Robbins Chapter 5: Hemodynamic Disorders, Thrombosis and Shock
Robbins Chapter 5: Hemodynamic Disorders, Thrombosis and Shock
60% of lean body weight is water.
5% of total body water is in plasma.
Losses of >20% of blood volume lead to hemorrhagic shock.
Edema def. fluid in interstitial tissue.
|Increased Hydrostatic Pressure||Impaired venous return (CHF, cirrhosis, thrombosis)
Arteriolar dilation (heat)
|Reduced Plasma Oncotic Pressure||Nephrotic syndrome, Malnutrition, Cirrhosis|
|Lymphatic Obstruction||Inflammatory, Neoplastic, Post-surgical|
|Sodium Retention||Renal insufficiency, Hyperaldosterone|
|Inflammation||Acute, Chronic, Angiogenesis|
Transudate: def. protein-poor, s.g.< 1.012, secondary to hydrodynamic impairments
Exudate: def. protein-rich, s.g.>1.012, secondary to inflammation and increased vascular permeability
Hyperemia and Congestion
Hyperemia def. active process of arteriolar dilation leading to local increase in blood volume.
Congestion def. passive process of increase in blood volume due to impaired outflow.
Chronic pulmonary congestion: septa thickened and fibrotic, hemosiderin-laden macrophages (heart failure cells)
Acute hepatic congestion: central veins and sinusoids are distended and there may be central necrosis.
Chronic passive congestion: nutmeg liver, centrilobular necrosis and hepatic fibrosis (cardiac cirrhosis).
def. extravasation of blood because of vessel rupture. Accumulation is a hematoma.
1-2 mm petichiae: thrombocytopenia, uremia, clotting factor deficiencies
> 3 mm purpura: trauma, vasculitis, amyloidosis.
> 1-2 cm ecchymoses: trauma, clotting factor deficiencies, worsened by all of the above… hemoglobin (red-blue)… bilirubin (blue-green)… hemosiderin (gold-brown).
Hemostasis and Thrombosis
1. vasoconstriction – endothelin
2. platelet adherence and activation – primary hemostatic plug
3. coagulation cascade stimulated by the release of tissue factor – leads to activation of thrombin – secondary hemostatic plug
4. permanent plug – counterregulatory mechanisms [t-PA]
Endothelium: has procoagulant and anti-thrombotic properties.
Intact endothelium is anti-platelet (PGI2, NO, ADP), anti-coagulant (heparin-like molecules, thrombomuodulin, antithrombin III), fibrinolytic (t-PA)
Endothelial injury leads to adhesion of platelets via vWF, synthesizes tissue factor (TNF, IL-1), PAIs (plasminogen activator inhibitors)
Alpha granules: P-selectin, fibrinogen, fibronectin, factor V, vWF, plateket factor 4, PDGF, TGF-b
Dense bodies (d granules): ADP, ATP, Ca, histamine, serotonin, epinephrine
Adhesion: vWF – glycoprotein Ib, fibrinogen
Secretion: granules, ADP mediates aggregation
Aggregation: ADP, TXA2, thrombin, platelet contraction, GpIIb-IIIa receptors
Once activated must be restricted to the site of vascular injury to prevent clotting of the entire vascular tree.
Antithrombin III: inactivates IX, X, XI, XII and II
Protein C & S: inactivate V and VIII
Plasmin: breaks down fibrin into FSP (fibrin split products), which can act as local, weak anticoagulants
urokinase-like tPA, tissue-type tPA
PGI2: vasodilator, inhibits platelet aggregation
TXA2: vasoconstrictor, activates platelet aggregation (aspirin blocks synthesis, by acetylating cyclooxygenase)
Virchow’s triad: endothelial injury, stasis, hypercoagulability
Hypercoagulable states: Factor V Leiden, Protein C/S deficiency, homocysteine, prothrombin mutations
Hyperestrogenic states (pregnancy, OCP): increased hepatic synthesis of certain coagulation factors and reduced synthesis of antithrombin III.
Disseminated cancers: procoagulant tumor products
Age: increasing platelet aggregation and reduced PGI2.
Factor V Leiden
Clinical: 2-15% white population
Pathophysiology: Mutant factor V Leiden cannot be inactivated by protein C
Cytogenetics: arginine ® glutamine at position 506
Clinical: 5% of population
Pathophysiology: Rx with unfractionated heparin results in formation of antibodies to heparin platelet factor 4.
Treatment: low molecular weight heparin preparations, retain anticoagulant activities but do not interact with platelets
Antiphospholipid Antibody Syndrome
Clinical: Multiple thromboses associated with high serum titers to membrane phospholipids (cardiolipin). Autoimmune associated type exists.
Recurrent venous or arterial thrombi, repeated miscarriages, cardiac valce vegetations, thrombocytopenia, 7% increased risk of sudden death.
Two clinical groups: one associated with SLE, the other shows only hypercoagulability without lupus.
Arterial thrombi occur in sites of injury while venous occur due to stasis.
Pathophysiology: Abs interfere with coagulation in vitro but induce hypercoagulative state in vivo (via direct platelet activation, PGI2 or protein C inhibition)
Micro: Lines of Zahn imply thrombosis at sites of blood flow. Arterial thrombi (retrograde propagation) at coronary, cerebral and femoral arteries. Venous thrombi propagate in the direction of blood flow; 90% lower extremities.
Diagnosis: False positive VDRL (embedded in cardiolipin). Also present in 5-15% of normal individuals.
Treatment: Anticoagulation with aspirin, heparin, coumadin, prednisone for recurrent miscarriages and immunosuppression in refractory cases.
Fate of a Thrombus:
4. Organization & Recanalization.
With older thrombi extensive fibrin polymerization renders the thrombus more resistant to proteolysis.
May become a culture medium for bacteria – mycotic aneurysm.
Venous thrombi: asymptomatic in 50%. Risk factors include CHF, trauma, surgery, burns, puerperal and postpartum states, disseminated cancers (see TRousseau’s syndrome – migratory thrombophlebitis).
Cardiac thrombi: brain, kidneys and spleen are prime targets.
DIC is a potential complication of any condition associated with widespread activation of thrombin.
Embolism def. detached intravascular solid, liquid, or gaseous mass that is carried by the blood to a site distant from its point of origin. 99% are dislodged thrombi.
Clinical: 20-25/100,000 hospitalized patients; 95% from deep leg vein thrombi above the knee.
Rarely may pass through an interatrial or interventricular defect to gain access to the systemic circulation (paradoxical embolism).
60-80% clinically silent (small). When 60% or more of the pulmonary circulation is obstructed leads to sudden death, right heart failure or cardiovascular collapse.
Micro: Usually causes pulmonary hemorrhage not infarction(dual blood supply) unless in the setting of left sided cardiac failure.
Clinical: 80% arise from intracardiac mural thrombi (2/3 assoc with LVW infarcts, 1/4 with dilated L atria); remainder arise from aortic aneurysms, plaques or valve vegetations. 75% go to lower extremities and 10% go to the brain.
Clinical: After fractures of long bones, soft tissue trauma or burns. 90% of individuals with severe skeletal injuries, though <10% have any clinical findings. Fat embolism syndrome begins 1-3 days after injury with tachypnea, dyspnea and tachycardia, neurologic sx, diffuse petechial rash (20-50%), thrombocytopenia, anemia.
Pathophysiology: Mechanical obstruction and biochemical injury. Free fatty acids cause local toxic injury to endothelium, platelet activation.
Prognosis: Syndrome fatal in 10%.
AKA: Decompression sickness, “the bends” or “the chokes”, caisson disease
Clinical: In excess of 100cc required to have a clinical effect. Painful muscle cramps, respiratory insufficiency, neurological sx.
Pathophysiology: Formation of gass bubbles within skeletal muscle, soft tissues and joints causes pain. Focal ischemia to brain and heart.
Micro: Pulmonary edema and hemorrhage, focal atelectasis or emphysema. Persistence of gas emboli in the skeletal system leads to multiple foci of ischemic necrosis (femoral head, tibia and humerus).
Amniotic Fluid Embolism
Clinical: 1 in 50,000 deliveries. 80% mortality rate. Sudden severe dyspnea, cyanosis, and hypotensive shock, followed by seizures and coma. Pulmonary edema and DIC.
Micro: Pulmonary microcirculation with epithelial squamous cells shed from fetal skin, lanugo hair, fat from vernix, mucin from GI tract. Pulmonary edema and DAD. Systemic fibrin thrombi (DIC).
Infarction def. area of ischemic necrosis caused by occlusion of either arterial supply or venous drainage. 99% from thrombotic or embolic events. Remainder: local vasospasm, extrinsic compression, hemorrhage within a plaque, torsion, traumatic rupture. Infarcts caused by venous thrombosis are more common in organs with single venous outflows: e.g. testis, ovary.
Red Infarct (hemorrhagic): venous occlusions, loose tissues (lung), dual circulations, congested, when flow reestablished
White Infarcts (anemic): arterial occlusions or solid organs (heart, spleen, kidney).
Micro: wedge-shaped, overlying fibrinous exudate, margins better defined with time.
minutes to hours – usu no demonstrable changes
12-18 hrs – hemorrhage
few hours to 1 -2 days – inflammatory response, parenchymal regeneration
Factors That Influence Development of an Infarct:
1. vascular supply
2. rate of development of occlusion (time for development of alternate perfusion pathways)
3. vulnerability of the tissue to hypoxia (neurons 3-4 minutes, myocardium 20-30 minutes)
4. the blood oxygen content (e.g. ventilation)
Cardiogenic – myocardial pump failure
Hypovolemic – loss of blood or plasma volume
Septic – 25-75% mortality rate; 70% gram-negative bacilli. Endotoxins are LPS released when cell wall is degraded. LPS directlt activates complement. Monocytes respond by producing TNF, IL-1® fever and synthesis or acute phase reactants.
· systemic vasodilation
· ¯ myocardial contractility
· endothelial injury ® leukocyte adhesion ® ARDS
Neurogenic – spinal cord injury, anesthesia
Anaphylactic – IgE mediated
Stages of Shock: nonprogressive (compensated), progressive (widespread hypoxia), irreversible
brain – ischemic encephalopathy
heart – contraction band necrosis
kidneys – ATN
lungs – DAD
adrenal – cortical cell lipid depletion
GI tract – patchy mucosal hemorrhages
liver – fatty change, centilobular necrosis
Prognosis: varies with origin and duration. 80-90% of young, healthy survive hypovolemic shock with management. 75% mortality for cardiogenic shock with MI and gram negative septic shock.