Primary Hemostatic Abnormalities and Secondary Hemostasis

There are four types of hemostatic abnormalities:

1.) primary hemostasis disorders

2.) secondary hemostasis disorders

3.) fibrinolysis disorders

4.) thromboembolic disease

primary hemostasis disorders

disorder involving the interaction of platelets and endothelial cells in the formation of a primary platelet plug

A primary hemostasis disorder leads to abnormal bleeding due to two things:

1.) thrombocytopenia (decreased platelet number)

2.) impaired platelet function/vascular disease

Four clinical signs of a primary hemostatic disorder:

1.) petechiae

2.) ecchymoses

3.) spontaneous bleeding from mucosal surfaces (such as nosebleed (epistaxis))

4.) prolonged bleeding after trauma or venipuncture

If a patient has clinical signs of a primary hemostatic disorder, what should be your first step?

determine the total platelet count and decide if thrombocytopenia could be the cause of abnormal bleeding

If a patient has clinical signs of a primary hemostatic disorder and platelets are normal, what should be your second step?

if the platelet count is normal (no thrombocytopenia), evaluate platelet function through Buccal mucosal bleeding time (BMBT)

thrombocytopenia

Platelet number decreased below RI; most common cause of primary hemostatic disorder!

With true thrombocytopenia, there might also be increased _________ and _________ present

MPV; macroplatelets

Increased MPV and macroplatelets are suggestive of...

immature platelets and platelet regeneration

Three major causes of thrombocytopenia:

1.) consumption

2.) destruction by immune mediated thrombocytopenia

3.) decreased production

consumption and thrombocytopenia

platelets are being utilized during hemostasis, so their numbers decrease

immune mediated thrombocytopenia

Destruction of platelets or megakaryocytes by macrophages of animal's own immune system, leading to thrombocytopenia

immune mediated thrombocytopenia is the most __________ cause of thrombocytopenia

common!

What is the body's response to immune mediated thrombocytopenia? Why is this significant?

produce more platelets to replace those that have been attacked by immune system; leads to immature platelets entering the bloodstream

Morphology of immature platelets

larger platelets (macroplatelets)

Therefore, MPV for animals with immune mediated thrombocytopenia will be ________

increased (due to increased circulation of immature platelets)

Examples of causes of immune mediated thrombocytopenia

-autoimmune disorder

-vaccines

-drugs

-infectious agents invading platelets

Animals with immune mediated thrombocytopenia will have a concurrent...

IMHA (Evan's syndrome)

Decreased production and thrombocytopenia

reduced production of platelets by megakaryocytes

Four potential causes of decreased production of platelets:

1.) myelophthisis

2.) infectious agents

3.) drugs/toxins

4.) irradiation

myelophthisis and decreased production of platelets

replacement of hematopoietic cells in the marrow with something else, disrupting the bone marrow's ability to produce platelets

infectious agents and decreased production of platelets

can directly infect and destroy megakaryocytes

Lab findings of decreased platelet production

-platelet count

-MPV

-megakaryocytes

-severe thrombocytopenia

-no macroplatelets in circulation

-decreased megakaryocytes in the bone marrow

Disorders of platelet function

platelets are not functioning correctly, leading towards thrombocytopenia

Three disorders of platelet function:

1.) Von willebrand disease

2.) inherited defects of platelet function

3.) acquired defects of platelet function

What is the most common disorder of platelet function?

Von willebrand disease

Von willebrand disease

inherited disease that causes thrombocytopenia due to defective or deficient Von willebrand factor (vWF)

Von willebrand factor (vWF)

Assist platelets to adhere to the collagen fibers making up endothelium

Do animals with Von willebrand disease have normal or abnormal platelet count?

normal! just can't adhere to the endothelium

What test is used to diagnose Von willebrand disease?

buccal mucosal bleeding time test

Will animals with Von willebrand disease have normal or abnormal coagulation tests?

usually normal; APTT might be mildly prolonged as there is less vWF to protect factor VIII from proteolysis

Three other inherited disorders of platelet function:

1.) Chediak-Higashi Syndrome

2.) Glanzmann thrombasthenia

3.) Bernard-Soulier syndrome

Chediak-Higashi Syndrome

abnormal platelet granulation; platelets do not form tight aggregates

Glanzmann thrombasthenia

Due to a genetic GPIIb/IIIa deficiency; platelet aggregation is impaired

GPIIb/IIIa receptor

platelet receptor for fibrinogen

Bernard-Soulier syndrome

genetic GPIB deficiency; platelet adhesion impaired since platelets do not adequately bind to cWF to adhere to subendothelium

GPIB

receptor on surface of platelet for von Willebrand factor

Acquired platelet function defects

drug induced platelet disorder; platelet function is affected by an external source

Two drugs that cause platelet disorders:

1.) NSAIDS

2.) aspirin

NSAIDs and aspirin prevent __________ of platelets

aggregation

Are NSAIDS irreversible?

Is aspirin irreversible?

yes

no!

Thrombocytosis

an abnormal increase in the number of platelets in the circulating blood

Three causes of thrombocytosis:

1.) physiologic

2.) reactive

3.) essential thrombocytothemia

physiologic thrombocytosis

increase in platelets due to release of epinephrine during exercise, excitement, etc

Why does epinephrine lead towards thrombocytosis?

epinephrine causes splenic contraction, which causes platelets within the spleen to move into circulation temporality (transient thrombocytosis)

Will morphology of platelets be normal with physiologic thrombocytosis?

yes; megakaryocytes are NOT increased

Reactive thrombocytosis

increased production of platelets secondary to inflammation

Will morphology of platelets be normal with reactive thrombocytosis?

no! megakaryocytes are increased since during inflammation, mature platelets are used up and immature platelets are recruited

What causes reactive thrombocytosis?

increased thrombopoietin due to cytokine stimulation

thrombopoietin

stimulates production of platelets

Essential thrombocythemia

Neoplastic proliferation of mature platelets; rare disorder

Secondary hemostasis

production of a more stabilized platelet plug through the formation of insoluble, cross-linked fibrin

fibrin

insoluble protein that forms the basis of a blood clot during secondary hemostasis

fibrinogen

plasma protein that is converted to fibrin in the clotting process

What converts fibrinogen to fibrin?

thrombin (II)

Coagulation factors

Proteins produced in the liver which help initiate the blood coagulation process

Coagulation factors start as proenzymes that circulate in an __________ form

inactive

What will cause coagulation factors to become activated?

injury to the blood vessel

Coagulation cascade

The series of steps beginning with the intrinsic or extrinsic pathways of coagulation and proceeding through the formation of a fibrin clot

What molecule initiates the coagulation cascade?

tissue factor

tissue factor

aka coagulation factor III; released from the endothelium once it is injured to begin the coagulation cascade

Where does the coagulation cascade take place?

on the surface of the platelet

What is the end goal of the coagulation cascade?

production of thrombin to convert fibrinogen to fibrin

Three pathways of the coagulation cascade:

1.) extrinsic pathway

2.) intrinsic pathway

3.) common pathway

The extrinsic pathway and intrinsic pathway of the coagulation cascade converge at the...

common pathway

Extrinsic pathway

initiates coagulation and

forms a small amount of

thrombin

What coagulation factors are involved in the extrinsic pathway?

coagulation factors III and VII

coagulation factor III

tissue factor; released in response to tissue damage; initiates the coagulation cascade

Activation of coagulation factors III and VII together will lead to the activation of...

coagulation factor X

coagulation factor X

coagulation factor part of the common pathway

Which coagulation factors are involved in the intrinsic pathway?

coagulation factors XII, XI, IX, VIII

*trick to remember: start wil 12, then everything is on "sale" and will be $11.98 (the remaining coagulation factors), so 12, 11, 9, 8

The coagulation factors of the intrinsic pathway also lead to the production of...

coagulation factor X

Which coagulation factors are part of the common pathway?

coagulation factors X, V, II, and I

coagulation factor II

Prothrombin, precursor to thrombin

thrombin

enzyme that converts fibrinogen (coagulation factor I) to fibrin during coagulation

coagulation factor I

fibrinogen, precursor to fibrin

thrombin also causes production of...

coagulation factor XIII

coagulation factor XIII

forms cross links on fibrin to make is non-soluble and eve more stable, and therefore more difficult to degrade

What vitamin is involved in the coagulation cascade?

vitamin K

Function of vitamin K

converts the coagulation factors from their proenzyme form into their active form

Four coagulation factors activated by vitamin K:

1.) coagulation factor II

2.) coagulation factor VII

3.) coagulation factor IX

4.) coagulation factor X

Coagulation inhibition

prevention of uncontrolled clotting, or removal of the clot when it is no longer needed

Four components that inhibit clot formation:

1.) constant blood flow

2.) removal of activated coagulation factors

3.) coagulation inhibitors

4.) fibrinolytic system

How does constant blood flow inhibit clot formation?

it will keep coagulation factors flowing throughout the blood so they don't accumulate in one spot and cause clotting

What organ is involved with removal of activated coagulation factors?

liver; macrophages in the liver move activated coagulation factors that are no longer needed

Four coagulation inhibitors:

1.) antithrombin III (ATIII)

2.) tissue factor pathway inhibitor (TFPI)

3.) thrombomodulin

4.) proteins C and S

antithrombin III (ATIII)

anticoagulant factor that binds activated coagulation factors ICX, X, and XI and thrombin

Why would inactivation of thrombin through antithrombin III (ATIII) inhibit coagulation?

prevents fibrin from being produced

antithrombin III (ATIII) inhibits the ________ and _________ coagulation pathways

intrinsic and common (through inactivation of coagulation factor X and thrombin)

tissue factor pathway inhibitor (TFPI)

inhibits tissue factor (coagulation factor III)

tissue factor pathway inhibitor (TFPI) inhibits the __________ coagulation pathway

extrinsic

thrombomodulin

inactivates thrombin

proteins C and S

inactivates coagulation factors V and VIII

Fibrinolysis

enzymatic process of breaking down fibrin in clots

What protein is used during fibrinolysis to destroy clots?

Plasmin

Plasmin

fibrinolytic enzyme that breaks down fibrinogen and both soluble and insoluble fibrin

Plasmin breaks down two things:

1.) fibrinogen

2.) fibrin

Once fibrin is broken down by plasmin, two breakdown products are created:

1.) Fibrin(ogen) degradation

products (FDPs)

2.) D-Dimers

Fibrin(ogen) degradation

products (FDPs)

degradation of fibrinogen and fibrin by plasmin that are in circulation

D-Dimers

Breakdown product of cross-linked fibrin by plasmin