MECANISM HEMOSTASIS & FIBRINOLYSIS

Hemostasis or haemostasis is a complex process which causes the bleeding

process to stop.

Intact blood vessels are central to moderating blood's tendency to clot.
The endothelial cells of intact vessels prevent thrombus ("clot") formation by
1.secreting tissue plasminogen activator (t-PA)
2.inactivating thrombin and adenosine diphosphate (ADP).
Injury to vessels overwhelms these protective mechanisms and hemostasis
ensues.

HEMOSTASIS IS MAINTAINED IN THE BODY VIA THREE MECHANISMS:
1.Vascular spasm - Damaged blood vessels constrict. .( vascular spasm
maintained by serotonin and epinefrin)
2.Platelet plug formation - Platelets adhere to damaged endothelium to form
platelet plug (primary hemostasis) and then degranulate.
3.Blood coagulation - Clots form upon the conversion of fibrinogen to fibrin,
and its addition to the platelet plug (secondary hemostasis).
Damage to small blood vessels and capillaries frequently occurs.
When these vessels are damaged, there are three basic mechanisms
that promote hemostasis or the stoppage of bleeding.



























Following damage, there is an immediate reflex that promotes
VASOCONSTRICTION/VASO SPASM , thus diminishing blood loss.
Exposed collagen from the damaged site will promote the PLATELETS TO
ADHERE.




























When platelets adhere to the damaged vessel, they undergo degranulation and release
cytoplasmic granules, which contain
1.Serotonin, a vasoconstrictor,
2.ADP and
3.Thromboxane A2.

















The ADP attracts more platelets to the area, and the thromboxane A2 promotes
platelet aggregation, degranulation, and vasoconstriction.
Thus ADP and thromboxane A2 promote more platelet adhesion and therefore
more ADP and thromboxane.
The positive feedback promotes the formation of a platelet plug.
THE FINAL HEMOSTATIC MECHANISM IS COAGULATION.












Damaged tissue releases factor III, which with the aid of Ca++ will activate factor VII, thus
initiating the extrinsic mechanism.
Factor XII from active platelets will activate factor XI, thus initiating the intrinsic
mechanism.


















Both active factor VII and active factor XI will promote cascade reactions, eventually
activating factor X.












Active factor X, along with factor III, factor V, Ca++, and platelet thromboplastic factor (PF3), will
activate prothrombin activator.

















Prothrombin activator converts prothrombin to thrombin.
Thrombin converts fibrinogen to fibrin.

























Fibrin initially forms a loose mesh, but then factor XIII causes the formation of
covalent cross links, which convert fibrin to a dense aggregation of fibers.
Platelets and red blood cells become caught in this mesh of fiber, thus the
formation of a blood clot


FIBRINOLISIS
1.Aktifasi Plasminogen menjadi plasmin
2.Aktifator plasminogen : intrinsik: XII a,Kalikrein (dlm circ drh)
ekstrinsik : t PA (dlm endothel pemb drh
eksogen : Urokoinase
3.Inhibitor plasmin


Fibrinolysis is the process wherein a fibrin clot, the product of coagulation, is
broken down.
Its main enzyme plasmin cuts the fibrin mesh at various places, leading to the
production of circulating fragments that are cleared by other proteases or by
the kidney and liver.

Plasmin is produced in an inactive form, plasminogen, in the liver.
Although plasminogen cannot cleave fibrin, it still has an affinity for it, and is
incorporated into the clot when it is formed.


Tissue plasminogen activator (t-PA)and urokinase are the agents that convert
plasminogen to the active plasmin, thus allowing fibrinolysis to occur.
t-PA is released into the blood very slowly by the damaged endothelium of the
blood vessels / after several days (when the bleeding has stopped), the clot is
broken down.
This occurs because plasminogen became entrapped within the clot when it
formed; as it is slowly activated, it breaks down the fibrin mesh.
t-PA and urokinase are themselves inhibited by plasminogen activator inhibitor-1
and plasminogen activator inhibitor-2 (PAI-1 and PAI-2).

In contrast, plasmin further stimulates plasmin generation by producing more
active forms of both tPA and urokinase.

Alpha 2-antiplasmin and alpha 2-macroglobulin inactivate plasmin.
Measurement

When plasmin breaks down fibrin, a number of soluble parts are produced.
These are called fibrin degradation products (FDPs).


Pharmacology

Fibrinolytic drugs are given after a heart attack to dissolve the thrombus
blocking the coronary artery, experimentally in stroke to reperfuse the affected
part of the brain, and in massive pulmonary embolism. The process is called
thrombolysis.

Antifibrinolytics, such as aminocaproic acid (-aminocaproic acid) and tranexamic acid are used as inhibitors of fibrinolysis.
Their application may be beneficial in patients with hyperfibrinolysis because they arrest bleeding rapidly if the other components of
the haemostatic system are not severely affected.
This may help to avoid the use of blood products such as fresh frozen plasma with its associated risks of infections or anaphylactic
reactions. The antifibrinolytic drug aprotinin was abandoned after identification of major side effects, especially on kidney.
Tissue plasminogen activator (abbreviated tPA or PLAT) is a protein
involved in the breakdown of blood clots.
As an enzyme, it catalyzes the conversion of plasminogen to
plasmin, the major enzyme responsible for clot breakdown. Because
it works on the clotting system, tPA is used in clinical medicine to
treat only embolic or thrombolytic stroke.
Use is contraindicated in hemorrhagic stroke and head trauma.

tPA may be manufactured using recombinant biotechnology
techniques. tPA created this way may be referred to as recombinant
tissue plasimogen activator or rtPA.
The classic role of tPA is in the clotting system.
Specifically, tPA catalyzes the conversion of plasminogen into
plasmin. It does so by cleaving the single-chained plasminogen into
two chains. These two chains are linked by a disulfide bond and the
resulting molecule is called plasmin.

Increased enzymatic activity causes hyperfibrinolysis, which
manifests as excessive bleeding. Decreased activity leads to
hypofibrinolysis which can result in thrombosis or embolism.


SCREENING TEST FOR BLEEDING DISORDERS :
1. PLATELET COUNT
Generaly spontaneous bleeding rarely occurs with platelet counts greater than 20.000 PER MM3.
Surgically induced bleeding may be severe if the count range between 40.000 70.000/mm3.

2.BLEEDING TIME
Bleeding time is prolong in disorders affecting the microvascular system, such as
scurvy and the inherited collagen disorder Ehlers Danlos Syndrome.
Hemophilia ( deficiency of factor VIII) , not to be characterized by prolong bleeding time, may
manifest this abnormality in up 20 % of case.

3.PROTHROMBIN TIME
Pro long in :
a. Levels of factors V, VII, X falls below 50 % and when prothrombin level are less than 30 % or
normal.
b.The fibrinogen level is less than 100 mg / dl.
c.Fibrinogen level < 100 mg/Dl
d.Severe hepato cellular disease
e.DIC
f.Vit K deficiency
g.Monitor Warfarin therapy
4.ACTIVATED PARTIAL THROMBOPLASTIN TIME
- Measured the integruty of the entire intrinsic pathway of coagulation --- Sensitive to
deficiency of all factors other than VII AND XIII
- Prolong if any of intrinsic or common path way factors decrease.
- Also prolong in presence of certain anticoagulants and is used to monitoring heparin
therapy.

5.FIBRINOGEN LEVEL
- Concentration decrease in :
DIC and severe liver disease