Chapter 4: Haemodynamic Disorders, thromboembolic disease and shock

Question 1

Oedema fluids and effusions may be inflammatory or non-inflammatory. Describe the differences.

Answer 1

Inflammatory: protein rich - due to increases in vascular permeability caused by inflammatory mediators.

Non-inflammatory: protein poor fluids (transudates)

Question 2

What are the 4 contributing causes to oedema?

Answer 2

Increased hydrostatic pressure (e.g. DVT -> impairs venous return; CCF -> increase systemic venous pressure)

Reduced plasma oncotic pressure (e.g. inadequate synthesis or increased loss of albumin e.g. severee liver disease + protein malnutrition, nephrotic syndrome).

Sodium and water retention -> causes obligate retention of water with increases hydrostatic pressure and diminished vascular colloid osmotic pressure (due to dilutuion). E.g. Na retention occurs wheneever renal function is compromise or CVD that leads to renal hypoperfusion. Increased RAAS

Lymphatic obstruction -> impairs the clearance of interstitial fluid.

Question 3

Describe how the mechanisms between hyperemia and congestion differ?

Answer 3

Hyperemia is an active process in which arteriolar dilation (e.g. at sites of inflammation or in skeletal muscle during exercise) leads to increased blood flow. Affected tissues turn red from increased delivery of oxygenated blood.

Congestion is a passive process resulting from reduced venous outflow of blood from a tissue. Can be localised vs systemic. Have abnormal blue-red color from deoxygenated blood.

Question 4

Describe the morphological features of chronic pulmonary oedema (often caused by CCF).

Answer 4

septa are thickened and fibrotic and alveoli often contain heart failure cells i.e. macrophages laden with hemosiderin dervied from phagocytosed red cells.

Question 5

Nutmeg liver is a sign of acute or chronic hepatic congestion?

Answer 5

Chronic
The centrilobar regions are grossly red-brown and slightly depressed (because of cell death) and are accentuated against the surrounding zones of uncongested tan liver.
Microscopically there is centrilobular congestion and hemorrhage, hemosiderin-laden macrophages and variable degress of hepatocyte dropout and necrosis

Question 6

What three elements are required for normal hemostasis?

Answer 6

platelets
Clotting factors
Endothelium

Question 7

Briefly, give an overview of the 4 stages of normal haemostasis? (4)

Answer 7

1. Arteriolar vasoconstriction - mediated by reflex neurogenic mechanismss e.g. endothelin. Transient effect.
2. Primary hemostasis: formation of the platelet plug. Exposed subendothelial vWBF and collagen -> promote plt adhesion + activation (change in shape + granule release) -> recruit additional platelets.
3. Secondary hemostasis: deposition of fibrin. Exposed TF (procoagulant glycoprotein) -> binds and activates VII-> thrombin generation -> fibrinogen to fibrin.
4. Clot stabilisation + resorption: Clot retraction + counterregulatory mechanisms (e.g. t-PA) mad eby endothelial cells lead to clot resorption + tissue repair.

Question 8

What are the two types of granules in platelets?

Answer 8

alpha: adhesion molecule P-selectin, fibrinogen, coagulation factor VV, vWF, fibronectin etc.
Dense: ADP, ATP, Ca, serotonin, adrenaline

Question 9

Which platelet surface receptor binds to vWF in teh subendothelial matrix (during formation of the platelet plug i.e. primary hemostasis)

Answer 9

Glycoprotein Ib

Question 10

Which platelet receptor binds to exposed collagen?

Answer 10

Glycoprotein 1a/IIa.

Question 11

Genetic deficiences of Gp1b results in a bleeding disorder by the name of?

Answer 11

Bernard Soulier syndrome

Question 12

After platelet adhesion (to collagen or vWF) what happens to platelets and what role does this have in the development of secondary hemostasis (2 events)

Answer 12

–> Platelet activation: change in shape and release reaction.

1. Platelets rapidly change shape. - > spikey sea urchins. Also results in conformational changes in cell surface glycoprotein IIb/IIIa that increase its affinity for fibrinogen and by the translocation of negatively charged phospholipids to the plt surface. These phospholipids bind calcium and serve as nucleation sites for hte assembly of coagulation factor complexes.
2. Secretion of granule contents: Plts activated by thrombin (via PAR-1, G protein-coupled receptor, protease-activated receptor-1) and ADP (ADP acts by binding 2 G-P coupled receptors. P2Y1 and P2Y12.

Question 13

How does aspirin work to prevent hemostasis?

Answer 13

inhibits plt aggregation by inhibiting COX (enzyme required to produce TxA2 synthesis (= potent inducer of platelet aggregation).

Question 14

clopidogrel acts on which G-protein coupled receptors?

Answer 14

P2Y12

Question 15

Describe the overall sequence of steps in platelet in clot formation?

Answer 15

Platelet adhesion
Platelet change in shape
Platelet release of granules
Platelet aggregation. 
Platelet contraction

Question 16

When platelets change shape they become spikey urchins and expose a surface receptor. Name this receptor and describe its role in platelet aggregation?

An inherited deficiency of this receptor results in which syndrome?

Answer 16

GpIIb/IIIa
Binds fibrinogen that bridges platelets and allows platelet aggregation.

Glanzmann thrombasthenia

Question 17

How do the intrinsic and extrinsic pathways differ with respect to initiating events?

Answer 17

Intrinsic: negatively charged surface cause XII > XIIa
Extrinsic: exposure of vascular TF leads to activation of VII > VIIa

Question 18

Which coagulation factors are vit K dependent?

Answer 18

II (prothrombin), VII, IX, X

Question 19

Activated Xa converts prothrombin (II) to thrombin using which cofactor?

Answer 19

Va

Question 20

Assembly of coag factors occurs on the negatively charged phospholipid surface of plts and requires ca2+ binding to which residues on which coag factors?

What else is required?

Answer 20

Assembly requires ca to bind to y-carboxylated glutamic acid residues that are present in factors II, VII, IX and X. the reaction uses Vit K as a cofactor.

Question 21

What does the PT time assay assess for?

Answer 21

The function of the proteins in the extrinsic pathway (factors VII, I, V, II, and fibrinogen). It involves TF, phospholipids and ca added to plasma and time for a clot to form.

Question 22

The partial thromboplastin time (PTT) screens the function of which proteins?

Answer 22

proteins in the intrinsic pathway (factors XII, XI, IX, VIII, X, V, II, and fibrinogen).

negatively charged particles (e.g. ground glass) activate factor XII (Hageman fator) together with phospholipids and ca, time for fibrin clot to form recorded)

Question 23

Which coagulation factor deficiency is only associated with mild bleeding?

Answer 23

XI

Question 24

Clotting in vivo is different to clotting in the lab. In vivo, which clotting factor deficiencies are the most important ?

Answer 24

Factor VIIa/TF complex is the most important activator of IX and that factor IXa/factor VIIIa complex is the most important activator of factor X.

Question 25

As well as converting fibrinogen into cross-linked fibrin, thrombin also activates…?

Answer 25

thrombin also activates factor XI, factors V and VIII - a feedback mechanism that amplifies the coagulation cascade.

(By activating factor VIII, thrombin stabilises the secondary hemostatic plug as factor VIII covalently cross-links fibrin.)

Thrombin also activates platelets via PAR-1 (thereby linking plt activation to coagulation) (PAR = protease activated receptor 1)

Question 26

What is thrombin’s role in anticoagulation?

Answer 26

On encountering normal endothelium, thrombin changes from a procoagulant to an anticoagulant.

Question 27

What factors limit coagulation/clot formation?

Answer 27

1. Simple dilution of clotting factors away from the site of coagulation.
2. Requirement of negatively charged phospholipids which are provided by activated platlets (activated by subendothelial matrix at sites of vascular injury).
3. Factors expressed by intact endothelium adjacent to the site of injury (MOST IMPORTANT):
   - Plasmin: enzyme that breaks down fibrin (fibrinolysis). Plasmin is generated by enzymatic catabolism of the inactive circulating precursor plasminogen, either by a factor XII-depedent p/w or plasminogen activators. Most important is t-PA.
   - t-PA is synthesised by endothelium. t-PA is most active when bound to fibrin (henced limited to sites of recent thrombosis). t-PA itself is tightly controlled by counterregulatory factors such as a2-plasmin inhibitor.

Question 28

In vivo, what is the most important initiator of the coag cascade?

Answer 28

Tissue factor