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
 

TOXOPLASMOSIS

Infection with Toxoplasma gondii, causing a spectrum of manifestations ranging from asymptomatic benign lymphadenopathy to life-threatening CNS disease, chorioretinitis, and mental retardation.

Symptomatic infections may present in several ways

Acute toxoplasmosis may mimic infectious mononucleosis with lymphadenopathy, fever, malaise, myalgia, hepatosplenomegaly, and pharyngitis. Atypical lymphocytosis, mild anemia, leukopenia, and slightly abnormal liver function tests are common. The syndrome may persist for weeks or months but is almost always self-limited.

A severe disseminated form characterized by pneumonitis, myocarditis, meningoencephalitis, polymyositis, diffuse maculopapular rash, high fevers, chills, and prostration. Acute fulminating disease is uncommon.

Congenital toxoplasmosis usually results from a primary (and often asymptomatic) acute infection acquired by the mother during pregnancy. The risk of transplacental infection increases from 15% to 30 to 60% for maternal infections acquired in the 1st, 2nd, or 3rd trimester of gestation, respectively

Graves disease 

Graves disease is an organ-specific autoimmune disorder that results in thyrotoxicosis due to overstimulation of the thyroid gland by autoantibodies. 
- It is the most common form of thyrotoxicosis, females being affected more than males by 8: 1. 
- It is usually associated with a diffuse enlargement of the thyroid.

Pathogenesis
 
IgG-type immunoglobulins bind to TSH membrane receptors and cause prolonged stimulation of the thyroid, lasting for as long as 12 hours 
(cf. 1 hour for TSH). The autoantibody binds at a site different to the hormone-binding locus and is termed the TSH-receptor autoantibody (TRAb); 95% of Graves’ disease patients are positive for TRAbs

Gross features 
- The thyroid gland is diffusely and moderately enlarged
- It is usually smooth, soft, and congested  

Histologically
- the gland shows diffuse hypertrophy and hyperplasia of acinar epithelium, reduction of stored colloid and local accumulations of lymphocytes with lymphoid follicle formation.

Clinical features

- Exophthalmos (protrusion of the eyeballs in their sockets)—due to the infiltration of orbital tissues by fat, mucopolysaccharides and lymphocytes. May cause compression of the optic nerve, hence blindness. However, only about 5% of Graves’ patients show signs of exophthalmos.
- Thyroid acropachy—enlargement of fingernails. 
- Pretibial myxoedema—accumulation of mucoproteins in the deep dermis of the skin.

Treatment is as for thyrotoxicosis.

Str. Pneumoniae

Probably the most important streptococci.  Primary cause of pneumonia.  Usually are diplococci.  Ste. pneumoniae are α-hemolytic and nutritionally fastidious.  Often are normal flora.

Key virulence factor is the capsule polysaccharide which prevents phagocytosis.  Other virulence factors include pneumococcal surface protein and α-hemolysin.

Major disease is pneumonia, usually following a viral respiratory infection.  Characterized by fever, cough, purulent sputum.  Bacteria infiltrates alveoli.  PMN’s fill alveoli, but don’t  cause necrosis. Also can cause meningitis, otitis, sinusitis.

There are vaccines against the capsule polysaccharide.  Resistance to penicillin, cephalosporins, erythromycins, and fluoroquinalones is increasing.

Varicose Veins  
- are abnormally dilated, tortuous veins produced by prolonged increase in intraluminal pressure and loss of vessel wall support. 

- The superficial veins of the leg are typically involved  

-venous pressures in these sites can be markedly elevated -> venous stasis and pedal edema (simple orthostatic edema)

-Some 10% to 20% of adult males and 25% to 33% of adult females develop lower extremity varicose  veins  

RISK FACTORS 
-> obesity  
-> Female gender  
-> pregnancy.  
-> familial tendency (premature varicosities results from imperfect venous wall development) 

 Morphology
 
- wall thinning  
- intimal fibrosis in adjacent segments 
- spotty medial calcifications (phlebosclerosis) 
- Focal intraluminal thrombosis 
- venous valve deformities (rolling and shortening) 

COMPLICATIONS
 
- stasis, congestion, edema, pain, and thrombosis 
- chronic varicose ulcers 
- embolism is very rare. 

Parvoviruses
 - smallest DNA virus
 - erythema infectiosum (fifth disease) is characterized by a confluent rash usually beginning on the cheeks ("slapped face") which extends centripetally to involve the trunk; fever, malaise and respiratory problems; and arthralgias and joint swelling (50%).
 
 other associations:
 - aplastic anemia in patients with chronic hemolytic anemias (e.g., sickle cell disease, spherocytosis).
 - repeated abortions associated with hydrops fetalis.
 - pure RBC aplasia by involving the RBC precursors (no reticulocytes peripherally).
 -chronic arthritis