HAEMORRHAGE

Haemorrhage is the escape of blood from the cardiovascular system, and occurs by two processes:

1) Haemorrhage by rhexis - when there  is a rent or tear in the blood  vessel wall;
2) Haemorrhage by diapedesis - when  blood escape passively in events  of hyperaemia of inflammation.

I. Causes of Haemorrhage:

1. Trauma
2. Systemic damage to vascular radicals due to septicaemia, viraemic or toxaemic conditions.
3. Haemorrhagic diatheses (Deficiency in blood coagulation) such as in Prothrombin deficiency following Vitamin K deficiency or in liver disease; Hereditary deficiency of clotting factors as in Haemophilia; Disease processes that cause Thrombocytopenia (deficiency in platelets) as in Erlichiosis.

II. Clinical Significance: Dependent  on:

1. Location of haemorrhage - the critical sites are the central nervous system and the heart.
2. Volume of blood lost - when a critical amount of blood is lost (about 20-40% total blood volume) may lead to haemorrhagic shock (circulatory collapse due to haemorrhage). In the gastrointestinal tract, if the voided faeces contain blood (bloody diarrhoea), the condition usually has a very poor prognosis and may be fatal. This is because the amount of blood lost is great before clinical signs of bloody diarrhoea appear.
3. Rate of blood loss - the more rapid the blood is lost, the less is the total volume required to produce shock.

III. Resolution of haemorrhage:

1. Reabsorption - usually limited for extravascular blood clots. If haemorrhage occurs in body cavities, drainage by lymphatics may be possible, but not sufficient to maintain a minimum amount of blood for circulation. In the peritoneal cavity, active reabsorption of blood lost in this cavity is suggested by the post mortem finding of accentuated lymphatic vessels in the diaphgram.
2. Organisation - phagocytosis and fibrous tissue organisation. The masses of fibrin and red cells are surrounded by vascular connective tissue.

IV. Terminologies:

Petechiae - minute, pin-point foci of  haemorrhage up to two  millimeters in diameter.
Ecchymosis - larger than petechiae and  are usually blotchy or irregular  areas up to three centimeters in  size.
Extravasation - extensive haemorrhage  within the substance of a  tissue.
Paint brush haemorrhage - linear or  streaked appearance of  haemorrhage.
Purpura - when petechiae, ecchymoses  or larger areas of haemorrhage  are scattered on many body  surfaces (generalised).
Haematocyst (haematoma) - the  accumulation of blood producing  a three dimensional  extravascular coagula.
Haemopericardium - haemorrhage into  the pericardial sac.
Haemothorax - haemorrhage into the  thoracic cavity.
Haemarthrosis - haemorrhage into the  joint spaces.
Haemoptysis - coughing out blood.
Epistaxis - bleeding from the  nostrils.
Entorrhagia - passage of blood from  the alimentary tract.
Metrorrhagia - passage of blood  through the uterus.
Haematemesis - vomition of blood.
 

THROMBOSIS

Thrombosis is the formation of ante mortem clots within the blood vessels, and the clot so formed is called thrombus (plural: thrombi). There are three major determinants in the pathogenesis of thrombosis (classically called the Virchow's Triad) and are grouped as follows:

 1) Damage to vessel wall endothelia
 2) Changes in the blood components itself   (hypercoagulability)
 3) Haemodynamic and rheological   changes.

Damage to vessel wall endothelia:

Normally, intact endothelial cells do not promote activation of either intrinsic or extrinsic clotting mechanism, and do not promote the adherence of blood cells. This phenomenon is explained in the following theories:

1. Glycocalyx theory - the non-thrombogenic property of endothelial lining cells of blood vessels is due to the carbohydrate-rich cell coat (glycocalyx).

2. Surface negativity theory - the negatively charged surface of endothelial lining lead to mutual electrostatic repulsion between two sets of negatively charged cells (endothelial cells and blood cells).

3. Surveillance system theory - this theory is anchored on the ability of endothelial cells to synthesise Prostacyclin (Prostaglandin I2) that prevents aggregation of platelets by converting the Platelet aggregating factors (Endoperoxidase and Thromboxane A2) into unstable substances. In events of endothelial injury, prostacyclin is absent or not synthesised by the damage endothelial cells.

In events of endothelial damage following trauma, electrical damage, chemical injury, and infectious diseases that manifest inflammation of blood vessels and damage to vessel walls (bacterial endotoxins), the injured vessel wall along with platelets, blood cells, and fibrinolytic factors combines in a series of interlacing reactions. This result to vasoconstriction and the formation of the coagulum consisting of platelets and fibrin.

Changes in the composition of Blood

A hypercoagulable state might result from either:

1) Increased activation of clotting factors as in pregnancy (increased levels of fibrinogen), and post partum (increased levels of Factor VII, VIII, and X);

2) Decreased inhibitory activity in four major groups of inhibitors as:

(a) inhibition of activated clotting  factors as in deficiency of  anti-thrombin
(b) anticoagulant
(c) irreversible inhibitors that  destroy clotting factors via the  immunologic mechanism
(d) Reversible inhibitors that  interfere with coagulation  mechanism but do not destroy the  clotting factors themselves.

Haemodynamic and rheological changes

Normally, blood flow in vessels is laminar, i.e. blood flow as a series of concentric fluid cylinders. The innermost stream move forward at the fastest rate, and with each "layer" moving successively slower as one moves toward the wall of blood vessel. Immediately next to the endothelium is a thin layer of plasma, preventing contact between endothelial cells and blood cells. The rheological (flow) properties of blood are such that a drop in flow rate results to an increase in viscosity. Thus, altered rheology   favours   thrombosis by:

1) creating altered turbulence to  accelerate the cellular and  enzymatic reactions important in  thrombogenesis
2) by producing further injury to  vessel wall itself.

Morphology and morphogenesis

Arterial thrombi are usually pale gray-tan mass consisting of nearly concentric layers of alternating bands of fibrin and platelets mixed with scanty amount of coagulated red blood cells. This laminated appearance of such thrombi relates to rapid flow of blood in artery which sweeps many components of blood. Currents conducive to activation and accumulation of clotting factors are found only in the peripheral recesses of the developing low profile thrombi. Thus, during propagation, concentric laminations are formed (lines of Zahn). Arterial thrombi are rarely occlusive at first, but consequent slow build up make it so. In such a situation, the head of the thrombi remains pale while the tail tends to be dark red.

 Venous thrombi resemble intravascular clots of whole blood due to slow blood flow as influenced by gravity. These are usually dark red, moist or gelatinous, and are easier to dislodge. The distributions of the formed elements are almost random. Venous thrombi are rarely mural and tend to be occlusive.

 Once thrombi are formed, there are four outcomes as follows:

1) Propagation - it becomes larger and  eventually obstructs the vessel
2) Fragmentation to form thrombo- emboli (see later)
3) Removed by fibrinolysis/  thrombolysis via plasma-derived  fibrinolytic system or through  phagocytosis by phagocytic cells
4) Organisation - invasion and growth  of fibrous tissue, or re- canalisation with restoration of  blood flow.
 

COMPARISON BETWEEN POST MORTEM CLOT AND THROMBUS
 

CLASSIFICATION OF THROMBI

I. BASED ON LOCATION IN BLOOD VASCULAR SYSTEM:

1. Cardiac thrombi     4. Lymphatic thrombi
2. Arterial thrombi       5. Capillary thrombi
3. Venous thrombi

II. BASED ON LOCATION WITHIN HEART OR BLOOD VESSEL:

 1. Mural thrombi - attached to endocardial wall
 2. Valvular thrombi - attached to heart valves
 3. Occluding thrombi - blocks the entire circumference of the blood vessel
 4. Canalised thrombi - allows partial blood flow
 5. Saddle thrombi - straddle the bifurcation of blood vessel
 6. Obturating thrombi - trailing thrombi with one end attached to vessel   wall and the other end freely moving

III. BASED ON CONTENT OF PATHOGENIC AGENT:

 1. Septic thrombi - contain bacteria
 2. Aseptic thrombi - no pathogenic agent present
 3. Parasitic thrombi - contain parasites such as filarial nematodes

IV BASED ON COLOUR:

 1. Red thrombi - composed of all blood cell components
 2. Pale or white thrombi - composed entirely of platelets
 3. Laminated or mixed thrombi - composed of red and white thrombi
 

EMBOLISM

Embolism is the process by which a solid mass is transported from one part of the body to another through the circulatory system. The solid mass is called embolus (plural: emboli). Emboli may be fragments of a thrombus (thrombo-emboli), fat cells (fat emboli), tumour cells, aggregates of bacteria or parasites, bone marrow cells, amniotic cells, and foreign bodies that gained entry into the circulation. Lodgement of emboli is observed only in blood vessels with gradual narrowing of the lumen at its termination. The common sites are those organs with end-artery supply such as the brain, kidneys, spleen, and myocardium. If such an embolus will lodge in organs with end-artery blood supply, ischaemia will result (see later). If there exist collateral arterial blood supply to an organ, the effects may be least. It may progress to a reduction of the number or size of cells composing such organ (atrophy). If it occurs in veins (rarely), congestion will result and will favour thrombogenesis. Valvular thrombosis of the left chamber of the heart usually produces emboli in the systemic circulation. In contrast, thrombosis of the right chambers of the heart produces emboli in the lungs.
 

ISCHAEMIA

Ischaemia is a reduction in the flow of blood to an area and usually refers to the flow of arterial blood. Following the reduction of blood supply, partial (Hypoxia) or complete (Anoxia) reduction in oxygen received by the tissue from blood occurs and eventually necrosis of the affected part. The result of ischaemia is dependent on:

1) the organ involved - if in an end- artery (see later), leads to  infarction if total, and  if   gradual  leads  to atrophy
2) Degree  of  occlusion  or anoxia
3) Degree of collateral circulation
4) Size of the vessel involved.

Ischaemia may be caused by compression of the blood vessels from without (example tumour growth, pregnancy). Obstruction in the blood vessel may be partial and leads to atrophy, or complete to cause infarction. It may also be functional (tissue anoxia) and occur in four ways:

1) Stagnant anoxia - due to reduced flow of oxygenated blood as in shock (see later)
2) Anoxic anoxia - resulting from insufficient oxygenation of blood as in severe pneumonia
3) Anaemic anoxia - caused by low haemoglobin or reduced capacity of blood to carry oxygen as in carbon monoxide poisoning
4) Histotoxic anoxia - in which the oxygenation of blood is normal but the tissues cannot utilise oxygen as in cyanide poisoning.
 

INFARCTION

An infarct is an area of necrosis caused by ischaemia, and is due to obstruction in artery or vein following thrombosis or embolism. The process by which this develops is called infarction. The cells and tissues most susceptible to infarction are those biologically active cells and include the brain, renal tubular epithelia, heart muscles, and most parenchymal tissues. Mesenchymal cells such as fibroblasts are resistant to infarction such that the stromal support of infarcted tissue survives although parenchymal tissues succumb to ischaemic injury. In understanding the effects of infarction in the arterial system, it is best to review the three basic anatomic patterns of the arterial system in organs as follows:

1. Functional end-artery (single vessel) - the artery ramifies into smaller radicles at its end. Organs include the kidneys, brain, spleen, and heart. Thrombotic or embolic occlusion invariably leads to infarction.

2. Parallel system - there is separate blood supply which often has several functional anastomotic channels. Organs include skeletal muscles, and most tubular organs (example: intestines, uterus). Thrombotic or embolic occlusion rarely leads to infarction. However, if the occluded portion is that part near its origin at abdominal aorta, infarction will occur. An example of this condition is thrombo-embolic colic in the horse (verminous arteritis caused by Strongylus vulgaris obstructing the cranial mesenteric artery).

3) Dual blood supply - there are two blood vessels supplying an organ which originates from different points. This includes the lungs (pulmonary arterial system, and bronchial arterial system), and the liver (portal vein and hepatic artery). Hepatic and pulmonary infarction are uncommon events, but may occur (rarely) in association with chronic passive congestion in which the dual blood supply is compromised.

Classification and morphology

 Infarcts are classified based on:

1) Bacterial contamination as septic,  or bland
2) Colour as white or anaemic infarct,  and red or haemorrhagic infarct.

Venous infarcts are intensely haemorrhagic as blood back up into affected tissue behind the obstruction. Arterial infarcts are generally pale, except in loose tissues such as the lungs which are usually haemorrhagic. Solid parenchymatous organs like the heart and kidneys tend to have pale infarcts. Obstruction of vein is not apt to produce infarction but to cause slowly developing stasis with engorgement of the tributaries of the venous system. Usually, obstruction in arterial system produces infarction, but collateral compensatory blood channels may be formed. For example, blockage of carotid arteries if gradual in development, will shunt the blood into the vertebral arteries. This will incite development of anastomotic connections to internal carotid to the maxillary and ascending pharyngeal arteries and upward to supply the structures of the head. Also, when posterior vena cava is blocked, blood is shunted to the azygous vein.
 

DISSEMINATED INTRAVASCULAR COAGULATION (DIC)

Disseminated intravascular coagulation is the pathological formation of blood clots in the living animal body. It is essentially a defect in haemostasis and the mechanisms involved include the following:

1) Activation of the intrinsic clotting mechanism independent of tissue damage - through the activation of the Hageman Factor following sludging of blood as in shock (see later), loss of fibrinolysis during renal disease, increase in fibrinogen in severely ill and pregnant animals;

2) Activation of the extrinsic clotting mechanism following vascular injury with release of tissue thromboplastin - as may occur in widespread neoplasms, tissue necrosis following infectious diseases, surgery and severe trauma;

3) Direct activation of Prothrombin (Factor X) by proteolytic enzymes -  as in release of trypsin in the circulation following pancreatitis, and in snake bites.

Phases of reactions

1. Hypercoagulable Phase - associated with subsequent formation of Thrombin. This leads to platelet aggregation and fibrin formation resulting to thrombosis of capillaries, arterioles, venules, and infarction in many organs. This phase is followed by the hypocoagulable phase.

2. Hypocoagulable Phase - associated with the following mechanisms:

(a) Activation of the fibrinolytic system with consequent release of fibrin and fibrinogen degradation products which suppress fibrin polymerisation.

(b) Depletion of thrombocytes

(c) Depletion of clotting factors particularly Fibrinogen, Factor VIII (anti- haemophilic factor) and Factor V (Proaccelerin)

Net effects of DIC

1. Haemorrhagic diatheses (synonyms: Consumption coagulopathy; Defibrination syndrome) - marked bleeding tendencies associated with inhibiting effects on both platelet function and blood coagulation.

2. Shock - associated with the release of vasoactive agents from thrombocytes, and the interaction of clotting mechanism with the kallikrein-kinin system which leads to vascular dilatation, hypotension, and vasomotor collapse.
 

SHOCK

Shock is a syndrome resulting from hypotension caused by acute generalised circulatory failure of the capillary bed. It is a state of acute peripheral circulatory failure caused by sudden and severe injury. The fundamental disturbance is that blood volume is too small to fill the vascular system, and the common denominator is a fall in blood pressure.

 In a state of shock, the accompanying cell damage is due to hypoxia (decreased oxygen tension in the circulation) which lead to decreased oxidative phosphorylation and ATP production. Pyruvate cannot enter the citric acid cycle, such that the cells are forced to obtain energy through anaerobic glycolysis. This leads to the accumulation of lactate with associated metabolic acidosis. Normal arterial blood pressure is maintained by cardiac output and by the total vascular peripheral resistance. Depression of these mechanisms leads to shock.

Stages of Shock

1. Stage of ischaemic hypoxia - reflex  arterial vasoconstriction;
2. Stage of stagnant hypoxia -  associated with:

 (a) gradual fading of pre-  capillary vasoconstriction
 (b) pooling of blood in the   capillary
 (c) decline in venous return
 (d) diminished cardiac output
 (e) diminished blood pressure.

3. Stage of irreversibility - shift of  fluid from intravascular to  extravascular space and micro- embolisation of capillaries  (refractory state)

Counter-regulatory mechanism

Counter regulatory mechanisms are activated by low blood pressure and diminished cardiac output via the pressure receptors (carotid sinus) irrespective of the inciting cause of shock. The counter regulatory mechanisms operating in events of shock are as follows:

1) Sympathetic nervous system - produces peripheral vasoconstriction, tachycardia, and redistribution of blood to vital organs

2) Central nervous system (Apneustic and pneumotaxic areas) - activation due to hypoxic stimulation caused by reduced ventilatory surfaces in events of haemodynamic alterations in the lungs

3) Adrenal gland - stimulated to release cathecolamines (epinephrin and norepinephrine secreted by medullary cells), and glucocorticoids (secreted by cortical cells)

4) Renin-Angiotensin-Aldosterone axis - stimulation of juxtaglomerular cells in kidneys resulting to conservation of sodium ions and water by renal tubular reabsorption.

Consequences of shock

1. Vasomotor effects - includes:

(a) Spasm of blood vessels with a rise  in blood pressure following  activation of renin-angiotensin- aldosterone axis;
(b) Renal cortical shut down due to  failure of cortical perfusion;
(c) Ischaemic injury

2. Systemic pH changes (metabolic  acidosis)
3. Disseminated intravascular
 coagulation

Lesions of shock

Lesions of shock vary according to the severity and duration of the condition. During necropsy, lesions indicative of shock are as follows:

1) Severe congestion and oedema of the lungs (congestive atelectasis);
2) Visceral pooling of blood and fluids; the fluid may be found inside the gastrointestinal tract. Acute ulcerations and haemorrhages may be seen in the GIT.
3) Subendocardial haemorrhages in the heart;

 Microscopically, the lesions of shock include the following:

1) Microthrombi in the lungs and kidney glomeruli (indicative of disseminated intravascular coagulation);
2) Fatty changes or necrosis of the hepatocytes;
3) Haemorrhage and necrosis of cortical cells in the adrenal glands;
4) Acute renal tubular necrosis.