Chapter 4: Hemodynamic Disorders, Thromboembolic Disease, and Shock

Question 1

Edema may be caused by..?

Answer 1

• Increased hydrostatic pressure (e.g., heart failure)
• Decreased colloid osmotic pressure caused by reduced plasma albumin, either due to decreased synthesis (e.g., liver disease, protein malnutrition) or to increased loss (e.g., nephrotic syndrome)
• Increased vascular permeability (e.g., inflammation)
• Lymphatic obstruction (e.g., infection or neoplasia)
• Sodium and water retention (e.g., renal failure)

Question 2

Endothelial injury exposes the underlying basement membrane ECM; platelets adhere to the ECM primarily through the binding of..?

Answer 2

…platelet GPIb receptor (platelet) to vWF (subendothelial matrix).

Question 3

Platelet adhesion leads to platelet activation, an event associated with..?

Answer 3

• Secretion of platelet granule contents, including calcium (a cofactor for several coagulation proteins) and ADP (a mediator of further platelet activation)
• Dramatic changes in shape and membrane composition
• Activation of GpIIb/IIIa receptors

Question 4

Activation of GpIIb/IIIa receptors on activated platelets does..?

Answer 4

The GpIIb/IIIa receptors on activated platelets form bridging cross-links with fibrinogen, leading to platelet aggregation.

Question 5

What process is responsible for cementing the platelet plug in place?

Answer 5

Concomitant activation of thrombin promotes fibrin deposition, cementing the platelet plug in place.

Question 6

The prothrombin time (PT) assay assesses the function of the proteins of which pathway. Also list those proteins.

Answer 6

Extrinsic pathway: factors VII (7), X, V, II [prothrombin], and fibrinogen.

PT –> Play Tennis –> extrinsic (outdoor) –> 7up (refreshment)

Question 7

The partial thromboplastin time (PTT) assay assesses the function of the proteins of which pathway. Also list those proteins.

Answer 7

Intrinsic pathway: factors XII, XI, IX, VIII (8, 9, 11, 12), X, V, II [prothrombin], and fibrinogen.

PTT –> Table tennis –> intrinsic (indoor)

Question 8

Among thrombin’s most important activities are the following..?

Answer 8

• Conversion of fibrinogen into cross-linked fibrin. Thrombin directly converts soluble fibrinogen into fibrin monomers that polymerize into an insoluble fibril, and also amplifies the coagulation process, not only by activating factor XI, but also by activating two critical cofactors: factors V and VIII. It also stabilizes the secondary hemostatic plug by activating factor XIII, which covalently cross-links fibrin.
• Platelet activation. Thrombin is a potent inducer of platelet activation and aggregation through its ability to activate PAR-1, thereby linking platelet function to coagulation.
• Pro-inflammatory effects. PARs also are expressed on inflammatory cells, endothelium, and other cell types (Fig. 4.8), and activation of these receptors by thrombin is believed to mediate pro-inflammatory effects that contribute to tissue repair and angiogenesis.
• Anticoagulant effects. Remarkably, on encountering normal endothelium, thrombin changes from a procoagulant to an anticoagulant; this reversal in function prevents clots from extending beyond the site of the vascular injury.

Question 9

Hypercoagulability has a particularly important role in which type of thrombosis?

Answer 9

Venous thrombosis

Question 10

Inherited causes of hypercoagulability?

Answer 10

• Factor V Leiden. Approximately 2% to 15% of Caucasians carry a single-nucleotide mutation in factor V that is called factor V Leiden, after the city in the Netherlands where it was discovered. Among individuals with recurrent DVT, the frequency of this mutation is considerably higher, approaching 60%. This mutation renders factor V resistant to cleavage and inactivation by protein C. As a result, an important antithrombotic counterregulatory pathway is lost (see Fig. 4.10). The inheritance pattern for factor V Leiden is autosomal dominant. Heterozygotes have a fivefold increased relative risk of venous thrombosis, and homozygotes have a 50-fold increase.
• Prothrombin gene mutation. A single nucleotide change (G20210A) in the 3′-untranslated region of the prothrombin gene is another common mutation (1% to 2% of the population) associated with hypercoagulability. It leads to elevated prothrombin levels and an almost threefold increased risk of venous thrombosis.
• Other inherited causes. Rare inherited causes of primary hypercoagulability include deficiencies of anticoagulants such as antithrombin III, protein C, or protein S; affected individuals typically present with venous thrombosis and recurrent thromboembolism beginning in adolescence or early adulthood.
• Homocysteinemia. Elevated levels of homocysteine may be inherited or acquired. Marked elevations of homocysteine may be caused by an inherited deficiency of cystathione β-synthetase. Acquired causes include deficiency of vitamin B6, B12, and folic acid. Prothrombotic effects of homocysteine may be due to thioester linkages formed between homocysteine metabolites and a variety of proteins, including fibrinogen.
• Increased levels of factors VIII, IX, XI, or fibrinogen (genetics unknown).

Question 11

List strong risk factors for thrombosis (acquired hypercoagulability).

Answer 11

• Prolonged bed rest or immobilization
• Myocardial infarction
• Atrial fibrillation
• Tissue injury (surgery, fracture, burn)
• Cancer
• Prosthetic cardiac valves
• Disseminated intravascular coagulation
• Heparin-induced thrombocytopenia (HIT syndrome)
• Antiphospholipid antibody syndrome

Question 12

Different fates of a thrombus..?

Answer 12

• Propagation. Thrombi accumulate additional platelets and fibrin.
• Embolization. Thrombi dislodge and travel to other sites in the vasculature.
• Dissolution. Dissolution is the result of fibrinolysis, which can lead to the rapid shrinkage and total disappearance of recent thrombi. In contrast, the extensive fibrin deposition and cross-linking in older thrombi render them more resistant to lysis. This distinction explains why therapeutic administration of fibrinolytic agents such as t-PA (e.g., in the setting of acute coronary thrombosis) is generally effective only when given during the first few hours of a thrombotic event.
• Organization and recanalization. Older thrombi become organized by the ingrowth of endothelial cells, smooth muscle cells, and fibroblasts. Capillary channels eventually form that reestablish the continuity of the original lumen, albeit to a variable degree. Continued recanalization may convert a thrombus into a smaller mass of connective tissue that becomes incorporated into the vessel wall. Eventually, with remodeling and contraction of the mesenchymal elements, only a fibrous lump may remain to mark the original thrombus.

Question 13

Components of Virchow’s triad with one cause for each?

Answer 13

• Endothelial injury (e.g., by toxins, hypertension, inflammation, or metabolic products) associated with endothelial activation and changes in endothelial gene expression that favor coagulation
• Abnormal blood flow—stasis or turbulence (e.g., due to aneurysms, atherosclerotic plaque)
• Hypercoagulability, either primary (e.g., factor V Leiden, increased prothrombin synthesis, antithrombin III deficiency) or secondary (e.g., bed rest, tissue damage, malignancy, or development of aPL antibodies [antiphospholipid antibody syndrome]) or antibodies against PF4/heparin complexes [heparin-induced thrombocytopenia])

Question 14

Situations giving rise to hemorrhagic (“red”) infarcts?

Answer 14

• With venous occlusions (e.g., testicular torsion)
• In tissues previously congested by sluggish venous outflow
• In loose, spongy tissues (e.g., lung) where blood can collect in the infarcted zone
• In tissues with dual circulations (e.g., lung and small intestine) that allow blood to flow from an unobstructed parallel supply into a necrotic zone
• When flow is reestablished to a site of previous arterial occlusion and necrosis (e.g., following angioplasty of an arterial obstruction)

Question 15

Different types of shock?

Answer 15

• Cardiogenic shock results from low cardiac output due to myocardial pump failure. This can be due to intrinsic myocardial damage (infarction), ventricular arrhythmias, extrinsic compression (cardiac tamponade), or outflow obstruction (e.g., pulmonary embolism).
• Hypovolemic shock results from low cardiac output due to low blood volume, such as can occur with massive hemorrhage or fluid loss from severe burns.
• Septic shock (infections).
• Less commonly, shock can occur in the setting of a spinal cord injury (neurogenic shock), or an IgE-mediated hypersensitivity reaction (anaphylactic shock). In both of these forms of shock, acute vasodilation leads to hypotension and tissue hypoperfusion.

Question 16

Factors believed to play major roles in the pathophysiology of septic shock include the following..?

Answer 16

• Inflammatory and counter-inflammatory responses. In sepsis, various microbial cell wall constituents engage receptors on cells of the innate immune system, triggering pro-inflammatory responses. The hyperinflammatory state, initiated by sepsis, triggers counter-regulatory immunosuppressive mechanisms, which may involve both innate and adaptive immune cells.
• Endothelial activation and injury. The pro-inflammatory state and endothelial cell activation associated with sepsis lead to widespread vascular leakage and tissue edema, which have deleterious effects on both nutrient delivery and waste removal. One effect of inflammatory cytokines is to loosen endothelial cell tight junctions, making vessels leaky and resulting in the accumulation of protein-rich edema fluid throughout the body. This alteration impedes tissue perfusion and may be exacerbated by attempts to support the patient with intravenous fluids. Activated endothelium also upregulates production of NO and other vasoactive inflammatory mediators (e.g., C3a, C5a, and PAF), which may contribute to vascular smooth muscle relaxation and systemic hypotension. Another feature of sepsis is microvascular dysfunction. There is an increase in capillaries with intermittent flow, and heterogeneity of flow in various capillary beds, and the normal autoregulation of flow based on tissue metabolic environment is lost. These changes cause a mismatch in oxygen needs and oxygen delivery.
• Induction of a procoagulant state. The derangement in coagulation is sufficient to produce the formidable complication of DIC in up to one-half of septic patients.
• Metabolic abnormalities. Septic patients exhibit insulin resistance and hyperglycemia. Hyperglycemia decreases neutrophil function—thereby suppressing bactericidal activity—and causes increased adhesion molecule expression on endothelial cells. Although sepsis is initially associated with an acute surge in glucocorticoid production, this phase may be followed by adrenal insufficiency and a functional deficit of glucocorticoids. This may stem from depression of the synthetic capacity of intact adrenal glands or frank adrenal necrosis resulting from DIC (Waterhouse-Friderichsen syndrome). Finally, cellular hypoxia and diminished oxidative phosphorylation lead to increased lactate production and lactic acidosis.
• Organ dysfunction. Systemic hypotension, interstitial edema, microvascular dysfunction, and small vessel thrombosis all decrease the delivery of oxygen and nutrients to the tissues that, because of cellular hypoxia, fail to properly use those nutrients that are delivered. Mitochondrial damage resulting from oxidative stress impairs oxygen use. High levels of cytokines and secondary mediators diminish myocardial contractility and cardiac output; increased vascular permeability and endothelial injury can lead to the acute respiratory distress syndrome. Ultimately, these factors may conspire to cause failure of multiple organs, particularly the kidneys, liver, lungs, and heart, culminating in death.

In short: Septic shock is caused by a dysregulated host response to bacterial or fungal infections; it is characterized by endothelial cell activation, vasodilation, edema, DIC, and metabolic derangements.