Overview haemostasis 2

OLAGBENRO MICHAEL, DR.
REGISTRAR IN HISTOPATHOLOGY
NATIONAL HOSPITAL ABUJA.
Overview of
Hemostasis -2.

Objectives.
1. To appreciate the clinical import.
2. To appreciate the basic chemistry of mediators.
3. To understand the physiology of hemostasis.
4. To highlight clinical conditions
2
OLAGBENRO: overview of haemostasis-2

Outline.
1. Introduction.
1. Definition. Burden of illness.
2. Homeostasis: hemostasis; coagulation, inhibition of
coagulation & fibrinolysis.
2. Basic chemistry : Coagulation factors.
3. Physiology.
Components. Process. Regulation.
4. Highlight of clinical correlates.
5. Summary.
3

Introduction.
4

5OLAGBENRO: overview of haemostasis-2

Definitions.
 Part of cardio-vascular and immunological
homeostasis.
 Maintain vessel patency and vessel wall integrity.
 Carefully choreographed symphony with feedback
and feed-forward agents.
6

Prevalence
*Registers of Haematology Dept NHA
7
 50% of ward consults (19 of 38)*.
 17% of cumulative clinic visits (85 of 493)*.
 9% of admissions (9 of 54)*.
 VTE most common.
 UCH: 35.6 patients/year with VTE
 (Kotila et al, Afr J Med Med Sci. 2013 Jun;42(2):177-81).
 Autopsies may detect missed cases.

Components of hemostasis.
8
 Blood vessels.
 Platelets.
 Coagulation factors.
 Inhibitors of coagulation.
 Fibrinolysis.

In summary (role of stasis)
9

Hemostasis -1.
 Balance between
 Pro- and anti-coagulation
mediators
 Pro- and anti-fibrinolytic
mediators.
 Balance can be upset if any
components are
 Inadequate
 Excessive
10

Hemostasis -2.
11
 Development of thrombi
 Excessive local or
systemic activation of
coagulation
 Sustained bleeding
 Excessive local or
systemic fibrinolytic
activity

12

Chemicial mediators of haemostasis.
13

Clotting Factors –chemistry.
14
Schema of
categorization:
 Substrate –fibrinogen
(Factor I): main
substrate, makes fibrin
 Co-factors –
accelerate enzymatic
reactions (factors V and
VIII, HK, S, and C)
 Enzymes
• Serine proteases in
active form
• Transaminase in active
form

Contact proteins
15
 Factors XII, and XI,
Prekallikrein (PK), and
Kininogen (HMWK).
 Involved in earliest
phases of clotting
 Partially consumed
during coagulation
 Found in serum
 Also involved in
Fibrinolysis, kinin
formation, activation of
complement,
inflammation.
 Congenital
deficiencies often
asymptomatic,
 except XI deficiency
which usually results in
a mild bleeding disorder

Prothrombin Group
16 Vitamin-K
Dependant Clotting
Factors.
 Factors-II, -VII, -IX, -
X, Prt C and S (and
Z).
 All contain γ-
carboxyglutamic acid
• Critical for Ca++
binding
properties.
• Need Ca++ to
bind to
phospholipid
surface
 All but Factor-II
found in serum.
 Vitamin K
antagonists
(Warfarin and
Coumadin) inhibit
the Vitamin K
dependent
carboxylation of
glutamic acid

Fibrinogen Group
17
 Thrombin-Sensitive Clotting Factors
 Factors I (fibrinogen), -V, -VIII, and –XIII
 All are acted upon by thrombin in the process of
blood coagulation
 None found in serum

18

Clotting factors-2.
19

Clotting Factors-3.
Factor Half life (hours) Comment
II 65 Prothrombin group.
VII 5 Vitamin K needed
IX 25 For synthesis
X 40 Require Ca² for activation
I 90 Thrombin interacts with
them
V 15 Increase in pregnancy,
VIII 10 Inflammation, OCP use.
XI 45
XIII 200
20

Coagulation pathway
21

Coagulation Pathway
22

Coagulation Pathway with regulation points
23

Cell theory of coagulation.
24
 New understanding. Explains in-vivo & in-vitro.
 Stages.
 Initiation. Amplification. Propagation. (Cessation).
 Cell surfaces and factors.
 Platelet phospholipids & Factor-2.
 Role of thrombin.

25
 Initiation phase:
 Tissue factor (TF) is released
from injured tissue cells,
endothelial cells and
monocytes.
 TF and Factor VIIa form the
TF / Factor VIIa complex.
 TF / Factor VIIa activates a
small amount of Factor IX
and X to generate a small
amount of thrombin.
 Factor XII (and other
“contact” factors) play a
minor role in the activation
of Factor XI.
 Amplification phase
 Thrombin activates Factor V
to Va,
 Factor VIII to VIIIa and
activates more platelets.
 Thrombin also activates FXI
to FXIa.

26
 Propagation phase:
 Additional Factor Xa is produced when TF / Factor VIIa
complex activates Factor IX.
 The resultant Factor IXa along with Factor VIIIa forms the
tenase complex which then
 converts more Factor X to Xa.
 Factor Xa and Va along with calcium and a phospholipid
(PL) surface (activated platelets) form the prothrombinase
complex which converts
 prothrombin (Factor II) to large amounts of thrombin
(Factor IIa).

27

3 stages of conversion of fibrinogen to fibrin
 Proteolysis
 Thrombin cleavage of fibrinogen results in fibrin monomers
 Polymerization
 Spontaneous self-assembly into fibrin polymers
 Stabilization
 Introduction of covalent bonds into fibrin polymers by XIIIa
28

Inhibition of coagulation
29
 Thrombin binds to the membrane
receptor thrombomodulin and
activates Protein C to Activated
Protein C (APC).
 APC combines with its co-factor
Protein S which then inhibits
Factors Va and VIIIa, slowing down
the coagulation process.
 Thrombin bound to
thrombomodulin becomes inactive
and can no longer activate
procoagulant factors or platelets.
 The endogenous anticoagulant,
antithrombin inhibits the activity of
thrombin as well as several of the
other activated factors, primarily
Factor Xa.

30

31

Fibrinolysis.
32

Fibrinolysis.
33
 Tissue plasminogen activator
(t-PA) converts plasminogen
to plasmin
 which breaks down cross-
linked fibrin to several fibrin
degradation products,
 the smallest of which is D-
dimer.
 Thrombin activatable
fibrinolysis inhibitor (TAFI)
prevents the formation of
plasmin.
 Anti-plasmin and
plasminogen activator
inhibitor-1 (PAI-1) inhibit
plasmin and t-PA
respectively.

Plasminogen activators
34
 Tissue PA
 endothelial cells
 arm>legs
 Increased by venous
occlusion, exercise,
thrombin, adrenaline,
vasopressin.
 Binds lysin residues on
fibrin or to tPAI and
cleared by the liver.
 uPA(urokinase):
 renal tubules and GIT.
 activated by kallikrein.
 Exogenous PA:
 snake venom, saliva of
vampire bats,plants and
microorganisms like b
haemolytic streptococci.
 bind plasminogen and then
activates other
plasminogen.

Inhibitors of fibrinolysis
 tPAI:
 Type I- secreted by the endothelium, also in platelets and
granulocytes.
 Type 2- placenta, monocytes and epidermal cells.
 Inhibitors of plasmin: serine proteases, chief among
these is a2 antiplasmin

Tests.
36

OLAGBENRO: overview of haemostasis-2 37

Factors affecting test results
38
 Blood collected into incorrect type of tube (not a sodium
citrate tube).
 Incorrect plasma to citrate ratio (e.g. under filling of tube or
patient’s hematocrit > 0.55 L/L).
 Heparin contamination of sample (e.g. incorrect order of draw
or sample taken from central lines).
 Clotting in tube from traumatic venipuncture or inadequate
mixing.
 Hemodilution of sample

Clinical correlates.
39
 AML cases.
 Pregnancy, eclampsia.
 Immune thrombocytopenia.
 Malignancies.
 Hemophilia.

Short video
40

In summary.
41
 Homeostasis: haemostasis.
 Clinical burden.
 Components.
 Coagulation, anticoagulation & fibrinolysis.
 Tests.

References:
42
 Textbooks:
 Hoffbrand Text of Haematology, 6e.
 Websites:
 https://www.hopkinsmedicine.org/hematology/Coagulation.swf
 wikipedia
 Journal:
 Afr J Med Med Sci. 2013 Jun;42(2):177-81
 “Bloody Easy Coagulation”, Ontario Regional Blood Coordinating
Network
 Presentations:
 Vitamin K & Coagulation, Ahmad Shihada Silmi Msc, FIBMS, IUG, Medical Technology
Dept. (accessed on slideshare)
 Discussion with Senior Registrars

43
Thank you…

Questions, comments
&
contributions.(Why is DVT more in the left lower limb?)
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Overview haemostasis 2

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