Hemodynamic Disorders

Question 1

In a normal 70 kg male, what is the composition of water in the body?

Answer 1

TBW is approximately 60% of the total body weight. In a normal, 70 kg male, this would be approximately 42 L.

The two main compartments in the body are ECF (extracellular fluid) and ICF (intracellular fluid). ECF is ⅓ of TBW (14L) and ICF is ⅔ of TBW (28L).

The ECF is composed of an additional three compartments: Interstitial fluid, plasma, and trans cellular fluid. Interstitial fluid contains ¾ of the ECF (or 10.5L), plasma is ¼ of ECF (or 3L) and transcellular fluid is .5L (or ~5%)

Question 2

What is the role that heart failure, malnutrition, decreased hepatic synthesis and nephrotic syndrome play in edema?

Answer 2

Heart failure: Heat failure produces edema by two main mechanisms: increased hydrostatic pressure and decreased renal blood flow. The decrease in renal blood flow will activate the RAAS, causing an increase in blood volume via retention of sodium and water. Note that DVT can also increase hydrostatic pressure.

Malnutrition, decreased hepatic synthesis, and nephrotic syndrome role in causing edema is largely through a decrease in plasma albumin. Albumin is required on the venous side of capillaries and its presence will pull fluid back into the venules. Reduction of albumin causes a decrease in plasma on optic pressure.

Note that inflammation plays a role in edema formation as it causes increased vascular permeability. Impaired lymphatic drainage can also cause an increase in edema.

Question 3

Differentiate between hyperemia and congestion.

Answer 3

Hyperemia:

• active process where there is an increased inflow of blood
• can be caused by inflammation or exercise
• tissue appears red due to enlargement of blood vessels that contain well-oxygenated blood

Congestion:

• passive process where there is a decreased outflow of blood
• most usually caused by CHF or venous obstruction
• tissue appears cyanosis due to accumulation of deoxygenated blood.

Question 4

What are the sequence of events in the coagulation cascade? Include details of the mechanisms found in the sequence of events.

Answer 4

1. Vasoconstriction
   - Endothelin is released from endothelial cells, causing vasoconstriction
2. Primary hemostasis
   - Exposure of collagen on the BM causes platelet adhesion. Platelets change shape and release their granules, including ADP and TXA2. Other platelets are further recruited and aggregation (platelet plug) is formed.
3. Secondary hemostasis
   - Tissue factor is released, phospholipid complex is expressed, thrombin is activated, and fibrin polymerized.
4. Thrombus and antithrombotic events
   - release of: t-PA (fibrinolysis), thrombomodulin (blocks coagulation cascade)
   - trapping of neutrophils, red blood cells within mesh of polymerized fibrin.

Question 5

Platelets are produced from megakaryocytes in bone marrow. List the products usually found in the storage granules of platelets.

Answer 5

• Adhesion molecule P-selection on surface
• Fibrinogen
• Factor V
• vWF
• ADP, ATP, calcium

Question 6

Given the following congenital and acquired disorders of platelet function, describe the mutations/mechanism behind each disorder.

Congenital: von Willebrand’s disease, Bernard-Soulier, Glanzmann’s thrombasthenia

Acquired: Aspirin, myeloproliferative disorders (such as chronic leukemia), and disseminated intravascular coagulation (DIC)

Answer 6

Congenital:

• von Willebrand’s disease: defect in the vWF (FVIII). Von Willebrand’s factor is normally found on endothelial collagen, and is vital for the binding of platelets to the endothelial collagen for formation of platelet plug.
• Bernard-Soulier: defect in Glycoproteins 1B, found on the cell membrane of platelets. Clycoprotein 1B is vital for the binding of vWF.
• Glanzmann’s thrombasthenia: defect in glycoprotein IIb/IIIa. This glycoprotein is important for linking platelets with one another through fibrin.

Acquired:

• Aspirin- inhibits COX enzymes, thus decreasing formation of TXA2. TXA2 is required for storage granule release.
• Myeloproliferative disorders: low levels of platelets can increase risk of bleeding (ie subarachnoid hemorrhage)
• DIC:

Question 7

What are the four categories for platelet count. Describe any complications that may be seen for each concentration of platelets.

Answer 7

Normal: 50,000 to 100,000/mm3 - shows no bleeding unless major trauma

• 20,000-50,000/mm3 - unlikely to have spontaneous bleeding but may have prolonged bleeding after trauma
• <20,000/mm3 - associated with spontaneous skin or mucosal bleeding (gingiva, nose, uterus, and GI, urinary or respiratory tracts)
• <5,000/mm3 - life-threatening bleeding from the GI tract or CNS

Question 8

Explain process of platelet activation: Shape change and granule release

Answer 8

• Shape change increases surface area
• alterations in glycoprotein IIb/IIIa causes increased fibrinogen affinity
• Negatively charged phospholipids to platelet surface. Phospholipids bind calcium at the site of coagulation.

Note that the coagulation cascade occurs on platelet surface.

Question 9

What are the clotting factors that require Vitamin K. Also, what drug can be used to inhibit these factors?

Answer 9

II, VII, IX, X all require vitamin K (gamma carboxylation involved in synthesis)
Coumadin (warfarin) can inhibit the gamma carboxylation

Question 10

All clotting factors are synthesized in the liver with the exception of what two clotting factors? Where are these synthesized?

Answer 10

Exceptions: vWF and FVIII, synthesized in endothelial cells and platelets

Question 11

Detail the actions of thrombin on the basis of its effects on coagulation, platelet activation, pro-inflammatory effects and anticoagulation.

Answer 11

1. Converts fibrinogen to fibrin monomers
2. Activates factors V, VIII, XI, and XIII (this factor is important in cross-linking fibrin)
3. For platelet activation, thrombin induces protease activated receptor (PAR) and granule secretion.
4. Pro-inflammatory: PARS are located on endothelial cells and inflammatory cells. PAR activation leads to tissue repair and angiogenesis.
5. Anti-coagulation: prevents extension of clot beyond tissue site by acting as a anti-coagulant in the presence of normal endothelium.

Question 12

Both heparin and warfarin are used as anti-coagulants. Describe the mechanism of action of these drugs:

Answer 12

Warfarin- Vitamin K antagonist- blocks the function of the vitamin K epoxied reductase complex in the liver, leading to depletion of the reduced form of vitamin K that serves as a cofactors for gamma carboxylation of vitamin K dependent coagulation factors. Recall that Factors II, VII, IX, and X require Vit. K

Heparin- Forms a complex with Antithrombin III (ATIII) that works to neutralize coagulation factors including thrombin (FIIa), FXa, IX, XI, XII and plasmin. ATIII normally inhibits IIa and Xa, but at a slow rate. The heparin-ATIII complex works at very fast rate. Note, heparin is NOT a thrombolytic or fibrinolytic. It simply prevents the progression of existing clots. The lysis of existing clots relies on endogenous thrombolytics.

Question 13

Compare and contrast prothrombin time (PT) and activated partial thromboplastin time (aPTT)

Answer 13

PT: screens for extrinsic (FVII) problems. If prolonged, can be due to vit. K deficiencies, FVII deficiency, low fibrinogen levels, inhibitors, and DIC. Assay: Pt. Plasma + tissue thromboplastin + CaCl2

aPTT: screens for intrinsic problems, or monitoring heparin use. If prolonged (longer than 26-38 seconds), may indicate DIC, inhibitors, factor deficiencies (hemophilia), heparin use/contamination
Assay: Pt. Plasma + partial thromboplastin + CaCl2

Question 14

Explain the use of the International Normalized Ratio to evaluate Coumadin (Warfarin) therapy.

Answer 14

INR- (Patient PT/ mean normal PT)^ISI

ISI= International Sensitivity Index

Question 15

What coagulation factors are inhibited by protein C and S?

Answer 15

Factors Va and VIIIa

Question 16

List characteristics that makes the endothelium antithrombic:

Answer 16

Antiplatelet: ex. Produces NO and PGI2 which prevents platelet adhesion to endothelium, adenosine diphosphate degrades ADP, ADP is required for platelet activation and aggregation.

Fibrinolytic: tPA breaks down fibrin clot

Anticoagulant: produces heparin-like molecules, thrombomodulin, which binds thrombin, produces protein C and S

Question 17

List anticoagulants important for the balance of coagulation:

Answer 17

• Protein C/S
• Thrombomodulin
• Antithrombin III
• Fibrinolysis
• Tissue Factor pathway inhibitors
• Heparin-like molecules

Question 18

How can [D-Dimer] be useful in determining the presence of DIC?

Answer 18

DIC is widespread coagulation. With DIC, there is rapid formation and breakdown of clots. D-Dimer is produced by the breakdown of fibrin clots by plasmin. Thus, increased [D-Dimer] identifies that there is enhanced coagulation/breakdown, and possible DIC.

Question 19

What is the difference between white and red infarcts?

Answer 19

White infarcts: due to arterial insufficiency, not reperfused, and from a single blood supply.

Red infarcts: due to venous insufficiency, reperfused, and dual blood supply

Question 20

What are the top two locations for the mobilization of thrombi from the heart/systemic circulation?

Answer 20

1. Lower extremities
2. Brain

Recall, for DVT, 50% are clinically silent due to collaterals. In pulmonary embolism, 60-80% are clinically silent.

Question 21

In ages less than 50 with DVT, evaluation for inheritable conditions that cause hypercoagulable states should be performed. Explain the relationship of Factor V Leiden and activated protein C resistance.

Answer 21

Protein C is important for inhibiting activated Factor V, a cofactors for Factor 10 which will convert fibrinogen to fibrin > clot formation. In Factor V Leiden, there is a mutation of Factor V, and it becomes unresponsive to Protein C. Thus, it is constitutively active and induces a hypercoagulable state. Persons with this disease have an increased risk for DVT development.

Question 22

How does antiphospholipid antibody syndrome (aka lupus anticoagulant syndrome) cause recurrent miscarriages and DVT?

Answer 22

Antibodies inhibit t-PA, which is required for trophoblastic invasion of the uterus.

Question 23

Describe Trousseau Syndrome

Answer 23

Tumor production of tissue factor, factor VIII, and/or mucin. Can result in venous thrombosis.

Question 24

List key points of pulmonary embolism:

Answer 24

• 95% due to lower extremity DVT
• 60%-80% are clinically silent
• sudden death and right-sided heart failure with >60% obstruction of pulmonary circulation.
• usually no infarction due to dual lung’s blood supply

Question 25

What amount of air is needed for an air embolism to be clinically significant?

Answer 25

At least 100 cc to be clinically significant in the pulmonary circulation.

Question 26

Watershed infarcts are most likely in what two tissues?

Answer 26

Brain and Heart: portions of tissue farthest from the blood supply are most vulnerable

Question 27

• Tissue vulnerability to hypoxia: neurons and cardiac myocytes are more sensitive than connective tissue fibroblasts *

Answer 27

See front.

Question 28

Septic shock is defined as a medical emergency wherein systemic vasodilation and peripheral blood pooling leads to tissue hypoperfusion. Endothelial activation and injury (endotoxins) can also lead to DIC. Discuss a few factors that may be seen in septic shock, causing multi organ failure.

Answer 28

Endotoxins and other microbial products can cause…

• DIC (micro vascular thrombosis)
• Tissue ischemia
• Vasodilation, increased permeability and decreased perfusion
• Systemic effects: fever, diminished myocardial contractility, metabolic abnormalities
• immunosuppression

Question 29

List symptoms of irreversible shock:

Answer 29

Widespread cell injury > lysosomal leakage of enzymes
Worsening of myocardial contractility
Bowel ischemia > bacterial entrance into bloodstream
Renal failure due to acute tubular necrosis
Fatal

Question 30

DIC

Answer 30

What is it?

• acquired deficiency of coagulation factors and platelets due to activation of coagulation system after massive tissue injury or sepsis
• normal coagulant and fibrinolytic systems are overwhelmed and systemic coagulation occurs

Major mechanisms:

• release of tissue factor of thromboplastin substances into the circulation
• widespread injury to the endothelial cells

Features:

• thrombosis leading to microangiopathic hemolytic anemia
• consumption of coagulation factors and platelets resulting in bleeding
• production of fibrin degradation products due to fibrinolysis and plasmin activation

Symptoms:
- diffuse bleeding from many sites

Question 31

Describe features of early, non-progressive (or compensated) shock:

Answer 31

The main goal is to maintain cardiac output and blood pressure, which on the large scale can be down via tachycardia and peripheral vasoconstriction.
Smaller components include:
- shunting blood away from organs like the GI or skin to more vital organs like the heart and brain
- RAAS activation
- Baroreceptor reflex
- ADH release
- Sympathetic stimulation

Question 32

Describe features of progressive shock:

Answer 32

Progressive shock is widespread and tissue experience an oxygen deficit. Thus, lactic acid builds up with increased anaerobic glycolysis, resulting in lowered tissue pH. Arterioles begin to dilate, allowing for blood to pool. Cardiac output continues to worsen and and i injury to the endothelium can increase a risk for DIC.