Chapter 4: Hemodynamic Disorders, Thromboembolic Disease, and Shock Flashcards
Disorders that perturb cardiovascular, renal, or hepatic function are often marked by the accumulation of fluid in the tissues or body cavities. What is this called?
Edema: accumulation of fluid in tissues
Effusion: accumulation of tissues in body cavities
What two pressure changes in vessels disrupt the vascular fluid balance, resulting in movement of fluid out of vessels (i.e. edema, effusion)?
- Elevated hydrostatic pressure
- Diminished colloid osmotic pressure
Factors influencing fluid movement across capillary walls. Normally, hydrostatic and osmotic forces are nearly balanced so that there is little net movement of fluid out of vessels. Many different pathologic disorders (Table 4-1) are associated with increases in capillary hydrostatic pressure or decreases in plasma osmotic pressure that lead to the extravasation of fluid into tissues. Lymphatic vessels remove much of the excess fluid, but if the capacity for lymphatic drainage is exceeded, tissue edema results.
Edema fluids and effusions can be inflammatory or noninflammatory. What are some differences?
Inflammatory exudates:
- accumulate due to increased vascular permeability
- protein-rich
- higher cellularity
Noninflammatory transudates:
- accumulate due to changes in pressures (e.g. heart failure, liver failure)
- lower protein
- lower cellularity
Pathophysiologic mechanisms of edema/effusions
1. Increases in hydrostatic pressure (usually due to impaired venous return) (e.g. congestive heart failure - systemic, DVT - localized)
2. Reduced plasma oncotic pressure: Under normal circumstances, albumin accounts for almost half of the total plasma protein; inadequate synthesis or increased loss of albumin are common causes of reduced PCOP (e.g. liver failure, protein malnutrition, nephrotic syndrome)
3. Salt and water retention: Increased salt retention - with obligate retention of associated water - causes both increased CHP (due to intravascular fluid volume expansion) and decreased PCOP (dilutional). Salt retention occurs with renal failure (intrinsic or 2ndary to CV disease and dec. perfusion). CHF results in activation of RAAS (beneficial early in CHF to increase vascular tone and improve CO to restore renal perfusion, but harmful as CO diminishes with progressive CHF - retained fluid just increases hydrostatic pressure)
4. Lymphatic obstruction: Trauma, fibrosis, invasive tumors, and infectious agents can all disrupt lymphatic vessels and impair interstital fluid clearance, resulting in lymphedema.
TABLE: Pathophysiologic categories of edema
Mechanisms of systemic edema in heart failure, renal failure, malnutrition, hepatic failure, and nephrotic syndrome.
Edema morphology
KEY CONCEPTS: Edema
Hyperemia and congestion
Hyperemia and congestion both stem from increased blood volumes within tissues, but have different underlying mechanisms and consequences.
- Hyperemia*: an active process; arteriolar dilation leads to increased blood flow - affected tissues turn red due to increased delivery of oxygenated blood
- Congestion*: passive process resulting from reduced outflow of blood from a tissue. (e.g. systemic - cardiac failure, localized - isolated venous obstruction). Leads to high CHP and edema. Long-standing congestion can lead to chronic hypoxia and ischemic injury / scarring.
Congestion morphology
Liver with chronic passive congestion and hemorrhagic necrosis.
A, Central areas are red and slightly depressed compared with the surrounding tan viable parenchyma, forming a “nutmeg liver” pattern (so-called because it resembles the cut surface of a nutmeg).
B, Centrilobular necrosis with degenerating hepatocytes and hemorrhage.
Hemostasis, hemorrhagic disorders, thrombosis - definitions
- Hemostasis*: Process by which blood clots form at sites of vascular injury
- Hemorrhagic disorders:* Excessive bleeding, due to either blunted or insufficient hemostatic mechanisms
- Thrombotic disorders:* Blood clots forming within intact vessels or in the heart
- Disseminated intravascular coagulation (DIC)*: generalized activation of clotting, leading to consumption of coagulation factors and an often fatal clinical bleeding syndrome
Hemostasis
Detailed definition, basic steps involved
Hemostasis is a precisely orchestrated process involving platelets, clotting factors and endothelium that occurs at the site of vascular injury and culminates in the formation of a blood clot, which serves to prevent or limit the extent of bleeding.
- Arteriolar vasoconstriction:* Occurs immediately and transiently, markedly reducing blood flow to the area. Mediated by reflex neurogenic mechanisms and augmented by local secretion of factors (e.g. endothelin).
- Primary hemostasis: formation of a platelet plug:* Disruption of endothelium exposes subendothelial vWF and collagen, which promote platelet adherence and activation.
- Secondary hemostasis:* deposition of fibrin: Tissue factor is also exposed at injury site, which stimulates extrinsic pathway via activation of factor VII. This and the intrinsic pathway converge on the common pathway, which leads to activation of thrombin and fibrinogen cleavage
- Clot stabilization and resorption*: Polymerized fibrin and platelet aggregates are broken down and clotting is limited by counterregulatory mechanisms (e.g. t-PA)
Platelets:
Role in hemostasis and morphology
Platelets play a critical role in hemostasis by forming the primary plug that initially seals vascular defects and by providing a surface that binds and concentrates activated coagulation factors.
disc-shaped, anucleate cell fragments with alpha- and dense- cytoplasmic granules
Contents of alpha- and dense- granules of platelets
Alpha granules:
- P-selectin on their membranes
Coagulation proteins
- fibrinogen
- factor V
- factor VIII
- vWF
Wound healing factors
- fibronectin
- platelet factor 4 (heparin-binding chemokine)
- PDGF
- TGF-b
- *Dense granules:**
- ADP
- ATP
- iCa
- Serotonin
- Epinephrine
Steps of platelet plug formation (i.e. primary hemostasis)
- *1. Platelet adhesion**
- Mediated via vWF, which is exposed by subendothelial collagen when there is an endothelial defect
- vWF binds GpIb on paltelet membrane
- *2. Platelet shape change**
- Following adhesion, platelets go from somoth discs to spiky ‘sea urchins’ with greater surface area
- GP IIb/IIIa undergoes changes, which increase it’s affinity for fibrinogen
- phosphatidylserine translocates to the outer leaflet of plasma membrane which provides a negative surface for coagulation
- *3. Secretion of granule contents**
- Shape change + granule secretion = platelet activation
- Triggered by thrombin, ADP, and others
- Thrombin activates platelets via a protease-activated receptor (PAR), a G-protein coupled receptor
- Activated platelets produce TxA2, which induces platelet aggregation. Aspirin inhibits COX, decreasing TxA2 synthesis, and inhibiting platelet aggregation
- *4. Platelet aggregation**
- Conformational change in gp IIb/IIIa makes it bind fibrinogen more, which is the platelet-platelet bridge
- initial wave of aggregation is reversible, but concurrent activation of thrombin stabilizes the plug by causing further platelet activation and aggregation, promoting irreversible platelet contraction
Platelet adhesion and aggregation. Von Willebrand factor functions as an adhesion bridge between subendothelial collagen and the glycoprotein Ib (GpIb) platelet receptor. Aggregation is accomplished by fibrinogen bridging GpIIb-IIIa receptors on different platelets. Congenital deficiencies in the various receptors or bridging molecules lead to the diseases indicated in the colored boxes. ADP, adenosine diphosphate.
Coagulation cascade:
Definition, Different pathways and how they’re tested
The coagulation cascade is a series of amplifying enzymatic reactions that leads to the deposition of an insoluble fibrin clot.
Intrinsic and common pathways are tested with aPTT: negatively-charged particles (e.g. ground glass) are added with phospholipids and calcium, and time to clot formation is recorded (tests factors XII, XI, IX, VIII, X, V, II, fibrinogen)
Extrinsic and common pathways are tested with PT: tissue factor, phospholipids, and calcium are added to plasma and time to clot formation is recorded (tests factors VII, X, V, II, fibrinogen
The coagulation cascade in the laboratory and in vivo.
A, Clotting is initiated in the laboratory by adding phospholipids, calcium, and either a negative charged substance such as glass beads (intrinsic pathway) or a source of tissue factor (extrinsic pathway).
B, In vivo, tissue factor is the major initiator of coagulation, which is amplified by feedback loops involving thrombin (dotted lines). The red polypeptides are inactive factors, the dark green polypeptides are active factors, while the light green polypeptides correspond to cofactors..
Schematic illustration of the conversion of factor X to factor Xa via the extrinsic pathway, which in turn converts factor II (prothrombin) to factor IIa (thrombin). The initial reaction complex consists of a proteolytic enzyme (factor VIIa), a substrate (factor X), and a reaction accelerator (tissue factor), all assembled on a platelet phospholipid surface. Calcium ions hold the assembled components together and are essential for the reaction. Activated factor Xa becomes the protease for the second adjacent complex in the coagulation cascade, converting prothrombin substrate (II) to thrombin (IIa) using factor Va as the reaction accelerator.
Deficiencies of which factors are associated with moderate to severe bleeding disorders
Which factor deficiency only leads to only mild bleeding, if any?
V, VII, VIII, IX, X
XII
Which coagulation factor is most important?
What are some of its most important functions?
Among the coagulation factors, thrombin is the most important, in that its various enzymatic activities control diverse aspects of hemostasis and link clotting to inflammation and repair.
- Conversion of fibrinogen to crosslinked fibrin: Thrombin directly converts fibrinogen into fibrin, and also does so by amplifying the coagulation cascade (activating factors XI, V, VIII). It also activates factor XIII which covalently cross-links fibrin
- Platelet activation: Thrombin is a potent inducer of platelet activation and aggregation through its activity with PARs
- Pro-inflammatory effects: PARs are expressed on inflammatory cells and endothelium; activation by thrombin mediates pro-inflammatory effects
- Anticoagulant effects: When it encounters normal endothelium, thrombin changes from pro- to anti-coagulant, preventing excessive clotting
Role of thrombin in hemostasis and cellular activation. Thrombin plays a critical role in generating cross-linked fibrin (by cleaving fibrinogen to fibrin and by activating factor XIII), as well as activating several other coagulation factors (see Fig. 4-6B). Through protease-activated receptors (PARs, see text), thrombin also modulates several cellular activities. It directly induces platelet aggregation and TxA2 production, and activates endothelial cells, which respond by expressing adhesion molecules and a variety of fibrinolytic (t-PA), vasoactive (NO, PGI2), and cytokine mediators (e.g., PDGF). Thrombin also directly activates leukocytes. ECM, extracellular matrix; NO, nitric oxide; PDGF, platelet-derived growth factor; PGI2, prostacyclin; TxA2, thromboxane A2; t-PA, tissue plasminogen activator. See Figure 4-10 for additional anticoagulant activities mediated by thrombin.
Factors that limit coagulation
- Simple dilution: blood flowing past injury site washes out coag factors, which are then removed by the liver
- Requirement for negatively charged phospholipids, provided by platelets that are activated by contact with subendothelial matrix
- Factors expressed by intact endothelium adjacent to the site of injury
Activation of coagulation cascade also sets into motion a fibrinolytic cascade which limits the size of the clot and contributes to its dissolution.
Plasmin, the activated form of plasminogen is a key enzyme which breaks down fibrin. Plasminogen is activated by a factor XII-dependent pathway or by plasminogen activators (e.g. t-PA, produced by endothelium)
Fibrin breakdown products (e.g. D-dimers) are useful markers of thrombotic states.
The fibrinolytic system, illustrating various plasminogen activators and inhibitors (see text).
Anticoagulant activities of normal endothelium. NO, nitric oxide; PGI2, prostacyclin; t-PA, tissue plasminogen activator; vWF, von Willebrand factor. The thrombin receptor is also called a protease-activated receptor (PAR).
Normal hemostasis.
A, After vascular injury, local neurohumoral factors induce a transient vasoconstriction.
B, Platelets bind via glycoprotein Ib (GpIb) receptors to von Willebrand factor (vWF) on exposed extracellular matrix (ECM) and are activated, undergoing a shape change and granule release. Released adenosine diphosphate (ADP) and thromboxane A2 (TxA2) induce additional platelet aggregation through platelet GpIIb-IIIa receptor binding to fibrinogen, and form the primary hemostatic plug.
C, Local activation of the coagulation cascade (involving tissue factor and platelet phospholipids) results in fibrin polymerization, “cementing” the platelets into a definitive secondary hemostatic plug.
D, Counterregulatory mechanisms, mediated by tissue plasminogen activator (t-PA, a fibrinolytic product) and thrombomodulin, confine the hemostatic process to the site of injury.
A, Punctate petechial hemorrhages of the colonic mucosa, a consequence of thrombocytopenia.
B, Fatal intracerebral bleed.
The Virchow triad in thrombosis. Endothelial integrity is the most important factor. Injury to endothelial cells can alter local blood flow and affect coagulability. Abnormal blood flow (stasis or turbulence), in turn, can cause endothelial injury. These factors may promote thrombosis independently or in combination.
TABLE: Hypercoagulable states
KEY CONCEPTS: Thrombosis
KEY CONCEPTS: Embolism
MORPHOLOGY: Infarcts
KEY CONCEPTS: Infarction
TABLE: Three major types of shock
Major pathogenic pathways in septic shock. Microbial products (PAMPs, or pathogen-associated molecular patterns) activate endothelial cells and cellular and humoral elements of the innate immune system, initiating a cascade of events that lead to end-stage multiorgan failure. Additional details are given in the text. DIC, Disseminated vascular coagulation; HMGB1, high mobility group box 1 protein; NO, nitric oxide; PAF, platelet activating factor; PAI-1, plasminogen activator inhibitor 1; TF, tissue factor; TFPI, tissue factor pathway inhibitor.
MORPHOLOGY: Shock
KEY CONCEPTS: Shock
