What is hemostasis?

Cellular and biochemical events that:

1. keep blood liquid within veins and arteries

2.prevent blood loss from injuries by the formation of thrombi

3. reestablish blood flow during healing process 

What is the sequance in normal hemostasis?

1.Vascular injury

2.Vascular constriction

caused by: reflex action & local secreation of constriction factors

What is primary hemostasis and what does it involve?

It is a platelet event, platelets form primary platelet plug

Involves:

-adhesion

-activation

-aggregation(gets biggger as plug)

-contraction

What happens during secondary hemostasis?

-coagulation pathway

-tissue factor acts with platelet factors(activates coagulation cascade)

-thrombin is produced

-thrombin converts to fibrinogen to fibrin

-fibrin deposits at site of injury

What happens during tertiary hemostasis?

-regulatory proteins that keep coagulation cascade at site of injury

-coagulation cascade actively ceases 

-clot is dissolved though proteolysis

What are the two types of hemostatic problems?

Bleeding - inability to form platelet plug or fibrin clot

Thrombosis - inability to regulate the hemostatic system

Localized vs. General bleeding

an important tool in ruling out the cause of hemorrhage

Localized- trauma or acute injury

Generalized- some underlying defect in the primary or secondary hemostatic system

Mucocutaneous vs. anatomic bleeding

another important too in ruling out the cause of hemorrhage

mucocutaneous-primary hemostatic defects (gingiva/nosebleeds)

anatomic- secondary hemostatic defect (deeper tissue involvement, bruises occur) 

Thombosis is..

a major pathology

-antithesis of hemostasis

-thrombotic occlusion of blood vessels after injury

An occlusion can.........

-be localized or travel

-grow suddenly or slowly

During primary hemostasis reactions involve...

1.platelets

2.vascular changes

3.von willebrands factor

What are the 2 major functional activities of platelets?

1. adherence- platelets stick to area around vessel injury

2. aggregation- platelets stick to each other

What are the size, shape, and distinct zones of resting platelets?

*2-4 micrometer

*oval/disc shape

*hyalomere- clear periphery

*granulomere- high stained, granule rich

How does a platelet change when activated?

-size remains about the same

-large # of spike like psuedopods develop

- the internal granular components may be expelled in the process of activation

Alpha granules contain:

-platelet derived growth factors

-endothelial growth factors

-fibronectin

-plasminogen

-thrombospondin

Dense granules contain....

-ADP

-ATP

-serotonin

-calcium ions

-magnesium ions

Membrane receptors play in important role in........... and some are not fully functioning until.........

Activation occurs due to...

Agonist- stimulating agents

What is the mechanism of agonist/agent during activation of platelets? 

-agonist binds to membrane receptor

-binding causes G-protein activation

-shape change and release of granules occurs

What is the agonist of the GP IA/IIA receptor?

Collagen

What is the agonist of the GP IB/IX receptor?

vWF(von willebrand factor)

What is the agonist of GP IIB/IIIA receptor?

Fibrinogen & vWF

During platelet activation G-protein complex activates...

phospholipase A2

During platelet activation phospholipase A2 leads to breakdown of...

phosphatidylinostol to arachidonic acid

During platelet activation Thromboxane A2 causes...

cAMP decrease

During platelet activation calcium is released from...

dense tubular system (DTS)

During platelet activation calcium activates..

the DTS and contraction and granule release can occur

What is adherence?

it is the initial phase of primary hemostasis

*vessel damage exposes collagen(agonist)

*adherence mechanisms differ based on site within vascular system

Adherence within veins mechanism..

-sheer forces are low

- platelets bind directly with collagen via GP IA/IIA

Adherence within the arterial and capillary circulation mechanism...

-sheer forces are higher

-vWF binds directly to collagen

-vWF forms a coating around collagen

-platelets bind to vWF via GP IB/IX

-direct platelet-collagen binding can still occur

Function of von Willebrand factor 

-forms bridge between exposed collagen & glycoprotein receptor (IB/IX) on platelets surface

-stabilized initial platelet adhesion against high sheer forces of flowing blood

What is aggregation?

-second phase of primary platelet plug formation

-platelet activation amplifies the responses

What happends during aggregation?

-vWF molecules connect to adhered platelets

-platelets then stick to vWF

-platelets also aggregate to fibrinogen, thrombin, and other molecules

Faciliated primarily by GP IIB/IIIA 

Platelet qauntitative measurements

platelet counts

platelet morphology

Platelet qualitative measurements

bleeding time 

platelet aggregometry tests

What is vonWillebrand’s Disease

·      a heterogeneous set of conditions that impact the synthesis of VWF

The vWF molecule is made up of which proteins?

1. platelet binding protein

2.collagen binding protein

3.Factor VIII binding protien (wimpy protein that VWF acts as a shielf to make it stronger)
4. VWF antigenic protein 

Qualitative or quanititative abnormalities of VWF decrease the abilitiy of....

What are the 3 types of vonWillebrands Disease?

o   Type 1: quantitative VWF deficiency

§  Autosomal dominant frameshift

o   Type 2: qualitative VWF abnormalities

o   Type 3: severe VWF deficiency (absence) (Rare)

§  Autosomal recessive deletion 

What are the lab results for vonWillebrands disease?

o   Bleeding time : prolonged

o   Platelet count: normal to decreased

o   PTT: normal to prolonged – because the test requires factor VII to work normally

o   Factor 8 : decreased 

What is Bernard-Soulier Syndrome?

·      AKA large platelet disease

·      Autosomal recessive inheritance pattern

·      Mutation in the gene(s) that code for:

o   GP Ib

§  Chromosome 17 & 22

o   GP IX

§  Chromosome 3 

What is the pathophyssiology in Bernard-Soulier Syndrom?

o   Qual. Defect in GP Ib/IX complex

o   Inappropriate platelet adhesion to vWF

o   Manifested in infancy or childhood

o   Severe bleeding (seldom spontaneous bleeding)

§  Bruising (purpura)

§  Epistaxis

§  Gingival bleeding

§  Gingival bleeding

§  Menorrhagia

§  Post-tramatic and postoperative bleeding may be severe

o   Bleeding time: prolonged (20 mins)

o   Platelet count : decreased 50,000 -80,000 /uL

o   Giant platelets: 5-8 um (often as large as 10 um)

o   Platelet aggregation

§  Absent with bovine vWF or ristocetin

§  Reduce with thrombin

§  Normal with ADP, collagen, epinephrine 

o   Platelet transfusions- appear affective

o   HLA-matched platelets -

o   DDAVP( vasopressin)

o   Recombinant factor Vlla 

·      Autosomal recessive inheritance pattern

·      Mutation in the genes that code for:

o   GP IIb

§  Chromosome 17

o   GP IIb/IIIa

§  Chromosome 17 

o   Qual. Defect in GP IIb/IIIa complex

o   Inappropriate platelet aggregation 

o   Appear in infancy or childhood

o   Severe and debilitating bleeding episodes

o   Same as Bernard soulier 

o   Normal platelet count and morphology ***key difference between this and Bernard soulier

o   Prolonged bleeding time

o   Platelet aggregation

§  No complete response to any agonists (biggest difference!!)