Thrombosis

Definition-The formation from constituents of the blood, of a mass within the venous or arterial vasculature of a living animal. Natural defense of the body to acute vascular injury.

Pathologic thrombosis includes deep venous thrombosis (DVT), pulmonary embolism (PE), coronary artery thrombosis leading to myocardial infarct and cerebrovascular thrombosis leading to stroke.

Coagulated blood- clots formed 

Clot – formation of solid mass of blood components formed outside the vascular tree
Thrombosis with resulting embolic phenomena is important cause of morbidity and mortality.

Haemostatic system allows blood to remain in fluid form under normal conditions and causes the development of temporary thrombus at site of vascular injury.

Components of haemostatic system:
1.    Platelets
2.    Vascular endothelium
3.    Procoagulant plasma protein clotting factors
4.    Natural anticoagulants
5.    Fibrinolytic proteins
6.    Antifibrinolytic proteins

Normal haemostasis:
1.    Primary haemostasis-platelet plug formation
2.    Secondary haemostasis-stable plug or thrombus
3.    Natural anticoagulants-confines thrombus site and size to maintain blood flow
4.    Fibrinolysis-degrades fibrin , limits thrombus size and dissolves thrombus once vessel injury is repaired

Changes in any of these factors may result in pathologic thrombosis.

Pathophysiology of thrombosis:
Virchow’s Triad-Thrombosis results from a) decreased blood flow b) vascular endothelial injury and c) alterations in the components of blood.

Vessel wall:
EC (intima), smooth muscle cells (media) and the connective tissue (adventitia).Vascular endothelium is thromboresistant. EC injury leads to TF expression and thrombosis.
Vessel wall has antiplatelet, anticoagulant and fibrinolytic activities which make it thromboresistant.
Antiplatelet activities:
1.    Prostacyclin synthesized by EC in response to thrombin. Inhibits platelet adhesion as well as causes vasodilation
2.    NO regulates vascular tone as well as functioning as inhibitor of platelet adhesion. Constitutive expression as well as induced expression by EC in response to cytokines
3.    Ectozymes which metabolize ADP and ATP to AMP and adenosine. Adenosine inhibits platelet function, ADP is platelet agonist

Anticoagulant activities:
1.    Synthesis of heparin like GAG which inactivate activated clotting factors
2.    Protein C and S and thrombomodulin-Thrombin generated binds to thrombomodulin which activates protein C which then binds to Protein S and this inhibits coagulation by its proteolytic effect on Factors Va and VIIIa
3.    TFPI is synthesized by EC and  regulates TF-VIIa activation of Factor X. Also inhibits vascular cell proliferation

Fibrinolytic activities:
1.    Secretion and synthesis of plasminogen activators TPA in response to thrombin and vasoactive stimulants such as vasopressin and histamine
2.    Synthesis of urokinase in response to inflammatory cytokines
3.    FDP’s generated have antiplatelet and antithrombin activity
4.    Secretion of PAI

Prothrombotic properties of vascular endothelium promote coagulation with appropriates stimuli.

EC exposure to stimuli such as trauma, cytokines, atherogenic stimuli, endotoxins and immune complexes result in increased TF expression, reduced Protein C activation and reduced fibrinolysis so converting an antithrombotic surface to a prothrombotic surface.
Inherited conditions which result in abnormalities of EC derived or regulated proteins will cause thrombosis.

Arterial thrombosis:
1.    Abnormal vessel wall due to atherosclerotic plaque rupture, arterial outflow obstruction, vessel dissection EC injury promote platelet adhesion and activation
2.    Release of contents of platelet granules cause recruitment  and activation of additional platelets
3.    Thromboxane synthesis induces platelet aggregation
4.    Thrombin generation due to presence of PL

Platelets are pathogenetically more important in arterial thrombi thus antiplatelet agents are very important in arterial thrombosis management.

Venous thrombosis:
1.    Vessel wall is usually normal except if there is direct vessel trauma, extrinsic venous compression or damage due to drugs like chemotherapy
2.    Reduction in venous tone is important in pathophysiology

Venous thrombi can be of two types.

A. Phlebo thrombosis 
This is thrombus formation in an uninflammed vein usually due to stasis or changes in coagulability of blood. This occurs mostly in deep calf veins and varicose veins in the legs originating near valve pockets. They may propagate to extend to popliteal ,femoral and iliac-veins. These are a common source of massive emboli ‘Phlegmasia alba dolens’  (painful white leg) is a condition seen in late pregnancy and puerperium.  In this condition, in addition to iliofemoral thrombosis , there is arterial spasm

B Thrombophlebitis:
In this condition venous wall is inflamed and initiates thrombosis. This is more firmly attached to the vessel wall and also there is much less tendency for propagation Hence there is little chance or embolism.

Cardiac Thrombosis
Intra cardiac thrombus formation can be at 3 sites 

•    Valvular: as in endocarditis
•    Atrial : as in atrial fibrilation ('ball valve thrombus") over MacCallum’s patch is Rheumatic Fever.
•    Ventricular mural thrombus  over site of MI

Fate of Thrombus

- Resolution : if small, the thrombus is rapidly covered by endothelial cells. Then it can Resolved by a combination of retraction, phgocytosis , platelet autolysis, and fibrinolysis 
-  Organisation: there is in growth of vascular granulation tissue. This can result in
 a. recanalisation
 b. collagenisation and-scarring
-    Detachment resulting in thromboembolism
 

Measles (rubeola) 

-incubation period 7 to 14 days 

-begins with fever (up to 40 degrees C), cough, conjunctivitis (photophobia is first sign), and coryza (excessive mucous production)Æfollowed by Koplik's spots (red with white center) in the mouth, posterior cervical Lymphadenopathy, and a generalized, blanching, maculopapular, brownish-pink rash (viral induced vasculitis) beginning at the hairline and extending down over the body which gradually resolves in 5 days with some desquamation. 

EXOCRINE PANCREAS

Congenital anomalies
1. Ectopic pancreatic tissue most commonly occurs in the stomach, duodenum, jejunum, Meckel's diverticulum, and ileum. It may be either asymptomatic or cause obstruction, bleeding, intussusception. 

2.Annular pancreas is a ring of pancreatic tissue that encircle the duodenum and may cause duodenal obstruction. 

Cystic fibrosis

Cystic fibrosis is a systemic disorder of exocrine gland secretion presenting during infancy or childhood. 
Incidence is 1:2500 in Caucasians; it is less common in Black and extremely rare in Asians. 

Pathogenesis. Cystic fibrosis shows autosomal recessive transmission; heterozygotes are unaffected. It results in a defective chloride channel, which leads to secretion of very thick mucus. 

Characteristics

- Tissues other than exocrine glands are normal, and glands are structurally normal until damaged by cystic fibrosis.
- The only characteristic biochemical abnormalities are an  elevation of sodium and chloride levels in sweat, and a decrease in water and bicarbonate secretion from pancreatic cells, resulting in a viscous secretion. 

Clinical features

- Fifteen percent of cases present with meconium ileus.
- Most cases present during the first year with steatorrhea (with resultant deficiencies of vitamins A, D, E, and K), abdominal distention, and failure to thrive.

Complications are also related to pulmonary infections'and obstructive pulmonary disease as a result of viscous bronchial secretions. 

Pathology
- There is mucus plugging of the pancreatic ducts with cystic dilatation, fibrous proliferation, and atrophy. Similar pathology develops in salivary glands. 

- Lungs. Mucus impaction leads to bronchiolar dilatation an secondary infection. 
- The gastrointestinal tract shows obstruction caused mucus impaction in the intestines with areas of biliary cirrhosis, resulting from intrahepatic bile duct obstruction

Diagnosis depends on demonstrating a "sweat test" abnomality associated with at least one clinical feature In sweat test, high levels of chloride are demonstrated.

Prognosis. Mean survival is age 20; mortality is most often due to pulmonary infections. 

Degenerative changes

1. Iron pigmentation (e.g., from hemochromatosis) may be deposited within acinar and islet cells and may cause insulin deficiency. 

2. Atrophy 
a. Ischemic atrophy is due to atherosclerosis of pancreatic arteries and is usually asymptomatic. 
b. Obstruction of pancreatic ducts affects only the exocrine pancreas, which becomes small, fibrous, and nodular.

Acute hemorrhagic pancreatitis 

presents as a diffuse necrosis of the pancreas caused by the release of activated pancreatic
enzymes. Associated findings include fat necrosis and hemorrhage into the pancreas. 

Incidence. This disorder is most often associated with alcoholism and biliary tract disease.
It affects middle-aged individuals and often occurs after a large meal or excessive alcohol ingestion; approximately 50% of patients have gallstones. 

Pathogenesis. There are four theories.
- Obstruction of the pancreatic duct causes an elevated intraductal pressure, which results in leakage of enzymes from small ducts. 
- obstruction may be caused by a gallstone at the ampulla of Vater; chronic alcohol ingestion may cause duct obstruction by edema. 
- Hypercalcemia may cause activation of trypsinogen; its mechanism is unclear. Pancreatitis occurs in 20% of patients with hyperparathyroidism. 
- Direct damage to acinar cells may occur by trauma, ischemia, viruses, and drugs. 
- Hyperlipidemia may occur as a result of exogenous estrogen intake and alcohol ingestion. 

Clinical features are typically the sudden onset of acute, continuous, and intense abdominal pain, often radiating to the back and accompanied by nausea, vomiting, and fever. This syndrome frequently results in shock. 

Laboratory values reveal elevated amylase (lipase elevated after 3-4 days) and leukocytosis. Hypocalcemia is a poor prognostic sign. 

Chronic pancreatitis 

It refers to remitting and relapsing episodes of mild pancreatitis, causing progressive pancreatic damage. 

Incidence is similar to acute pancreatitis. It is also seen in patients with ductal anomalies. Almost half the cases occur without known risk factors. 

Pathogenesis is unclear; possibly, there is excess protein secretion by the pancreas, causing ductal obstruction. 

Clinical features include flareups precipitated by alcohol and overeating, and drugs. Attacks are characterized by upper abdominal pain, tenderness, fever, and jaundice. 

Laboratory values reveal elevated amylase and alkaline phosphatase, X-rays reveal calcifications in the pancreas. Chronic pancreatitis may result in pseudocyst formation, diabetes, and steatorrhea. 

Carcinoma of the pancreas 

Incidence: 
Carcinoma of the pancreas accounts for approximately 5% of all cancer deaths. Increased risk is associated with smoking. high-fat diet, and chemical exposure. There is a higher incidence in the elderly, Blacks, males, and diabetics. 

Clinical features
- The disease is usually asymptomatic until late in its course. 
- Manifestations include weight loss, abdominal pain frequently radiating to the back, weakness, malaise, anorexia, depression, and ascites.
- There is jaundice in half of the patients who have carcinoma of the head of the pancreas.
- Courvoisier's law holds that painless jaundice with a palpable gallbladder is suggestive of pancreatic cancer. 

Pathology
Carcinomas arise in ductal epithelium. Most are adenocarcinomas. 
- Carcinoma of the head of the pancreas accounts for 60% of all pancreatic cancers. 
- Carcinoma of the body (20%) and tail (5%) produce large indurated masses that spread widely to the liver and lymph nodes. 
- In 15% of patients, carcinoma involves the pancreas diffusely. 

Complications 
include Trousseau's syndrome, a migratory thrombophlebitis that occurs in 10% of patients. 

Prognosis is very poor. if resectable, the 5-year survival rate less than 5%. The usual course is rapid decline; on average death occurs 6 months after the onset of symptoms.

HYPERPLASIA
It is the increase in the size of an organ or tissue due to increase in the number of its constituent cells. This is seen in organs made up of labile and stable cells.

Causes
I. Increased demand:
- Bone marrow in hypoxia and haemolytic states.
- Thyroid gland in puberty

2. Persistant Trauma:
- Acanthosis of the epidermis in chronic inflammations and in warts.
- Hyperplasia of oral mucosa due tooth and denture trauma.
- Mucosa at the edges of a gastric ulcer.

3. Endocrine target organ:
- Pregnancy hyperplasia of breast.
- Prostatic hyperplasia.

4. Compensatory:

Hyperplasia of kidney when the other kidney has been removed.

5. Idiopathic:
Endocrine organs like thyroid, adrenals, pituitary etc. can undergo hyperplasia with no detectable stimulus. .
 

Hematological examination

This is a method by which abnormalities of the cells of the blood and their precursors in the bone marrow are investigated to diagnose the different kinds of anemia & leukemia.

Urticaria (hives) refers to the presence of edema within the dermis and itchy elevations of the skin which may relate to either a Type I (MC) or Type III hypersensitivity reaction.

Type III hypersensitivity reaction.

 - exaggerated venular permeability MC related to IgE mediated disease and release of histamine from mast cells.