Haemorrhage and Red Cell Extravasation

Haemorrhage

• Involves the escape of blood into the environment, a body cavity, or intercellular spaces
• Can result from too much blood (hyperaemia & congestion) and too little blood (hypovolaemia, ischaemia) in circulation
• Includes physiological responses to haemorrhage and its resolution

Red Cell Extravasation

• Diapedesis: Red cells escape through intact vessel walls, seen in chronic passive hyperaemia and congestive heart failure
• Rhexis: (Greek "rhexis" = rupture) involves red cells escaping due to vessel rupture, such as from trauma to a blood vessel in a wound

Causes of Haemorrhage

• Vessel weakness: Arteriosclerosis or aneurysm
• Toxic endothelial damage: Viraemia, septicaemia, bracken, arsenic, and vitamin C deficiency
• Coagulation/bleeding disorders: Haemophilia, Vitamin K deficiency, and warfarin (rodenticide) ingestion

Nomenclature Examples

• Haemothorax: Blood in the chest cavity, often due to chest trauma
• Haemopericardium: Blood in the pericardial sac, which could be due to cardiac rupture or bleeding tumours
• Haemoperitoneum: Blood in the peritoneal cavity, often due to trauma to the spleen or liver
• Haemarthrosis: Blood in a joint, which is often associated with bleeding tendencies
• Haemoptysis: Coughing up blood, which may relate to tuberculosis or cancer
• Haematemesis: Vomiting blood, which relates to gastric ulcers or neoplasia
• Haematuria: Blood in urine, potentially a result of bladder or renal cancer, inflammation of bladder
• Melaena: Blood in the GIT
• Epistaxis: Nose bleed
• Penile Haematoma: Haematoma in the penis
• Subdural Haematoma: Haematoma in the subdural space
• Intestinal Haemorrhage: Haemorrhage in the intestines

Terminology Describing Haemorrhage

• Petechiae: Pinpoint haemorrhages of the mucosae, serosae or skin up to 1-2 mm and diapedesis
• Ecchymosis: Haemorrhage larger than 2-3 cm (bruise), associated with coagulopathies and vascular defects
• Haematoma: Focal abnormal space filled with clotted blood

Purpuric Tendency

• A condition characterized by widespread haemorrhages due to widespread endothelial damage, increased intravascular pressure, thrombocytopaenia (e.g., immune-mediated), or poor platelet function (inherited, or in uraemia)

Consequences of Haemorrhage

• Depend on the volume, rate of loss, and location of bleeding
• Loss of 100-500 ml of blood can occur during blood donation or subdurally after skull fracture
• Acute loss of 20-40% of total blood volume can be significant
• Chronic blood loss over years from gastric ulcers can lead to other complications

Physiological Response to Haemorrhage

• The body redistributes the remaining blood to maintain vital functions

Early Response

• Venous return, cardiac output, and arterial blood pressure fall
• Carotid and aortic bodies stimulate vasomotor centres to trigger tachycardia and vasoconstriction
• Adrenalin and noradrenaline are released to cause generalised vasoconstriction + coronary artery dilation
• Decreased venous blood pressure leads to Renin, to angiotensin production

Middle Phase

• Plasma proteins exert osmotic pressure, drawing fluid from the ECF

Late Phase

• Erythropoiesis is enhanced, leading to increased production of reticulocytes after 4 days
• Hepatic synthesis of proteins occurs

Resolution of Haemorrhage

• Erythrophagocytosis of the blood occurs
• Globin is seperated from heme
• Heme is broken down into Fe, which is further broken down to ferritin and haemosiderin
• Heme gets converted to bilirubin

The Role of Fibrin

• Blood comprises cells and plasma proteins
• Fibrinogen transforms to fibrin
• Fibrin appears white/cream and flocculent/strands
• Fibrin stains pink in H&E
• Fibroblasts are also found in the clots

Endothelial Cells

• Can have antithrombotic effects, includes platelet inhibition, fibrinolysis, anticoagulation, and vasodilation
• Can have prothrombotic effects, includes platelet co-factors, anti-fibrinolytic factors, coagulation, and vasoconstriction

Primary Haemostasis

• Platelets in 1° haemostasis: Prothrombotic anucleate cells responsible for 1° haemostasis
• Involves platelet adhesion to the extracellular matrix via vWF, vWF is released from endothelial cells when they are damaged
• Results in cover endothelium and increase surface area for binding and intracellular signalling and cytoskeleton rearrangement
• Platelet secretion is triggered (thrombospondin, ADP, 5HT, TXA2, PF3, TF, vWF, Fibrinogen)
• Followed by Platelet shape change & aggregation, Formation of the 1° haemostatic plug is reversible
• Concomitant activation of the coagulation pathway "glues" the platelet plug together with fibrin forming the 2° haemostatic plug which is irreversible

Soluble Clotting Factors

• Involve inactive circulating pro-enzymes, produced by the liver
• A cascade of reactions gets triggered, ultimately resulting in fibrin formation
• Fibrin stabilises the platelet plug into 2° haemostatic plug
• It stimulates fibroblastic proliferation and organisation by acting as a scaffold, which promotes an inflammatory response

Vitamin K and the Coagulation Cascade

• Vitamin K is essential for the synthesis of clotting factors
• Intrinsic Pathway: Involves factors 12, 11, 9, and 8
• Extrinsic Pathway: Involves TF which actives factor 7
• Common factors: 10, 5, 2, 1, 13
• These pathways lead to the formation of a fibrin clot

Steps of Haemostasis

• Tissue damage occurs
• Vascular endothelium releases more prothrombotic than antithrombotic substances
• Platelet adhesion occurs
• Activation of the coagulation cascade follows intrinsic and extrinsic pathways
• Fibrin release occurs

Abnormalities of Haemostasis

• Continued haemorrhage can lead to hypovolaemia (shock) and death
• Thrombosis involves inappropriate/excessive intravascular coagulation

Thrombi

• Solid aggregates of platelets, proteins, and blood cells formed inside a blood vessel of a living animal
• Thrombus formation can be triggered by damage to endothelial cells, sluggish/turbulent blood flow, and hypercoagulable blood
• Consequences include immediate death, lysis, organisation, and embolisation

Virchow's Triad

• Explains three broad categories of factors that are thought to contribute to thrombosis
• Hypercoagulability: Hypercoagulable states
• Haemodynamic changes: Stasis or turbulence of blood flow.
• Endothelial injury/dysfunction

Embolism

• A plug of material within the circulation that becomes lodged in a vessel too narrow to allow its passage
• Sources include thrombi, bacteria, parasites, fat, amniotic fluid, bone marrow, air, and tumour cells
• Consequences of embolism include ischaemia, spread of infection, systemic inflammation, or no significant consequence if there is collateral blood supply

Infarction

• Ischaemic death of tissue often stems from thromboemboli
• It can be due to venous and arterial obstruction, where thromboemboli and masses are common

DIC (Disseminated Intravascular Coagulation)

• Widespread activation of the coagulation cascade occurs
• Consumption of platelets and coagulation factors can lead to a haemorrhagic diathesis
• Severe tissue necrosis, sepsis, and systemic vascular damage can cause DIC

Breaking Down Thrombi

• Tissue plasminogen activator (tPA) is a serine protease found on endothelial cells
• tPA catalyses the conversion of plasminogen to plasmin, the major fibrinolytic enzyme
• tPA acts on the plasminogen to generate plasmin locally, which degrades the fibrin mesh and dissolves the clot, restoring blood flow
• Plasmin is tightly controlled by factors, such as a2-antiplasmin, which inhibits free plasmin