NEET MDS Synopsis
THROMBOSIS
General Pathology
THROMBOSIS
Pathogenesis (called Virchow's triad):
1. Endothelial* Injury ( Heart, Arteries)
2. Stasis
3. Blood Hypercoagulability
- Endothelial cells are special type of cells that cover the inside surface of blood vessels and heart.
CONTRIBUTION OF ENDOTHELIAL CELLS TO COAGULATION
Intact endothelial cells maintain liquid blood flow by:
1- inhibiting platelet adherence
2- preventing coagulation factor activation
3- lysing blood clots that may form.
Endothelial cells can be stimulated by direct injury or by various cytokines that are produced during inflammation.
Endothelial injury results in:
1- expression of procoagulant proteins (tissue factor and vWF)→ local thrombus formation.
2- exposure of underlying vWF and basement membrane collagen → platelet aggregation and thrombus formation.
RESPONSE OF VASCULAR WALL CELLS TO INJURY( PATHOLOGIC EFFECT OF VASCULAR HEALING)
Injury to the vessel wall results in a healing response, involving:
- Intimal expansion (proliferating SMCs and newly synthesized ECM). This involves signals from ECs, platelets, and macrophages; and mediators derived from coagulation and complement cascades.
- luminal stenosis & blockage of vascular flow
Causes of Endothelial injury
1. Valvulitis
2. MI
3. Atherosclerosis
4. Traumatic or inflammatory conditions
5. Increased Blood Pressure
6. Endotoxins
7. Hypercholesterolemia
8. Radiation
9. Smoking
Stasis
- Stasis is a major factor in venous thrombi
- Normal blood flow is laminar (platelets flow centrally in the vessel lumen, separated from the endothelium by a slower moving clear zone of
plasma)
- Stasis and turbulence cause the followings:
Disuption of normal blood flow
prevent dilution of activated clotting factor
retard inflow of clotting factor inhibitor
promote endothelial cell injury
Causes of Stasis
1. Atherosclerosis
2. Aneurysms
3. Myocardial Infarction ( Non-cotractile fibers)
4. Mitral valve stenosis (atrial dilation)
5. Hyper viscosity syndromes (PCV and Sickle Cell anemia)
Hypercoagulability
A. Genetic (primary):
- mutations in the factor V gene and the prothrombin gene are the most common
B. Acquired (secondary):
- multifactorial and more complicated
- causes include: Immobilization, MI, AF, surgery, fracture, burns, Cancer, Prosthetic cardiac valves
MORPHOLOGY OF THROMBI
Can develop anywhere in the CVS (e.g., in cardiac chambers, valves, arteries, veins, or capillaries).
Arterial or cardiac thrombi→ begin at sites of endothelial injury; and are usually superimposed on an atherosclerotic plaque.
Venous thrombi → occur at sites of stasis. Most commonly the veins of the lower extremities (90%)
Thrombi are focally attached to the underlying vascular surface; arterial and venous thrombi both tend to propagate toward the heart.
→ The propagating portion of a thrombus is poorly attached → fragmentation and embolus formation
LINES OF ZAHN
Thrombi can have grossly (and microscopically) apparent laminations called lines of Zahn; these represent pale platelet and fibrin layers alternating with darker erythrocyte-rich layers.
Such lines are significant in that they represent thrombosis of flowing blood.
Mural thrombi = Thrombi occurring in heart chambers or in the aortic lumen.
Causes: -Abnormal myocardial contraction (e.g. arrhythmias, dilated cardiomyopathy, or MI) -endomyocardial injury (e.g. myocarditis, catheter trauma)
Vegetations ->Thrombi on heart valves
1- Bacterial or fungal blood-borne infections - (infective endocarditis,).
2- Non-bacterial thrombotic endocarditis occur on sterile valves.
Fate of thrombi
1. Propagation → Thrombi accumulate additional platelets and fibrin, eventually causing vessel obstruction
2. Embolization → Thrombi dislodge or fragment and are transported elsewhere in the vasculature
3. Dissolution → Thrombi are removed by fibrinolytic activity (Usually in recent thrombi)
4. Organization and recanalization → Thrombi induce inflammation and fibrosis. - recanalization (re-establishing some degree of flow) - Organization = ingrowth of endothelial cells, smooth cells and fibroblasts into the fibrin rich thrombus.
5. Superimposed infection (Mycotic aneurysm)
Venous thrombi → most common in veins of the legs
a. Superficial: e.g. Saphenous veins. - can cause local congestion, swelling, pain, and tenderness along the course of the involved vein, but they rarely embolize
a. Deep: e.g. Popliteal, Femoral and iliac vein. - more serious because they may embolize - can occur with stasis or hypercoagulable states
Phenytoin
Pharmacology
Phenytoin (Dilantin): for tonic-clonic and all partial seizures (not effective against absence seizures)
Mechanism: ↓ reactivation of Na channels (↑ refractory period, blocks high frequency cell firing, ↓ spread of seizure activity from focus)
Side effects: ataxia, vertigo, hirsutism (abnormal hair growth), gingival hyperplasia, osteomalacia (altered vitamin D metabolism and ↓ Ca absorption), blood dyscrasias (rare; megaloblastic anemia, etc)
Drug interactions: induces hepatic microsomal enzymes (can ↓ effectiveness of other drugs); binds tightly to plasma proteins and can displace other drugs
Psoriasis
General Pathology
Psoriasis
1. Characterized by skin lesions that appear as scaly, white plaques.
2. Caused by rapid proliferation of the epidermis.
3. Autoimmune pathogenesis; exact mechanism is unclear.
Rheumatic fever
General Pathology
Rheumatic fever
Before antibiotic therapy, this was the most common cause of valvular disease.
1. Usually preceded by a group A streptococci respiratory infection; for example, strep throat.
2. All three layers of the heart may be affected. The pathologic findings include Aschoff bodies, which are areas of focal necrosis surrounded by a dense inflammatory infiltration.
3. Most commonly affects the mitral valve, resulting in mitral valve stenosis, regurgitation, or both.
COMPLEMENT
General Microbiology
COMPLEMENT
The complement system primarily serves to fight bacterial infections.
The complement system can be activated by at least three separate pathways.
1) alternative pathway -
- The alternative pathway of complement activation starts with the spontaneous hydroysis of an internal thioester bond in the plasma complement component C3 to result in C3(H2O).
- The smaller cleavage products C3a, C4a, C5a, sometimes called "anaphylatoxins", act as phagocytes, they cause mast cell degranulation and enhance vessel permeability, thereby facilitating access of plasma proteins and leukocytes to the site of infection
- alternative pathway provides a means of non-specific resistance against infection without the participation of antibodies and hence provides a first line of defense against a number of infectious agents.
2) Lecithin Pathway
The lectin pathway of complement activation exploits the fact that many bacterial surfaces contain mannose sugar molecules in a characteristic spacing. The oligomeric plasma protein mannan-binding lectin (MBL; lectins are proteins binding sugars) binds to such a pattern of mannose moieties, activating proteases MASP-1 and MASP-2 (MASP=MBL activated serine protease, similar in structure to C1r and C1s). These, by cleaving C4 and C2, generate a second type of C3 convertase consisting of C4b and C2b, with ensuing events identical to those of the alternative pathway.
3) classical pathway
The classical pathway usually starts with antigen-bound antibodies recruiting the C1q component, followed by binding and sequential activation of C1r and C1s serine proteases. C1s cleaves C4 and C2, with C4b and C2b forming the C3 convertase of the classical pathway. Yet, this pathway can also be activated in the absence of antibodies by the plasma protein CRP (C-reactive protein), which binds to bacterial surfaces and is able to activate C1q.
Pharmacology cross reference: humanized monoclonal antibody Eculizumab binds to complement component C5, inhibiting its cleavage and preventing activation of the lytic pathway. This is desirable when unwanted complement activation causes hemolysis, as in paroxysmal nocturnal hemoglobinuria or in some forms of hemolytic uremic syndrome. For the lytic pathway's importance in fighting meningococcal infections, Eculizumab treatment increases the risk of these infections, which may be prevented by previous vaccination.
BIOLOGICALLY ACTIVE PRODUCTS OF COMPLEMENT ACTIVATION
Activation of complement results in the production of several biologically active molecules which contribute to resistance, anaphylaxis and inflammation.
Kinin production
C2b generated during the classical pathway of C activation is a prokinin which becomes biologically active following enzymatic alteration by plasmin. Excess C2b production is prevented by limiting C2 activation by C1 inhibitor (C1-INH) also known as serpin which displaces C1rs from the C1qrs complex (Figure 10). A genetic deficiency of C1-INH results in an overproduction of C2b and is the cause of hereditary angioneurotic edema. This condition can be treated with Danazol which promotes C1-INH production or with ε-amino caproic acid which decreases plasmin activity.
Anaphylotoxins
C4a, C3a and C5a (in increasing order of activity) are all anaphylotoxins which cause basophil/mast cell degranulation and smooth muscle contraction. Undesirable effects of these peptides are controlled by carboxypeptidase B (C3a-INA).
Chemotactic Factors
C5a and MAC (C5b67) are both chemotactic. C5a is also a potent activator of neutrophils, basophils and macrophages and causes induction of adhesion molecules on vascular endothelial cells.
Opsonins
C3b and C4b in the surface of microorganisms attach to C-receptor (CR1) on phagocytic cells and promote phagocytosis.
Other Biologically active products of C activation
Degradation products of C3 (iC3b, C3d and C3e) also bind to different cells by distinct receptors and modulate their functions.
Osteoradionecrosis
Oral Pathology
Osteoradionecrosis
Clinical features
A reduction in vascularity, secondary to endarteritis obliterans, and damage to osteocytes as a consequence of ionising
Radiotherapy can result in radiation-associated osteomyelitis or Osteoradionecrosis. The mandible is much more commonly affected than the maxilla, because it is less vascular. Pain may be severe and there may be pyrexia. The overlying oral mucosa often appears pale because of radiation damage. Osteoradionecrosis in the jaws arises most often following radiotherapy for squamous cell carcinoma.
Scar tissue will also be present at the tumour site, often in close relation to the necrotic bone.
Radiology
Osteoradionecrosis appears as rarefying osteitis within which islands of opacity (sequestra) are seen. Pathological
fracture may be visible in the mandible.
Pathology
The affected bone shows features similar to those of chronic osteomyelitis. Grossly, the bone may be cavitated
And discoloured, with formation of sequestra.
Acute inflammatory infiltrate may be present on a background of chronic inflammation, characterized by formation
Of granulation tissue around the non-vital trabeculae.
Blood vessels show areas of endothelial denudation and obliteration of their lumina by fibrosis.
Small telangiectatic vessels lacking precapillary sphincters may be present.
Fibroblasts in the irradiated tissues lose the capacity to divide and often become binucleated and enlarged.
Management
Prevention of Osteoradionecrosis is vital. Patients who require radiotherapy for the management of head and
neck malignancy should ideally have teeth of doubtful prognosis extracted at least 6 weeks prior to treatment.
The dose of radiation,
The area of the mandible irradiated and
the surgical trauma involved in the dental extractions.
Surgical management of Osteoradionecrosis is similar to osteomyelitis.
Basic characteristics of enzymes
Biochemistry
The basic characteristics of enzymes includes
(i) Almost all the enzymes are proteins and they follow the physical and chemical reactions of proteins (ii) Enzymes are sensitive and labile to heat
(iii) Enzymes are water soluble
(iv) Enzymes could be precipitated by protein precipitating agents such as ammonium sulfate and trichloroacetic acid.
Cutting Edge Mechanics
Conservative DentistryCutting Edge Mechanics
Edge Angles and Their Importance
Edge Angle: The angle formed at the cutting edge of a
bur blade. Increasing the edge angle reinforces the cutting edge, which
helps to reduce the likelihood of blade fracture during use.
Reinforcement: A larger edge angle provides more
material at the cutting edge, enhancing its strength and durability.
Carbide vs. Steel Burs
Carbide Burs:
Hardness and Wear Resistance: Carbide burs are
known for their higher hardness and wear resistance compared to steel
burs. This makes them suitable for cutting through hard dental tissues.
Brittleness: However, carbide burs are more brittle
than steel burs, which means they are more prone to fracture if not
designed properly.
Edge Angles: To minimize the risk of fractures,
carbide burs require greater edge angles. This design consideration is
crucial for maintaining the integrity of the bur during clinical
procedures.
Interdependence of Angles
Three Angles: The cutting edge of a bur is defined by
three angles: the edge angle, the clearance angle, and the rake angle. These
angles cannot be varied independently of each other.
Clearance Angle: An increase in the clearance angle
(the angle between the cutting edge and the surface being cut) results
in a decrease in the edge angle. This relationship is important for
optimizing cutting efficiency and minimizing wear on the bur.