Fffd

1. 5 – 6th week Blood
physiology
Plan:
1. Principle of hemopoiesis
2. Regulation of erythropoiesis
3. Jaundice, Anemia and Polycythemia
4. Leucopoiesis and functions of WBC
5. Platelets
6. Hemostasis and Blood Coagulation
7. Blood groups
8. Rh factors
Lecturer: Ablaikhanova N.T.
Assistant: Balmaganbet Zarina

2. Haemopoisis
Haemopoiesis is derived from the Greek words for ‘blood’ and ‘to make’. The bone marrow is
the chief source of blood cells in children and adults.
Cells are derived from the progressive differentiation of primitive haemopoietic stem cells,
in the presence of soluble and cellular signals, and expression of key transcription factors.
Diagnostic bone marrow samples are usually taken from the posterior superior iliac crest in
adults, and occasionally the sternum or tibia in children. However, all skeletal bones are
active sites of haemopoiesis in children, whereas in adults this is limited to a few sites such
as the skull, vertebrae, ribs and scapulae.
Haemopoietic tissue occupies most of the bone marrow in children, but this declines progressively in adults, along
with redundant bone marrow capacity. Haemopoiesis outside the bone marrow (extramedullary) in viscera such as
the liver and spleen can occur with increased demand, for example chronic haemolytic anaemia.

3. The bone marrow
microenvironment
• Haemopoiesis takes place in the honeycomb spaces of trabecular
bone, interspersed with fat cells that increase in number with age.
The bone marrow microenvironment forms a stem cell niche around
self-renewing haemopoietic progenitor cells and is important for
controlling appropriate blood cell production.
• Haemopoiesis within the bone marrow is topographically organized,
with the stem cells and early progenitor cells being located
paratrabecularly.
• This organization facilitates progressive differentiation of developing
cells such that they can be released through the endothelial cell and
partial adventitial layers into central sinusoidal capillaries and then
the intravascular circulation outside the bone marrow.
• Released cells must thus be sufficiently deformable to enter the post-
sinusoidal capillaries through these layers.
• If there is increased demand or abnormalities within the bone marrow
niche, e.g. fibrosis or infiltration, nucleated erythrocytes, myelocytes
and megakaryocytes can, despite being less deformable, enter the
circulation through separation of the cells within these layers.

5. A multipotent haemopoietic stem cell can self-renew or differentiate into a multipotent progenitor (MPP). The ‘clonal succession’ hypothesis of
continuous differentiation remains controversial but is useful for understanding haemopoiesis MPP differentiation produces common myeloid progenitors
(CMPs, which express CD33) and common lymphoid progenitors (CLPs, which express CD10), both expressing CD38.
Emerging evidence suggests that interconversion between CMPs and CLPs is possible. In the presence of specific transcription factors and early-acting
growth factors (Figure 2), morphologically distinct cell lineages are formed. Neutrophil precursors are the most numerous nucleated cells and progress
from myeloblast, to promyelocyte, to myelocyte, to metamyelocyte and finally to neutrophil stage. Absence of key growth factors during differentiation
can result in apoptosis.
Haemopoietic stem cells differentiate into MPPs, then CMPs, then megakaryocyte erythroid progenitors (MEPs), then megakaryocytes and finally
platelets. Thrombopoietin (TPO), interleukin (IL)-6 and other cytokines and soluble growth factors stimulate maturation of megakaryocytes, where
rounds of DNA replication occur without intervening cell divisions; this forms polypoid cells that have up to 64N. The resulting abundant cytoplasm
facilitates the maturation of platelets. Megakaryocytes release platelets by crashing into sinusoids, so nuclei enter the circulation, being cleared by
pulmonary macrophages.
The liver predominantly produces TPO, which binds to its receptor MPL in response to low platelet concentrations. Eltrombopag and romiplostim are
TPO agonists used to treat thrombocytopenia.2,3 Given that TPO is also a growth factor for haemopoietic stem cells, it can also be used to treat aplastic
anaemia. Thrombocytosis associated with inflammation is in part related to IL-6 secretion.

7. Every second, the human body generates 2 million red blood cells, through the process of
erythropoiesis.
Human erythropoiesis is a complex, multi-step process, from the multipotent hematopoietic stem cell (HSC) to
the mature erythrocyte.
Erythropoiesis
Red Blood Cell Formation
1. Before birth
 Mesoblastic stage (week 3) – nucleated red blood cells form in the yolk sac and mesothelial layers of the
placenta.
 Hepatic stage (week 6) – erythropoiesis mainly in the liver and spleen.
 Myeloid stage (3rd month onwards) – bone marrow gradually becomes the principal source of red blood cells.
2. After birth
 Up to 5 years – bone marrow in all bones
 Age 5 to 20/25 years – marrow of long bones only
 Over 25 years – red blood cells produced mainly in the marrow of membranous bones e.g. vertebrae,
sternum, ribs, cranial bones, ilium

8. Erythropoiesis
Starts with the haematopoietic stem cell (haemocytoblast) in the marrow;
Differentiates into common myeloid progenitor (proerythroblast) – a stem cell for production of blood cells;
Develops into an erythroblast:
 Then undergoes successive changes where its nucleus progressively shrinks and its cytoplasm becomes filled
with haemoglobin;
 Haemoglobin causes the cytoplasm to turn clear;
The nucleus is expelled and becomes a reticulocyte:
 Some are released into the blood;
 Reticulocytes can mature into adult RBCs in the circulation.

9. Erythrocyte
 Round, biconcave disc shaped
 Smooth
 Diameter 7.8 um
 Stains with EOSIN (more stain at periphery)
 Can deform easily
 Volume of about 90 cu mm (1 cu µm = 1
femtolitre (fl)= 10-15 lt)
Reticulocyte
 Some ribosomes or ribosomal RNA shown as
dark markings
 About 1% of red blood cells are reticulocytes

10. —A two stage differentiation system
Stage 1: From Pluripotent stem cells to committed cells
Stage 2: From committed cells to the recognisable precursors
Erythropoisis

24. Erythropoietin
• The primary site of EPO production during fetal
development is the liver, while the kidney serves as the
principal physiological production source postnatally.
• However, the liver retains its ability to produce EPO,
contributing to about 10%-15% of total EPO production in
adults, and under certain stress conditions such as oxygen
scarcity (hypoxia) produces a third of total circulating EPO in
the blood.
• EPO production is regulated by a negative feedback loop
with tissue oxygen tensions being the main determinants of
this regulation. Under homeostatic conditions, EPO is present
in low amounts in circulation.
• The body contains no significant reserves of EPO, and
fluctuations in oxygen levels serve as a sensor for EPO
production.
• Hypoxic conditions or anemia can serve as triggers,
leading to increased EPO production in the kidney, resulting
in a rise in circulating EPO levels and a consequent increase
in erythropoiesis through activation of the EPO-EpoR
(receptor) signaling cascade. Increase in RBC mass leads to
enhanced oxygen carrying capacity in the blood.
• The restored oxygen levels counteract the hypoxic signals,
leading to suppression of EPO production, thereby completing
the feedback loop.

25. Control of
Erythropoiesis
Controlled by erythropoietin (EPO), a protein produced in fibroblast
interstitial cells in the kidney around the proximal tube
The kidney has a tightly regulated glomerular filtration rate, and a
steady usage of oxygen (oxygen levels not altered by exercise or
changes in blood pressure, determined by Hb in arterial blood)
The EPO secreting cells are sensitive to hypoxia:
If hypoxia occurs, it must be due to reduced carriage of
oxygen
The hypoxia stimulates EPO release which acts on
erythropoeitic stem cells to increase RBC production

26. Hormonal Control
of Erythropoiesis
• Effects of EPO
o More rapid maturation of
committed bone marrow cells;
o Increased circulating reticulocyte
count in 1 – 2 days ;
• Testosterone also enhances EPO
production, resulting in higher
RBC counts in males
• EPO acts to stimulate maturation of
erythroblasts in the red bone
marrow

27. Energy Metabolism of RBCs
 RBCs do not have mitochondria so cannot use oxidative metabolism to make ATP
o They require a small amount of ATP to power sodium pumps in the membrane (cell would burst without)
o Also need ATP to power GLUT1 transporters which take up glucose
 They make ATP via anaerobic glycolysis and use the pentose phosphate pathway for NADPH
 The end product of the glycolytic pathway in erythrocytes is lactic acid
 After about 120 days RBCs are removed from the blood by macrophages as they pass through the spleen
o Cells in the spleen detect worn out RBCs via surface antigens
o Lack of deformability – old cells become more rigid
 Trapped RBCs are engulfed by splenic macrophages and broken open by osmotic lysis

28.  The haem groups are removed from the globin proteins
o Globin proteins broken down to amino acids
o The haem is then broken open by the haemoxygenase
enzyme
 Iron atom removed for reuse
 The opened porphyrin ring without iron is now called
biliverdin (green colour)
o Biliverdin is then converted to bilirubin in the macrophage
by biliverdin reductase

29.  Bilirubin is bound to albumin in the splenic
macrophages and released into the blood –
unconjugated bilirubin;
 When the unconjugated bilirubin reaches the liver, it is
attached to glucuronic acid by the hepatocytes to make
it more soluble:
o When bound to glucuronic acid it is conjugated
bilirubin;
o Normal level of conjugated bilirubin in blood is 0.1 –
0.3 mg/dL ;
 Conjugated bilirubin passes in the bile to the small
intestine where bacteria converts it into urobilinogen:
o Most urobilinogen passes out of the body in faces,
about 10% passes back in the portal vein to the liver;
 The urobilinogen leaves the liver and reaches the
kidney where it is excreted in urine (yellow collour);

30. Erythropoietic disorders
 Altered red cell production can be caused by direct impairment in medullary erythropoiesis as seen in the
thalassemia syndromes, the anemia of chronic illness and polycythemia vera, a myeloproliferative bone marrow
disorder with disordered erythropoiesis.
 Pathophysiology of sickle cell disease: Sickle cell disease is an autosomal recessive disorder caused by a point
mutation in the β-globin chain resulting in the single amino acid substitution of valine rather than glutamic acid at
position 6. The inheritance of βS from both parents results in the most common and severe form of the disease,
Hb SS.
 Polycythemia vera (PV) is a clonal disorder of myeloproliferation in the bone marrow. It is characterized by
increased red cell mass associated with the proliferation of the erythroid, megakaryocytic and granulocytic cell
lines.

33. Causes of Anaemias
1. Dyshaemopoietic anaemias: Due to insufficient blood production.
2. Haemolytic anaemias: Due to excessive intra-vascular destruction.
3. Haemorrhagic anaemias: Due to extravascular blood loss.
4. Anaemias of unknown causes.

34. Dyshaemotopoietic
Anaemias

35. Haemolytic
Anaemias

36. Haemorrhagic
Anaemias

38. What is Thalassemia?
Thalassemia is an inherited (i.e., passed from parents to
children through genes) blood disorder caused when the
body doesn’t make enough of a protein called
hemoglobin, an important part of red blood cells. When
there isn’t enough hemoglobin, the body’s red blood cells
don’t function properly and they last shorter periods of
time, so there are fewer healthy red blood cells traveling
in the bloodstream.

39. Jaundice
disease
• Jaundice is a condition in which a yellowish tinge appears on the skin, mucous
membranes, and the whites of the eye. Body fluids may also change color.
• Jaundice frequently indicates a problem with the liver or bile ducts. When the liver
is not working properly, it can cause a waste material called bilirubin to build up in
the blood.
• With moderate bilirubin levels, a person’s skin, eyes, and mucous membranes can
turn yellow. As it progresses, the color can also change from yellow to green. The
green color occurs due to biliverdin, the green pigment present in bile.
• Jaundice can develop in people of all ages and is normally the result of an
underlying condition. Newborns and older adults have the highest likelihood of
developing jaundice.

40. Infant jaundice
 Infant jaundice is yellow discoloration of a
newborn baby's skin and eyes. Infant jaundice
occurs because the baby's blood contains an
excess of bilirubin, a yellow pigment of red
blood cells.
 Infant jaundice is a common condition,
particularly in babies born before 38 weeks'
gestation (preterm babies) and some breast-fed
babies. Infant jaundice usually occurs because a
baby's liver isn't mature enough to get rid of
bilirubin in the bloodstream. In some babies, an
underlying disease may cause infant jaundice.
 Most infants born between 35 weeks' gestation
and full term need no treatment for jaundice.
Rarely, an unusually high blood level of
bilirubin can place a newborn at risk of brain
damage, particularly in the presence of certain
risk factors for severe jaundice.
Symptoms
 Yellowing of the skin and the whites of the eyes — the
main sign of infant jaundice — usually appears between
the second and fourth day after birth.
 To check for infant jaundice, press gently on your baby's
forehead or nose. If the skin looks yellow where you
pressed, it's likely your baby has mild jaundice. If your
baby doesn't have jaundice, the skin color should simply
look slightly lighter than its normal color for a moment.
When to see a doctor
• Most hospitals have a policy of examining babies for jaundice
before discharge. The American Academy of Pediatrics recommends
that newborns be examined for jaundice during routine medical
checks and at least every eight to 12 hours while in the hospital.
• Your baby should be examined for jaundice between the third and
seventh day after birth, when bilirubin levels usually peak. If your
baby is discharged earlier than 72 hours after birth, make a follow-
up appointment to look for jaundice within two days of discharge.

42. Leukopoiesis, or the production of white blood cells, is stimulated by chemical
messengers. These messengers, which can act either as paracrines or hormones, are
glycoproteins that fall into two families of hematopoietic factors, interleukins and colony-
stimulating factors, or CSFs.
Hematopoietic factors, released by supporting cells of the red bone marrow and mature
WBCs, not only prompt the white blood cell precursors to divide and mature, but also
enhance the protective potency of mature leukocytes.
Leukopoiesis

43. An early branching of the pathway of leukocytes
differentiation divides the lymphoid stem cells, which
produce lymphocytes, from the myeloid stem cells, which
give rise to all other formed elements. In each granulocyte
line, the committed cells, called myeloblasts, accumulate
lysosomes, becoming promyelocytes. The distinctive granules
of each granulocyte type appear next in the myelocyte stage
and then cell division stops. In the subsequent stage, the
nuclei arc, producing the band cell stage. Just before
granulocytes leave the marrow and enter the circulation, their
nuclei constrict, beginning the process of nuclear
segmentation.The bone marrow stores mature granulocytes
and usually contains about ten times more granulocytes than
are found in the blood. The normal ratio of granulocytes to
erythrocytes produced is about 3:1, which reflects
granulocytes’ much shorter life span (0.25 to 9.0 days). Most
die combating invading microorganisms.

44. Despite their similar appearance, the two types of
agranulocytes have very different lineages:
 Monocytes are derived from myeloid stem cells, and
share a common precursor with neutrophils that is not
shared with the other granulocytes. Cells following the
monocyte line pass through the monoblast and
promonocyte stages before leaving the bone marrow and
becoming monocytes.
 T and B lymphocytes are derived from T and B
lymphocyte precursors, which arise from the lymphoid
stem cell. The T lymphocyte precursors leave the bone
marrow and travel to the thymus, where their further
differentiation occurs. B lymphocyte precursors remain
and mature in the bone marrow.Monocytes may live for
several months, whereas the life span of lymphocytes
varies from a few hours to decades.

46.  Leukemia is cancer of the body's blood-forming tissues, including the bone marrow and
the lymphatic system.
 Many types of leukemia exist. Some forms of leukemia are more common in children.
Other forms of leukemia occur mostly in adults.
 Leukemia usually involves the white blood cells. Your white blood cells are potent
infection fighters — they normally grow and divide in an orderly way, as your body
needs them. But in people with leukemia, the bone marrow produces an excessive
amount of abnormal white blood cells, which don't function properly.
Leukemia

49. Thrombopoiesis
• Due to their short life span of only a few days, anuclear platelets
are continuously replenished and thus provide a classic system to
study hematopoiesis.
• The hematopoietic growth factor thrombopoietin (TPO) is the
major cytokine triggering platelet production. TPO supports the
self-renewal of hematopoietic stem cells (HSCs)
and megakaryocytes (MKs) in the bone marrow (BM) produce
blood platelets, required for hemostasis and thrombosis.
• MKs originate from hematopoietic stem cells and are thought to
migrate from an endosteal niche towards the vascular sinusoids
during their maturation. Through imaging of MKs in the intact
BM, here we show that MKs can be found within the entire BM,
without a bias towards bone-distant regions.

50. The regulation of thrombopoietin levels.
• A steady-state amount of hepatic thrombopoietin
(TPO) is regulated by platelet c-Mpl receptor–mediated
uptake and destruction of the hormone. Hepatic
production of the hormone is depicted. Upon binding to
platelet c-Mpl receptors, the hormone is removed from
the circulation and destroyed, which reduces blood
levels. In the presence of inflammation, IL-6 is released
from macrophages and, through TNF-α stimulation, from
fibroblasts and circulates to the liver to enhance
thrombopoietin production. Thrombocytopenia also leads
to enhanced marrow stromal cell production of
thrombopoietin, although the molecular mediator(s) of
this effect is not yet completely understood.

52.  Blood platelets are formed from the cytoplasm of rare myeloid cells called megakaryocytes, which are the largest
cells residing primarily within the bone marrow. Besides the bone marrow, there has been mounting evidence
suggesting that platelet release could occur in the pulmonary circulation, making the lungs a possible birthplace for
platelets.
 Platelet production in the lung circulation is the result of proplatelets and megakaryocytes released in spleen and
bone marrow sinusoids. We can thus differentiate two levels of regulation: 1) proplatelet release and megakaryocyte
egress from spleen and bone marrow, and 2) platelet shedding in the lung vasculature.

57.  Thrombocytopenia refers to an abnormally low level of platelets in the bloodstream.
 Platelets are important for normal blood clotting.
 With severe thrombocytopenia, excessive bleeding may occur.
 Thrombocytopenia occurs because there is decreased production or increased destruction of
platelets. It also can occur when the spleen enlarges and sequesters more platelets than usual.
 Heparin-induced thrombocytopenia (HIT) arises due to immune-mediated destruction of platelets
that may occur with the blood thinner heparin and its related drugs.
 Other prescription drugs also may cause thrombocytopenia in certain cases.
 Viral infections may cause thrombocytopenia due to their effect on bone marrow, leading to
decreased production of platelets.
 A blood test is used to diagnose thrombocytopenia. It often is identified when blood tests are
ordered for other reasons or during routine screening.
 Signs of thrombocytopenia can include small pinpoint hemorrhages (petechiae) or bruises known
as purpura.
 Treatment of thrombocytopenia, when necessary, consists of platelet transfusions. Most patients
with thrombocytopenia do not require regular platelet transfusion. If surgery is planned in a patient
with a platelet count less than 50,000, then transfusion may be necessary.

60.  “Platelets are minute fragments of blood cells that help in the formation of clots in the
body to stop bleeding.”
 Any damage in the blood vessels sends signals to the platelets. The platelets rush to the
site of damage and form clots to repair the damage.
 The activated platelets stick together to form a platelet plug which in turn activates the
coagulation factor. Vitamin K is beneficial for the proper functioning of the coagulation
factor.
Platelets, Coagulation and
Haemostasis

62.  The larger cells called megakaryocytes are disintegrated to form thrombocytes. Each megakaryocyte
contains 2000-3000 platelets. Each platelet contains several vesicles but no nucleus.
 The endothelial cells present on the inner surface of blood vessels. When the endothelial layer is
injured, it exposes collagen and all other factors that help in blood clotting. These factors attract
platelets to the wounded site.
 The activated platelets clump together to form a platelet plug, releasing their contents. These contents
activate other platelets and interact with other coagulation factors.
 “Coagulating factors are proteins present in blood plasma that helps in converting fibrinogen to
fibrin, that strengthens platelet plug.”
Platelets and Coagulation

63. “Hemostasis is a physiological defensive reaction to an injury or a cut that seals the blood vessels and thus helps in healing.”
Mainly platelets, endothelial cells of blood vessels, and blood proteins are responsible for hemostasis. Hemostatic mechanism
proceeds in the following series of steps:
Changes in blood vessel cells
Blood clot formation
Platelet plug formation
Stages of Hemostasis
Hemostasis takes place in two stages:
Primary Hemostasis
It is caused when bleeding ceases or gets reduced by contraction of the blood vessels, and thrombin signals for platelet
assembly and forms a loose platelet plug.
Secondary Hemostasis
It includes the action of blood proteins and coagulation factors in a sequence to reinforce the platelet plug and marks the
onset of the healing process. Blood coagulation is provoked by the extrinsic pathway i.e. tissue damage, but the intrinsic
pathway (internal messengers) intensifies the coagulation.
Coagulation of blood is a lengthy process occurring within a few minutes where numerous coagulation factors come into
play.
Hemostasis

64. Hemostasis mechanism of preventing blood loss
One drawback of a circulatory system such as ours, in which the liquid blood is under
high pressure, is that serious bleeding can take place after even a slight injury.
To prevent the possibility of uncontrolled bleeding, we have a three-part hemostatic
mechanism consisting of:
The constriction of blood vessels
The clumping together (aggregation) of platelets
Blood clotting
Overall, hemostasis is a specific type of homeostasis that prevents blood loss.

65. • Vascular spasm
• Immediately after a blood vessel is cut, the vessel
wall contracts, this reduces blood flow from the
ruptured vessel. The contraction results from:
• Nervous reflexes initiated by pain.
• Local myogenic contraction of the blood vessels.
• Humoral factors from the traumatized tissues
and platelets.
• Platelets mediate much of the vasoconstriction by
releasing the vasoconstrictor substances,
thromboxane A2 & serotonin, Also, thrombin that is
generated in the coagulation cascade, triggers the
endothelium to release the powerful vasoconstrictor,
endothelin-1.
• This local vascular spasm can last for many
minutes or even hours during which the process of
platelet plugging and blood coagulation can take
place.

66. Formation of the platelet plug
• When the receptors on the platelet membrane
come in contact with damaged endothelium or
collagen fibers in the vascular wall,
the platelets immediately change their shape.
They become sticky and develop finger-like
processes so that they stick to the collagen fibers,
a process called platelet adhesion. This is
followed by platelet activation. Activated
platelets release the contents of their dense
granules, including ADP, thromboxane A2, and
serotonin.
• These 3 agents in turn act on
nearby platelets to activate them, causing them to
adhere to the originally activated platelets,
resulting in platelet aggregation. Thus, a platelet
plug is formed, which is usually successful in
stopping blood loss if the vessel opening is
small. If there is a large hole, a blood clot is
required.

67. Formation of the blood clot (coagulation)
• The clot begins to develop a few seconds
after the vascular injury. Coagulation factors
are essential to coagulation. They are mostly
plasma proteins (inactive proteolytic enzymes)
synthesized by the liver. However, some are
not protein (e.g. calcium ions) and some are
released by the platelets.
• Steps of coagulation
• Formation of prothrombin activators (active
factor X, active factor V, Ca+2, and
phospholipids), This is done by either the
intrinsic or the extrinsic pathways.
• Conversion of prothrombin into thrombin
(by prothrombin activators).
• Conversion of soluble fibrinogen into
insoluble fibrin threads (by thrombin).

68. Formation of prothrombin activators
In the body, two different pathways start coagulation:
The intrinsic pathway becomes activated when blood comes into contact with a rough
surface (contact activation). In the lab, this occurs when putting blood into a glass test tube.
The extrinsic pathway is activated when blood comes in contact with the material from
damaged tissues (tissue factor activation). i.e. the stimulus is trauma to the blood vessel wall
or surrounding tissues.
In both cases, a chain reaction is triggered in which inactive coagulation factors in the
circulation, are sequentially activated. The extrinsic and intrinsic pathways converge on a that
ends by converting the soluble plasma protein, fibrinogen (coagulation factor I), to insoluble
fibrin, the main constituent of the clot.

69. The intrinsic pathway (contact
activation)
It starts by activation of factor XII by contact of blood with
collagen fibers under the injured endothelium. This activation is
catalyzed by high-molecular-weight kininogen and
prekallikrein. Active factor XII then activates factor XI and
active factor XI activates factor IX, Activated factor IX forms a
complex with active factor VIII, which activates factor X,
Phospholipids from platelets (PL) and Ca+2 are necessary for
full activation of factor X.
It is believed that at first, small amounts of factor X are
activated without the help of factor VIII. Then, when factor Xa
activates prothrombin to thrombin, thrombin activates factor
VIII. This results in the feedback activation of the coagulation
cascade, with the formation of more thrombin and further
activation of factor VIII.

70. The extrinsic pathway of blood clotting (tissue factor
activation)
It is initiated by factors outside the vascular
system. Nonvascular cells express the membrane protein
tissue factor (tissue thromboplastin, or factor III).
Tissue factor acts as a receptor for factor VII, which is a
plasma protein. When injury to the endothelium allows
factor VII to come in contact with tissue factor, tissue
factor activates factor VII. Tissue factor, factor VIIa,
and Ca+2 from a complex that proteolytically activates
factor X to factor Xa. Factor Xa, which arises by both
the intrinsic and extrinsic pathways, proceeds along the
common pathway.

71. The final common pathway
 Prothrombin activators (Factor Xa from the extrinsic or intrinsic pathway, factor Va, Ca+2, and phospholipids) convert prothrombin
(factor II, one of the plasma proteins) into thrombin. Thrombin (proteolytic enzyme) catalyzes the conversion of soluble fibrinogen
(factor I) to insoluble fibrin threads.
 Thrombin first converts fibrinogen to fibrin monomers, then many fibrin monomers polymerize into fibrin threads that form the
clot. This reaction requires Ca++. Thrombin also activates factor XIII (fibrin-stabilizing factor), which mediates the covalent
crosslinking of the fibrin polymers to form a mesh called stable fibrin that is even less soluble than fibrin polymers.
 There is a cross-talk between the intrinsic and extrinsic pathways. After blood vessels rupture, clotting is initiated by both pathways
simultaneously. However, the extrinsic pathway is very fast, particularly if a large amount of tissue factor is available, while the
intrinsic one is much slower. In addition, both pathways augment each other. For example, the [tissue factor + Factor VIIa + Ca+2]
complex of the extrinsic pathway, activates factors IX and XI of the intrinsic pathway.

74. Blood clotting inhibitors
i. Anticoagulant:
•As many as 35 compounds may be required for blood coagulation.
•Such a complex system of checks and balances is necessary to prevent clotting when there is
no bleeding.
•An unwanted clot in a blood vessel that cuts off the blood supply to a vital organ is one of the
body’s worst enemies.
•Most of the body’s anticoagulant substances circulate within the blood, and the blood vessels
themselves help prevent clotting.
•The blood vessels contribute in two ways.
•First, the smoothness of the inner walls normally prevents activation of the intrinsic clotting
mechanism.
•Second, a thin layer of negatively charged protein molecules attached to the inner walls repels
the clotting factors, preventing the initiation of clotting.
•Injury to a blood vessel removes both of these safeguards.
•The rough damaged wall of the vessel and the negatively charged collagen layer beneath the
smooth endothelium initiate the platelet phase of hemostasis.
•If the platelet plug that forms cannot stop the loss of blood, factor XII is activated, along with
the rest of the intrinsic pathway.

75. ii. Heparin and antithrombin:
•One of the most powerful anticoagulants in the blood is heparin, a polysaccharide
produced by mast cells and basophils.
•Heparin is concentrated mostly in the liver and lungs.
•Minute quantities of heparin in normal circulating blood also prevent clotting by
combining with the antithrombin-heparin cofactor (also called antithrombin or
antithrombin III) to induce the co-factor to combine with thrombin 1000 times more
rapidly than usual.
•Such a rapid binding to thrombin removes it almost instantly from the bloodstream and
makes clotting almost impossible.
•Without heparin, antithrombin-heparin cofactor binds to thrombin molecule for
molecule, removing it from the blood in about 15min.
•The combination of heparin and antithrombin-heparin cofactor also reacts with several
clotting factors in the extrinsic and intrinsic pathways, further inhibiting blood clotting.
•Thrombin itself acts as an anticoagulant.
•When its concentration becomes too high, it destroys factor VIII to prevent clotting.

76. iii. Fibrinolysis by plasmin:
•Clot prevention is important, but so is clot destruction, or fibrinolysis
(‘fibrin breaking’).
•Small blood clots form continually in blood vessels throughout the body.
•If they are not removed promptly, the blood vessels become clogged.
•In the process of fibrinolysis, a blood protein called plasminogen is
activated into an enzyme called plasmin.
•The plasmin digests the threads of fibrin by first making them soluble and
then breaking them into small fragments.
•The fragments are removed from the bloodstream by phagocytic white
blood cells and macrophages.
•Excessive amounts of coagulants are routinely removed by the liver.

77. Anticoagulant drugs:
•The best-known anticoagulant drug is aspirin (acetylsalicylic acid), which works by preventing platelets from sticking
together to form a plug.It also inhibits the release of clot-promoting substances from platelets.
•One drug that digests the fibrin threads of a clot is streptokinase, which is released by certain streptococcal
bacteria.Streptokinase activates plasminogen to speed fibrinolysis.It is used to dissolve blood clots (thrombi) in veins and
arteries.Streptokinase also helps dissolve the fibrin threads in a blood clot by converting plasminogen into plasmin, the fibrin-
destroying enzyme.
•Genetically engineered (recombinant) tissue-plasminogen activator (rt-PA) is effective in dissolving intravascular blood clots
when delivered directly to a clotted area through a catheter.
•When vitamin K is in short supply, the liver produces enough prothrombin and other clotting substances for normal clotting.
•Dicumarol is a compound that resembles vitamin K to such an extent that the liver enzymes that form prothrombin will pick
up dicumarol instead of vitamin K.
•The anti-coagulatory effect of dicumarol is often used to prevent clotting after surgery.
•In addition to being used to remove blood clots and keep blood from coagulating during surgery, anti-coagulant drugs may
be necessary to prevent clotting in blood that will be used later for blood transfusions.
•To avoid such clotting, a dilute sterile solution of a citrate or an oxalate salt is added to collected blood.
•Clotting doesnot occur because citrate ions or oxalate ions combine with the available calcium ions, making calcium
unavailable for its usual blood-clotting functions.

78. Blood coagulation tests:
•Several tests are used to determine blood-clotting time.
•The most popular ones are platelet count, bleeding time, clotting time, and prothrombin time.
•The blood platelet count must be greater than 150,000 per cubic millimeter in order for normal coagulation to take place.
•Also, if platelet function is not normal, normal coagulation may not occur.
•A pierced fingertip or earlobe usually bleeds for 3 to 6 min.
•A longer bleeding time for this wound generally indicates a platelet deficiency.
•Clotting time is determined by placing blood in a test tube and tipping it back and forth every 30sec or until it clots.
•This usually occurs in 5 to 8 min.
•Because the condition and size of test tubes vary, standardization is necessary to obtain accurate results.
•The test for prothrombin time (PT) indicates the amount of prothrombin in the blood.
•Immediately after blood is removed, oxalate is added to prevent the prothrombin from being converted into thrombin.
•Then calcium ions and tissue extract containing thromboplastin are added to the blood.
•The calcium offsets the effect of the oxalate, and the tissue extract activates the conversion of prothrombin.
•The time usually required for blood to clot, referred to as the prothrombin time, is about 12 sec.
•A longer prothrombin times also mean a decreased quantity of some factor other than prothrombin.
•Similar tests are used to determine the relative quantities of other clotting factors.

79. Hemophilia
 Hemophilia is a rare disorder in which the blood doesn't clot
in the typical way because it doesn't have enough blood-
clotting proteins (clotting factors). If you have hemophilia,
you might bleed for a longer time after an injury than you
would if your blood clotted properly.
 Small cuts usually aren't much of a problem. If you have a
severe form of the condition, the main concern is bleeding
inside your body, especially in your knees, ankles and
elbows. Internal bleeding can damage your organs and
tissues and be life-threatening.
 Hemophilia is almost always a genetic disorder. Treatment
includes regular replacement of the specific clotting factor
that is reduced. Newer therapies that don't contain clotting
factors also are being used.

81. Hemophilia and families
• The hemophilia gene runs in families;
this is passed on by the parents to their
children. While women who own the
hemophilia gene usually do not suffer
from clotting factor problems, they carry
the gene, which can then be passed on to
the next generation. A boy can inherit a
genetic mutation only from his mother,
and the disease always affects him. The
chances of an individual developing
hemophilia can be determined using the
table below:

83. Blood groups
• The term “blood group” refers to
the entire blood group system
comprising red blood cell (RBC)
antigens whose specificity is
controlled by a series of genes which
can be allelic or linked very closely
on the same chromosome. “Blood
type” refers to a specific pattern of
reaction to testing antisera within a
given system.

86.  Rh factor (or Rhesus factor) is a type of protein on the outside
or surface of your red blood cells. You inherit the protein,
which means you get your Rh factor from your biological
parents. If you have the protein, you’re Rh-positive. If you
don’t have the protein, you’re Rh-negative. The majority of
people, about 85%, are Rh-positive.
 During pregnancy, complications may occur if you’re Rh-
negative and the fetus is Rh-positive. This is called Rh factor
incompatibility. Treatments are available to prevent
complications of Rh incompatibility.
Rh factor