Physiology & Pathophysiology of Blood

2nd lecture: Blood coagulation & Anticoagulants
• Physiology & pathophysiology of blood

coagulation:
A. Blood coagulation: means the conversion of fluid
blood to a solid gel or clot
-The process of spontaneous arrest of bleeding from
injured or damaged blood vessels by which blood
clotting occurs is called “coagulation”
-The total process of blood clotting followed

by the clot dissolving & repair of the injured
tissue is termed “hemostasis”
-Therefore → hemostasis is the arrest or cessation of
blood loss from damaged blood vessels → prevent
further bleeding & allow tissue healing/recovery
take place
2 prepared by Dr.Hala zaqout

• Mechanism of blood coagulation:
Initiates a complex series of interactions between
vascular endothelial cells , platelets & coagulation
cascade
3 Prepared by : Dr.Hala Zaqout

• Physiological hemostasis consists of 4 steps:

- Step 1: When blood vessel is injured → a localized
vasoconstriction → limiting blood flow to the area
that has been injured
- Step 2: Platelet adhesion, activation & aggregation

→ leading to“unstable” platelet plug formation at
the injured site → provides the initial or primary
hemostatic response

- Step 3: The blood vessel injury &platelet plug
formation → trigger activation of the coagulation
cascade which eventually lead to → “stable” fibrin
clot formation to arrest bleeding

- Step 4: The activation of fibrinolysis pathway
→ removal of the clot once the injured vessel is
repaired
[Disruption of this physiological hemostatic

mechanism under pathophysiological conditions
may lead to → bleeding or thrombosis]
- Under “normal” circumstances → a delicate balance
between “naturally” occurring endogenous
circulating anticoagulants [as antithrombin III,
protein C&S] & procoagulant factors [as platelets]
→ prevents both thrombosis & hemorrhage
→ Either excessive bleeding or thrombosis represents
a breakdown of the hemostatic mechanism → leads
to disease processes

→Imbalance or alteration of this delicate balance
in favor of coagulation→ results in hypercoagulable
condition → “pathologic thrombus” formation
-Thrombosis is defined as the formation of unwanted
clot (thrombus) within a blood vessel → it is the most
common abnormality or disorders of hemostasis
-It is necessary to distinguish two related terms:
thrombus & embolus
-Thrombus refers to a clot that adheres to a vessel
wall, whereas
-Embolus refers to a detached thrombus or a small
part of a clot that breaks off & travels to another
• Abnormality or disorders of hemostasis:
Classified into thromboembolic disorders &bleeding
disorders
-Common thromboembolic disorders & consequences
of pathological blood clotting include:
-Deep vein thrombosis(DVT), pulmonary embolism(PE)
-ACS & acute ischemic stroke
• Coagulation cascade:
The coagulation pathway can be activated by one of
two pathways termed:
→ 'extrinsic' because some components

come from outside the blood
→ 'intrinsic' because all the components

are present in the blood
1-The extrinsic pathway :
-Tissue factor III (tissue thromboplastin) is exposed by

damaged endothelium
→ Tissue factor (TF)→ activates factor VII → into it’s
active form VIIa
→ VIIa → activates factor X → into it’s active form Xa

2-The intrinsic pathway:
- Contact activation →conversion of factor XII
→into it’s active form XIIa

Both ways (common pathway)
leads to the formation of:
→ activated X (Xa)
→ activate prothrombin (II)
into thrombin (IIa) → converts
soluble fibrinogen into
→ “insoluble” fibrin mesh
→ entraps further blood cells
→ stable fibrin clot

18
Extrinsic &Intrinsic pathway lab. measurement:
- Partial thromboplastin time (PTT)→ measures the
function of intrinsic system
-Laboratory test used aPTT to monitor the
anticoagulant effect of UFH & direct thrombin
inhibitors → aPTT prolonged when anticoagulant
drug effect is adequate
- Prothrombin time (PT) → measures the extrinsic

system
-Laboratory test used PT to monitor the anticoagulant
effect of Warfarin → PT prolonged when
24
anticoagulant drug effect is adequate
Prepared by : Dr.Hala Zaqout
• Risk factors for (VTE) disorders :
1- Primary/idiopathic/genetic/inherited
hypercoagulable states
As antithrombin III deficiency, protein C& S deficiency
, factor V mutation

2- Secondary/acquired/transient hypercoagulable
states due to : abnormalities of blood flow,
abnormalities of blood composition, abnormalities
of vessel wall
As hyper-viscosity, venous stasis /immobility ,
postoperative state, trauma especially fractures ,
malignancy, oral contraceptive agent , pregnancy
• Anticoagulant drugs:
- Anticoagulants do not influence
the established thrombus
(once thrombus has already formed)
-Thus →anticoagulant does not have
thrombolytic/ fibrinolytic action
- Therefore, anticoagulants are mainly used for:
→ prevention further thrombus formation & prevent
the extension of already formed thrombus
→ prophylactic with the aim of preventing blood clot
formation
→↓ Morbidity & ↓mortality from thromoembolic
diseases
Q- What’s the difference between anticoagulants ,
antiplatelets & thrombolytic agents?
1 - Anticoagulants: prevent clot formation& extension
As Heparin , Warfarin
2- Antiplatelets : interfere with platelet activity

As Aspirin
3- Thrombolytic agent (fibrinolytic( :

dissolve existing newly formed thrombi
As Streptokinase
• Classification of anticoagulants:
- Heparins
- Selective factor Xa (SFXa) inhibitors
- Direct thrombin inhibitors (DTIs)
- Vitamin K antagonists

• Therapeutic uses of anticoagulants:
The main indications for anticoagulant therapy are:
Treatment or prophylaxis of :
-Venous thromboembolic (VTE) disease: deep venous
thrombosis (DVT) or pulmonary embolism (PE)
- Atrial fibrillation (AF) → especially if the patient is

very elderly , has poor left ventricular function (LVD)
- Mechanical prosthetic heart valve
- Acute coronary syndrome (ACS) as unstable angina

33
1- Heparin:
-Active in vivo & in vitro
-Heparin is naturally occurring mixture of sulphated
mucopolysaccharide
- Heparin has large molecular weight
- Strongest natural organic acid in the body → it has
“negative charge”
-Heparin negative charge are significant in several
aspects:
1- They contribute to complex formation with
antithrombin III (AT III) → anticoagulant effect
2- They permit binding of Heparin to its antidote
Protamine (polycationic protein)
3- They confer poor membrane penetration → not
absorbed from GIT → not given orally → given by
injection
-Sources of heparin:
Heparin can be obtained from pig intestinal mucosa
or from beef lung, where heparin is present
(together with histamine) in storage vesicles of
mast cells
Does heparin exist normally

within our body!!!
• Mechanism of action of heparin:
- Heparin binds to Antithrombin III (AT III)
→ Heparin enhances & accelerates AT III
anticoagulant effect > 1000-fold
→ AT III complexes with Heparin
AT III + Thrombin Heparin Inactive complex of AT III & thrombin
- “Antithrombin III → ATIII naturally occurring
endogenous anticoagulant”

- Heparin- AT III complex→ irreversibly inactivates
clotting factors of the intrinsic & common pathway
(IIa, IXa, Xa , XIa, XIIa & XIIIa) by forming stable
complexes with them
→ prevents thrombin from converting fibrinogen to
fibrin → inhibit clot formation

• Mode of heparin administration:
“Heparin given parenterally (SC or IV) not orally!!!”
- Heparin is rapid-acting anticoagulant
- IV injection → heparin has an immediate onset of
action after IV administration, short half-life → it’s
effects last a few hours→ in emergency situation
given IV “bolus” followed by a constant rate
“infusion” to maintain continuous anticoagulation
for treatment
- SC route mostly for prophylaxis
- IM may cause hematoma (should
not be used IM)
• Pharmacokinetic of heparin:
- Absorption: Heparin is not absorbed orally from the
gut →precipitated by gastric acid & digested by
enzymes
- Distribution: Highly large MWT → doesn’t cross BBB

or placental barrier → safe during pregnancy
UFH binds to a variety of plasma proteins → ↓ its
bioavailability → levels of these heparin-binding
proteins can vary significantly
The dose-response curve is difficult to predict→ so the
dose must be individualized in every patient → with
frequent measurements of aPTT
40
- Metabolism& excretion: Heparin is metabolized or
inactivated in the liver by heparinase enzyme →
excreted via the kidney
• Monitoring of Heparin:
-Monitored by measuring the aPTT
- aPTT → used for detecting abnormalities in blood
clotting & to monitor the treatment effects with
Heparin → the higher/longer the aPPT number than
a normal control value → the more strongly a
patient is anticoagulated
• Note: there is no need to monitor the degree of
anticoagulation when SC Heparin is used as
prophylaxis, nor when LMWHs are used
• Therapeutic uses of heparin:
- Heparin is used for the prophylaxis & treatment of
inappropriate thrombosis: “limits the expansion of
thrombi”
Venous thrombosis & PE caused by :
– Stasis: prolonged inactivity:
airplane, surgery
– Endothelial damage: common in
orthopedic surgery
– Hypercoagulable states: the balance
of thrombogenesis > thrombolysis
- For “treatment” of established thrombosis → as
an initial management of :
• Unstable angina (UA) or acute myocardial infarction
(MI) → in which heparin has additive effect to
Aspirin
• Coronary angioplasty or
stent placement
• Cardiac surgery
• Clotting in extracorporeal
circulations (e.g. during hemodialysis)
• Side effects of heparin:
1- Bleeding/ hemorrhage
2- Heparin-induced thrombocytopenia (HIT):
Heparin rarely but its serious complication causes
thrombocytopenia due to antiplatelet antibodies
→ Antibodies against platelet factor 4
are produced & bind to platelets
→ Platelets get activated &sticky
→ this causes:
-Thromboses
-Platelet consumption resulting in thrombocytopenia
44
-Bleeding may occur as a result of thrombocytopenia
prepared by Dr.Hala zaqout
-The incidence with UFH > LMWHs
• Note:
Platelet counts should be measured necessary if UFH
used for > 5-7 days
3- Hypersensitivity: may occur rarely , commercial
preparations of heparin are obtained from animal
tissues & can cause allergy as skin rash, uriticaria,
fever
4- Osteoporosis: dose & time dependent may occur in
long-term therapy 6months
5- Hyperkalemia due to heparin-induced aldosterone

suppression
5- Alopecia : transient & reversible hair loss in
long-term use
• Heparin antagonist:
Protamine: specific heparin antagonist (heparin
antidote), obtained from fish salmon sperm
It is a strongly basic protein & hence rapidly

neutralizes the anticoagulant effect of heparin
• Note:
Against fractionated heparins
(LMWHs) → Protamine is
less/not effective
• Heparin contraindications:
- Previous heparin-induced thrombocytopenia
syndrome (HITS(
- Coagulopathies: hemophilia, thrombocytopenia
- Active bleeding: intracranial hemorrhage, GI ulcers

Q- True or false
Heparin:
A. Can be taken orally
B. Activity may be enhanced by drugs that are
heavily protein bound
C. By the SC route reduces the risk of thrombo-
embolic disease in hospitalized patients
undergoing orthopedic surgery
D. Is antagonized by Protamine
E. Dosage is monitored by the INR

2- Low-molecular-weight heparin :
As Enoxaparin, Daltaparin & Tinzaparin
- LMWH are manufactured or isolated from UFH

produced by cleavage or fragmentation of native
heparin
-Therefore → LMWH is : Heparin preparations
composed of molecules that shorter than those
found in UFH

• Mechanism of action of LMWHs:
-Have greater ability than UFH to inactivate
factor Xa
-Less effect against thrombin (IIa) →lesser incidence

to cause bleeding
-Less effect against platelet → lesser incidence to

cause thrombocytopenia
LMWHs can be given in patients who have

developed HIT due to Heparin treatment…..WHY!!!
Advantages of LMWHs:
1- LMWHs have low affinity for
plasma proteins
→ 90% bioavailability after
SC injection as compared to
30% bioavailability after
Heparin SC injection
-Therefore →LMWHs have higher SC bioavailability
as compared to UFH
2- LMWHs interact < UFH with endothelium, plasma
proteins & platelets → making LMWH effect is
more predictable than UFH
3- They have longer duration of action, LMWH dosing
< frequent than UFH (once or twice a day) → better
patient compliance
4- LMWH doesn’t require aPTT monitoring → lab.

monitoring unnecessary → so, aPTT is not used to
measure LMWH activity, but sometimes factor Xa
levels can be measured (not commonly performed)
5- There is a lower incidence of thrombocytopenia

Therapeutic uses of LMWH:
- Prevention of DVT (as a prophylactic)
following surgery
- Prevention of ischemic complications
- Treatment of established DVT
• Side effects of LMWH:

- Bleeding < than UFH
- Immune-mediated thrombocytopenia < than UFH
- Cost > UFH
LMWH in patients with RF!!!

3- Selective factor Xa -inhibitor [SFXa inhibitors]
- Fondaparinux:(SC) route
- Fondaparinux is indirect selective factor Xa –inhibitor

- Fondaparinux is a synthetic derivative of 5 saccharide
sequence that found in both UFH & LMWH that binds to
ATIII to inactivate factor Xa
- The binding region of heparin &LMWH is only
5 saccharide units → the basis for the pentasaccharide
structure of fondaparinux
• MOA:

• Pharmacokinetic of Fondaparinux : [as LMWH]
- Fondaparinux has a predictable pharmacokinetic
profile
- Fondaparinux has a long elimination half-life
[17-21hr] → allowing for once-daily SC
administration at a fixed dose without the need for
routine coagulation monitoring
- Fondaparinux is eliminated in urine mainly as
unchanged → contraindicated in patients with
severe renal impairment (Crcl<30ml/min)

-Direct SFXa inhibitors: (oral)
- Apixaban & Rivaroxaban
- They do not require ATIII for antithrombotic activity
- Apixaban & Rivaroxaban → inhibit free& clot‐bound
factor Xa
- Used in patients with AF to reduce the risk of
stroke
• Therapeutic uses/indications of SFXa -inhibitors :

4- Direct Thrombin Inhibitors (DTIs):
Parenteral: as Lepirudin, Bivalirudin
Oral :as Dabigatran
Hirudins & its analog:
-Hirudins are based on the anticoagulant activity of
leeches
- Leeches → secrete hirudin (polypeptide
anticoagulant secreted by salivary glands of leech)
→ that facilitates their ability to draw blood from
their victim
-The recombinant form of Hirudin(lepirudin) → is used
clinically

• MOA:
- DTIs effect on soluble thrombin (IIa) & fibrin-bound

thrombin
- All DTIs bind to & block thrombin(IIa) directly at its
“active site”
-Thrombin has an “active site” as well as 2 other sites,
referred to as: “exosite 1 "& “exosite 2"
- “univalent” DTIs (as Argatroban & Dabigatran) :
only bind at the “active site”, therefore→ bind
thrombin reversibly
- “bivalent” DTIs (-irudins): bind at 2 binding sites

“active site & exosite 1” ,
therefore→ bind thrombin irreversibly

- Lepirudin: (bivalent inhibitor)
- It’s MOA is independent of AT III & no effects on
factor Xa
- It’s directly& irreversibly inactivates IIa
- Administered IV & cleared by the kidneys (requires
renal function monitoring)
- It requires aPTT monitoring
- It is used as anticoagulants in patients with HIT
- The most serious side effect is bleeding → no
antidote is available
-Bivalirudin :administered IV & has rapid onset&offset
- Can be used as an alternative to heparin in HIT
patients undergoing coronary angioplasty
-Dabigatran :
- Dabigatran is oral anticoagulant
- Dabigatran does not require routine monitoring
(INR) & has few drug-drug interactions compared to
warfarin
- Currently approved for prevention of stroke in
patients with AF
69y prepared by Dr.Hala zaqout

• Advantages of new oral direct thrombin inhibitors:
-Rapid onset & offset of action → allow for immediate
anticoagulation→ thus avoiding the need for overlap
with additional anticoagulant drugs
- Predictable pharmacokinetics& bioavailability →
allow for fixed dosing
-Predictable anticoagulant response
-Unnecessary routine coagulation monitoring
- Do not interact with P450-interacting drugs

- Warfarin is a synthetic derivative of coumarin,it is a
Vitamin K antagonists
- Active in vivo only
- Clotting factors → II, VII, IX , X &
protein C &S
→ are dependent
upon vitamin K for
their synthesis
in the liver
• Administration of vitamin K to a newborn!!!
- Vitamin K is used to create several factors in the
clotting cascade (the system that ends in a blood
clot)
-If Vitamin K isn't there, then those factors are

deficient & blood won't clot as well
-This is why newborns get a Vit K shot → to avoid

”hemorrhagic disease of the newborn”
• Mechanism of action of warfarin
-Warfarin is structurally similar to vitamin K &
competitively inhibits epoxide reductase enz
→ that is responsible for the reactivation of vit K to
form coagulant factors(2,7,9,10 &anticoagulant
protein C & S)
Epoxide reductase enzyme function:
74
-Therefore →vit K interferes with the carboxylation
of glutamic acid residues in clotting factors
II,VII, IX & X
-Warfarin inhibits the synthesis but not the actions of
these 4 clotting factors
-Warfarin as Heparin slow the production of a clot
but they do not dissolve the thrombus or clots
already present

• Onset of action of warfarin:
-There is a delay in the onset & duration of anti-
coagulant effect of warfarin because the levels of
clotting factors already in plasma decline or
depletes slowly over a period of 1-3 days → the time
taken for the degradation &clearance of already
preformed clotting factors
-Thus → the onset of action of

warfarin depends on the elimination
half-lives of the already formed
relevant factors
→ Factor VII is “1st affected” → quickly depleted (6hrs)
→ IX (24 hrs)
→ X (48hrs)
→ Prothrombin II (60-72hrs)
- ˜ 72-96 hours to achieve its full effects

- The duration of action of a single dose of warfarin is
2–5 days
- The anticoagulant effects may persists for 4-5 days
after withdrawal of Warfarin

• Pharmacokinetics of Warfarin:
- Absorption: Warfarin is completely absorbed by the
GIT after oral administration
Food interferes with the absorption of Warfarin
- Distribution: highly & extensively protein bound

(98-99%)
- Metabolism & excretion: metabolized by

cytochrome P450 enzymes of the liver
• Monitoring of warfarin:
Warfarin has a narrow therapeutic index →needs to
be monitored closely
Monitoring of anticoagulant therapy by
INR (International Normalized Ratio)→ which is the
ratio of prothrombin time (PT) in the patient to that
in a normal (un-anticoagulated) person→ (pt’s
PT/control PT) → INR should be > 2
→Warfarin dose adjusted &determined individually

for each patient to achieve the desired ratio (INR)
within therapeutic range → 2.0 – 3.0
• Therapeutic uses of Warfarin:
- Prophylaxis against thrombosis in patients with

atrial fibrillation (AF),post-prosthetic or mechanical
heart valve replacement,previous DVT, repeated PE
- Treatment of established DVT , PE
Warfarin is used for long-term anticoagulation

• Side effects of Warfarin :
1- Bleeding or hemorrhage (especially in GIT) is the
most common side effect
2- Cutaneous reactions: Warfarin-induced purple toe

syndrome & skin necrosis
Apart from purpura & ecchymosis, in those who are
excessively anticoagulated → skin necrosis due to a
mixture of hemorrhage & thrombosis occurs rarely
where abrupt induction of Warfarin therapy
& /or the patient has a genetically determined
deficiency of the anticoagulant protein C & S
3- Fetal hemorrhage & teratogenenic from use during
pregnancy: Warfarin readily & easily crosses the
placenta→ effects fetal bone formation ,
disturbances of fetal cartilage &CNS abnormalities
in developing fetus
“Warfarin is contraindicated in pregnant patients”

• Dose of Warfarin:
1. Start with known dose : the usual dose to initiate
therapy is 5-10 mg daily for 2 days, with the
maintenance dose then adjusted according to the
INR
2. Check INR on Day 4-5 & adjust dose
3. Stop Heparin when INR reach therapeutic level
[There is much inter-individual variation in dose

requirements]
• Target INR when use Warfarin in:
- Prophylaxis of DVT) INR 2-2.5)
- Treatment of DVT&PE, AF , mural thrombus

following MI ( INR 2.5)
- Recurrent DVT & PE ,mechanical prosthetic heart

valve (INR 3.5)

• Warfarin antidote:
-1st step to stop Warfarin administration
- Reversal of Warfarin effects but don’t affect plasma
warfarin concentration by given:
→ Vitamin K1 (phytonadione) oral, IV → specific
antagonist→ this will take several hours to act
- In emergency or urgent cases → management of

bleeding caused by warfarin necessary to replace
the deficient clotting factors → blood replacement ,
Prothrombin Complex Concentrate PCC (containing
factor II, IX & X) , fresh frozen plasma (FFP)
• Drug- drug interactions:
There are a large number of pharmacokinetic &
pharmacodynamic drug-drug interactions with
warfarin activity
↑ Warfarin activity → unexpected haemorrhage
↓ Warfain action → ineffective treatment
As: - Drugs with potent inducers of hepatic

cytochrome P450 system →↓Warfarin activity
- Drugs with potent inhibitors of the cytochrome

P450 system system → ↑ Warafrin activity
• Drug interactions with warfarin:

INR Condition Management advice!!!
1- At any INR Major/serious bleeding…………………….

2- INR 5-9 Without significant bleeding ……………….
3- INR >9 Without bleeding ……………………………….
4- INR 5-6 No bleeding ……………………………………..
5- INR<5 No bleeding……………………………………..
Unexpected bleeding at therapeutic INR levels (always

investigate possibility of underlying cause)

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2nd lecture: Blood coagulation & Anticoagulants

• Physiology & pathophysiology of blood

-The total process of blood clotting followed

2 prepared by Dr.Hala zaqout

3 Prepared by : Dr.Hala Zaqout

5 prepared by Dr.Hala zaqout

- Step 2: Platelet adhesion, activation & aggregation

6 prepared by Dr.Hala zaqout

7 prepared by Dr.Hala zaqout

[Disruption of this physiological hemostatic

9 Prepared by : Dr.Hala Zaqout

→ 'extrinsic' because some components

→ 'intrinsic' because all the components

-Tissue factor III (tissue thromboplastin) is exposed by

15 Prepared by : Dr.Hala Zaqout

16 Prepared by : Dr.Hala Zaqout

17 Prepared by : Dr.Hala Zaqout

- Prothrombin time (PT) → measures the extrinsic

26 Prepared by : Dr.Hala Zaqout

2- Antiplatelets : interfere with platelet activity

3- Thrombolytic agent (fibrinolytic( :

31 Prepared by : Dr.Hala Zaqout

- Atrial fibrillation (AF) → especially if the patient is

- Mechanical prosthetic heart valve

- Acute coronary syndrome (ACS) as unstable angina

Does heparin exist normally

36 Prepared by : Dr.Hala Zaqout

37 Prepared by : Dr.Hala Zaqout

- Distribution: Highly large MWT → doesn’t cross BBB

5- Hyperkalemia due to heparin-induced aldosterone

It is a strongly basic protein & hence rapidly

- Coagulopathies: hemophilia, thrombocytopenia

- Active bleeding: intracranial hemorrhage, GI ulcers

49 prepared by Dr.Hala zaqout

- LMWH are manufactured or isolated from UFH

50 prepared by Dr.Hala zaqout

-Less effect against thrombin (IIa) →lesser incidence

-Less effect against platelet → lesser incidence to

LMWHs can be given in patients who have

4- LMWH doesn’t require aPTT monitoring → lab.

5- There is a lower incidence of thrombocytopenia

• Side effects of LMWH:

LMWH in patients with RF!!!

- Fondaparinux is indirect selective factor Xa –inhibitor

60 prepared by Dr.Hala zaqout

61 prepared by Dr.Hala zaqout

• Therapeutic uses/indications of SFXa -inhibitors :

64 prepared by Dr.Hala zaqout

- DTIs effect on soluble thrombin (IIa) & fibrin-bound

- “bivalent” DTIs (-irudins): bind at 2 binding sites

67 prepared by Dr.Hala zaqout

69y prepared by Dr.Hala zaqout

70 prepared by Dr.Hala zaqout

-If Vitamin K isn't there, then those factors are

-This is why newborns get a Vit K shot → to avoid

76 prepared by Dr.Hala zaqout

-Thus → the onset of action of

- ˜ 72-96 hours to achieve its full effects

78 prepared by Dr.Hala zaqout

- Distribution: highly & extensively protein bound

- Metabolism & excretion: metabolized by

→Warfarin dose adjusted &determined individually