Fluid and haemodynamics

Oedema

• Movement of water and salts controlled by opposing effects of hydrostatic and colloid osmotic pressures
• Increased hydrostatic or decreased colloid pressure -> increased fluid interstitial spaces -> exceeds capacity of lymph system -> oedema
• Fluid in body cavity = hydrothorax, hydropericardium, hydoperitoneum (ascites)
• Anasarca = severe and generalised oedema
• Morphology = separation of ECM and subtle cell swelling

Causes =

Hyperaemia and Congestion

• Hyperaemia = active process whereby arteriolar dilation leads to increased blood flow
  • Sites of inflammation or skeletal muscle in exercise
  • Tissues turn red (erythema) due to engorgement of vessels with oxygenated blood
• Congestion = passive process resulting from reduced outflow of blood from tissue
  • Systemic (cardiac failure) or local (venous obstruction)
  • Dusky reddish blue (cyanosis) due to red cell stasis and accumulation of deoxygenated haemoglobin
  • Often leads to oedema
  • Chronic congestion -> lack of blood flow and hypoxia + capillary rupture and haemorrhage
  • Morphology =
    • Acute pulmonary congestion – engorged alveolar capillaries, alveolar septal oedema, focal intra-alveolar haemorrhage
    • Chronic pulmonary congestion – thickened fibrotic septa, haemosiderin laden macrophages “heart failure cells”
    • Acute hepatic congestion – distended central vein and sinusoids, ischaemic centrilobular hepatocytes, fatty change only in periportal hepatocytes
    • Chronic hepatic congestion
      • Macroscopic = red brown/ depressed centrilobular regions due to cell death – accentuated against surrounds -> “nutmeg liver”
      • Microscopic = centrilobular haemorrhage, haemosiderin laden macrophages, degeneration of hepatocytes
      • Centrilobular area – distal end of blood supply to liver – prone to ischaemia

Haemorrhage

• Extravasation of blood into the extravascular space
• In association with chronic congestion, haemorrhagic diathesis, inflammation, trauma, atherosclerosis or neoplastic erosion
• Significance = depends on volume + rate of bleeding + site (intracranial = raised ICP)
• Patterns:

Haemostasis and Thrombosis

• Haemostasis: NORMAL process = maintain blood in fluid state in blood vessels + permit formation of haemostatic clot at sites of vascular injury
• Thrombosis: pathologic process = blood clot within normal vessels

Normal Haemostasis

1. Initial injury -> reflex neurogenic mechanisms + local endothelin = brief arteriolar vasoconstriction
2. Endothelial injury exposes ECM -> platelet adherence and activation (shape change) = haemostatic plug PRIMARY HAEMOSTASIS
3. Tissue factor (TF) exposed -> coagulation cascade + factor VII = thrombin generation, cleaves fibrinogen to insoluble fibrin for meshwork + induces platelet activity
4. Polymerized fibrin + platelets = permanent plug SECONDARY HAEMOSTASIS
5. Counter regulatory mechanism (tissue plasminogen activator) activated to limit haemostatic plug at injury site

Endothelial cells

• Non-activated = inhibit platelet adhesion and clotting
  • Prostacyclin + NO impede platelet adhesion
  • Adenosine diphosphatase -> adenosine diphosphate, inhibits aggregation
  • Thrombomodulin -> inactivate thrombin via anti-thrombin III
  • Activates protein C & S and tissue factor pathway inhibitor (TFPI)
  • Synthesise tPA
• Endothelial injury by trauma/ infectious agents/ haemodynamic forces/ plasma mediators/ cytokines = procoagulant phenotype -> enhanced thrombus formation

Platelet contact with ECM -> adhesions via Von Willebrand factor + TF

Platelets

• Disc-shaped anucleate cell fragments
• Shed from megakaryocytes in bone marrow
• Function depends on glycoprotein R, contractile cytoskeleton and cytoplasmic granules:
  •  a-granules  = adhesion molecule P-selectin on membranes, contain fibrinogen/ fibronectin, factors V + VIII, platelet factor IV , PDGF and TGF-b
  • Dense/ d-granules = contain ADP + ATP, ionized calcium, histamine, serotonin and epinephrine
• Vascular injury -> contact ECM collagen + vWF -> 3 actions:
  • Adhesion
    • vWF acts as bridge between PLT surface R (glycoprotein Ib) and collagen
    • vWF – GpIb associations important in overcoming high shear forces of flowing blood
    • vWF disease (deficiency of factor)/ Bernard – Soulier Syndrome (vWF R)
  • Secretion: granule release
    • PLT activation by ADP -> conformational change in GpIIb-IIIa R -> induced fibrinogen binding -> promote aggregation
    • Glanzmann thrombasthenia (deficiency of GpIIb/IIIa)
  • Aggregation
    • Thromboxane A2 (TxA2) – amplifies aggregation
    • Platelet contraction = irreversible fused mass of PLT

Coagulation Cascade: Formation of thrombin

• Extrinsic = exogenous trigger by TF -> measured by prothrombin time (PT) to assess function of VII, X, II, V and fibrinogen
• Intrinsic = exposed factor XII (Hageman factor) -> measured by partial thromboplastin time (PTT) screens factors XII, XI, IX, VIII, X, V, II and fibrinogen
• Several interconnections, both ultimately converge to activate factor X
• Once activated, cascade must be restricted:
  • Anti-thrombins = inhibit thrombin/ factors via binding to heparin like molecules
  • Protein C and S = vitamin K dependent proteins, inhibit factor Va and VIIIa
  • TFPI
• Fibrinolytic cascade via plasminogen -> plasmin (via tPA or streptokinase), breaks down fibrin into fibrin split products (fibrin derived D-dimers) 

Anticoagulation

• Heparin – enhances action of anti-thrombin III
• Unfractionated heparin (UFH) = inhibits factor X, II and IX
• Low molecular weight heparin (LMWH) = inhibits factor X
• Warfarin – inhibit vitamin K metabolism and prevents carboxylation of clotting factors II, VII, IX, X and Protein C/S
• Direct factor X inhibitors (both free and prothrombinase bound forms)
• Rivaroxaban/Apixaban
• Direct thrombin (II) inhibitors
  • Dabigatran

Bleeding disorders

• Haemophilia A = factor VIII deficiency
• Haemophilia B = factor IX deficiency
• Parahaemophilia = factor V deficiency
• Von Willebrands disease = vWF deficiency

Thrombosis

Three primary abnormalities: Virchow’s triad

• Endothelial injury = dysfunctional endothelial cells -> procoagulants
• Stasis or turbulent blood flow = countercurrents and local pockets of stasis -> endothelial injury
  • Atherosclerotic plaques – turbulence
  • AMI/ aneurysm/ hyperviscosity – stasis
• Hypercoagulability = alteration of coagulation cascade that predisposes to thrombosis

• Morphology = thrombi are prone to fragmentation and embolization, have laminations “Lines of Zahn” -> platelet and fibrin deposits alternating with dark red cell-rich layers -> thrombus formed in flowing blood (s/o antemortem)
  • Cardiac mural thrombi
  • Cardiac valve thrombi “vegetations” = infective/ non bacterial/ associated with SLE (Libman- Sacks endocarditis)
  • Arterial thrombi (occlusive) = friable meshwork of platelets, fibrin, red cells etc.
  • Venous thrombi = red cells > platelets “red thrombi”
  • Post mortem clots = gelatinous, dark red lower portion (red cells settled) with yellow “chicken fat” upper portion
• Fate of thrombus = propagation (growth), embolization (dislodge and travel), dissolution (shrinkage) or organisation + recanalization (converted into connective tissue)

Embolism

= Detached intravascular solid/liquid/gaseous mass that is carried by blood to a site distant from its origin

Most represent dislodged thrombus ~thromboembolism

Rare forms include fat droplet, nitrogen bubbles, atherosclerotic debris, tumour fragments, bone marrow or foreign bodies

• PE = formed from fragmented thrombi of DVT -> main pulmonary artery, bifurcation or smaller vessels -> sudden death, RVF or cardiovascular collapse
• Systemic thromboembolism = intracardiac mural thrombi associated with AMI/ AF/ valve vegetations/ atherosclerotic plaques -> lower extremities, brain, bowel, other organs
• Fat/ marrow embolism = trauma, burns due to rupture of marrow vascular sinusoids or venules. Fat Emboli Syndrome:
  • Mechanical obs + biochemical injury
  • 1-3 days post injury, develop pulmonary insufficiency, neurologic symptoms, anaemia and thrombocytopaenia
    • Anaemia – RBC aggregation/haemolysis -> occlude pulmonary/cerebral vasculature
    • Thrombocytopaenia – PLT adhesion to fat globules -> diffuse petechial rash
    • Release of fatty acids -> toxic to endothelium
• Air embolism = gas bubbles coalesce to form frothy mass which obstructs vascular flow
  • Post operatively
  • ~100cc air required for clinical sx
  • Decompression sickness = rapid formation of gas bubbles within tissues. Air breathed at high pressure (diving) -> increased amount of gas (nitrogen) dissolved into blood. If diver ascends too rapidly (depressurises) nitrogen comes out of solution into tissues -> “bends”
• Amniotic fluid embolism = sudden post partum dyspnoea, cyanosis, shock -> neurologic impairment, APO, DIC secondary to thrombogenic substances released from amniotic fluid
  • Infusion of amniotic fluid into maternal circulation via tear in placental membrane/ rupture uterine veins
  • Findings = foetal skin squamous cells, lanugo hair, fat from vernix caseosa and mucin from foetal respiratory/ gastrointestinal tract

Infarction

= Area of ischaemic necrosis caused by occlusion of arterial supply or venous drainage

• Thrombotic or embolic occlusion OR local vasospasm, haemorrhage into atherosclerotic plaque, extrinsic vessel compression (tumour), torsion of vessel (testicular torsion), traumatic rupture or vascular compromise by oedema (compartment syndrome)
• Morphology: colour +/- infection
  • Red infarcts = haemorrhagic
    • venous occlusions (ovary)
    • loose tissues or tissues with dual circulations (lung) -> blood collects in infarcted zone
    • tissues previously congested with sluggish venous outflow
    • when flow is re-established (angioplasty to arterial obstruction)
  • White infarcts = anaemic
    • Arterial occlusions in solid organs, where tissue density limits seepage of blood from nearby capillary beds into necrotic area (kidney)
  • Wedge shaped with occluded vessel at apex
  • Ischaemic coagulative necrosis is dominant histologic feature
• Factors influencing development of infarct:
  • Nature of vascular supply (lungs/liver have dual supply – more resistant)
  • Rate of occlusion development (slow = collaterals = less likely infarct)
  • Vulnerability to hypoxia (neurons more sensitive than fibroblasts)
  • Oxygen content of blood (anaemia/ cyanosis = infarction)

Shock

= Systemic hypotension due to reduced cardiac output or reduced circulating blood volume -> impaired tissue perfusion and cellular hypoxia

Categories:

• Cardiogenic = myocardial pump failure
• Hypovolaemic = loss of volume
• Distributive = septic/anaphylactic
• Neurogenic = loss of vascular tone
• Obstructive = tamponade/pneumothorax/ PE

Septic Shock

• Systemic vasodilation + peripheral blood pooling -> hypoperfusion

• Stages of Shock:
  • Non progressive (compensatory mechanisms: RAAS, catecholamine release, ADH, sympathetic stimulation)
  • Progressive (hypoperfusion, lactic acidosis)
  • Irreversible (lysosomal leakage causing cell injury)
  • Death

• Morphology = changes seen in hypoxic injury in brain/ heart/ lungs (diffuse alveolar damage)/ kidneys (ATN), adrenals (cortical cell lipid depletion)

• 5 major factors contributing:

Last Updated on August 20, 2021 by Andrew Crofton