60% of the lean body weight is water; 2/3 intracelluar, 1/3 extracellular (mostly interstitium). Increased interstitial fluid is caused by increased capillary pressure, reduced colloid osmotic pressure, or lymphatic obstruction; fluid accumulates if this leak exceeeds lymphatic drainage. Oedema is excess interstitial fluid. Anasarca is severe generalised oedema incl subcutaneous swelling. Inflammatory oedema is protein-rich (exudate), from increased vascular permeability. Lymphoedema (from lymphatic obstruction) is usually localised; causes include chronic inflammation with fibrosis, invasive malignancy, physical disruption (eg surgery), radiation or certain infections (eg filariasis).
Hyperemia is from active arteriolar dilatation, increasing blood flow causing erythema. Congestion is passive reduced outflow from a tissue, causing cyanosis, usually oedema and occ haemorrhagic foci with haemosiderin. Acute hepatic congestion distends central vein and sinusoids with centrilobular ischaemia; periportal hepatocytes are better oxygenated, may only have fatty change. Chronic passive hepatic congestion causes cell death with depressed regions of red-brown surrounded by arsea of uncongested tan liver.
Extravasation of blood from the vascular space. Haematomas are accumulations of blood. Of the skin, petechiae are 1-2mm (local increased intravascualr pressure, thrombocytopenia or defective platelet function), purpura >/=3mm (causes as petechiae, also trauma, vasculitis, vascualr fragility), ecchymoses are >10-20mm SC bruises (red-blue haemoglobin converted to blue-green bilirubun then gold-brown haemosidern).
Normal haemostasis after vascular injury includes brief initial arteriolar vasoconstriction (neurologic, endothelin from endothelium), exposure of thrombogenic subendothelial ECM, palelet adherence (via interactions with von Willebrand factor vWF) and activation (degranulation and flattening to increase surface area), aggregation (from secreted products esp adenosine diphosphate ADP; released thromboxane A2 TxA2 causes vasoconstriction) forming a haemostatic plug (primary haemostasis). Tissue factor (factor III, thromboplastin) synthesised by endothelial cells initiates the coagulation cascade generating thrombin, which cleaves fibrinogen into insoluble fibrin, consolidating the platelet plug (secondary haemostasis). This plug forms a solid permanent plug, with regulatory mechanisms (eg tissue plasminogen activator rPA) limiting haemostasis. Normal endothelial cells inhibit haemostasis (antiplatelet, anticoagulant and fibrinolytic), prothombotic state (from trauma, inflammation) activates platelets, coagulation proteins and antifibrinolytics.
Thrombosis is pathological haemostasis. Virchow’s triad (main causes) include:
- Endothelial injury – Ulcerated plaques, trauma, vasculitis. Endothelium doesn’t neet to be denuded to develop thrombosis, only the dynamic balance of prothrombotic and antithrombotic effects of the endothelium. Dysfunctional cells can be induced by HTN, turbulent flow, bacterial endotoxins, radiation, metabolic (homocystinemia, hypercholesterolemia), cigarette toxins.
- Altered blood flow (stasis, turbulence) – Promotse endothelial activation, disrupts laminar flow brinnig platelets closer to the endothelium, and prevents washout of activated clotting factors. Hyperviscosity (polycythaemia) increases resistance to flow and stasis; deformed cells (eg sickle cell anaemia) causes microvascular occlusions and stasis.
- Hypercoagulability of blood (thrombophilia):
- Primary/genetic – Factor V Leiden, prothrombin mutation,, antitrombin III deficiency, protein C/S deficiency etc
- Secondary/acquired – High risk: immobilisation, MI, AF, tissue injury (surgery, fracture, burn), cancer, prosthetic valves, DIC, heparin-induced thrombocytopenia, antiphospholipid antibody syndrome (antibodies to plasma proteins eg prothrombin causign endothelial injury; secondary in autoimmune disease eg SLE; primary with no autoimmune disease eg drugs or infections). Lower risk: cardiomyopathy, nephrotic syndrome, hyperostrogenic state (pregnancy, postpartum), OCP, sickle cell, smoking.
Arterial thrombi usually propagate retrograde, venous antegrade (both towards the heart). The propagated portion is often poorly attached and prone to fragmentation/embolisation. Lines of Zahn or gros macro/micro-scopic laminations of pale platelet/fibrin alternating with darker red cell-rich layersion in flowing blood (ie antemortem). Mural thrombi are in the heart chambers of aortic lumen. Arterial thrombi are frequently occlusive (esp coronary, cerebral, femoral), usually frible mesh of platelets/fibrin/red cells. Venous thrombi (phlebothrombosis) are almost always occlusive forming a long cast within the lumen, containing more enmeshed red cells (few platelets) due to sluggish flow (red/stasis thrombi). Postmortem clots are gelatinous w dark red dependent (red cells) and yellow ‘chicken fat’ antidependent portions, not usually attached to the underlying wall. Vegetations are thrombi on heart valves, may be nonbacterial/sterile or infective.
Thrombi may undergo:
- Propagation – Accumulation of further platelets and fibrin
- dissolution – Fibrinolysis. Older thrombi with extensive fibrin deposition and crosslinking are more resistant.
- Organisation – Ingrowth of endothelial cells, smotth muscle cells and fibroblasts. Capillary channels re-establish continuity with original lumen, with smaller thrombi becoming incorporated into the vessel wall. Remodelling and contraction of mesenchymal elements eaves a small fibrous lump. Cnetres may be digested by lysosomal enzyme release of trapped leukocytes and pl,atelets. Bacteria may infect the thrombus which may lead to a mycotic naeurysm with erosion and weakening of the wall.
Detached intravascular solid, liquid or gasseous mass carried by the blood. Includes:
- Thromboemboism (most) – PE most from leg DVTs. Systemic 80% from intracardiac mural thrombi (2/3 LV wall infarcts, 1/4 LA dilatation and fibrillation), others include aortic aneurysms, ulcerated plaques, valvular vegetation, pradoxical emboli (DVT via R->L shunt); 75% embolise to lower extremities, 10% brain, rest incl intestines, kidneys, spleen, upper extremities.
- Fat and marow embolism – Long bone fractures, rarely soft tissue trauma or burns. Occurs in 90% of those with severe trauma, but <10% have clinical findings. Fat emboli syndrome is the minority that are symptomatic, from mechanical obstruction and biochemical injury (released fatty acids toxic to endothelium, activate platelets)
- Nitrogen/air embolism – Generally 100mL required before clinical effect in pulmonary circulation. Very small volumes in the coronary arteries (bypass surgery) or cerebral circulation (neurosurgery in sitting position) cause problems. Decompression sickness is rapid reducing in atmospheric pressure causing nitrogen to come out of solution in the blood.
- Amniotic fluid embolism – Infusion of amniotic fluid or fetal tissue via tear in plaental membranes or ruptured uterine veins. High mortality causing shock, pulmonary oedema, DAD, DIC (thrombogenic).
- Cholesterol emboli – From atherosclerotic debris.
- Tumour fragments
- Foreign bodies
Infarcts are wedge-shaped (apex at occluded vessel), fibrinous exudate over the serosal surface. Red (haemorrhagic) infarcts are ill-defined; occur with venous occlusions (esp single efferant vein eg testis, ovary), loos tissues (eg lung), dual circulation (eg lung, small intestine), previously congested by sluggish venous outflow, and re-establised flow in previous arterial occulsion and necrosis. White infarcts are well defined; occur with end-arterial circulations (eg heart, spleen, kidney) with tissue density limiting seepage of blood. Histological ischaemic coagulative necrosis after 4-12hrs (except liquefactive necrosis in CNS), marginal acute inflammation within a few hours. Neurons develop irreversible damage after 3-4min, myocardial cells after 20-30min, fibroblasts after many hours. Most infarcts are replaced by scar. Septic infarctions (eg bacterial endocarditis) convert into an abscess with increased inflammation.
Shock is systemic hypotension due to reduced cardiac output or reduced effective circulating blood volume, subsequently causing mipaired tissue perfusion and cellular hypoxia. Cardiogenic shock from MI, arrhtymia, tamponade, outflow obstruciton. Hypovolaemic shock from loss of plasma/blood volume in massive mhaemorrhage or severe burns. Septic shock from systemic vasodilatation, endothelial activation ± DIC.. Neurogenic shock is loss of vascular tone from anaesthetic accident or spinal corkd injury. Anaphylactic shock is systemic vasodilatation and icnreaed vascular permeability from IgE-mediated hyeprsisensitivity. Stages include initial nonprogressive phase (perfusion maintained by reflex comp), progressive stage (hypoperfusion, worsening circulatory/metabolic imbalance), irreversible stage (cellular and tissue injury, survival not possible). Hypoxic injruy most marked int he brain, heart, lungs, kidneys, adrenals and GIT. Adrenal cortical cell depletion – conversion of inactive vacuolated cells to metabolically active cells, synthesizing steroids. Renal acute tubular necrosis, shock lung (diffuse alveolar damage), DIC with consumptive coagulopathy leading to petecheal haemorrhages.