PATHOLOGYSubmitted To: Submitted By:Sir Mubin Mustafa Mehrwar Hijab

The primary abnormalities that lead to thrombosis are 1. Endothelial injury2. Stasis or turbulent blood flow3. Hypercoagulability of the blood(Virschow Triad)

THROMBOSIS

ENDOTHELIAL INJURY Endothelial injury leading to platelet activation almost inevitably

underlies thrombus formation in the heart and the arterial circulation, where the high rates of blood flow impede clot formation.

Severe endothelial injury may trigger thrombosis by exposing vWf and tissue factor.

Inflammation and other noxious stimuli may promote thrombosis by shifting the pattern of gene expression in endothelium to one that is “prothrombotic” (endothelial activation) which can be produced by physical injury, infectious agents, abnormal blood flow, inflammatory mediators, metabolic abnormalities and toxins.

Endothelial activation is believed to have an important role in triggering arterial thrombotic events:1. Procoagulant changes2. Antifibrinolytic effects

ALTERATIONS IN NORMAL BLOOD FLOW Turbulence contributes to arterial and cardiac thrombosis by causing

endothelial injury or dysfunction, as well as by forming countercurrents that contribute to local pockets of stasis.

Stasis is a major contributor in the development of venous thrombi. Stasis and turbulence therefore promote:

1. Endothelial activation, enhancing procoagulant activity and leukocyte adhesion, in part through flow-induced changes in the expression of adhesion molecules and pro inflammatory factors.

2. Disrupt laminar flow and bring platelets into contact with the endothelium.3. Prevent washout and dilution of activated clotting factor by fresh flowing blood

and the inflow of clotting factors inhibitors. Ulcerated and atherosclerotic plaques not only expose subendothelial vWF

and tissue factor but also cause turbulence. Aortic and arterial dilations called aneurysms result in local stasis and are

therefore fertile site of thrombosis. Acute myocardial infarctions result in areas of noncontractile myocardium

and sometimes in cardiac aneurysms. Rheumatic mitral valve stenosis results in left atrial dilation, in conjunction

with atrial fibrillation resulting in thrombosis.

HYPERCOAGULABILITY Hypercoagulability (thrombophilia) can be loosely defined as any

disorder of blood that predisposes to thrombosis. It has a particular important role in venous thrombosis and can be

devided into primary (genetic) and secondary (acquired) disorders. The most common thrombophilic genotypes found in various populations

impart only a moderately increased risk of thrombosis; when otherwise healthy are free from thrombotic complications. Factor V and prothrombin mutations are frequent enough that homozygosity and compound heterozygosity are not rare and such genotypes are associated with greater risk. Individuals with such mutations have a significantly increased frequency of venous thrombosis in the setting of other acquired risk factors. Inherited causes of hypercoagulability must be considered in patients younger than age 50 who present with thrombosis-even when acquired risk factors are present.

Pathogenesis of acquired thrombophilia is frequently multifactorial. Some cases, stasis or vascular injury may be most important. Oral contraceptive use or the hyperestrogenic state of pregnancy may also result in hypercoagulability. Hypercoagulabilty seen with advancing age may be due to reduced PGI2 production. Smoking and obesity are aslso aggravating factors. In cancers, release of various procoagulants from tumor predisposes to thrombosis.

Among the acquired state the heparin induced thrombocytopenia and the antiphospholipid antibody syndrome are most important clinically.

HYPERCOAGULABILITY

FATE OF THE THROMBUS If a patients survives the initial thrombosis, in the ensuing days

to weeks thrombi undergo some combination of the following events Propagation: thrombi accumulate additional platelets and fibrin. Embolization: thrombi dislodge and travel to other sites of

vasculature. Dissolution: it is the result of fibrinolysis, which can lead to the rapid

shrinkage and disappearance of recent thrombi. In contrast, the extensive fibrin deposition and cross-linking in older thrombi renders them more resistant to lysis.

Organization and recanalization: older thrombi become organized by the ingrowth of the endothelial cells, smooth muscle cells and fibroblasts. Capillary channels eventually form that reestablish the continuity of the original lumen, albeit to a variable degree. Continued recanalization nay convert a thrombus into a smaller mass of connective tissue that becomes incorporated into the vessel wall. With remodeling and contraction of the mesenchymal elements, only a fibrous lump may remain to mark the original thrombus.

An embolus is a detached intravascular solid, liquid or gaseous mass that is carried by the blood from its point of origin to a distant site, where it often causes tissue dysfunction or infarction.

EMBOLISM

PULMONARY EMBOLISM Pulmonary emboli originate from deep venous thrombosis and are the

most common form of thromboembolic disease In more than 95% of cases, PE originate from leg DVTs. Fragmented thrombi from DVTs are carried through progressively

larger veins and the right side of the heart before slamming into the pulmonary arterial vasculature.

Depending on the size of the embolus, it can occlude the main pulmonary artery, straddle the pulmonary artery bifurcation or pass out into the smaller, branching arteries.

Frequently there are multiple emboli, occurring either sequentially or simultaneously as a shower of smaller emboli from a single large mass.

A venous embolus passes through an interatrial or interventricular defect and gains access to the systematic arterial circulation (paradoxical embolism).

SYSTEMIC THROMBOEMBOLISM Most systemic emboli arise from intracardiac mural thrombi, two

thirds of which are associated with left ventricular wall infarcts and another one forth with left atrial dilation and fibrillation.

The remainder originates from aortic aneurysms, atherosclerotic plaques, valvular vegetations or venous thrombi.

Arterial emboli can travel to a wide variety of sites; the point of arrest depends on the source and the relative amount of blood flow that downstream tissues receive.

The consequences of the systemic emboli depends on the vulnerability of the affected tissues to ischemia, the caliber of the occluded vessels and whether a collateral blood supply exists; in general, however, the outcome is tissue infarction.

FAT AND MARROW EMBOLISM Microscopic fat globules can be found in the pulmonary vasculature after

fractures of long bones or rarely in the setting of soft tissue trauma and burns

Fat and marrow emboli are very common incidental findings after vigorous cardiopulmonary resuscitation and are probably of no clinical consequences.

Fat embolism syndrome is the term applied to the minority of patients who become symptomatic. Its is characterized by pulmonary insufficiency, neurologic symptoms, anemia and thrombocytopenia and is fatal in 5% to 15% of patients.

Typically, 1 to 3 days after injury there is a sudden onset of tachypnea, dyspnea and tachycardia; irritability and restlessness can progress to delirium or coma.

Thrombocytopenia is attributed to platelet adhesion to fat globules and subsequent aggregation or splenic sequestration; anemia can result from similar red cell aggregation or hemolysis.

The pathogenesis of fat emboli syndrome probably involves both mechanical obstruction and biochemical injury.

Fat microemboli and associated red cell and platelet aggregates can occlude the pulmonary and cerebral micro vasculature.

AIR EMBLOISM Gas bubbles within the circulation can coalesce to form frothy masses that

obstruct vascular flow and cause distal ischemic injury. A particular form of gas embolism called decompression sickness occurs

when individuals experience sudden decrease in atmospheric pressure. The rapid formation of gas bubbles within skeletal muscles and supporting

tissues in and about joints is responsible for the painful condition called the bends.

In the lungs gas bubbles in the vasculature cause edema, hemorrhage and focal atelactasis or emphysema, leading to a form of respiratory distress called the chokes.

A more chronic form of decompression sickness is called caisson disease in which persistence of gas emboli in the skeletal system leads to multiple foci of ischemic necrosis; the more common sites are the femoral heads, tibia and humeri.

Individuals affected by acute decompression sickness are treated by being placed in a chamber under sufficiently high pressure to force the gas bubbles back into solution. Subsequent slow decompression permits gradual resorption and exhalation of the gases, which prevents the obstructive bubbles from reforming.

AMNIOTIC FLUID EMBOLISM Amniotic fluid embolism is an ominous complication of labor and the

immediate postpartum period. The onset is characterized by sudden svere dyspnea, cyanosis and shock

followed by neurologic impairment ranging from headaches to seizures and coma.

If the patient survives the initial crisis, pulmonary edema typically develops, frequently accompanied by disseminated intravascular coagulation.

Much of the morbidity and mortality in amniotic fluid embolism may stem from the biochemical activation of coagulation factors and components of the innate immune system bys substances in the amniotic fluid, rather than the mechanical obstruction of pulmonary vessels by amniotic debris.

The underlying cause is the infusion of amniotic fluid or fetal tissue into the maternal circulation via a tear in the placental membranes or rupture of uterine veins.

Classical findings at autopsy include the presence of squamous cells shed from fetal skin, lanugo hair, fat from vernix caseosa and mucin derived from the fetal GIT or the respiratory tract in the maternal pulmonary microvasculature.

JAZAKALLAH!