HEMOSTASIS

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HEMOSTASIS
The ability of the body to control the flow of
blood
following vascular injury is
paramount to continued
survival.
- prevention of blood loss - to close the hole
in the vessel permanently - the process of
blood clotting and then the subsequent
dissolution of the clot, following repair of the
injured tissue
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• normal haemostasis
• complicated relations between the vessel
  wall,
• 
  trombocytes
• 
  and coagulation and fibrinolytic system
• the balanced system the mutual proportions are
  not impaired
• - is
  continuously maintained
• ENDOTHELIUM- the inner surface of vessels
• - a nontrombogenic
  barrier- its primary function
• - inhibiting the
  interaction of blood components with
  subendothelial structures
  (the thrombus formation initiated)
• - no tissue factor
  (strong activator of coagulation)

the systems inhibiting the disseminated thrombosis
the systems supporting the local haemostasis
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The hemostatic response can be divided into two
reactions
PRIMARY HEMOSTASIS
SECONDARY HEMOSTASIS
?
?
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• Primary hemostasis
• vascular constriction
• -the initial phase of the process
• -this limits the flow of blood to the area of
  injury
• - stimulus of the traumatized vessel
• ? nervous reflexes (pain)
• ? local myogenic spasm (direct
  damage)
• - many minutes or even hours
• adhesion, activation and ggregation of
  platelets,
• formation of platelets plug
• platelets - circulate in an inactive form
• are activated, if the endothelium is damaged

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• a) Vascular wall
• - active role , mainly endotel a subendotel
• - function mechanical ? VAZOCONSTRICTION
• synthetic ? formation
  and accumulation of substantions involved in
  hemostasis
• Important physiological anticoagulant
  instrument
• ?
• Endothelium no tissue factor
• - nontrombrogenic barrier-
• inhibits interaction between components of
  blood a subendothelial structures
• - expression of trombodulin , heparin (natural
  inhibitors of coagulation)

? ? ? intact , watter-repellent endothelium ? ?
?
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ADHESION OF PLATELETS TO SUBENDOTHELIAL FIBERS
OF COLLAGEN
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• ACTIVATION OF PLATELETS
• the initial activation is induced by binding to
  collagenous fibrils
• activation evoke also several agonists
  especially ADP, adrenaline , serotonin, some
  arachidonic acid metabolites
• triggers the action of thrombocyte contractile
  system. ---------change their shape -- to
  accommodate the formation of the plug
• - upon activation, platelets release large
  quanties of adenosine-5'-diphosphate, ADP and
  TXA2, serotonin, phospholipids, lipoproteins, and
  other proteins important for the coagulation
  cascade

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platelets secrete more adhesive proteins
(fibrinogen, vWF), that reinforce the stability
of the platelet agregate the damaged vascular
wall or extravascular tissues elicit a vicious
cycle of activation of successively increasing
numbers of platelets, these accumulate to form a
platelet plug
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SECONDARY HEMOSTASIS

• over 40 different substances
• balance between
• ? promoting coagulation . procoagulants
  
• ? inhibiting coagulation ...
  anticoagulants
• - the activation of plasma coagulation factors
• resulting in the formation of fibrin
• - fibrin reinforcement of the initial platelet
  aggregate
• is essential to prevent bleeding from larger
  lesions

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1.
2.
3.
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INITIATION OF COAGULATION FORMATION
OF PROTHROMBIN ACTIVATOR
Prothrombin activator can be formed in two
basic ways
intrinsic pathway
intrinsic pathway
- they are initiated by distinct mechanisms -
the two converge on a common pathway, that leads
to clot formation - both pathways involve
numerous proteins .. clotting factors
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the extrinsic mechanism for initiating clotting
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the intrinsic mechanism for initiating clotting
1,activation of factor XII, release of platelet
phospholipids by blood trauma trauma to the blood
alters two important factors factor XII and the
platelets -contact with collagen or with a
wettable surface ? ? ? activated factor
XII ? ? ? release of the platelets
platelet phospholipid 2.activation of factor
XI XIIa acts enzymatically on factor XI to
activate this as well 3.activation of factor IX
by activated factor XI XIa then acts
enzymatically on factor IX to activate this
factor 4.activation of factor X role of factor
VIII IXa VIII platelet phospholipids ? ?
activates factor X
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5.action of activated factor X to form
prothrombin activator- role of factor V -
the same as the last step inthe extrinsic
pathway

Xa platelet phospholipids factor
V  ? to form the complex prothrombin
activator
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• plasminogen plasmin
• PLASMIN digests the fibrin
• fibrinogen, factor V, factor VIII,
• prothrombin, factor XII
• - hypocoagulability of the blood
• is activated by
• 1. Thrombin
• 2. Activated factor XII,
• 3. lysosomal enzymes.
• - activator systems
• also occur within the blood itself,
• especially the thrombin formed
• during the clotting process

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DISSEMINATED INTRAVASCULAR COAGULATION

• pathophysiological process and not a disease
• inappropriate excessive and uncontrolled
  activation of haemostatic process
• systemic circulation of thrombin and plasmin
• characterised by consumption of clotting factors
  and platelets within circulation resulting in
  varying degrees of microvascular obstruction due
  to fibrin deposition

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• is a syndrome arising as a complication of
  many different serious and life-threatening
  illnesses
• ? in its acute form, DIC is usually an explosive,
  often life-threatening disorder
• ? when it is relatively mild or subclinical, DIC
  may not be so easy to spot.
• clinical manifestation of DIC relate to occlusion
  of the microvessels during the obstructive phase
  of the syndrome
• and hemorrhage secondary to consumption of
  plasma and cellular components in the hemorhagic
  phase
• the perpetuation of the process may be due to
  continuation of the stimulus and/or consumption
  of the natural inhibitors of hemostasis

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• in initiation ..may be adequate
  compensation
• ...defects only in the
  laboratory tests
• severe the initiating disorder... uncontrolled
  acute DIC ... systemic bleeding state ... end
  organ failure
• ACUTE (OVERT) FORM
• a hemorrhagic disorder.multiple
  ecchymoses,mucosal bleeding, and depletion of
  platelets and clotting factors
• CHRONIC (NONOVERT) FORM
• - involves thromboembolism accompanied by
  evidence of
• activation of the coagulation system
• - coagulation factors may be normal, increased,
  or moderately
• decreased, as may the platelet counts

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pathogenesis of DIC
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• Patophysiology of DIC
• - contemporary excess of thrombin a plazmin
  in blood
• oscilation of hemocoagulation balance to
  extrems hypo- hypercoagulation( thrombosis /
  bleeding )
• PRIMARY DISEASE
• ?
• 
  activation of coagulation cascade
• fibrinemia
• microvascular thombosis
• 
  konzsumption of trombocytes
  
  
  koagulat.
  factors ff., inhibitorsg
• 
  aktivation of
  fibrinolysis
• 
  
• 
  degradation of ff. a inhibitors
• MODS /MOF
  
  BLEEDING

TROMBIN
PLASMIN
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• mechanisms which may inappropriately
• activate haemostatic system
• 1.? activation of coagulation sequence by
  release of tissue thromboplastins into systemic
  circulation
• (eg extensive trauma, surgery, malignancy ,
  intravascular haemolysis)
• 2.? induction of platelet activation
• (eg septicaemia, viraemia, immune
  complexes)
• 3. ? vessel wall endothelial injury
• causing platelet activation followed by
  activation of the
• haemostatic systém(.e.g Gram-negative sepsis,
  extensive burns,
• prolonged hypotension, hypoxia or
  acidosis)

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pathogenesis of DIC

• DIC occurs when monocytes and endothelial cells
  are activated or injured in certain
  diseases
• ? monocytes and endothelial cells generate
• tissue factor on the cell surface
• ? activating the coagulation cascade
• acute DIC...? explosive generation of thrombin
• ? depletes clotting factors and platelets
• ? activates the fibrinolytic system

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• BLEEDING into the subcutaneous tissues, skin, and
  mucous membranes
• OCCLUSION of blood vessels caused by fibrin in
  the microcirculation
• significant platelet and coagulation factor
  consumption
• ? ? ? BLEEDING may become a major feature
• chronic DIC... less explosive, compensatory
  responses
• ? the likelihood of bleeding
• ? hypercoagulable state
• - changes can be detected by testing the
  coagulation system
• - thromboembolism

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• clinical features
• presentation varies
• mixture of thrombotic, haemorrhagic or mixed
• manifestations in various organ systems
• major problem and presenting feature of acute
  DIC is
• bleeding
• when occurs in patients with MOF prognosis is
  poor
• in some patients, Dic may be an agonal event
  and should not be treated
• presentation in pregnancy may be more sudden
  and
• unexpected

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• CONDITIONS ASSOCIATED WITH DIC
• INFECTION
• ? bacterial
• ? viral CMV, hepatitis viruses, HZV
• OBSTETRIC
• ? amniotic fluid embolism
• ? placental abruption
• ? eclampsia
• ? retained dead fetus
• ? septic abortion

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• INTRAVASCULAR HAEMOLYSIS
• ? haemolytic transfusion reaction
• ? massive transfusion
• ? minor haemolysis
• TRAUMA OR BURNS
• VENOMS AND TOXINS
• HEPATIC DISEASE
• PROSTHETIC DEVICES
• ? intra-aortic balloon pump
• ? Leveen shunt
• ? cardiopulmonary bypass

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• VASCULAR DISORDERS
• ? hereditary telangiectasia
• ? thrombotic thrombocytopaenic purpura
• ? vasculitis
• ? AV fistula
• ? angiosarcoma
• ? malignant hypertension
• MALIGNANCY
• ? adenocarcinoma prostate, lung, breast,
  pancreas
• ? haematological acute promyelocytic leukaemia,
  myeloproliferative disease, myeloma

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laboratory findings

• results may be variable and difficult to
  interpret
• significant DIC can be present despite normal
  PT, APTT and TT but conversely patients may have
  laboratory features of DIC without any clinical
  sequelae
• the key tests in diagnosis are those that provide
  evidence for excesseve conversion of fibrinogen
  to fibrin within the circulation and its
  subsequent lysis
• platelet- fibrin clots create a mesh in the
  microcirculation in which passing red cells may
  be traumatized, resulting in haemolysis

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diagnosis
combination of the clinical picture with
supportive pattern of laboratory tests of the
haemostatic systém evidence for the diagnosis
thrombocytopenia,hypofibrinogenaemia,
prolongation of the APTT, PT,TCT, elevation of
fibrin degradation products ( D- Dimer test)
- in chronic DIC,the laboratory findings are
different from acute DIC - many of the usual
tests of haemostasis are normal or near normal
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diagnosis of acute DIC

• clinical findings
• multiple bleeding sites,
• ecchymoses of skin, mucous membranes
• visceral hemorrhage, ischemic tissue
• laboratory abnormalities
• coagulation abnormalities prolonged prothrombin
  time, activated partial thromboplastin time,
  thrombin time
• decreased fibrinogen levels increased levels
  of FDP (eg, on testing for FDP, D dimer)
• platelet count decreased, schistocytes on
  peripheral smear

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diagnosis of chronic DIC

• clinical findings
• - signs of deep venous or arterial thrombosis or
  embolism
• - superficial venous thrombosis, without varicose
  veins
• - multiple thrombotic sites at the same time
• - serial thrombotic episodes
• laboratory abnormalities
• - modestly increased prothrombin time
• - shortened or lengthened partial
  thromboplastin time
• - normal thrombin time
• - high, normal, or low fibrinogen level
• - high, normal, or low platelet count
• - increased levels of FDP (eg, on testing for
  FDP, D dimer)

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therapy

• Blood component in haemorrhaging patient
• !!!! the use of heparin only in selected causes
  !!!
• FFP .contains all the coagulation factors, main
  inhibitors, antithrombin III, protein C, in near
  normal quantities and should be used if
  haemorrhage is occurring.
• Cryoprecipitate..contains VIII complex as well
  as fibrinogen , factor XIII in concentrated form
• Platelet transfusion .. in the presence of
  life-threatening haemorrhage

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TREATMENT
- treatment of the underlying disease is the
mainstay of management of either acute or
chronic DIC ! - additionally, acute DIC is
treated with blood products TREAT THE UNDERLYING
DISEASE - avoid delay - treat vigorously (eg,
shock, sepsis, obstetrical problems)
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manage the acute DIC

• !!! No treatment !!! blood components as
  needed
• ?fresh frozen plasma
• ? cryoprecipitate
• ? platelet
  transfusions
• ? anticoagulants (see "with thromboembolism"
  below)
• after bleeding risk is corrected with blood
  products

without bleeding
with bleeding
with ischemia
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manage the chronic DIC

• no specific therapy needed but prophylactic drugs
• (eg, low-dose heparin, low-molecular-weight
  heparin)
• may be used for patients at high risk of
  thrombosis
• ? heparin or low-molecular-weight heparin,
• ? trial of warfarin sodium (Coumadin).

without thromboembolism
with thromboembolism
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management of sudden massive obstetric haemorrhage

• is similar to other cases of DIC
• except!!!
• the onset is more likely to be fulminant and
  unexpected
• is associated with greater
  depletion
• of coagulation factors,
  especially fibrinogen
• ( marked fibrinolysis)
• fresh blood is possibly warranted
• !once the uterus has been emptied and contracted,
  the haemostatic failure quickly resolves!