1. The plan of lecture
• Hemostasis, definition. Components of
hemostasis system.
• Hemorrhagic diathesis, etiology,
pathogenesis
• Thrombotic syndrome, etiology,
pathogenesis
• DIC syndrome, etiology, pathogenesis
2. • HEMOSTASIS - (HAIMA - BLOOD, STASIS -
stoppage) - СESSATION OF BLEEDING
• " Hemostasis includes biological
processes that secure intact vascular
walls, maintain blood in a fluid, clot-
free state in normal vessels and also
prevent or stop bleeding inducing the
rapid formation of a localized
hemostatic plug at the site of vascular
injury." (Z.S. Barkagan, 1980)
3. The normal haemostatic
response involves
• The blood vascular wall
• Blood cells (mainly platelets)
• Plasma enzyme systems (clotting
system, anticlotting system,
fibrinolytic system, kallikrein-kinin
system)
5. Hemorrhagic syndrome
Pathogenetic classification
• Vasopathy
• Thrombocytopenia and
thrombocytopathy
• Coagulopathy
Disorders of vascular-
thrombocytic
mechanism of
hemostasis
Disorders of
coagulation
mechanism of
hemostasis
6. VASOPATHY
Is the hemorrhagic diathesis due to vascular
disorders (structural and functional)
• HEREDITARY
• ACQUIRED
HEREDITARY
• Hereditary hemorrhagic teleangiectasia
(Osler-Weber-Rendu disease)
PATHOGENESIS
• Inherited autosomal dominant
disorderlocal disorders of collagen
formation appearance of abnormally
teleangiectatic (dilated) capillaries
7. reduced thrombocyte adhesion bleeding
from dilated capillaries (frequent episodes of
bleeding from nose and gastrointestinal tract)
8. Acquired
• Schonlein-Henoch purpura – hemorrhagic
vasculites, the rash at infectious diseases
(measles, etc.)
Damage to endothelium by immune complexes
(Type III hypersensitivity) or toxins (viruses,
bacteria, drugs, food products may be antigens)
hemorrhagic purpura
• Vitamine-C deficiency
Defective collagen synthesis (reduced formation
of collagen from procollagen) petechiae,
ecchymosess)
9. Hemorrhagic vasculites: petechiae (minute
hemorrhages into skin, mucous membranes or
serosal surfaces), ecchymoses (over 1-2 cm
subcutaneous hemorrhages), bruises
Laboratory findings:
Normal platelet count and tests of coagulation,
bleeding time is usually normal
11. Platelet functions
(role in hemostasis)
1. Adhesion and aggregation function
Adhesion – is platelet ability to stick to the
subendothelium
Aggregation- is platelet ability to stick to each
other
2. Participation in the blood clotting process
( platelet clotting factors)
3. Synthesis of biological - active
substances (serotonin, TXА2 growth factors, ATP )
which cause:
vasoconstriction
tissue reparation, including endothelium -
(Angiothrophy function)
thrombocyte adhesion and aggregation
12.
13. THROMBOCYTOPENIA-
is a reduction in peripheral blood platelet
count below 150 x 109/l
(Normal count is 150-360 x109/l)
Platelet count in the range of 20 to 50 x 109/l
leads to post-traumatic bleeding;
platelet count below 20x109/l leads to
spontaneous bleeding
CLASSIFICATION BY ORIGIN
HEREDITARY
ACQUIRED
14. Pathogenetic classification
1.– Thrombocytopenias due to impaired
platelet production - hypoproductional
2. Thrombocytopenia due to accelerated
platelet destruction - immune
3. Thrombocytopenia due to increased
consumption
• DIC
• Thrombotic Thrombocytopenic Purpura
(TTP) and Hemolytic-Uremic Syndrome
(HUS)
• sequestration in spleen
15. • Thrombotic Thrombocytopenic Purpura
(TTP)
1.Fever
2.Thrombocytopenia
3.Microangiopathic hemolytic anemia
4.Transient neurologic deficits
5.Renal failure
• Hemolytic-Uremic Syndrome (HUS)
absence of neurologic symptoms, the
prominence of acute renal failure, and
frequent affliction of children.
16. • widespread formation of hyaline thrombi,
comprised primarily of platelet aggregates,
in the microcirculation Consumption of
platelets thrombocytopenia.
• Intravascular thrombi microangiopathic
hemolytic anemia and widespread organ
dysfunction.
• Pathogenesis: deficient in an enzyme
ADAMTS 13 - "vWF metalloprotease“. It
normally degrades very high molecular
weight multimers of von Willebrand factor
(vWF).
17. • absence of this enzyme very high
molecular weight multimers of vWF
accumulate in plasma platelet
microaggregate formation throughout
the microcirculation
• Superimposition of endothelial cell
injury (caused by some other
condition) may further predispose a
patient to microaggregate formation,
thus initiating or exacerbating clinically
evident TTP.
18.
19. • One important cause of HUS in children
and the elderly is infectious
gastroenteritis caused by E. coli strain
that elaborates a Shiga-like toxin that is
absorbed from the inflamed
gastrointestinal mucosa. It binds to and
damages endothelial cells in the
glomerulus and elsewhere, thus
initiating platelet activation and
aggregation
25. Pathogenesis of adhesion and
aggregation abnormalities
Structural and
functional defects of
platelet membranes
(inherited or acquired
abnormalities of
membrane receptors)
• Reduced synthesis of
granule products (ADP,
TXA2)
• Impaired release
reaction
• Ca, Mg, vWF –
deficiency
26. THROMBOCYTOPATHY
Inherited Acquired
Inherited
• Due to defective platelet
aggregation
-thrombasthenia - Glazmann’s
Disease (Inherited deficiency of
two of platelet’s membrane
glycoproteins)
• Due to defective platelet
adhesion
Bernand-Soulier syndrome
(inherited deficiency of platelet
Membrane glycoprotein)
27. Acquired
Platelet dysfunction at:
• Leukemias
• vitamin B12-deficiency anemia
• uremia
• liver cirrhosis
• DIC
• Aspirin therapy (use of aspirin leads to cyclooxygenase
inhibition and thereby suppresses the synthesis of
prostaglandins, which are involved in platelet aggregation,
as well as release reaction)
•Due to disorders of platelet release reaction (normal initial
aggregation of platelets, subsequent release of active
substances is defective)
•Due to factor 3 deficiency
•Complex abnormalities and dysfunctions
28. CONSEQUENCES OF PLATELET DISORDERS
• Bleeding from micro
vessels petechiae,
ecchymoses,
menorrhagia,
nosebleeds Tourniquet test
29. • Bleeding time is prolonged
• The time of clot retraction is prolonged
• Whole blood coagulation time is normal
30. COAGULOPATHY -
is clotting abnormalities
By origin:
Inherited
Acquired
PATHOGENESIS OF COAGULOPATHY
• Procoagulant deficiency
• Antycoagulant excess
• Fibrinolysis activation
33. Procoagulant deficiency
• Inherited ( 97%).The most common inherited
disorders are Hemophilia A and von
Willebrand disease
• Hemophilia A (80-85 %) - Factor VIII
deficiency, X-linked recessive trait
• Hemophilia B - Factor IX deficiency, X-linked
recessive trait
• Hemophilia C - Factor XI deficiency, autosomal
recessive trait
34. Symptoms
Massive hemorrhages after trauma or
operative procedures, hematomes,
hemarthrosis.
Manifests clinically in males, females are the
carriers.
Patients have a normal bleeding time, whole
coagulation time is prolonged
35. Acquired procoagulant deficiency
(3%)
• Hepatic insufficiency impaired synthesis of
clotting factors
• Deficiency of vitamin K reduced
carboxylation of factors II, VII, X, IX
• Hypocholia
• Dysbacteriosis
• Overdose of anticoagulants of indirect action
• At newborns
• Paraproteinemia inactivation of procoagulants
• Antibody formation against procoagulants
36. FIBRINOLYSIS ACTIVATION
plasminogen plasmin antiplasmin
•
Fibrinolysis activators
Fibrinolysis inhibitors
Fibrinolysis Activators:
Urokinase and other tissue kinases
Streptokinase and other microbe kinases
Proteases
Endothelial activator of fibrinolysis
Inhibitors
Degradation of fibrin, fibrinogen
37.
38. Von WILLEBRAND DISEASE
Inherited defect of vWF
synthesis (VWF is a carrier for
factor VIII and “glue” platelets
and subendothelial collagen)
platelet adhesion and
aggregation defects f. VIII
secondary deficiency
spontaneous bleeding from
mucous membranes,
excessive bleeding from
wounds, menorrhagia
Prolonged bleeding time in the
presence of a normal platelet
count
39. • Partial thromboplastin time (PTT). This assay tests
the intrinsic and common clotting pathways. The clotting
of plasma after addition of kaolin, cephalin, and calcium
ions is measured in seconds.
• Prolongation of the PTT can be due to deficiency or
dysfunction of factor V, VIII, IX, X, XI, or XII, prothrombin, or
fibrinogen.
• Prothrombin time (PT). This assay tests the extrinsic
and common coagulation pathways. The clotting of plasma
after addition of an exogenous source of tissue
thromboplastin (e.g., brain extract) and Ca2+ ions is
measured in seconds.
• A prolonged PT can result from deficiency or dysfunction
of factor V, factor VII, factor X, prothrombin, or fibrinogen.
42. Turbulence and slow blood flow:
• bring platelets into contact with the
endothelium,
• prevent dilution of activated clotting
factors by fresh flowing blood
• retard the inflow of clotting factor
inhibitors
• promote endothelial cell activation
44. Intact endothelial cells
• synthesize substances, preventing thrombocyte
aggregation and clotting (prostacyclin, NO, heparin-
like molecules, plasminogen activators, antithrombin
III activators)
• inactivate excessive amounts of procoagulants
(factors V, VIII, IX, X), thrombin, ADP, TXA2 and others
• Thrombomodulin-thrombin complex activates protein
C (cofactor protein S) which inhibits clotting by
enzymatic cleavage of factors Va and VIIIa
Injured endothelial cells
• activate thrombocytes
• activate clotting system, kallikrein-kinin system
• augment the catalytic activity of factors IX, X
• secrete inhibitors of plasminogen activator, which
depress fibrinolysis
45. • Endothelial injuryl
• Vasoconstriction and
thrombocyte activation,
adhesion
• Release reaction
• Thrombocyte aggregation
and formation of primary
plug
• Coagulation of blood
Formation of a blood clot
49. Deficiency of anticoagulants
Inherited
• mutations in factor V-gene (60% of patients with deep
vein thrombosis) –functional deficiency of protein C
• deficiency of antithrombin III ( inhibits the activity of
thrombin and factors IXa, Xa, XIa, XIIa)
Acquired
• Antithrombin deficiency
at liver diseases
at neoplasms
oral contraceptive use
• Heparin deficiency
all cases of hyperlipidemia ( heparin activates
lipoproteidlipase)
• Protein C and S deficiency (protein C and S inactivate
f. Va, VIIIa)
liver diseases
51. Fibrinolysis insufficiency
• Decreased synthesis of plasminogen in the liver
• Decreased formation of plasminogen tissue
activators
• Increased concentration of plasminogen
inhibitors
52. DISSEMINATED INTRAVASCULAR
COAGULATION
DIC-SYNDROME
is an acute, subacute or chronic
thrombohemorrhagic disorder that
occurs as a secondary complication in
a variety of diseases; it is nonspecific
pathological process, special form of
hemostasis disorders, characterized by
phase changes of blood clotting, when
hypercoagulability changes into
hypocoagulability and bleeding
57. Б-я: С.В., 57 лет. Диагноз: Острый промиелоцитарный лейкоз
58. ДВС-синдром
Стрептококковый сепсис
с остеомиелитом и септическим
артритом.
Результаты обследования
Протеин С <5%
Протеин S 30%
AT III 38%
Злокачественная пурпура новорожденных
Приведено по данным P. Bolton-Maggs [Consultant Paediatric Haematologist Royal Liverpool Children’s Hospital
(2003)]
Эффект от применения концентрата протеина С –
летальность снижается с 85% до 7%.