Formation of Atheromatous Plaque:

Steps of Athermoatous Plaque formation are : 1) Injury to the Epithelium is required as a first step of the formation. Moreover, this injury would produce many changes. 2) Endothelial injury would be firstly associated with increased permeability of substances that are present in the blood like lipid material. 3) This would be associated with attraction of macrophages particularly that might be present in the surrounding, as monocytes which are the source of the macrophages in blood. Those also Infiltrate through the wall. 4) These Macrophages, then,start engulfing the fat material, by which they get larger in size. 5) Macrophages have many growth factor and they can affect other cells, that's why macrophages can send signals that produce some factors causing proliferation of the fibroblast.

Once these Fibroblasts proliferate the deposition of fatty materials will continue to create this plaque which consists of fat deposits surrounded by activated macrophages that also engulf the fatty material.Thus,"Fibrosis"would be surrounding them with chronicity.That's why you could find areas covered by a fibrous called Fibrous Cap.

What is the importance of this fibrous cap?! Once Atheroma gets into this fibrous cap it would be protected against any

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other effect and it would be difficult to be removed , as soon as, it's surrounded by fibrous tissue. Thus, it can neither be removed ,dissolved nor even be affected by drugs.

Epidemiology: Atherosclerosis Disease predominates in the Western countries, e.g:Europe. Since they share a common food lifestyle, whereas, It's much less common in the Far East,Africa and Asia.-Atherosclerosis have got a close relationship with Ischemic Heart Diseases(IHD).Actually,mortality rate for IHD in USA is the highest in the world-approximately five times higher than that in Japan-. -Japanese who immigrate to USA and adopt American lifestyle and dietary customs would have a raised incidence of mortality, indocating the influence of the type of food which is one of the most known risk factors for IHD.

IHD is a chronic disease which would increase the economic burden in countries. That's why governments study the morbidity and mortality of this disease, then try to reduce the risk factors in order to avoid this disease. E.g:The government controls the food factories in order to decrease the incidence of IHD rate.

Risk Factors : The major risk factors are either could be modified or not.Major risk factors that cannot be modified:1)Increasing with age.

2)More common in males than females in certain age group.

3)Increases in patients with family history of the IHD.

4)Genetic predisposition for atherosclerosis.

Major risk factors that can be controlled:1)Hyperlipidemia: It is an increase of lipid levels in the blood and this is predisposed to IHD.2)Hypertension and diabetes: They should be controlled,unless they could cause injury to the epithelium,which is the first step in the formation of

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atheromas.3)Cigarrette smoking:It's believed that it contains toxic substances,which once are dissolved in the blood, Injury to the epithelium could be produced, predisposing the incidence of sclerosis.

Let's go back to the nonmodifiable major risk factors and discuss some of them:

1)Age: Incidence of Myocardial Infraction increases-in men-five times in the ages between 40-60 in comparison with a younger age group,and this is related to the development of the IHD incidence,which would be also increased with each decade in life.

2)Gender: There is a well significant difference between male and female regarding IHD particularly in the premenopausal women,who are relatively protected against atherosclerosis compared with age-matched men,due to the effect of the female.Therfore, that’s why the incidence of MI and IHD is much less in females than males .However ,if there are other predisposing factors like diabetes,hyperlipidemia and severe hypertension,the difference start to be less and these females could develop atherosclerosis complications in young age group. After menopause the incidence of these diseases in females increases rapidly and starts to be similar to that in males,and even exceeds that in males,due to decrease of the female estrogen level.3)Genetic predisposition could establish IHD.Genetic effect might be due to increase of the incidence of other predisposing factors like diabetes, hypertension,and other major risk factors.Thus the incidence of IHD would be increased as well.Sometimes people have some abnormalities in the lipids metabolism and that’s usually would cause a high levels of lipids,for example cholesterol, lipoprotein and other major fats in the blood that could increase the incidence of sclerosis. E.g:Familial hypercholesterolemia: They have different derangements of cholesterol metabolism and usually result in increased level of cholesterol and consequently increased incidence of atherosclerosis.

-Always about 20% of the cardiovascular patients might not have any of the major risk factors .For example, if someone got ischemic or cardiac attack

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without having any of the risks we know we would wonder why the attack is developed in the absence of any major risk factors!Thus, it might be due to something which is subclinically presents.

Additional risk factors for atherosclerosis :1)It's believed that the inflammation is simply a disposition of lipid material in the wall,however inflammation might affects blood vessels and this is initiated by a high level of C-reactive protein, which is one of the inflammatory markers and proteins that increase blood inflammation. -Patients with hyperhomocystinemia also have an increased risk for the disease.

-Lipoprotein a: also is incriminated, sometimes patients who have normal lipid levels may have a high level of lipoprotein a ,which is not measured by using a standard blood test for lever, and that’s why we have to ask for its special test separately. It was found that people who don’t have any of the previously explained known risk factors might have a hidden lipoprotein a high level.

So,nowadays, lipoprotein a special test is done with the normal lipid test.

-Some individuals might have factors affecting hemostasis, which is a process that causes bleeding to stop, meaning to keep blood within a damaged blood vessel. So in those individuals those factors controls the blood preventing its hypercoagulative state and it might be sequentially.. -It's also believed that the lack of exercise is associated with increased risk because it's associated with an increased weight ,metabolic abnormality and increased fat as well.-Stressful life, competitive "type A personality".-Obesity

-Postmenopausal estrogen deficiency in females. In general deficiency of estrogen at any stage of female life increases the incidence of atherosclerosis.-High carbohydrates intake could be considered. **The presence of more than one risk factor is associated with increase in the risk. That’s why the presence of 2 risk factors increase incidence about 4 times ,whereas, the presence of 3 risk factors such as: Hyperlipidemia, hypertension and smoking )is associated with increasing the rate of MI 7 times.

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Other types of vessels that can be affected by diseases are veins and lymphatics.

Veins Diseases

Varicose Veins

Veins are most commonly affected by what is known as Varicose Veins.

Varicose Veins: Abnormally dilated tortuous veins and is associated with an Increased Intraluminal pressure. Any condition that might increase the Intraluminal pressure of the vein can result in varicosity. The veins that can be affected by this condition are : Superficial veins "Subcutaneous veins", which once are dilated can be tortuous and seen by naked eye on the skin. Or it could be in deep veins as well. However, the most common veins affected are in the extremities.Increase in the Intravenous pressure in these veins can be associated with stasis ,that is accompanied with these tortuosity and dilation of veins. Stasis: Slowing of blood flow.

One of the main causes of edema is the vascular embolism, which increases the hydrostatic pressure of the blood, and consequently fluids will be pushed outside the blood vessels causing the edema. This is developed in 10-20% of adult male and 25-33% of adult females, particularly in the lower extremities.What are the Risk factors of this disease ? 1)Obisity : Associated with the pressure and obstruction of the veins 2)Female Gender: Female might have more relaxed veins, In addition they have more predisposing factors like Pregnancy. 3)Pregnancy: Associated with congestion and pressure on the lower limb veins 4)Familial tendency: That’s why some patients could have no risk factors but the disease still could be developed due to a defective walls of veins which are soft and might not stand the increase in pressure. Thus, varicosity is developed.Usually there is a dilatation, which means that thinning of walls is accompanied with a wall expansion and there might be a muscular hypertrophy, particularly in chronic varicosity. When the cause is the increase of Intraluminal pressure in veins this will affect the smooth muscle cells, which

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in turn, do some protection against this increased pressure, thus it could be thickened as that in the wall, still they are dilated, so fibrosis and calcification can also occur . Note : We said that the walls are thin, but in chronic conditions some walls could be thickened and that doesn’t mean that they got back to their normal size ,but instead the wall can be thickened even more than normal veins'.-It could also cause thrombosis because the congesting blood is one of the risk factors for increasing the liability of thrombosis.

-Veins have valves particularly in the lower limbs, where the flow is against the gravity. Valves could be destructed when there is a prolonged condition, which increases the severity of the varicosity. That’s why the treatment would be a release of these varicosities, otherwise destruction cannot be solved.

Why Varicose is an important disease ?!It has many complications which are: 1) Stasis :2) Congestion of blood vessels: Associated with other clinical consequences. 3) Edema: That’s why we see those patients with bulgy areas. 4)Pain: Edematous fluid ,which is outside the blood vessels, can compress the nerves in the area causing pain.5)Thromboiss6)Chronic varicose ulcers : Congestion of blood vessels causes ulcers and the main problem that there would be an abnormal blood flow, therefore, it's hard to treat these ulcers without a normal blood flow. 7)Embolism: It's very rare but a serious condition. Why is it rare ? Because thrombosis and embolism usually take place in deep veins, however, we know that varicose veins disease usually affects the superficial veins.

Thrombophlebitis

The development of venous thrombosis.They commonly occurs in the deep leg veins and account for more than 90% of cases.The most important clinical predispositions are: 1)Congestive heart failure: When the right side of heart is in failure, It's associated with congestion of the deep veins, because the returning blood comes from those deep veins toward heart and if the right side of heart is in failure heart cannot receive the blood flow. Therefore, blood vessels would

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be congested starting to have some thrombosis. 2)Neoplasia: Some of the cancers can produce substances stimulating the coagulation system. These tumors are well known to induce thrombosis, and some tumors can grow within the blood vessels, where tumors enter and start growing, causing an obstruction. Moreover, this can occur in liver and renal cancers .3)Pregnancy : Enlargement of the uterus causes pressure.4) Obesity.5) Postoperative state: Any condition which is associated with a major surgery in the pelvis or abdomen increases the risk of venous thrombosis

6)Prolonged bed rest or immobilization : Like in postoperative, comatose and paralyzed patients. 7)Migratory Thrombophlebitis: Some Tumors Induce substances that is associated with clot formation ,such as: Pancreatic Tumor. This is known as Paraneoplastic syndrome,which is due to the ability of malignant cells to produce malignant substances,of which ,some may have neurological manifestations, although it's not even related to nerves nor blood itself, but because they are able to produce these factors they can initiate thrombosis. E.g: Pancreatic Tumor which is associated with what's known as Migratory thrombophlebitis and they can develop a large number of thrombi within small blood vessels. The scientist who discovered it called "Trousseau", and that’s why it's clinically known as "Trousseau sign". Accordingly, when we've got a multiple venous thrombi present ,we should immediately think of the possibility of having malignancy underneath.

Local Manifestations , including :

1-distal edema

2-cyanosis

3-superficial vein dilation

4-heat

5-tenderness, redness, swelling, and pain

6-The Superior Vena Caval Syndrome

This is caused by a tumor that compresses or invades the superior vena cava ,however, invasion of vena cava could do a "metastasis" which means

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that part or group of cells leave the major place of tumor to the blood and extends ,this is associated with obstruction of the superior vena cava in the head,neck and arms.7-The Inferior Vena Caval Syndrome

Here, Neoplasms compress and invade the inferior vena cava, particularly the Hepatocellular carcinoma and renal cell carcinoma. It induces a marked lower extremity edema, distention of the superficial collateral veins of the lower abdomen.(Collateral veins are usually closed, unless the main vein is obstructed and only then these veins open), and-with renal vein involvement-massive proteinuria-level of proteins rises-.

Lymphangitis

It's an acute Inflammation of lymphatics, caused by a bacterial infections.It can be extended to lymphatics and cause more serious conditions. -The Most common cause is group A β-hemolytic streptococci.

When lymphatics are involved by inflammation, walls would be inflamed and dilated ,the neutrophils increase and it's associated with swelling of the affected site. Note: Small wound in the leg could surprisingly get a redness, edema and inflammation involving the whole lower limb ,this is an indication of having lymphangitis. It's usually painful and can end up in acute lymphadenitis.Eventually,Lymphatics connect veins and this bacteria will reach the blood causing sepsis or bacteremia within the blood.

Primary LymphedemaA congenital maldevelopment of lymphatics ,which works on collecting the fluids escaping from the blood vessels, and if it's obstructed the fluid doesn’t go back to the vessels causing edema at that site. The most common cause of lymphedema is the Secondary or Obstructive Lymhpedema rather than the congenital one and this is due to blockage of a previously normal lymphatic which then could be associated with edema .

1-Malignant tumors: tumor causing obstruction could cause edema.

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2-Any surgical procedures which are associated with the removal of lymph nodes. E.g: In Breast tumor surgery when the Axillary Lymph Node is removed edema would be produced.

3-Postirradiation

4-Fibrosis

5-Filariasis: Filaria is a parasite that invades the body and lives in the lymphatic cell wall. Consequently,when these parasites grow they increase in number and size causing obstruction,so you could notice that the lower limbs are extremely edematous and the leg would look like the elephant's leg.(Look at the following picture of a patient with filariasis).

6-Postinflammatory thrombosis and scarring

Chylus -Milky accumulations of lymph in various spaces.

-Caused by rupture of dilated lymphatics, typically obstructed secondary to an infiltrating tumor mass.

-Chylous ascites (abdomen).

-Chylothorax (chest).

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Done by your colleague: Mahmoud Massalha

Good Luck

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