Coagulation Mechanism and blood disorders

1. Coagulation Mechanism
Sreenu Thalla
Assistant Professor
Department of Pharmacology

2. Fibrinolysis
Clot formation
Procoagulants Vs.
Anticoagulants
Coagulation
mechanism
Clotting
Factors
Intrinsic
&Extrinsic
Pathways
Plasmin
Natural
Anticoagulants
Heparin
Fibrin fibers Antithrombin III
Endothelial
surface factors
BLEEDING
DISORDERS

3. MECHANISM OF BLOOD COAGULATION
 A crucial physiological balance exists between
factors promoting coagulation (Procoagulants) and
factors inhibiting coagulation (Anticoagulants).
 Coagulation of blood depends on the balance
between these two factors.
 Disturbances in this balance could lead:
• Thrombosis
• Bleeding

4.  Hemostasis: prevention or stoppage of blood loss. (Hemo=blood & stasis=stopping)
 Hemostatic Mechanisms:
Platelets (Production and activation,
Blood coagulation (Formation of fibrin to form
• Vessel wall (vasoconstriction)
platelets plug formation)
a clot) Fibrinolysis
 Coagulation: is the formation of fibrin meshwork (threads) to form a clot
MECHANISM OF BLOOD COAGULATION

5. Factor Name
I Fibrinogen
II Prothrombin
III Thromboplastin (tissue factor)
IV Calcium
V Labile factor
VII Stable factor
VIII Antihemophilic factor
IX Christmas factor (Antihemophilic factor B)
X Stuart-Power factor
XI Plasma thromboplastin antecedent (PTA)
XII Hagman factor
XIII Fibrin stabilizing factors
BLOOD CLOTTING FACTORS
NB: there’s
no factor VI
1st letter of
each factor
Foolish People Try Climbing Long Slopes, After Christmas Some People Have Fallen

6. Prothrombin (factor II):
 A plasma protein, α2-globulin
 Present in normal plasma in a concentration of 15 mg/dl
 It is unstable protein (that can be split easily into thrombin)
 It is continually formed by the liver
 Vitamin K* is important for normal production of prothrombin by the liver
 Prothrombin formation decreases in:
- Liver diseases
- Lack of vit K leads to bleeding
Vitamin K is essential for synthesis of Factor II, VII, IX, X
Thrombin:
 Protein enzyme with weak proteolytic capabilities
 Acts on fibrinogen to form one molecule of fibrin monomer
 Fibrin monomers polymerize with one another to form fibrin fibers
 it activates factor XIII, V
 Thrombin stimulates platelets to release:
- ADP
- thromboxane A2
 Thrombin is essential in platelet morphological changes to form primary plug
stimulate further platelets aggregation

7. Fibrinogen (factor I):
 High-molecular-weight plasma protein
 It is continually formed by the liver
 Little or no fibrinogen leak from blood vessels
Fibrin-stabilizing factor (XIII):
 Plasma protein
 Released from platelets that is entrapped in the clot
 It must be activated before it affects the fibrin fibers
 Activated XIII factor operates as an enzyme causing additional strength of fibrin
meshwork
Blood Clot:
composed of a meshwork of fibrin fibers running in all directions and entrapping
blood cells, platelets, plasma.
BLOOD CLOTTING FACTORS
Dr.nervana said she
doesn’t care about the
details here, focus
more on the factor’s ID
(name and number)

8. A series of biochemical reactions leading to the formation of a blood clot
within few seconds after injury
Prothrombin (inactive thrombin) is activated by a long intrinsic or short
extrinsic pathways
This reaction leads to the activation of thrombin enzyme from inactive form
prothrombin
Thrombin will change fibrinogen (plasma protein) into fibrin (insoluble
protein)
BLOOD COAGULATION

9. Intrinsic Pathway Extrinsic Pathway
Pre k
Contact with foreign surface, injured
blood vessel, and glass
XIIa
IXa
X Xa X
kalik
HMWK*
XII
HMWK
XI XIa
IX
Ca++
Ca ,PL ,VIII
Tissue factor
(Factor III)
VIIa VII
Ca++
Prothrombin II thrombin IIa
Fibrinogen I Fibrin monomer Fibrin
Ca ,PL ,V
XIIIa
Ca++
XIII
*HMWK= High molecular weight kininogen *PL= Phospholipid
Things in grey in this slide are not extra, you shouldknow them
Common
Pathway
3 + 7 = 10.. Extrinsic pathway is
as simple as that!
You were counting down..
12,11,9- oh you missed 10..
Thus, you got the intrinsic
pathway

11. COAGULATION CASCADE
Intrinsic pathway Extrinsic pathway Common pathway
 Clotting factors are present
in the blood
1. The trigger is the activation
of factor XII by (foreign
surface, injured blood
vessel, and glass)
2. Activated factor XII will
activate factor XI
3. Activated factor Xl will
activate IX
4. Activated factor IX + factor
VIII + platelet phospholipid
factor (PF3)+ Ca activate
factor X
5. Common pathway follows..
 fast and short
 Triggered by material
released from damaged
tissues (tissue
thromboplastin)
 (Tissue thromboplastin + VII
+ Ca ) activate X
 Common pathway follows..
 Activated( factor X + factor V
+PF3 + Ca) activate
prothrombin activator; a
proteolytic enzyme which
activates prothrombin.
 prothrombin activates
thrombin
 Thrombin acts on fibrinogen
and change it into insoluble
thread like fibrin
 Factor XIII + Calcium = strong
fibrin

12.  Is present in the blood in an inactive form plasminogen
 Is activated by tissue plasminogen activators (t-PA) in blood.
 Digests intra & extra vascular deposit of Fibrin fibrin degradation products
(FDP)
 Unwanted effect of plasmin is the digestion of clotting factors
 Plasmin is controlled by:
 Tissue plasminogen activator inhibitor
 Antiplasmin from liver
 Tissue Plasminogen Activator (TPA) used to activate plasminogen to dissolve
coronary clots
Fibrinolysis (dissolving): Break down of fibrin by naturally occurring enzyme plasmin
therefore prevent intravascular blocking.
FIBRINOLYSIS
PLASMIN

13. FIBRINOLYSIS
Tissu
act
e
plasminogen
ivator (tPA)
Fibrinolysis
eg: D-dimer*
*Marker for fibrinolysis

14. Endothelial surface factors
-Smoothness of the endothelial cells (ECs)
-Glycocalyx layer
-Thrombomodulin protein
Thrombomodulin Protein binds to thrombin  Activates Protein C (with Protein
S)  inactivates factors V & VIII
Inactivates an inhibitor of tPA  increasing the formation of plasmin
 Fibrin fibers 90% of thrombin to removes it from circulating blood
Antithrombin III combines the remaining thrombin and removes it from blood
Heparin (Increase the effectiveness of Antithrombin III )combines with
Antithrombin III and quickly removes thrombin from blood Produced by
- Mast cells
- Basophil cells
Protein C (inhibits Va & VIIIa) & Protein S (Cofactor)
INTRAVASCULAR ANTICOAGULANTS

15. CONDITIONS THAT CAUSE EXCESSIVE BLEEDING
Bleeding
Vitamin K Deficiency:
Hepatitis, Cirrhosis, acute yellow
atrophy AND GI disease
Thrombocytopenia:
Very low number of platelets
in blood
Thrombocytopenia purpura,
hemorrhages throughout all
the body tissues
Idiopathic
Thrombocytopenia
Hemophilia
X-linked disease, Affects males.
85% due to Factor VIII deficiency (hemophilia A)
15% due to Factor IX deficiency (hemophilia B).

16. After blood coagulation markers raised in the blood:
• Prothrobin 1,2(F1,2)
• Thrombin –antithrombin complex(TAT)
has clinically significant value in the diagnosis of thrombotic events. Elevated
concentrations of TAT are found in persons predisposed to thrombosis
• D-dimer
(fibrin degradation products )
Prothrombin Thrombin
Fibrinogen Fibrin
Fraction 1+2 Antithrombin III
FPA
Fibrinolysis
(Plasmin) D-Dimer
Thrombin-antithrombin
Complex (TAT)
HEMOSTATIC ACTIVATION MARKERS
memorize names marked in red They are the activation markers of fibrinolysis and coagulation

17. Anti-thrombin III Protein C
Synthesized by hepatocytes and
endothelial cells
Action: ATIII + thrombin 
Thrombin-ATIII complex
Heparin dramatically enhances
this action
Synthesized by hepatocytes
Action: inhibts Va & VIIIa
Vitamin K-dependent
Protein S
Cofactor for protein C
Action of Protein C & S
NATURAL ANTICOAGULANTS
Activated protein C resistance (APC-R):
genetic abnormality of clotting factor V called factor
V Leiden mutation (ie. Factor V becomes resistant to
protein C and does not get inhibited)
labrotary test ? Functional Assay , Genetic assay

18. 21
MCQs
1- Prothrombin formation decreases in
A. Lack of Vit k
B. CNS disease
C. Liver dieses
D.A + C
2- Which of the following change fibrinogen to fibrin?
A. plasmin
B.plasminogen
C.thrombin
D.None
3- Plasmin is controlled by :
A.TPAI
B.TPA
C.Anti plasmin
D.A + C
4-Which of the following true about hemophilia ?
A. X linked disease
B. Affect female
C. Depend on vitamin K
D. A +C
5-Heparin enhance its action ?
A.ATlll
B.plasmin
C. Protein C
D.TPA
6-factor V Leiden mutation causes hypercoagulation
?
A.True
B. False
7-which of the following inactivates factor V and Vlll ?
A. Protein C
B. Endothelial Surface Factors
C.A and B
D.Heparin
8-Vitamin K Deficiency causes?
A. hepatitis
B.Liver cirrhosis
C.Bleeding
D.All of them
Answer key: 1:D 2:C 3:D 4: A 5:A 6: A 7:C 8:C

19. Types of Blood Disorders

20. Blood Disorders Affecting Red Blood Cells
Anemia
• People with anemia have a low number of red blood cells.
• Mild anemia often causes no symptoms.
• More severe anemia can cause fatigue, pale skin, and shortness of
breath with exertion.

21. Iron-deficiency Anemia
• Iron is necessary for the body to make red blood cells.
• Low iron intake and loss of blood due to menstruation are the
most common causes of iron-deficiency anemia.
• It may also be caused by blood loss from the GI tract because of
ulcers or cancer.
• Treatment includes iron pills, or rarely, blood transfusion.

22. Anemia of chronic disease
• People with chronic kidney disease or other chronic diseases tend
to develop anemia.
• Anemia of chronic disease does not usually require treatment.
• Injections of a synthetic hormone, epoetin alfa (Epogen or Procrit),
to stimulate the production of blood cells or blood transfusions
may be necessary in some people with this form of anemia.

23. Pernicious anemia (B12 deficiency)
• A condition that prevents the body from absorbing enough B12 in
the diet.
• This can be caused by a weakened stomach lining or an
autoimmune condition.
• Besides anemia, nerve damage (neuropathy) can eventually
result.
• High doses of B12 prevent long-term problems.

24. Aplastic anemia
• In people with aplastic anemia, the bone marrow does not
produce enough blood cells, including red blood cells.
• This can be caused by a host of conditions, including hepatitis or
HIV - to the side effect of a drug, to chemotherapy medications,
to pregnancy.
• Medications, blood transfusions, and even a bone marrow
transplant may be required to treat aplastic anemia.

25. Autoimmune hemolytic anemia
• In people with this condition, an overactive immune system
destroys the body's own red blood cells, causing anemia.
• Medicines that suppress the immune system, such as prednisone,
may be required to stop the process
Polycythemia vera
• The body produces too many blood cells, from an unknown cause.
• The excess red blood cells usually create no problems but may
cause blood clots in some people.

26. Thalassemia
• This is a genetic form of anemia that mostly affects people of
Mediterranean heritage.
• Most people have no symptoms and require no treatment.
• Others may need regular blood transfusions to relieve anemia
symptoms.

27. Sickle cell anemia
• A genetic condition that affects mostly people whose families
have come from Africa, South or Central America, the Caribbean
islands, India, Saudi Arabia, and Mediterranean countries that
include Turkey, Greece, and Italy.
• In sickle cell anemia, the red blood cells are sticky and stiff.
• They can block blood flow.
• Severe pain and organ damage can occur.

28. Malaria
• A mosquito's bite transmits a parasite into a person's blood, where
it infects red blood cells.
• Periodically, the red blood cells rupture, causing fever, chills, and
organ damage.
• This blood infection is most common in parts of Africa but can
also be found in other tropical and subtropical areas around the
world; those traveling to affected areas should take preventive
measures.

29. Blood Disorders Affecting White Blood Cells
Lymphoma
• A form of blood cancer that develops in the lymph system.
• In lymphoma, a white blood cell becomes malignant, multiplying
and spreading abnormally.
• Hodgkin's lymphoma and non-Hodgkin's lymphoma are the two
major groups of lymphoma.
• Treatment with chemotherapy and/or radiation can often extend
life with lymphoma, and sometimes cure it.

30. Leukemia
• A form of blood cancer in which a white blood cell becomes
malignant and multiplies inside bone marrow.
• Leukemia may be acute (rapid and severe) or chronic (slowly
progressing).
• Chemotherapy and/or stem cell transplantation (bone marrow
transplant) can be used to treat leukemia, and may result in a
cure.

31. Multiple myeloma
• A blood cancer in which a white blood cell called a plasma cell
becomes malignant.
• The plasma cells multiply and release damaging substances that
eventually cause organ damage.
• Multiple myeloma has no cure, but stem cell transplant and/or
chemotherapy can allow many people to live for years with the
condition.

32. Myelodysplastic syndrome
• A family of blood cancers that affect the bone marrow.
• Myelodysplastic syndrome often progresses very slowly, but may
suddenly transform into a severe leukemia.
• Treatments may include blood transfusions, chemotherapy and
stem cell transplant.

33. Blood Disorders Affecting Platelets
Thrombocytopenia
• A low number of platelets in the blood; numerous conditions
cause thrombocytopenia, but most do not result in abnormal
bleeding.
Idiopathic thrombocytopenic purpura
• A condition causing a persistently low number of platelets in the
blood, due to an unknown cause; usually, there are no symptoms,
yet abnormal bruising, small red spots on the skin (petechiae), or
abnormal bleeding can result.

34. Heparin-induced thrombocytopenia
• A low platelet count caused by a reaction against heparin, a blood
thinner given to many hospitalized people to prevent blood clots
Thrombotic thrombocytopenic purpura
• A rare blood disorder causing small blood clots to form in blood
vessels throughout the body; platelets are used up in the process,
causing a low platelet count.
Essential thrombocytosis (primary thrombocythemia)
• The body produces too many platelets, due to an unknown cause; the
platelets do not work properly, resulting in excessive clotting,
bleeding, or both.

35. Blood Disorders Affecting Blood Plasma
Hemophilia
• A genetic deficiency of certain proteins that help blood to clot;
there are multiple forms of hemophilia, ranging in severity from
mild to life-threatening.
Deep venous thrombosis
• A blood clot in a deep vein, usually in the leg; a deep venous
thrombosis can dislodge and travel through the heart to the lungs,
causing a pulmonary embolism.

36. Hypercoaguable state (hypercoagulable state)
• A tendency for the blood to clot too easily; most affected people
have only a mild excess tendency to clot, and may never be
diagnosed.
• Some people develop repeated episodes of blood clotting
throughout life, requiring them to take a daily blood thinning
medicine.

37. Disseminated intravascular coagulation (DIC)
• A condition that causes tiny blood clots and areas of bleeding
throughout the body simultaneously; severe infections, surgery,
or complications of pregnancy are conditions that can lead to
DIC.

38. von Willebrand disease
• von Willebrand factor is a protein in blood that helps blood to
clot.
• In von Willebrand disease, the body either produces too little of
the protein, or produces a protein that doesn't work well.
• The condition is inherited, but most people with von Willebrand
disease have no symptoms and don't know they have it.
• Some people with von Willebrand disease will have excessive
bleeding after an injury or during surgery