Today we will continue what we stop last lecture "the hepatic congestion morphology" ..

We have 2 types of hepatic congestion: acute and chronic one. --> Whenever I have an acute hepatic congestion, we will see under the microscope that the central vein will be congested along with the sinusoidal spaces, because there will dilation and increased blood volume within these spaces; they will be distended with blood. --> Whenever I have a chronic condition, I will have a resultant fibrosis; an end stage of fibrosis, and in this case, I will notice that the hepatic lobules (around the central vein) will be grossly red-brown in color, because of the engorgement (increased) blood volume, and the depression is caused by the inviability of the cells; they will be necrotic, and the blood itself isnt a healthy blood, it is deoxygenated and it lacks the nutrients important & crucial for the cellular life.

The peripheral regions of the hepatic lobules will not be affected so we will have a heterogeneous process; it wont be involving all the zones in the early stages-however with time it can involve all zones- , but in early stage, only the central area around the central vein will be involved. And this appearance will cause what is described as nutmeg liver, which illustrates the heterogeneity of the color that can be seen on cut sections. So grossly I will see nutmeg liver, and microscopically I will see centrilobular necrosis, zone 3 of hepatocytes will be lost. << Liver is divided histological into lobules. The center of the lobule is the central vein. At the periphery of the lobule are portal triads. Functionally, the liver can be divided into three zones, based upon oxygen supply. Zone 1 encircles the portal tracts where the oxygenated blood from hepatic arteries enters. Zone 3 is located around central veins, where oxygenation is poor. Zone 2 is located in between. >> SAMA archive

the passive acute congestion central vein will be dilated , they are spaces between hepatic paratial cells is called sinusoid , this sinusoid as a result congestion will become dilated as well , so blood in central vein might be distended by this sinusoid . "THIS IS ACUTE HEPATIC CONGESTION" In the Chronic congestion as i told you before "because this one is less oxygenated", so chronic congestion will lead to a sort of relative ischemia in this cells. This cell will become injured, become necrotic and will appear as necrosis so this is the change to chronic state.

Central area are red and slightly depressed compared with surrounding tan viable parenchymal, forming a "nutmeg liver" pattern (so called because it resemble the altering pattern of light and dark seen when a whole nutmegis cut). "ROBBINS" Nutmeg liver, which illustrates the heterogeneity of the color that can be seen on cut sections. "SAMA archive"

If you see this appearance grossly, if you take cross section from liver and see it by naked eye the color will be seen "nutmeg",, nutmeg: different colors "redpale, red-pale" , this somehow look like the nutmeg so this by naked eye .

Now microscopic appearance:

- Centrilobular will become necrotic and also as we discussed before in chronic congestion there is hemorrhage where the blood will be degraded and this degradation will result in morphologic change in the heme and that will lead to

dissolve hemosedren this hemosedren will engulf by macrophages that will give the yellow color.
- Red area represent the congested area (centralvenuoles) and the pale

represent the hepatic parietal cells that are still not congested , and this chronic congestion is usually secondary to right heart failure .

Liver with chronic passive congestion and hemorrhagic necrosis. - Hepatocyte failure Centrilobular necrosis with degenerating hepatocytes, hemorrhage, and acute inflammation.

NOW we can say " grossly I will see nutmeg liver, and microscopically I will see centrilobular necrosis, hepatocytes will be lost, hemorrhage... " remember it ;)

If you take section from the central lobule this central necrotic or this surrounding area this are hepatocyte and this pale is called sinusoid so the change dilated in sinusoid between the liver parital cells and congestion or necrosis of the central lobule so this the change that see in the liver once there's chronic congestion usually secondary to right sided heart failure. "The hepatocytes around the central vein will be dead (necrotic), so this will create what is seen grossly as collapse or depression, and hepatocytes will be failing to function as well, we will see areas of hemorrhage (this is because of extravasation or increased blood volume within the blood vessels), we will also notice hemosiderin-laden macrophages as within the lung, and the end stage will be fibrotic because the cells -in order to regenerate- need a good blood supply." SAMA archive

"In Chronic congestion of the liver in the central region of hepatic lobules are grossly red-brown and slightly depressed (because loss of a cell ) and are accentuated against the surrounding zones of uncongested tan sometimes fatty (nutmeg liver), microscopically there's centrilobular necrosis with hepatocyte dropout, hemorrhage, and hemosidrien laden machrophages. In long-standing severe hepatic congestion (most commonly associated with heart faliure), hepatic
fibrosis ("cardiac cirrhosis") can develop , it is important to note that because the central portion of the hepatic lobule is the last to receive blood, centrilobular necrosis can also occur whenever there is reduced hepatic blood flow (including shock from any cause); there need to be previous hepatic congestion. " ROBBINS ... this paragraph from the book summarize what dr talk about chronic hepatic congestion, so i advice to read it ;) .

We have two types of edema in cavities: 1. Exudates>>> specific gravity is more than 1.02, protein rich. 2. Transudate>>> specific gravity is less than 1.02, protein poor. Causes of transudate usually different from causes of exudates, heartfalilur transudate due to increase hydrostatic pressure still the wall of blood vessels stiffness in normal so protein keep inside the blood vessels, in case of inflammation and neoplasia the type usually is exudates due to obstruction the blood vessel wall.

Hemorrhage
Extravasations of blood into the extra vascular space , the blood in the vessels well get in to the outer space due: -Trauma -Atherosclerosis -Inflammation, -Neoplastic erosion -Vascular disorders -Thrombocytopenia -Platelet function defects

Hemorrhage can be external bleeding outside toward to the cavity or can be caused within a tissue , we have external internal bleeding this clinical definition external it can you see by the naked eye internal that you can't see by the clinical terms .

If there is no tissue around the bleeding it will just keep going freely to the outside , if it's in the stomach the bleeding will go through the anal canal to the outside .if it's in the colon the same thing the blood just keep going toward the anal canal and toward the inside. any injury to the skin its external, hemorrhage can we see by the naked eye, if the bleeding stay in the body or fined cyst like or wall like tissue the blood will keep accumulating within the space this is called a hematoma so a hematoma is bleeding in to a sac the wall of this sac either anormal structure or a fibrotic tissue that is was present originally so hematoma sac like collection of blood surrounded by wall or tissue or fibrous tissue. One the source of bleeding stops, the hematoma will stay in the body the failed hematoma it's what either the blood will be restored by the body or the chronic hematomas this blood will become compromised ,organized thromboses and classified sometimes hematoma can present as normal blood by classified mass only.

hematoma formation: if this hematoma stat for while this hematoma

will become compromised , organized , thrombosis and classified and present as a soft tissue mass so hematoma usually either can be drained by surgery or can be drained accidently for more than one reasons or just can stays fine within this sac and become thrombosis and classified. (Rupture of dissecting aortic aneurysm cause massive retroperitoneal hematoma).

Clinical significant depend on volume and rate of blood loss and where the bleeding is. The bleeding of skin not dangerous but the bleeding of heart or brain are dangerous even it small amount. Rapid loss of up to 20%= 1L , volume blood in body 5-6 L ,depending on the rate and amount if the rate is very rapid sometimes the body can developed a shock ,in the blood donation we get half liter.

Type of hemorrhage
1. Pitechiae: this mean minute hemorrhage the size is (1-2mm) usually in the skin or mucous membrane. Causes: Intravascular pressure, Platelet counts, Defective platelet function, Clotting factors. These small dotes here red dotes represent what we called pitechiae or pitechiae colonic size in the skin or mucous membrane.

2. Purpuras: something like (3-5 mm) hemorrhages the same causes for Pitechiae and 3.ecchymoses: are large hemorrhages (1-2 cm) subcutaneous hematomas (bruises).

Represent sort of bleeding subcutaneous bleeding because it large it's called ecchymoses , the color will doesn't stain constant depending on the change so once this happening it become bluish ,pale after while

become green then yellow depending on the degradation of the heme and hemoglobin .

Type of hemorrhage (cont...):

Hemothorax, Hemopericardium, Hemarthrosis, Hemoperitoneum. Just bleeding on to these cavities. And this is an example of hemopericardium or cardiac tamponade:

Clinical terms denoting various forms of hemorrhages:

-Hemoptysis (spitting of blood) >>> coughing blood -Hematemesis (vomiting of blood) -Hematochezia (passage of fresh bloody stool) main cause is hemorrhoid. -Melena (passage of altered bloody stool) Main cause is bleeding in stomach because blood passage from the stomach to intestine through the colon through this passage the color will become black. Mainly this bleeding through the gastric ulcer or a gastric cancer or duodenal ulcer so that mean the blood take its time to become alter. -Hematuria (blood in urine) main causes bladder stones, neoplasia and glomerulonephritis.

Homeostasis and thrombosis

Homeostasis: blood with constant condition to be in the fluid state in order to move within blood vessels maintains blood in fluid condition

and clot-free state in normal vessels, and inducing a rapid and localized haemostatic plug at sites of vascular injury. So fluid and clot and localized plug at site of injury so these 3 elements are needed to keep blood in haemostatic condition. Thrombosis: pathologic process, formation of intra-vascular solid mass (thrombus) from the elements of circulating blood (Platelets, clotting factor, and the fibrin) The vessel may be uninjured or with minor injury. Homeostasis and thrombosis depend on the:
- Integrity of blood vessels, - Platelets - Coagulation cascade

STEPS IN HEMOSTASIS
When we have injury or bleeding what's the immediate response for blood vessels?

Transient vasoconstriction due to reflex neurogenic mechanism and augmented by secretion of endothelin. What's the aim of vasoconstriction? To decrease the blood flow to the site of injury. Just to benefit if you see someone is hemorrhage just press on the site of bleeding. How we differentiate between arterial bleeding and venous bleeding? Arterial high depend on the pumping, bright red venous just continuously and dark red. So once there is a bleeding there is anuroginc reflex and endothelin release which will lead to vasoconstriction of blood vessels and become smaller and this will lead to decrease the amount of blood in the site of injury but this transient and immediate. After that the vasoconstriction is go away and platelets will start to stick in to the injury area usually to endothelial cells once they are present this prevent the platelets from aggregation once this discounted in the

endothelial cells this will exposed the underlining tissue mainly the collagen or the extracellular matrix to the blood this by the self will induce the matrix to attached to this area so the platelets will attach this call adhesion . This adhesion take by tow mechanism the first one platelets attach to the collagen directly especial receptor for that and the second by vWF: von Willebrand factor will help as bridge between collagen and platelets. Adhesion platelets to the subendothelial matrix via vWF then this adhesion will lead to more activation of platelet and the platelet will release its content (TXA2, ADP) both of these material will lead to platelet aggregation and formation of platelet plug so this plug named is primary homeostasis (the first plug seal in this injury), so the primary plug is formed from platelets alone. To make this primary plug strong enough to stand the flow forces of blood, so we need further mechanism in order to strengthen this primary plug. The conversion in to permanent plug is supported by fibrin clot so fibrin like a cement that strength the primary blood and conversion it to secondary or permanent plug. Fibrin will result from the activation of coagulation system and we have the platelets and coagulation system and all this factor play together in order to stop the bleeding and form the thrombus at the site of injury. At site of injury the tissue what secrete what is called a tissue factor .a tissue factor will activate apart of coagulation cascade this will lead to formation of thrombin , thrombin will convert fibrinogen( soluble one) to insoluble fibrin, fibrin will be deplete in the platelet blood and stabilize it and this is called secondary haemostasis. So this plug permanent, strong enough to stand the flow forces from the blood. Polymerized fibrin and platelet aggregates form a solid permanent plug to prevent any further hemorrhage. After that there are specific mechanism what is called the tissue plasma activator (TPA) this material or this growth factor will help

the plug from forming at site of normal endothelial cells, so this TPA will help in preventing the plug from overlying to the normal tissue. Lysis of fibrin and confinement of clot to the site of injury. So we have thrombosis so we have factors that prevent this thrombosis from overlying to adherent tissue what's called TPA.

Roll of endothelial
endothelial cells play two roles either PREVENT THROMBOSIS or help in THROMBOUS FORMATION so antithrombotic and prothrombotic features , the antithrombotic features happened by: - Antiplatelet properties -Anticoagulant properties -Fibrinolytic properties The roll in prothrombos is happened by Procoagulant functions .

Antiplatelet effect from the epithelial cells by separation of blood

from subendothelium once they exposure to the extracellular matrix beneath the endothelial cells this is a very thrombotic event once the blood touches the extracellular matrix so this very prothrombitic event. So this separation will prevent activation of more platelets and the initiation of blood coagulation. Other factor are released is called prostacyclin or PGI2 and nitric oxide (their synthesis is stimulated by thrombin and cytokines produced during coagulation) so separation the blood from the matrix release of prostacyclin and this mediated also vasodilator and inhibit platelet aggregation , other mechanism is Elaborate adenosine diphosphatase which degrades ADP and inhibits platelet aggregation in normal condition that release adenosine diphosphatase this enzyme will break down the ADP so preventing this function .

Anticoagulant effects are mediated by heparin like molecules and

thrombomodulin. ***Heparin like molecules act indirectly, they interacts with antithrombin III to inactivate thrombin, factors Xa and IXa this factors are member of coagulating factor . ***Thrombomodulin binds thrombin converting it from a procoagulant thrombin which just converts this coagulant to an anticoagulant capable of activating the anticoagulant protein C you (DR Saied you will understand them later on by yourself). ***Activated protein C inhibits clotting by proteolytic cleavage of factors Va and VIIIa (protein S cofactor). ***These proteins will discussed next lecture you dont need to know what it is but just clinically when you have deficiency in it you will know what will happen and what the disease.

Fibrinolytic Effects: synthesize tissue-type plasmimogen activator

that clears fibrin deposits from endothelial surfaces. All these events called Prothrombotic effects of endothelial cells. Now the opposite the Prothrombotic Functions, epithelial cell it performed the tow function the anti and the pro thrombosis. Platelet effects: von Willebrand factor (in plasma) facilitates adhesion of platelet to subendothelial collagen, vWF it will bined the platlets to extracellulare matrix, GPIb (receptor which bind vWF to the platlets) receptor is bind to the vWF. vWF its like protein C , protein S we have diseases effecting this factor ***. *** Platelet a little bit guided rather than guiding factor. *** Procoagulant effects (coagulant proteins): ECs (induced by TNF, IL-1 & Bacterial endotoxin).

Synthesize tissue factor (TF) which activates extrinsic clotting ***pathway. ***By binding to IXa and Xa, and increases its catalytic effects.

So the mechanism of this effect by the activation of the extrinsic factor , binding factor IXa and Xa so this the way to prothrombosis by procoagulant way . Antifibrinolytic effects; Secretion of plasminogen activator inhibitors (PAIs), antithrombosis it will activator (here we have inhibitor to inhibit the plasminogen function in the platelet) .

Platelet
The main thing you should to know what is we called the dense () granules Alpha (a) granule this granules containing max material that aid in the thrombus formation, the once they activate the thrombosis they become degranulated.

Platelet Granule content

Dense bodies ( granules): ADP, ATP, Ca++, histamine, serotonin, and epinephrine. Alpha granules express P-selectin and contain: Fibrinogen, Fibronectin, PDGF, TGF-, Platelet Factor 4 (heparin binding chemokine), Factor V & VIII. Glycoproteins of Platelet Membrane (receptors that present on the | platlets):

-GP Ia-IIa: adhesion to collagen.so its directly aied -GP Ic-IIa: laminin receptor. -GP IIb-IIIa: binding to fibrinogen. -GP Ib-IX: adhesion to subendothelial tissue via vWF

factor

Platelet response after injury once the interact to the extracellular matrix activation platelet result in: @ Adhesion & shape change. This will lead the blug to be strong. Secretion of contents of granules (Release @Reaction)(degranulation ) @Aggregation. ***So it will activation of the platelets.

Role of Platelets in Coagulation

1. Adherence to ECM (vWF - GpIb) @Secretion of granules contents (degranulation) this will lead to: . Platelet activation results in surface expression of phospholipids complexes (binding site for Ca++ and coagulation factors) (crucial for intrinsic pathway) @Ca++ is required for coagulation cascade @ADP is mediator of platelet aggregation like TXA2 @ADP RELEASE BY DEGRANULATION , TXA2is made within platelets.

2. Platelet aggregation:

@ ADP, TXA2 (vasoconstrictor) stimulate aggregation (autocatalytic reaction primary haemostatic plug). @Activation of coagulation cascade thrombin formation which binds to platelet surface receptor causes further aggregation @ Platelet contraction creating irreversibly fused mass of platelets (secondary hemostatic plug) @ Thrombin converts fibrinogen to fibrin which stabilizes and anchors the aggregated platelets @ Fibrinogen binds to GpIIb-IIIa receptors connects large number of platelets with each other Platelets Role in Coagulation Platelet aggregation: @ ADP, TXA2 (vasoconstrictor) stimulate aggregation (autocatalytic reaction primary hemostatic plug). @ Activation of coagulation cascade thrombin formation which binds to platelet surface receptor causes further aggregation @ Platelet contraction creating irreversibly fused mass of platelets (secondary hemostatic plug) @ Thrombin converts fibrinogen to fibrin which stabilizes and anchors the aggregated platelets @ Fibrinogen binds to GpIIb-IIIa receptors connects large number of platelets with each other

The End

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: Done by Deya mohammad & Ghofran mestarehi