HaemostasisMarwa fathy oraby

AGENDANormal haemostasisFunctions of

vessel wall,platelets andcoagulation factors in bleeding,coagulation and

thrombosisClinical correlation in defects of

vessel wall,platelets and coagulation factors

thrombosis

Definition

Heme= blood

stasis= to halt

Process of retaining blood within the vascular system

BLOOD VESSELPLATELETES COAGULATION CASCADE

cascade inhibition• TFPI• ATIII• Proteins C, S

clot lysis• t-PA• plasmin

There is a state of continous Balance between bleeding (hemorrhage) and clotting (thrombosis)

Imbalance in one direction can lead to:

bleeding : hypocoagulable state (poor clot formation or excessive Fibrinolysis) OR

thrombosis: hypercoagulable state

Components– Vascular System

• Controls rate of blood flow

– Platelet System

• Interaction of vasculature and platelets form a temporary plug

– Coagulation System

• Forms a stable insoluble plug (i.e) fibrin forming

– Fibrinolytic System

• Fibrin lysing

– Coagulation Inhibition System

• Natural inhibitors

• Control fibrin formation and fibrin lysis

• Failure or deficiencies in any of the five systems involved with hemostasis can leads to varying degrees of uncontrolled hemorrhaging or clotting

• The hemostatic components remain inert in the presence of intact vascular tissue or endothelium

• Following injury, each component must function optimally.

Haemostasis:

Vasoconstriction

Platelet activation

Haemostatic plug

Coagulation

Stable clot formation

Clot dissolution

Hemostasis: OverviewConsists of three stages

– Primary Hemostasis: platelet and vascular response to vessel injury.

• Blood vessels (vasculature) and platelets are the main “players.”

• Process of blood clotting in response to injury or desquamation of dying /damaged endothelial cells

• Primary Hemostatic plug is formed

• Platelet plug temporarily arrests bleeding. Insoluble fibrin strands deposit on the initial plug to reinforce and stabilize. The fibrin originates from soluble plasma proteins.

– Secondary Hemostasis: coagulation factors response to such injury.

• form fibrin in response to injury

• Fibrin is stabilized by Factor XIII

• At this time, blood has changed into a solid state

– Fibrinolysis

• Clot is removed following healing of wound

Haemostatic Trigger

• Once vessel damage occurs, action begins!

– Arteries and arterioles vasoconstrict

– Smooth muscle cells contract to reduce blood flow

– The endothelium becomes thrombogenic• Platelets and coagulation proteins are activated

• Fibrinolysis initiated

How Does the Endothelium Become Thrombogenic?

– Actions• Von Willebrand’s Factor is made and released to

assist the platelets in primary hemostasis• Produce tissue factor needed for secondary

hemostasis• Collagen is exposed which secretes platelet

activating factor which in turn activates platelets

• Subendothelium promote the binding of leukocytes

• Plaminogen activator inhibitor is released to inhibit fibrinolysis

Vascular System: Function Following Injury

• Initiate haemostasis: FIRST RESPONSE– Vasoconstriction of the arterioles

• Minimizes blood flow to injured area

• Prevents blood loss

• Delivers platelets and plasma proteins to the vessel wall

• Immediate

• Short-lived

Vasoconstriction

• Mechanism– Neurogenic factors

– Regulatory substances• Prolong vasoconstriction

– Serotonin ( made by platelet activation & endothelium)

– Thromboxane A2 ( made by platelet activation & endothelium)

– Endothelin-1 (made by damaged endothelial cells)

Roles of the Healthy Endothelium

• Prostaglandin (PGI2)/ Prostacyclin– Vasodilates to increase blood flow to bring

fresh supplies of clotting substances

– Inhibits platelet aggregation

– Causes redness at the injury site

Additional Roles

• Contraction of venules– Causes gaps between them which pushes

fluids causing edema or swelling

• Inflammatory response

Coagulation

• Contact activation-Intrinsic system

• Tissue factor activation – Extrinsic

• Common path- amplification

• Fibrin formation

• Fibrin lysis.

Fibrinolysis and repair• Plasminogen binds fibrin and tissue plasminogen

activator (tPA).• This complex then converts the plasminogen to

plasmin.• Plasmin cleaves fibrin in addition to fibrinogen

and a variety of plasma proteins and clotting factors.

• tPA is an endothelial cell enzyme that is released in response to thrombin, serotonin, bradykinin, cytokines and epinephrine.

• When fibrin is degraded by plasmin it exposes new lysine terminals on the clot that act as further binding sites for plasminogen creating a positive feedback loop

HEMOSTATIC DISORDERS

BLEEDING

DISORDERS

COAGULTION

DISORDERSTHROMBOTICDISORDERS

BLEEDING DISORDERS

VASCULAR DISORDERS

PLATELET

DISORDERS

COAGULATION

DISORDERS

VASCULAR DISORDERS• Characterized by normal bleeding time & coagulation tests.

• Hess test is positive in:

1- hereditary causes

• Hereditary hemorrhagic telangiectasia

• Ehlers-Danlos

• Osteogenesis imperfecta

• Pseudoxanthoma elasticum

2- acquired causes

• Simple easy bruising

• Senile purpura

• Purpura of infection

• Henoch – schonlein syndrome

• Scurvy

• Steroid purpura

PLATELET DISORDERS

COUNT

THROMBOCYTOPENIA

• INHERITED

• ACQUIRED

FUNCTION

• INHERITED

• ACQUIRED

THROMBOCYTOPENIA

CAUSES:• Failure of platelet production: drugs,

chemicals, viral infection. • Part of general bone marrow failure : cytotoxic

drugs, aplastic anemia, BM infiltration.• Increased consumption of platelets: immune,

DIC, TTP.• Abnormal distribution of platelets:

splenomegaly.• Dilutional loss: massive transfusion of stored

blood to bleeding patient.

THROMBOCYTOPENIA

LABORATORY INVESTIGATIONS:

• platelet count is usually 10-50.000/cmm.

• Bone marrow shows normal or increased numbers of megakaryocytes.

• Platelet associated IgG antibodies.

• Demonstration of platelet glycoprotiensGPIIb/IIIa, or Ib antibodies.

• Screening tests for DIC.

FUNCTIONAL PLATELET DISORDERS

• Abnormal platelet function should be suspected in cases where bleeding is prolonged despite a normal platelet count and diagnosed by:

1- Platelet count normal.2- Prolonged bleeding time.3- Abnormal platelet aggregation studies with ADP,

adrenaline, ristocetin & collagen.

4- Abnormal adhesion studies & nucleotide pool measurement.

5- Factor VIII assay for von-willebrand disease.

FUNCTIONAL PLATELET DISORDERS

• Hereditary disorders:1- Platelet storage pool disease.2-Thrombasthenia ( glanzman’s disease).3- Bernard – soulier syndrome.4- Von Willebrand disease.

• Acquired disorders:1- Aspirin therapy.2- Hyperglobulinemia.3- Myeloproliferative disorders.

INHERITED COAGULATION DISORDERS

VON WILLEBRAND DISEASE• The most common inherited disorder due

to deficiency or dysfunction of vWF.• vWF stabilizes factor VIII in blood.• Important in interaction of platelet with

injured vessel wall through platelet GPIb. • Typically , there is mucous membrane

bleeding.

VON WILLEBRAND DISEASE

Laboratory diagnosis :

• Complete blood count.• Bleeding time can be prolonged.• PTT may be prolonged.• VWF is usually low.• Defect in platelet aggregation with

ristocetin.• Reduced ristocetin cofactor activity.• Collagen binding function is reduced

INHERITED COAGULATION DISORDERS

HEMOPHILIA (A&B ) :

• Due to deficiency or dysfunction of coagulation factors VIII ( for A ) or IX ( for B)

Laboratory diagnosis :

The following tests are abnormal:• PTT• Factor VIII or IX or both.• BT & PT are normal.

ACQUIRED COAGULATION DISORDERS

(DIC)• Wide spread activation of coagulation

with formation of microthrombi in small blood vessels.

• Bleeding diathesis secondary to depletion of coagulation factors & platelets.

DIC

Laboratory diagnosis of acute DIC:

• Low platelet count or falling platelets on repeated testing.

• Prolonged PT &PTT.

• Low fibrinogen or falling fibrinogen on repeated testing.

• Fragmented RBCs in blood smear.

• Increased FDPs & D-dimer.

DIC

Laboratory diagnosis of chronic DIC :

• Platelet count: normal

• PT & PTT : normal

• FDPs & D-dimer : increased

VITAMIN K DEFICIENCY

• Vit. k is required for gamma carboxylationof glutamic acid residues (that is important for calcium binding) of factors II,VII, IX, X, protein C & protein S.

• In absence of vit k. , gamma carboxylationfail to occur & non functional forms of vitk. dependant factors circulate in the blood.

Laboratory diagnosis:• Both PT&PTT are prolonged.• Platelet count & fibrinogen are normal with absent FDPs.

LIVER DISEASE

• Decreased clearance of activated clotting factors & increased level of fibrinogen /fibrin degradation products.

• Liver disease with portal hypertension & splenomegaly --- thrombocytopenia.

• Hepatoma & cirrhosis---dysfibrinogenemia which is better to be diagnosed by thrombin time & functional fibrinogen assay.

LIVER DISEASE

• The Liver is the major site of clotting factor synthesis

• Hemorrhagic diathesis occur in acute hepatitis or cirrhosis.

• In these conditions, vitamin K- dependant factors II,VII, IX, X, protien C & S are reduced.

• Factors V,VIII are not synthesized by hepatic parenchymal cells but they are increased as acute phase reactants.

• vWF synthesized by endothelial cells is increased as an acute phase reactant.

Thrombosis

Haemostasis is normally beneficial BUT if inappropriately activated can be harmful

Three predisposing situations/factors - Known as Virchow’s triad

• Changes in the intimal surface of the vessel

• Changes in the pattern of blood flow• Changes in the blood constituents

Thrombus formation: Virchow’s triad

Hypercoagulable states

• PRIMARY (GENETIC)– Common

• Factor V mutation (G1691A mutation; factor V Leiden)

• Prothrombin mutation (G20210A variant)• 5,10-Methylenetetrahydrofolate reductase

(homozygous C677T mutation)• Increased levels of factors VIII, IX, XI, or

fibrinogen

– Rare• Antithrombin III deficiency• Protein C deficiency• Protein S deficiency

Hypercoagulable states

• SECONDARY (ACQUIRED)– High Risk for Thrombosis

• Prolonged bed rest or immobilization• Myocardial infarction• Atrial fibrillation• Tissue injury (surgery, fracture, burn)• Cancer• Prosthetic cardiac valves• Disseminated intravascular coagulation• Antiphospholipid antibody syndrome

Hypercoagulable states

• SECONDARY (ACQUIRED)• Lower Risk for Thrombosis

– Cardiomyopathy– Nephrotic syndrome– Hyperestrogenic states (pregnancy and

postpartum)– Oral contraceptive use– Sickle cell anemia– Smoking