26.8.2015koage15.ppt1 Disorders of haemostasis - I The new conception of coagulation Lectures from pathological physiology Study materials from pathological.
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19.04.2023 koage15.ppt 1
Disorders of haemostasis - IDisorders of haemostasis - IThe new conception of The new conception of
coagulationcoagulation
Disorders of haemostasis - IDisorders of haemostasis - IThe new conception of The new conception of
coagulationcoagulation
Lectures from Lectures from patpathhologicologicalal phphyyssioliolooggyy
Study materials from pathological physiology, school year 2014/2015
System of haemostasis• Maintains blood fluidity• Local clot formation after vessel injury• Maintains vessel wall integrity• Cooperation of vessel wall cells,
thrombocytes, other blood cells, coagulation/anticoagulation factors & the fibrinolytic system
• Nonhaemostatic functions of the system
– Inflammation, immunity, glucose and lipid metabolism, angiogenesis, etc
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HistoryBleeding after circumcision – TalmudSchmidt 1861 - Morawetz 1905
I. ThromboplastinII. ThrombinIII. FibrinogenIV. Calcium
• 7 factors belong to group of serine proteases (inactive zymogens)
• Activation cascade - amplification and possibility of regulation
• Example: transformation of prothrombin to thrombin by activated factor X
S S
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Basic principle - proteolytic cascade
• Example: transformation of prothrombin to thrombin by activated factor X
S S
Xa
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Basic principle - proteolytic cascade
• Example: transformation of prothrombin to thrombin by activated factor X
S S
Xa
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The role of vitamin K• Rats with vitamin K deficiency• PIVKA = protein induced in vitamin K absence• Similar to prothrombin - not active• Vitamin K is the coenzyme of glutamate
carboxylase, which converts
• glutamic acid -carboxyglutamic acid
• Two COO- s bind Ca2+
• In prothrobin there are 10 such places
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O
-NH-CH-C-
CH2
CH2
COO-
O
-NH-CH-C-
CH2
CH- COO-
COO-
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Postsynthetic modification of coagulation factors
S-S
S-S
Enzyme with vit K
Glutamic acids
-carboxyglutamic acids
PIVKA
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New conception• Initiation – minimal transformation
of prothrombin to thrombin (no clot)
• Amplification• Termination• Doubts about the in vivo role of
„contact“ system (XII)
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Initiation of coagulation
Monocyte
TFVII
X II
TF = FIII, (thromboplastin) CD142 A TRANSMEMBRANE RECPTOR
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Amplification of coagulation IActivation of thrombocytes
II vWfVIII
X
XI
IX
V
thrombocyte
flip-flop of
phospholipids
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Amplification of coagulation II
Internal amplification loop
XI
II VIIIvWf
VX
IX
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Amplification of coagulation IIIActivation of IX/VIII, formation of tenase
XIIX/VIII
II vWf
VX
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Amplification of coagulation IVformation of prothrombinase
XI
X/V
IX/VIII
II
vWf
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Amplification & termination
• Activation of thrombocytes, flip-flop of phospholipids
• Activation of XI – amplification loop• Activation of IX and VIII → TENASE• Tenase activates X and V – PROTHOROMBINASE• production of huge amounts of thrombin• Transformation of fibrinogen to fibrin → CLOT• Formation of crosslinks in fibrin network (XIII) →
STABLE CLOT
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Revision of „contact“ system
• John Hageman (deficiency of XII) died in 1968 on thrombembolic disease after a trauma
• He probably did not read the textbooks of physiology!
• According to current opinion the system has rather nonhaemostatic functions
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Structure of fibrinogen
6 chains, 2*
Proteolytic removal of peptides A,B
Polymerisation
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Polymerisation of fibrinogen
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Stabilisation of fibrin and fibrinolysis
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The anticoagulant system
• Serpins – inhibitors of proteases– Inhibitor of initiation - TFPI– Antithrombin (III)
• Protein C together with S are the most important inhibitors of amplification – proteolytic degradation of V and VIII
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The fibrinolytic – plasminogen system
• PLASMINOGEN – 92 kDa glykoprotein• Two step activation to active form, PLASMIN by
tissue PLASMINOGEN ACTIVATOR - tPA• Plasmin degrades fibrin clot (and has a lot of
nonhaemostatic functions)• The process is inhibited by PAI – 1, an
antagonist of tPA Important – the activities of tPA and PAI are
oscillating in a broad range – effects of stress, adrenaline, antidiuretic hormone, obesity (!) and gene polymorphism
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FIBRIN CLOT
PLASMINOGEN
PLASMIN
FDP
D-DIMERS
PAI-1tPA- +
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Disorders of haemostasis - IIDisorders of haemostasis - IIPrinciples of diagnosticsPrinciples of diagnostics
Disorders of haemostasis - IIDisorders of haemostasis - IIPrinciples of diagnosticsPrinciples of diagnostics
Lectures from Lectures from patpathhologicologicalal phphyyssioliolooggyy
Study materials from pathological physiology, school year 2005/2006
• Step 1: Anticoagulated blood (Ca2+ binding by citrate);• Step 2: Removal of RBC, LE, TH (centrifugation)• Step 3: Addition of surplus Ca2+ & activators to plasma• Step 4: Measurement of time until the first fibrin filaments
are formed• Expression of results
A. In seconds (international standardized calibrators, QC)B. In relative units compared to norm (time patient/control)
C. INR = International Normalized Ratio
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Diagnostics IIIcoagulation tests - examples
Prothrombin time - QuickOral anticoagulant therapy control (OAC)
– D-dimer, degradation product of fibrin clot by plasmin
diagnostics of DIC
exclusion of deep venous thrombosis and pulmonary embolism (limit 500 g/l)
• Special assays – aggregometry, adhaesion of thrombocytes
• Direct measurement of factors
•Assays of polymorphisms, mutations
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Disorders of haemostasis - IDisorders of haemostasis - IIIIIThe most important diseasesThe most important diseasesDisorders of haemostasis - IDisorders of haemostasis - IIIIIThe most important diseasesThe most important diseases
Lectures from Lectures from patpathhologicologicalal phphyyssioliolooggyy
Study materials from pathological physiology, school year 2005/2006
Pathogenesis of DICA. Generalised activation of coagulationB. Thrombosis
Microthrombi in circulation;Deposits of microthrombi in tissues and
their damageC. Decreased haemostasis
Decrease of platelet number, factor concentration
Activation of fibrinolysisD. BleedingE. Disorder of nonhaemostatic functions
of the system
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BLEEDING
GENERALISED ACTIVATION OF COAGULATION
MICROTHROMBI
DECREASE OF PLATELETS & COAGULATION FACTORS
ACTIVATION OF FIBRINOLYSIS
EMBOLISATION
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BLEEDING
GENERALISED ACTIVATION OF COAGULATION
MICROTHROMBS
DECREASE OF PLATELETS & COAGULATION FACTORS
ACTIVATION OF FIBRINOLYSIS
EMBOLISATION
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Symptoms and forms tissue ischaemia, gangrena of fingers bleeding (after injections); kidney failure, anuria; haemorrhagic necrosis of adrenal cortex - sy
Waterhouse-Friderichsen; haemolytic anaemia, haemoglobinuria;Beginning acute or subacuteStages: Compensated, decompensated and
manifest
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Case studyParameter before beginning DIC!
Th 200 60 20
Quick 12 12 23
aPTI 35 35 63
Fibrinogen 3,0 1,5 0,5
FDP negat + +++
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Our case study• As an editor of a medical journal I
visited our publisher, a cca 50 y old lady.
• Complaining about respiratory condition, therapy resistant
• And also swelling of the legs• Nothing serious?
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Our case study• Complaining about respiratory
condition, therapy resistant• And also swelling of the legs• Nothing serious?• Immediately sent to hospital:
– D-dimers extremely high– X-ray repeated small embolisation