Hemostasis Disorders

Chapter 14 Hemostasis Disorders



I. Normal Hemostasis and Hemostasis Testing

• Prevention of blood loss while maintaining maximal perfusion requires the interaction of the blood vessels, platelets, coagulation factors, and fibrinolytic agents.

A. Factors preventing thrombus formation in small blood vessels

• Small blood vessels include capillaries, venules, arterioles.

1. Heparin-like molecules


Heparin-like molecules: enhance ATIII activity


a. Enhance antithrombin III (ATIII) activity


ATIII: neutralizes activated serine protease coagulation factors



b. Neutralize activated serine protease coagulation factors

• Factors XII, XI, IX, and X; thrombin (activated prothrombin)

2. Prostaglandin (PG) I2 (prostacyclin)

a. Synthesized by intact endothelial cells

b. PGH2 is converted by prostacyclin synthase to PGI2.


PGI2: vasodilator, inhibits platelet aggregation


c. Vasodilator; inhibits platelet aggregation

d. Aspirin does not inhibit synthesis of PGI2 by endothelial cells.

3. Proteins C and S

a. Vitamin K–dependent factors

b. Inactivate factors V and VIII

c. Enhance fibrinolysis


Proteins C and S: inactivate factors V and VIII, enhance fibrinolysis


4. Tissue plasminogen activator (tPA)

a. Synthesized by endothelial cells

b. Activates plasminogen to release plasmin

c. Plasmin degrades coagulation factors and lyses fibrin clots (thrombi).


tPA: activates plasminogen to release plasmin


B. Factors enhancing thrombus formation in small vessel injury

1. Thromboxane A2 (TXA2)

a. Synthesized by platelets

(1) PGH2 is converted into TXA2 by thromboxane synthase.

(2) Aspirin irreversibly inhibits platelet cyclooxygenase.

• Prevents formation of PGH2, the precursor for TXA2

(3) Other NSAIDs reversibly inhibit platelet cyclooxygenase.

(4) Prostacyclin synthase in endothelial cells is minimally affected by NSAIDs.

b. Functions of TXA2 in hemostasis

• Vasoconstrictor, enhances platelet aggregation


TXA2: vasoconstrictor; enhances platelet aggregation


2. Von Willebrand factor (vWF)

a. Synthesized by endothelial cells and megakaryocytes

(1) Synthesized in Weibel-Palade bodies in endothelial cells

(2) Platelets carry vWF in their α-granules.

b. Functions of vWF

(1) Platelet adhesion molecule


vWF: platelet adhesion molecule; synthesized in Weibel-Palade bodies in endothelial cells


(a) Binds platelets to exposed collagen

(b) Platelets have glycoprotein (Gp) Ib receptors for vWF.

(2) Complexes with factor VIII coagulant activity (factor VIII:c) in the circulation

(a) Factor VIII:c is synthesized by the liver and other sites.


Factor VIII:c: synthesized in the liver + reticuloendothelial cells


(b) VIII:vWF complexes with VIII:c in the circulation.

• Prevents degradation of factor VIII:c


vWF: ↓ vWF causes ↓ VIII:c


(c) Decrease in vWF secondarily decreases VIII:c activity.


vWF: platelet adhesion; prevents degradation of VIII:c in plasma



Factor VIII:c is synthesized by the liver and reticuloendothelial tissues. When VIII:c is activated by thrombin, it dissociates from the VIII:vWF complex and performs its procoagulant function in the intrinsic coagulation cascade system.


3. Tissue thromboplastin (factor III)

a. Noncirculating ubiquitous substance

• Released from injured tissue

b. Activates factor VII in the extrinsic coagulation system


Tissue thromboplastin: activates factor VII in extrinsic coagulation system


4. Extrinsic and intrinsic coagulation systems (see later)

C. Platelet structure and function

1. Derivation

a. Cytoplasmic fragmentation of megakaryocytes

b. Approximately 1000 to 3000 platelets are produced per megakaryocyte.

2. Locations

a. Peripheral blood (live for ∼︀9–10 days)

b. Approximately one third of the total platelet pool is stored in the spleen.

3. Platelet receptors


Platelet receptors: GpIb (binds to vWF); GpIIb-IIIa (binds to fibrinogen)


a. Glycoprotein (Gp) receptors for vWF are designated GpIb.

b. Glycoprotein receptors for fibrinogen are designated GpIIb-IIIa.

(1) Ticlopidine and clopidogrel

(a) Inhibit adenosine diphosphate (ADP)-induced expression of platelet GpIIb-IIIa receptors

(b) Prevents fibrinogen binding and platelet aggregation

(2) Abciximab

• Monoclonal antibody that is directed against the GpIIb-IIIa receptor


Ticlopidine, clopidogrel, abciximab: interfere with GpIIb-IIIa receptor function


4. Platelet factor 3 (PF3)

a. Located on the platelet membrane

b. Phospholipid substrate required for the clotting sequence

5. Platelet structure

a. Contractile element

(1) Called thrombosthenin

(2) Helps in clot retraction

b. Dense bodies contain:

(1) ADP, an aggregating agent

(2) Calcium, a binding agent for vitamin K–dependent factors

c. α-Granules contain:

(1) vWF, fibrinogen

(2) Platelet factor 4 (PF4)

• Heparin neutralizing factor


Important platelet storage proteins: ADP, vWF, fibrinogen


6. Platelet function

a. Fill gaps between endothelial cells in small vessels


Platelet function: stabilizes intercellular adherens junctions in venular endothelial cells


(1) Prevents leakage of RBCs into the interstitium

(2) Platelet dysfunction causes leakage of RBCs, producing petechiae.

b. Formation of the hemostatic plug in small vessel injury

c. Platelet-derived growth factor stimulates smooth muscle hyperplasia.

• Important in the pathogenesis of atherosclerosis

D. Coagulation system (Fig. 14-1)

1. Coagulation cascade

a. Extrinsic system (factor VII)

b. Intrinsic system (factors XII, XI, IX, VIII)

2. Extrinsic system

image

14-1: Coagulation cascade. Both the extrinsic and intrinsic coagulation systems use the final common pathway for the formation of a fibrin clot. a, activated; HMWK, high-molecular-weight kininogen; PF3, platelet factor 3.



Extrinsic system: factor VII; activates factors IX and X


a. Factor VII is activated (factor VIIa) by tissue thromboplastin.

b. VIIa activates factors IX and X (intrinsic + final common pathway).

3. Intrinsic system


Intrinsic system: factors XII, XI, IX, VIII


a. Factor XII (Hageman factor) is activated by:

(1) Exposed subendothelial collagen

(2) High-molecular-weight kininogen (HMWK)

b. Functions of factor XIIa

(1) Activates factor XI

(2) Activates plasminogen (produces plasmin)

(3) Activates the kininogen system (produces kallikrein and bradykinin)


Factor XIIa: activates the kininogen system


c. Factors XIa and VIIa activate factor IX to form IXa (see Fig. 14-1).

(1) Four-component complex is formed (IXa, VIII, PF3, calcium).

(2) Calcium in the complex binds IXa, a vitamin K–dependent coagulation factor.

(3) Complex is more potent than VIIa in activating factor X.

(4) VIIa activation of factor X is more effective if the complex is present.

4. Final common pathway


Final common pathway: factors X, V, II, I


a. Includes factors X, V, prothrombin (II), and fibrinogen (I)

b. Prothrombin complex

(1) Four-component system consisting of factor Xa, factor V, PF3, and calcium

(2) Calcium binds factor Xa, a vitamin K–dependent coagulation factor.

(3) Complex cleaves prothrombin into thrombin (enzyme).

c. Functions of thrombin

(1) Acts on fibrinogen to produce fibrin monomers plus fibrinopeptides A and B

(2) Activates fibrin stabilizing factor XIII

(a) Factor XIIIa converts soluble fibrin monomers to insoluble fibrin.

(b) Enhances protein-protein cross-linking to strengthen the fibrin clot

• Cross-links are detected in D-dimer assay.


Factor XIII: cross-links insoluble fibrin monomers


(3) Activates VIII:c in the intrinsic system

5. Vitamin K–dependent factors

a. Factors II, VII, IX, X, protein C, and protein S


Vitamin K–dependent factors: procoagulants II, VII, IX, X; anticoagulants protein C and S


b. Synthesized in the liver as nonfunctional precursor proteins

c. Function of vitamin K

(1) Vitamin K is activated in the liver by epoxide reductase.


Vitamin K: liver–activated by epoxide reductase


• Majority of vitamin K is synthesized by colonic bacteria.

(2) Activated vitamin K γ-carboxylates each factor.

• Carboxylated factors can bind to calcium and PF3 in the cascade sequence.


Calcium: binds γ-carboxylated vitamin K–dependent factors


6. Certain coagulation factors are consumed in the formation of a fibrin clot.

• Consumed factors are fibrinogen (I), factor V, factor VIII, and prothrombin (II)


When blood is drawn into a clot tube (no anticoagulant is added), a fibrin clot is formed. When the tube is spun down in a centrifuge, the supranate is called serum, which, unlike plasma, is missing fibrinogen, prothrombin (II), factor V, and factor VIII.



Factors consumed in a clot to produce serum: I, II, V, VIII


E. Fibrinolytic system

1. Activation

a. tPA activates plasminogen to release the enzyme plasmin.

• Alteplase and reteplase are recombinant forms of tPA used in thrombolytic therapy.

b. Other activators of plasminogen


Plasminogen activators: tPA, streptokinase, urokinase


(1) Factor XIIa

(2) Streptokinase

• Derived from streptococci

(3) Anistreplase

• Complex of streptokinase and plasminogen

(4) Urokinase (derived from human urine)


Aminocaproic acid: inhibits plasminogen


c. Aminocaproic acid

• Competitively blocks plasminogen activation, thereby inhibiting fibrinolysis

2. Functions of plasmin

a. Cleaves insoluble fibrin monomers and fibrinogen into fibrin(ogen) degradation products (FDPs)

• Fragments of cross-linked insoluble fibrin monomers are called D-dimers.


D-Dimers: cross-linked fibrin monomers


b. Degrades factors V, VIII, and fibrinogen

c. α2-Antiplasmin inactivates plasmin.

• Synthesized in the liver

F. Small vessel hemostasis response to injury (Fig. 14-2)

1. Sequence involves vascular, platelet, coagulation, and fibrinolytic phases.

2. Vascular phase

a. Transient vasoconstriction occurs directly after injury.

b. Factor VII (extrinsic system) is locally activated by tissue thromboplastin.

c. Exposed collagen activates factor XII (intrinsic system).

d. Thrombin converts fibrinogen holding platelets together into fibrin at the end of the platelet phase.

3. Platelet phase

image

14-2: Small vessel hemostasis response to injury. See the text for discussion. TXA2, thromboxane A2; vWD, von Willebrand disease; vWF, von Willebrand factor.



Platelet sequence in hemostasis: adhesion, release reaction, synthesis TXA2, temporary plug


a. Platelet adhesion

• Platelet GpIb receptors adhere to exposed vWF in damaged endothelial cells.

b. Platelet release reaction

(1) Release of ADP

(2) Produces conformational changes in GpIIb-IIIa receptor

c. Platelet synthesis and release of TXA2

TXA2: enhances fibrinogen attachment to GpIIb-IIIa receptors


(1) TXA2 is a vasoconstrictor, which reduces blood flow.

(2) TXA2 is a platelet aggregator.

• Enhances fibrinogen attachment to GpIIb-IIIa receptors

d. Temporary platelet plug stops bleeding.


Temporary platelet plug: held together by fibrinogen


(1) Unstable plug that can easily be dislodged

(2) Only held together by fibrinogen (no cross-links)

(3) Correlates with the end of the bleeding time (BT)

4. Coagulation phase

a. Fibrinogen attached to GpIIb-IIIa receptors is converted by thrombin (see above) to insoluble fibrin monomers (cross-linked).

b. Stable platelet plug is formed.

• Held together by fibrin, not fibrinogen


Stable platelet plug: held together by fibrin


5. Fibrinolytic phase

a. Plasmin cleaves the insoluble fibrin monomers holding the platelet plug together.

b. Blood flow is eventually re-established.

G. Platelet tests

1. Platelet count

a. Normal count is 150,000 to 400,000 cells/mm3.

b. A normal count does not guarantee normal platelet function.

2. Bleeding time

a. Evaluates platelet function up to the formation of the temporary platelet plug


BT: test of platelet function to formation of temporary plug


(1) Normal reference interval is 2 to 7 minutes.

(2) Many laboratories have discontinued the BT.

b. Disorders causing a prolonged BT are listed in Table 14-1.

3. Platelet aggregation test

a. Evaluates platelet aggregation in response to aggregating reagents

b. Aggregating agents include ADP, epinephrine, collagen, and ristocetin.

Related posts:

  1. White Blood Cell Disorders
  2. Vascular Disorders
  3. Genetic and Developmental Disorders
  4. Red Blood Cell Disorders

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Jun 25, 2017 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Hemostasis Disorders

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