Thrombosis and embolism, Disseminated Intravascular Coagulation

Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood
through the circulatory system. When a blood vessel is injured (due to trauma, surgery, infection, or
turbulent flow at bifurcations) the body uses platelets (thrombocytes) and fibrin to form a blood clot to
prevent blood loss (the main mechanism is exposure of tissue factor to the blood coagulation system).
However, under certain conditions, blood clots may form in the body even when a blood vessel is not
injured.

Thus, the main causes of thrombosis are given in Virchows triad which lists hypercoagulability,
endothelial cell injury and disturbed blood flow.

Causes of disturbed blood flow include stagnation of blood flow past the point of injury, or venous
stasis, which may occur in heart failure, or after long periods of sedentary behavior, such as sitting on a
long airplane flight. Also, atrial fibrillation causes stagnant blood in the left atrium (LA) or left atrial
appendage (LAA), and can lead to a thromboembolism. Cancers or malignancies such as leukemia
may cause increased risk of thrombosis by possible activation of the coagulation system by cancer cells
or secretion of procoagulant substances (paraneoplastic syndrome), by external compression on a blood
vessel when a solid tumor is present, or (more rarely) extension into the vasculature (for example, renal
cell cancers extending into the renal veins). Also, treatments for cancer (radiation, chemotherapy) often
cause additional hypercoagulability.

When a thrombus is significantly large enough to reduce the blood flow to a tissue, hypoxia can occur
and metabolic products such as lactic acid can accumulate. A larger thrombus causing a much greater
obstruction to the blood flow may result in anoxia the complete deprivation of oxygen and infarction,
tissue death. There are also a number of other conditions that can arise according to the location of the
thrombus and the organs affected.

A clot that breaks free and begins to travel around the body is known as an embolus.
Thromboembolism is the combination of thrombosis and its main complication, embolism.

There are two distinct forms of thrombosis, venous thrombosis and arterial thrombosis, each of
which can be presented by several subtypes.

Venous thrombosis is the formation of a thrombus (blood clot) within a vein. There are several
diseases which can be classified under this category:

- Deep vein thrombosis

Deep vein thrombosis (DVT) is the formation of a blood clot within a deep vein. It most commonly
affects leg veins, such as the femoral vein. Three factors are important in the formation of a blood clot
within a deep veinthese are the rate of blood flow, the thickness of the blood and qualities of the
vessel wall. Classical signs of DVT include swelling, pain and redness of the affected area.

- Portal vein thrombosis

Portal vein thrombosis affects the hepatic portal vein, which can lead to portal hypertension and
reduction of the blood supply to the liver. It usually has a pathological cause such as pancreatitis,
cirrhosis, diverticulitis, or cholangiocarcinoma.

- Renal vein thrombosis

Renal vein thrombosis is the obstruction of the renal vein by a thrombus. This tends to lead to reduced
drainage from the kidney.

- Jugular vein thrombosis

Jugular vein thrombosis is a condition that may occur due to infection, intravenous drug use or
malignancy. Jugular vein thrombosis can have a varying list of complications, including: systemic sepsis,
pulmpnary embolism, papiledema. Though characterized by a sharp pain at the site of the vein, it can
prove difficult to diagnose, because it can occur at random.

- Budd-Chiari syndrome

Budd-Chiari syndrome is the blockage of the hepatic vein or the inferior vena cava. This form of
thrombosis presents with abdominal pain, ascitis and hepatomegaly. Treatment varies between
therapy and surgical intervention by the use of shunts

- Paget-Schroetter disease

Paget-Schroetter disease is the obstruction of an upper extremity vein (such as the axilary or
subclavian vein) by a thrombus. The condition usually comes to light after vigorous exercise and
usually presents in younger, otherwise healthy people. Men are affected more than women.

- Cerebral venous sinus thrombosis

Cerebral venous sinus thrombosis (CVST) is a rare form of stroke which results from the blockage of the
dural venous sinuses by a thrombus. Symptoms may include headache, abnormal vision, any of the
symptoms of stroke such as weakness of the face and limbs on one side of the body and seizures. The
diagnosis is usually made with a CT or MRI scan. The majority of persons affected make a full recovery.
The mortality rate is 4.3%.

- Cavernous sinus thrombosis

Cavernous sinus thrombosis is a specialized form of cerebral venous sinus thrombosis, where there is
thrombosis of the cavernous sinus of the basal skull dura, due to the retrograde spread of infection and
endothelial damage from the danger triangle of the face. The facial veins in this area anastomose with
the superior and inferior ophthalmic veins of the orbit, which drain directly posteriorly into the
cavernous sinus through the superior orbital tissue. Staphylococcal or Streptococcal infections of the
face, for example nasal or upper lip pustules may thus spread directly into the cavernous sinus, causing
stroke-like symptoms of double vision, squint as well as spread of infection to cause meningitis.

Arterial thrombosis

Arterial thrombosis is the formation of a thrombus within an artery. In most cases, arterial thrombosis
follows rupture of atheroma and is therefore referred to as atherothrombosis.

Another common cause of arterial occlusion is atrial fibrillation, which causes a blood stasis within the
atria with easy thrombus formation. Thromboembolism strikes approximately 5% of cases not receiving
anticoagulant therapy. When cardiac rhythm is restored clots are pushed out from atria to ventricles
and from these to the aorta and its branches.

Arterial thrombosis can embolize and is a major cause of arterial embolism, potentially causing
infarction of almost any organ in the body.

Stroke
A stroke is the rapid decline of brain function due to a disturbance in the supply of blood to the brain.
This can be due to ischemia, thrombus, embolus or hemorrhage. In thrombotic stroke, a thrombus
(blood clot) usually forms around atherosclerotic plaques. Since blockage of the artery is gradual,
onset of symptomatic thrombotic strokes is slower. Thrombotic stroke can be divided into two
categorieslarge vessel disease and small vessel disease.

Myocardial infarction

Myocardial infarction (MI) or heart attack, is caused by ischemia, (restriction in the blood supply), often
due to the obstruction of a coronary artery by a thrombus. This restriction gives an insufficient supply of
oxygen to the heart muscle which then results in tissue death (infarction). MI can quickly become fatal
if emergency medical treatment is not received promptly. If diagnosed within 12 hours of the initial
episode (attack) then thrombolytic therapy is initiated.

Other sites

Hepatic artery thrombosis usually occurs as a devastating complication after liver transplantation. An
arterial embolus can also form in the limbs.

Supporting conditions leading to thrombus formation are:

Venous stasis, usually from immobilization
Chronic Heart Failure
Policytemia
Sickle cell disease
Visceral malignancies
Use of oral contraceptives, especially in association with cigarette smoking

Difference between clotting and Thrombosis

Clotting Occurs:
- in vessels after death (postmortem clotting of blood).
- in tissues when blood escapes from an injured vessel (hematoma formation).
- in vitro (in a tube outside the body).
- blood clot contains randomly oriented fibrin with entrapped platelets and red cells.

Thrombus is:

- generally attached to the endothelium

- composed of layers of aggregated platelets and fibrin.

- a normal hemostatic mechanism, that acts to stop bleeding when a vessel is injured.

Pathogenesis

1. Endothelial damage (Alters usual charge of endothelium, Decreases production of

prostacyclin. Laminar flow of blood becomes turbulent ).

2. Platelet adhesion - accumulation of blood cells at the site of injury and process of
platelets adhesion.
 3. Release reaction (Histamin, serotonin, ADP, ATP, PDGF (platelet derived growth
factor), Thromboplastic substances)

4. Activation of coagulation cascade - due to entry of thromboplastic substances

into the blood stream results in throbin formation.

5. Platelet aggregation (Agonists that promote aggregation are ADP, thrombin, TxA 2
collagen, epinephrine, platelet activating factor).

6. Stabilization and retraction of platelet plug (by thrombasterin)

7. Limitation of platelet plug formation (via the endothelial prostacyclin which is

platelet TxA2 antagonist).

If a thrombus forms inside a blood vessel, without medical intervention the

thrombosis may proceed to several possible outcomes:

1. Embolisation: the thrombus detaches from the underlying endothelial wall, leading to distal
embolisation and vessel occlusion. An arterial thromboembolus may lead to a stroke, central
artery occlusion, ischemic limb,mesenteric ischemia or some form of localized
ischemia depending on the arterial circulation of the embolus. A venous thromboembolus may
occlude the pulmonary artery leading to pulmonary embolism.
2. Lysis: the thrombus may be acutely lysed by circulatory plasmin. This is essentially the
physiological equivalent to pharmacological thrombolysis performed in the hospital.

3. Ischemia/infarction: if an arterial thrombus cannot be lysed by the body and it does not
embolise, and if the thrombus is large enough to impair or occlude blood flow in the involved
artery, then local Ischemia/ or infarction will result. A venous thrombus may or may not be
ischaemic, since veins distribute deoxygenated blood that is less vital for cellular metabolism.
Nevertheless, non-ischaemic venous thrombosis may still be problematic, due to the swelling
caused by blockage to venous drainage. In deep vein thrombosis this manifests as pain,
redness, and swelling; in retinal vein occlusion this may result in macular edema and visual
acuity impairment, which if severe enough can lead to blindness.

4. Organization: following the thrombotic event, residual vascular thrombus will be re-organized
histologically with several possible outcomes. For an occlusive thrombus (defined as thrombosis
within a small vessel that leads to complete occlusion), wound healing will reorganize the
occlusive thrombus into collagenous scar tissue, where the scar tissue will either
permanently obstruct the vessel, or contract down with myofibroblastic activity to
unblock the lumen. For a mural thrombus (defined as a thrombus in a large vessel that
restricts the blood flow but does not occlude completely), histological reorganization of the
thrombus does not occur via the classic wound healing mechanism. Instead, the platelet-
derived growth factor degranulated by the clotted platelets will attract a layer of smooth
muscle cells to cover the clot, and this layer of mural smooth muscle will be vascularised by the
blood inside the vessel lumen rather than by the vasa-vasorum.

5. Recanalyzation - Occurs slowly over several weeks. Across the thrombus may establish
channel, through which some blood flow may be restored.
Embolization

If a bacterial infection is present at the site of thrombosis, the thrombus may break down, spreading
particles of infected material throughout the circulatory system (pyemia, septic embolus) and setting
up abscess of metastatic nature wherever they come to rest. Without an infection, the thrombus may
become detached and enter circulation as an embolus, finally lodging in and completely obstructing a
blood vessel, which unless treated very quickly will lead to tissue necrosis in the area past the
occlusion.

Most thrombi however, become organized into fibrous tissue and the thrombozed vessel is gradually
unblocked.

Prevention

Prophylaxis of venous thrombo-embolizm with heparin in medical patients does not appear to decrease
mortality and while it may decrease the risk of pulmonary embolism and deep vein thrombosis it
increases the risk of bleeding and thus results in little or no overall clinical benefit. Evidence supports
the use of heparin following surgery which has a high risk of thrombosis to reduce the risk of DVTs;

Treatment

Warfarin and Vitamin K antagonists are anticoagulants that can be taken orally to reduce
thromboembolic occurrence. Where a more effective response is required, heparin can be given (by
injection) concomitantly. As a side effect of any anticoagulant, the risk of bleeding is increased.

Anticoagulants

Antithrombin plasma protein produced by the liver is used to deactivate thrombin.

Heparin produced by basophiles and endothelial cells increases the potency of antithrombin
where combined with antithrombin it quickly deactivates thrombin.

Prostacyclin produced by the endothelial cells of the damaged blood vessel to counter the
actions of thrombin. Prostacyclin causes vasodilatation and inhibits the release of coagulation factors
from platelets.

Disseminated Intravascular Coagulation - DIC

DIC is a syndrome arising as a complication of many different serious and life-threatening illnesses. In
its acute form it is a hemorrhagic disorder, characterized by multiple ecchymoses, mucosal bleeding,
and depletion of platelets and clotting factors in the blood.

Chronic DIC, on the other hand, is more subtle and involves thrombo-embolism accompanied by
evidence of activation of the coagulation system. With chronic DIC, coagulation factors may be normal,
increased, or moderately decreased, as may the platelet counts.

Pathogenesis of DIC
DIC occurs when monocytes and endothelial cells are activated or injured by toxic substances
elaborated in the course of certain diseases. The response of monocytes and endothelial cells to injury
is to generate tissue factor on the cell surface, activating the coagulation cascade. In acute DIC, an
explosive generation of thrombin depletes clotting factors and platelets and activates the fibrinolytic
system. Bleeding into the subcutaneous tissues, skin, and mucous membranes occurs, along with
occlusion of blood vessels caused by fibrin in the microcirculation.

Reasons leading to DIC:

- Snakebite
- Diffuse endothelial injury due to gram-negative bacteria
- Immunologic injury to the endothelium as occurs in type II and III hypersensitivity
- Promyelocytic leukemia
- Amniotic fluid embolism

Symptoms of DIC include:

Bleeding - Sometimes severe, from multiple locations in the body. Unknown cause
Gastrointestinal bleeding
Blood clot formation causing fingers or toes to look blue
Sudden bruising

Treatment

Administration of heparin to inhibit the formation of thrombi and

Administration of Platelets and Plasma as well to restore the depleted coagulation factors