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
 

Bacillus anthrax
 - large Gram (+) rods that produce heat resistant spores; Clostridia and Bacillus species are the two bacterial spore formers; they do not form spores in tissue; produces a powerful exotoxin.
 - contracted by direct contact with animal skins or products  
 
 - four forms of anthrax are recognized → cutaneous (MC), pulmonary, oraloropharyngeal, and gastrointestinal.
 - cutaneous anthrax (90 to 95% of cases) occurs through direct contact with infected or contaminated animal products.
 - lesions resemble insect bites but eventually swell to form a black scab, or eschar, with a central area of necrosis ("malignant pustule").

Hypopituitarism

Hypopituitarism is caused by

1. Loss of the anterior pituitary parenchyma
    a. congenital 
    b. acquired  
    
2. Disorders of the hypothalamus e.g. tumors; these interfere with the delivery of pituitary hormone-releasing factors from the hypothalamus.  

Most cases of anterior pituitary hypofunction are caused by the following:
1. Nonfunctioning pituitary adenomas 
2. Ischemic necrosis of the anterior pituitary is an important cause of pituitary insufficiency. This requires destruction of 75% of the anterior pituitary. 

Causes include  

a. Sheehan syndrome, refers to postpartum necrosis of the anterior pituitary, and is the most cause. During pregnancy the anterior pituitary enlarges considerably because of an increase in the size and number of prolactin-secreting cells. However, this physiologic enlargement of the gland is not accompanied by an increase in blood supply. The enlarged gland is therefore vulnerable to ischemic injury, especially in women who develop significant hemorrhage and hypotension during the peripartum period. The posterior pituitary is usually not affected. 

b. Disseminated intravascular coagulation 
c. Sickle cell anemia 
d. Elevated intracranial pressure 
e. Traumatic injury
f. Shock states

3. Iatrogenic i.e.  surgical removal or radiation-induced destruction
4. Inflammatory lesions such as sarcoidosis or tuberculosis
5. Metastatic neoplasms involving the pituitary. 
6. Mutations affecting the pituitary transcription factor Pit-1 

Children can develop growth failure (pituitary dwarfism) as a result of growth hormone deficiency.

Gonadotropin or gonadotropin-releasing hormone (GnRH) deficiency leads to amenorrhea and infertility in women and decreased libido, impotence, and loss of pubic and axillary hair in men. TSH and ACTH deficiencies result in symptoms of hypothyroidism and hypoadrenalism. Prolactin deficiency results in failure of postpartum lactation. 

Cryptococcosis

An infection acquired by inhalation of soil contaminated with the encapsulated yeast Cryptococcus neoformans, which may cause a self-limited pulmonary infection or disseminate, especially to the meninges, but sometimes to the skin, bones, viscera, or other sites.

Cryptococcosis is a defining opportunistic infection for AIDS, although patients with Hodgkin's or other lymphomas or sarcoidosis or those receiving long-term corticosteroid therapy are also at increased risk.

AIDS-associated cryptococcal infection may present with severe, progressive pneumonia with acute dyspnea and an x-ray pattern suggestive of Pneumocystis infection.

Primary lesions in the lungs are usually asymptomatic and self-limited

Pneumonia usually causes cough and other nonspecific respiratory symptoms. Rarely, pyelonephritis occurs with renal papillary necrosis development.

Most symptoms of cryptococcal meningitis are attributable to brain swelling and are usually nonspecific, including headache, blurred vision, confusion, depression, agitation, or other behavioral changes. Except for ocular or facial palsies, focal signs are rare until relatively late in the course of infections. Blindness may develop due to brain swelling or direct involvement of the optic tracts. Fever is usually low-grade and frequently absent.

Cor pulmonale
a failure of the right side of the heart. It is caused by prolonged high blood pressure in the right ventricle of the heart, which in turn is most often caused by pulmonary hypertension - prolonged high blood pressure in the arteries or veins of the lungs. People with heart disease, or lung diseases such as cystic fibrosis, are at greater risk.

Pathophysiology

There are several mechanisms leading to pulmonary hypertension and cor pulmonale:
Pulmonary vasoconstriction
Anatomic changes in vascularisation
Increased blood viscosity
Primary pulmonary hypertension

Causes

Acute: 
•    Massive pulmonary embolization
•    Exacerbation of chronic cor pulmonale
Chronic: 
•    COPD
•    Loss of lung tissue following trauma or surgery
 

Tuberculosis

Causative organism

-Mycobacterium tuberculosis 
-Strict aerobe 
-Pathogenic strains
-hominis, bovis, avium, murine& cold blooded vertebrate strain 

Koch’s bacillus
-small slender, rod like bacillus, 4umnon-motile, aerobic -high lipid content 
-divides every 16 to 20 hours, an extremely slow rate 
-stains very weakly Gram-positive or does not retain dye due to the high lipid & mycolicacid content of its cell wall 
-can withstand weak disinfectant and survive in a dry state for weeks. 

Demonstrated by 
-ZiehlNeelsenstaining 
-Fluorescent dye method 
-Culture in LJ media 
-Guinea pig inoculation

Modes of transmission

Inhalation , Ingestion, Inoculation , Transplacental

Route Spread 
Local , Lymphatic , Haematogenous , By natural passages, 

Pathogenesis 

- Anti‐mycobacterial CMI, confers resistance to bacteria → dev. of HS to tubercular Ag 
- Bacilli enters macrophages 
- Replicates in phagosomeby blocking fusion of phagosome&  lysosome, continues for 3 weeks →bacteremiabut  asymptomatic 
- After 3 wks, T helper response is mounted by  IL‐12 produced  by macrophages 
- T cells produce IFN, activates macrophages → bactericidal  activity, structural changes 
- Macrophages secrete TNF→ macrophage recruitment,  granuloma& necrosis

Fate of granuloma 
- Caseousmaterial undergo liquefaction---cold abscess 
- Bones, joints, lymph nodes & epididymis---sinuses are formed & sinus tract lined by tuberculousgranulation tissue 
- Dystrophic calcification

Types of TB

1. Primary Pulmonary TB 
2. secondary TB (miliary, fibrocaseous, cavitary) 
3. Extra-pulmonary TB (bone, joints, renal, adrenal, skin… )

Primary TB
Infection in an individual who has not been previously infected or immunised 
Primary complex 
Sites
    -lungs, hilarlymph nodes 
    -tonsils, cervical lymph nodes 
    -small intestine, mesenteric lymph nodes

Primary TB
In the lung, Ghon’scomplex has 3 components: 
1. Pulmonary component -Inhalation of airborne droplet ~ 3 microns. 
    -Bacilli locate in the subpleuralmid zone of lung 
    -Brief acute inflammation –neutrophils. 
    -5-6 days-invoke granulomaformation. 
    -2 to 8 weeks –healing –single round ;1-1.5 cm-Ghon focus. 
2. Lymphatic vessel component 
3. Lymph node component

Fate of primary tuberculosis

- Lesions heal by fibrosis, may undergo calcification, ossification 
    -a few viable bacilli may remain in these areas  
    -bacteria goes into a dormant state, as long as the person's immune system remains active 
- Progressive primary tuberculosis: primary focus continues to grow & caseousmaterial disseminated to other parts of lung 
- Primary miliarytuberculosis: bacilli may enter circulation through erosion of blood vessel 
- Progressive secondary tuberculosis: healed lesions are reactivated, in children & in lower resistance

Secondary tuberculosis

-Post-primary/ reinfection/ chronic TB 
-Occurs in immunized individuals. 
-Infection acquired from 

    -endogenous source/ reactivation 
    -exogenous source/ reinfection 

Reactivation
-when immune system is depressed 
-Common in low prevalence areas. 
-Occurs in 10-15% of patients 
-Slowly progressive (several months) 

Re-infection 
-when large innoculum of bacteria occurs 
-In areas with increased personal contact

Secondary TB

-Sites-Lungs 1-2 cm apical consolidation with caseation 
-Other sites -tonsils, pharynx, larynx, small intestine & skin

Fate of secondary tuberculosis

•Heal with fibrous scarring & calcification 
•Progressive secondary pulmonary tuberculosis: 
    -fibrocaseoustuberculosis 
    -tuberculouscaseouspneumonia 
    -miliarytuberculosis

Complications: 
a) aneurysm of arteries–hemoptysis 
b) bronchopleuralfistula 
c) tuberculousempyema 

MiliaryTB

• Millet like, yellowish, firm areas without caseation 
• Extensive spread through lympho-hematogenousroute 
• Low immunity 
• Pulmonary involvement via pulmonary artery 
• Systemic through pulmonary vein: 
    -LN: scrofula, most common 
    -kidney, spleen, adrenal, brain, bone marrow

Signs and Symptoms of Active TB

• Pulmonary-cough, hemoptysis, dyspnea 
• Systemic: 
• fever 
• night sweats 
• loss of appetite 
• weight loss 
• chest pain,fatigue 

•If symptoms persist for at least 2 weeks, evaluate for possible TB infection

Diagnosis

•Sputum-Ziehl Neelsen stain –10,000 bacilli, 60% sensitivity 
    -release of acid-fast bacilli from cavities intermittent. 
    -3 negative smears : low infectivity 

•Culture most sensitive and specific test.
     -Conventional Lowenstein Jensen media-10 wks. 
     -Liquid culture: 2 weeks 

•Automated techniques within days 
    should only be performed by experienced laboratories (10 bacilli) 

•PPD for clinical activity / exposure sometime in life 
•X-ray chest 
•FNAC

PPD Tuberculin Testing

- Read after 72 hours. 
- Indurationsize -5-10 mm 
- Does not d/s b/w active and latent infection 
- False +: atypical mycobacterium 
- False -: malnutrition, HD, viral, overwhelming infection, immunosuppression 
- BCG gives + result.

Tuberculosis Atypical mycobacteria 

- Photochromogens---M.kansasii 
- Scotochromogens---M.scrofulaceum 
- Non-chromogens---M.avium-intracellulare 
- Rapid growers---M.fortuitum, M.chelonei

5 patterns of disease 

- Pulmonary—M.kansasii, M.avium-intracellulare 
- Lymphadenitis----M.avium-intracellulare, M.scrofulaceum 
- Ulcerated skin lesions----M.ulcerans, M.marinum 
- Abscess----M.fortuitum, M.chelonei 
- Bacteraemias----M.avium-intracellulare as in AIDS