INTRODUCTION - Bleeding from blood vessels due to trauma or injury is common ; mechanism of the

body to arrest bleeding is called Haemostasis

Mechanism can be divided into two parts
1. Primary Haemostasis
2. Secondary Haemostasis

Immediately after injury, small vessels (arterioles) constrict i.e vasoconstriction

Vasoconstriction is achieved mainly by 2 mechanisms
1) Neural e.g. sympathetic vasoconstrictor nerves
2) Locally released chemicals mainly serotonin and endothelium
When a vessel is cut, its endothelial lining is damaged and the subendothelial tissue which is highly
thrombogenic get exposed. The circulating platlets stick over the subendothelial tissue > aggregation and
activation platlets-> platlet plug formation that seals the blood vessels
This mechanisms of vasoconstriction + platlet plug formation stops the bleeding in few seconds to minutes.
This is known as Primary Haemostasis
Time between the onset of bleeding and primary homeostasis is called the bleeding time.
Bleeding time is prolonged in the deficiency of number or quality of platlets
After platlet plug formation over the platlet plug a fibrin clot develops. Fibrin clot develops by a mechanism called
coagulation mechanism, Because of this fibrin clot no bleeding occurs after vasoconstriction disappears. This mechanism of
formation of fibrin clot is called Secondary haemostasis which stabilizes the platlet plug. Fibrin clot which occludes
the vessel lumen is lysed by fibrinolytic mechanism and recanalization of vessel occurs.
PLATLETS - Platlets are small disk shaped (diameter 2-4um) non-nucleated man of protoplasm. Platlets
serves many function in haemostatic and defensive mechanism of the body. Normal platelet count is about
1.5-4 lakhs /ml in the They arise from budding of cytoplasm of their Progenitors, the megakaryocyte which
are derived from the primitive hematopoetic stem cells.
In the normal adult megakaryocyte are found exclusively in bone marrow in new born and under certain
pathological condition megakaryocyte are also found in the liver, lungs and other organs.
Each megakaryocyte gives rise to 1000-15000 platlets. The life span of individual platlet is about 8-12 days
aged as damaged platlets are removed from the circulation by the Recticulo endothelial system. The spleen is
important site of removal.
Morphology-PIatlets in inactive form are disc like in shape but when activated during
hemostasia it become spherical. The membrane of the platlet has 2 layers-
Outer Glycolyd layer which contains glycoprotein
Inner lipoprotein layer
Platlet membrane contains various receptors which are chemically glycoproteins In the lipoprotein layer these are various
types of lipts molecules including phospholipids. These phospholipids are precursors of some very important chemical
molecules like TXA2

FUNCTIONS OF PLATLETS
ROLE OF PLATLET IN PRIMARY HEMOSTASIS
After injury to the blood vessels, subendothelial tissue becomes exposed which contains collagen having extreme affinity
for platlets. Platlets have receptors for collagen (chemically which are glycoprotein) Binding between collagen arid collagen
receptors of platlet occurs and is enhanced by von will brand factor .This phenomenon is called adhesion. Following
adhesion platelet scretes contents of both L and dense granules, chemical changes it leads to thromoboxane A2 (TXA2)
formation via cyclolygenase enzyme which is responsible for secretion from L and dense granules peripheral blood.
Dense granules secrete ADP and Ca ++, ADP causes platlet aggregation i.e. other platlets are drawn to the site to form
a lump of platelets. TXA2 also helps in aggregation and also causes vasoconstriction and produce the primary
hemostasis.

ROLE OF PLATLET IN COAGULATION

(Secondary Hemostasis)
Coagulation of Blood is secondary hemostasis which starts little after the primary hemostasis
Normally blood contains two sets of materials
1) One set consists of procoagulants (who help in clothing).
2) Other set consists of inhibitors of coagulation, those who oppose the coagulation
Normally effect of the inhibitors dominate but after injury to the vessel the effects of procogagulants
dominated
Procoagulants in the blood are proenzymes and once the process of clotting starts they get activated one after
another in a sequential manner. The final end product in fibrin (blood clot also called as fibrin clot)
Large number of fibrin threads crises cross with one another and RBC S fill up the gaps between them (e.g.
Fibrin threads containing Blood cells) which form the clot.

MECHANISM OF COAGULATION
In Coagulation fibrin is formed from its precursor fibrinogen. Thrombin acts upon fibrinogen to form fibrin.
Thrombin is formed from prothrombin. The key agent to convert prothrombin to thrombin. is Factor XA
Factor XA can be produced by any one of the two major pathways
Intrinsic path (Intrinsic mechanism)
Extrinsic path (extrinsic mechanism)
Intrinsic pathway- vascular injury causes exposure of the vascular subendothelium (highly thrombogenic) inactive factor
XII(Hageman factor) which is normally present in the blood together with two substances e.g. high molecular weight
riminogen and prekallakrein comes into contact with thrombogenic subendothelium ,
factor XII is converted to XII a (activated XTT) this causes 2 things:

1) Causes prekallikrein to become rallekrin which converts Factor XII to XII very rapidly
2) Causes conversion of Factor XI to XIa
Inactive factors present in other blood becomes active once the clotting mechanism starts, one active factor converts the next
inactive factor into active form.
The first inactive factor e.g. factor XII become active by suffix A and activates the other inactive factor and continues until
X a is formed . Once Factor X a is formed ,it converts prothrombin into thrombin &Thrombin converts Fibrinogen into
Fibrin

II )Extrinsic pathway - Damage to the cells, a notably vascular endothelium causes release of tissue thromboplastin (tissue
factor). Tissue thromboplastin is found principally in cell membranes of almost every cell.
Tissue promboplastin is composed of a heat stable phospholipids and heat labile glycoprotein
Removal of phospholipid from tissue factor inactivates its clot promoting properties. The clot promoting properties of
tissue thromboplastin are mediated through its action on Factor V which is synthesized when vit. K is available
completed with Tissue thromoboplastin Factor VII is complexed with tissue thromboplastin, Factor VII is transformed to an
enzymetically active form VII A that activate factor X into XA
Factor VII -Tissue thromboplastin complex also activates Christmas factor .(FactorIX) Thus reactions of the extrinsic
pathway affect the intrinsic pathway
Coagulant Factors
There are 13 clotting factors. Roman numerical has been given to most of the clotting factors

Factors
(International
nomenclature ) trival names Activate or Altered State
Factor I Fibrinogen Fibrin
Factor II Prothorombin Thrombin
Factor III Tissue Promboplastin (TF) -

Factor IV CA++
Factor V Proaccelerin ,Ac globulin Altered proaccelerin
Factor VI No factor
Factor VII Proconvertin VIIA
Factor VIII Anti hemophilic Factor Altered
Von Willebrand factor factor VIIA

Factor IX Christmas factor Factor IX A

Factor X Stuart Prower factor Factor X A
Factor XI Plasma thromboplastin Factor XIA
Antecedent (PTA)
Factor XII Hageman factor Factor XIIA
Factor XIII Fibrin stabilizing factor Factor XIIIA

SYNTHESIS OF CLOTTING FACTORS

All the clotting factors except factor VIII/ Von Willebrand factor completed (VII/VWF) are synthesized
mainly in the liver
Factor VIII can be disassociated into 2 components of unequal size.
The larger subcomponent e.g. Von Willebrand factor is synthesized in vascular endothelial cell, &
Megakaryocytes under direction of autosomal gene. The smaller component factor VIII or factor VIIIa is probably
the liver
ROLE OF VITAMIN K & LIVER
VITAMIN K-
required for synthesis of factorsII,VII,IX,,X by liver, thus they are called “vitamin K dependent
procoagulants” .Vitamin K is also required for the synthesis of protein C and protein S
Liver
synthesis prothrombogin, fibrinogen ,factorsV ,VII, IX, X, XII, antithrombinIII ,heparin, protein C&S

Typical vit k deficiency is seen in

 1. Patients on prolonged antibiotic therapy which destroys the bacterial flora of the gut
2. In the new born in which gut bacterial flora is yet to develop

PLASMA FIBRINOGEN AND FORMATION OF FIBRIN

Clotting of blood is the result of the conversion of a soluble plasma protein, fibrinogen into an insoluble network of
fibrin,
Polymerized Fibrin polymeric (insoluble)
The concentration of Fibrinogen in normal human plasma arranges 270-300 mg/dl thus, about 0 g of fibrinogen is present
in the circulating blood.. Concentration of Fibrinogen is increased in pregnancy and conditions associated with
inflammation.. Increase in fibrinogen accelerates the setting of RBC when blood is allowed to stand This leads to rapid
E.S.R setting ,because amount of fibrinogen neutralize the electrostatic forces on the surface of red cells and normally
prevent these cells from sticking each other Biological half life of fibrinogen is about 3-4 days Thus about 15 % of plasma
fibrinogen must be replaced daily by its synthesis in the parenchymal cells of the liver.

INHIBITORS OF CLOTTING
Blood clot forms normally on the platlet plug subsequently, blood clot is lysed by a mechanism that is normally present in
the blood and the canal of the obliterated vessel is reopened.
Some naturally occurring inhibitors of coagulation (called circulatory Anti coagulants) which prevents extensive clotting
They are:-
 Anti thrombin
 Heparin
 Protein C and S

I. Anti thrombin - well known as anti thrombin III it binds with factors like IX a, X a XIa, XIIa well as prothrombin and
inhibit them ,. The inhibitory properties of Ant thrombin III is greatly potentiated by addition of heparin

II. Heparin- it is present in the granules of most cells. .Without Antithrombin III heparin is not a anticoagulant, it
powerfully inhibits several procoagulant factors.With anthithrombin III it is widely used in the prevention and
treatment thromboitic state
III. Protein C it is a proenzyme but is converted into its active form by thrombin, Activated protein C
particularly in presence of protein S inhibits Factor V and VIII.

FIBRINOLYTIC MECHANISM
Plasminogen is normally synthesized by the lives and normally present in the circulating blood as clot forms,
plasminogen is absorbed on the clot Local endothelial cells produce plasmin activators which are
 Tissue plasminogen Activator (TPA)
 Urokinase (UPA)
The TPA and VPA converts plasminogen into plasmin the TPA and Vpa converts plasminogen into plasmin
breaks down the fibrin threads which are engulfed by Reticulo endothelial system and clot is lysed

Endothelial cells
Plasminogen ---------►absorbed by clot ----------------►TPA AND UP A-----------------------►
(Synthesized in liver)
Plasminogen to plasmin-----► Breaks fibrin threads------------------► Engulfed by R. E system

----------------►Clot lysis

TEST OF COGULATION SYSTEM

A. Screening tests are important for assessing the overall integrity of the coagulation system and fro
determining where in the cascade a defect may exist.

Partial thromboplastin time (PTT) &activated partial thromboplastin time (APTT) screen the intrinsic
and common coagulation pathways
a. Purpose The PTT&APTT are used detect significant deficiencies of all the intrinsic and common coagulation
factors except XIII. The PTT and APTT are commonly used to monitor heparin therapy |
b. PTT METHOD Phospholipid is added to platlet-poor plasma taken form blood
that is anticoagulated with citrate. Clotting is then initiated by the addition of Ca•++ . The time for formation of the first
fibrin strands is the PTT.
c. APTT METHOD. The APTT is performed in the same manner as the PTT except
for the addition of an activating agent such as kaolin or ellagic acid before recalcification

B. Prothromibin time (PT)

Purpose- The PT measures the function of the extrinsic and common coagulation pathways. It is commonly used to
monitor oral anticoagulant therapy
Method-. A source of phospholipids and tissue thromboplastin (rabbit or human brain extract) is added to platelet-poor
plasmas, and Ca + + is added to initiate coagulation The time to the appearance of fibrin strands (the PT) is measured and
compared with that of a control

C. Quantitative fibrinogen
Purpose- It must be emphasized that fibrinogen quantization measures quantities of protein, not function, Quantitative
fibrinogen determination is useful in Interpreting functional tests of fibrinogen, in addition, the fibrinogen level may be
slightly low without detectable abnormalities of the PT OR PTT
Method- Fibrinogen can be quantitated by a variety of techniques, including protein precipitation and immunologic
methods

D. Thrombin time
Purpose- Thrombin time screens the thrombin-fibrinogen reaction
(1) Because thrombin acts of fibrinogen directly, the time it takes for a clot to form In plasma to which
thrombin has been added is directly related to the amount of functional fibrinogen in the sample
(2). This test is affected not only by the amount of fibrinogen in the sample but also by inhibitors to fibrin
formation or by the Presence of functionally abnormal fibrinogen, in addition, the test is very sensitive to the
antithrombin effect of heparin,

Method- Thrombin is added to the patient's platelet-poor plasma, and the time to
fibrin strand formation is measure. The normal range is influenced by the amount
of thrombin added, and a "dilute thrombin time" is sometimes used for its added sensitivity

Screening test for factor XIII

Purpose- A deficiency of factor XIII cannot be detected by the above tests. A simple screening test for the
presence of factor XIII is based on the fact that fibrin that has not been cross-linked will dissolve in urea,
whereas fibrin that has been cross-linked by the action of factor XIII.
Method- A small amount of plasma that has been clotted is placed in a solution of urea, and an identical clot
is placed in saline s a control; both are incubated
overnight and compared. Dissolution of the clot in the urea, solution confirms
factor XIII deficiency.

Concept of International Normalized Ratio and Management of a patient on

oral Anticoagulants *

The prothrombin time (PT) has been the conventional means used to monitor the degree of anticoagulation.
Prothrombin ratio(PTR) is the ratio of patient's PT divided by control PT from the laboratory. A PTR of 2-
2.5 is considered to be the therapeutic range.ln an effort to standardize the results of the PT, WHO
introduced the "concept of 1NR. INR is the PTR that would have been obtained if a standard
thromboplastins reagent had been used..The INR relates all thromboplastins to the standard of human brain
thromboplastin with the use of internal sensitivity index (ISI). The ISI established the reference standard of
1.0 to human brain derived thromoboplastin.

INR = (patient's PT/control PT) isi

With the use of INR variations due to differences in nature of source and potency of thromboplastin has been
standardized. INR for a normal healthy adult is 1.0. Recommended intensity of INR for patients on oral
anticoagulants varies from 2.0 to 4.5 depending on indication for use. For example recommended INR for
deep vein thrombosis , Valvular heart disease.pulmonary embolism ,myocardial infarction is 2.0 to 3.0 and
in case of artificial mechanical heart value is 3.0 to 4.5.

CLOTTING DISORDERS

TYPES OF CLOTTING DISORDERS

A. Congenital Coagulation Disorders

The hemophilias
 Hemophilia A (Classical hemophilia)
Hemophilia B (Christmas disease)
Von willebrand's disease
Other congenital deficiency disorders
Fibrinogen (factor I) absence or deficiency
Prothrombin (factor II) deficiency
Factor V deficiency
Factor VII deficiency
Factor X (Stuart factor) deficiency
Factor XI (plasma thromboplastin antecedent) deficiency
Factor XII (Hageman factor) deficiency
Factor XIII (fibrin-stabilizing factor) deficiency
Fletcher factor (pre-kallikrein) deficiency
Fitzgerald factor (high molecular weight kininogen) deficiency.

B. Acquired Coagulation Disorders

Vitamin K deficiency
Liver disease
Anticoagulant drugs
Disseminated intravascular coagulation (DIC)
Acute primary fibrinolysis
Massive transfusion of stored blood.
Circulating inhibitors of coagulation

THE PATHOGENESIS OF COAGULATION ABNORMALITIES

From a consideration of the physiology of coagulation it is evident that impairment of coagulation, and thus
a hemorrhagic tendency, may result from one or more of the following mechanisms.

Deficiency of one or more blood coagulation factors

Deficiency may be due either to defective synthesis or excessive utilization with normal synthesis. Defective
synthesis of the plasma protein coagulation factors results from many causes: (a) genetic causes which
usually lead to the deficiency or reduced activity of a single coagulation factor; (b) rarely in-association with
other diseases. Excessive utilization of some coagulation factors occurs with intravascular coagulation and in
some cases of pathological fibrinolysis.
 Inhibition of coagulation by acquired inhibitors

Changes in the naturally occurring inhibitors do not cause pathological inhibition of coagulation. However,
in certain circumstances, abnormal inhibitors appear and interfere with blood coagulation. Acquired inhibitors
of coagulation, although rare, are well recognized and are usually auto-antibodies with specificity for a
particular coagulation factor. This is in contrast to the naturally occurring inhibitors whose action is against
the active intermediate products of coagulation. Monoclonal immunoglobins produced in multiple myeloma
and Waldenstrom's macroglobulinaemia may interfere with coagulation reactions; particularly fibrin
polymerization, in a non-specific fashion. The syndromes associated with acquired inhibitors are described
on.
It should be noted also that the fibrinogen and fibrin breakdown products which occur in acute pathological
fibrinolysis are potent, though transient' inhibitors of fibrin polymerization and thus blood clotting.

Fibrinolysis
In certain uncommon conditions, large amounts of tissue activator may be released into the bloodstream,
producing a transient but marked hyperplasminaemic state. Abnormal bleeding may then occur because:
a. Fibrin which is present in wounds or haemostatic plugs is rapidly digested,
b. The products of fibrinogen and fibrin digestion (breakdown products) act as anticoagulants which
interfere with fibrin clot formation and platelet function;
c. The plasmin digests fibrinogen and factors V and VIII.

Miscellaneous
Congenital and acquired disorders of platelets sometimes result in the diminished availability of platelet
factor III in vitro or other platelet procoagulant activity.
In patients with primary and secondary polycythaemia, abnormal bleeding not uncommonly complicates
surgery The bleeding probably results from an abnormally high concentration of red cells in the haemostatic
plug, disordered platelet function, the effect of slugging in small vessels, and, occasionally, disseminated
intravascular coagulation.

GENERAL PRINCIPLES IN THE TREATMENTOF COAGULATION OF DISORDERS

Four main points should be considered in the management of patients, with coagulation disorders; they are:
a) treatment of the underlying causes;
b) Correction of the abnormality with drugs and replacement transfusions;
c) Treatment at the bleeding site; and
d) General supportive measures.
An accurate diagnosis is most important, as treatment of the individual disorders differs considerably. The
remaining part of this section summarizes the various measures that are used; further details are given in
discussion of the individual disorders.
Treatment of the underlying causative disorder
Most of the acquired coagulation disorders are secondary to an underlying disorder, and recognition and
treatment of the underlying condition after results in relief or cure of the coagulation abnormality. The
disorders include:
a) Biliary tract obstruction and intestinal diseases which cause
mal-absorption of vitamin K
 b) Liver disease in which there is impaired synthesis of coagulation factors;
c) The ingestion of oral anticoagulant drugs or heparin therapy and
Many disorders which cause the defibrination syndrome and pathological fibrinolysis.
Correction of the coagulation abnormality with drugs and transfusion replacement therapy
Drugs that are useful in the correction of coagulation abnormalities are usually specific and of value only in
a limited number of disorders. They include vitamin K, protamine sulphate, calcium gluconate,
antifibrinolytic agents, e.g. amino-caproic acid, and the kallikerin inhibitor trasylol, heparin, desarnmo-8-D-
argmine vasopressin, androgens, and topical haemostatic such as thrombin. Replacement Therapy has the
object of achieving repid correction of the deficiency of one or more coagulation factors. Factors may be
given in the form of whole blood, fresh frozen plasma, or one of the various concentrates of factor VIII or
factors II, VII, IX, and X.
The broad indications for replacement therapy are:
a) Early treatment of spontaneous bleeding episodes;
b) Established prolonged wound and tissue bleeding and
c) Control of bleeding during and after surgery and trauma.
Long-term prophylactic replacement therapy in the inherited disorders, especially severe hemophilia A and
Christmas disease, may be beneficial, but is generally not practiced in view of the storage of materials and
the possible increased risk of development of inhibitors due to antibody formation.
The type of blood product indicated depends on a number of considerations, including the diagnosis of the
bleeding disorder, the type and site of bleeding, the availability of the different blood products, and response
to therapy as judged clinically and by laboratory tests.
Irrespective of the type of coagulation abnormality, acute blood loss must always be replaced blood or
appropriate fractions. When there is no indication for whole blood, and it is necessary to institute of maintain
corrections of the clotting factor deficiency, this can usually be achieved by the transfusion of fresh frozen
plasma or an appropriate concentrate. Platelet concentrates may also be required if there is associated
thrombocytopenia
Concentrates of fibrinogen, factor VIII, and a mixture of factors II, VII, XI, and X (PPSB), or E, XI, and X
(prothrombinex), are indicated in many bleeding episodes in patients with known deficiencies of these
factors. If insufficiencies amount of these factors are available, fresh frozen plasma must be used. There is
also a growing tendency to encourage home therapy with concentrates, after appropriate instruction of the
family (Levine & Britten 1971). This requires careful supervision under the direction of established
hemophilia treatment centers

The amount of material which should be given at a single transfusion depends on the severity o f the
coagulation defect, the amount of tissue damaged, and the site of bleeding. In general, the most important
factor for determining the amount to be given is the extent of tissue damage. When it is not great, as in
spontaneous episodes of bleeding and following mild trauma, a single transfusion of plasma amounting to 7-
10 ml/kg bodyweight usually arrests bleeding .When tissue damage is greater or bleeding is present in a
dangerous site, e.g. the tongue, it is usual to give twice this amount. In major trauma, including surgery,
greater correction of the coagulation abnormality is usually it is then necessary to use concentrates of clotting
factors to avoid fluid overload. Treatment with concentrates should be controlled with factor assays, and the
amount required adjusted accordingly.
The duration of replacement therapy depends on the cause of the bleeding disorder, the severity of tissue
damage, and the response to treatment. Frequently, a single transfusion arrests bleeding due to minimal
tissue damage in patients with very severe coagulation abnormalities. When tissue damage is greater, and
other treatment is ineffective in correcting the underlying cause, it is usually advisable to repeat the
transfusion at intervals of 24 hours or less for several days.
Following major surgery, it is essential to continue correction of the coagulation abnormality until healing
occurs; it is usually essential to monitor replacement therapy and adjust the dose and its frequency according
to the results of laboratory tests.
The rate of administration should be rapid in order to obtain high peak blood concentrations of the deficient
clotting factor and thus optimum haemostatic effect.
Mild complications of plasma component infusions include pyrogenic and allergic reactions, usually transient
and requiring no specific treatment. Occasionally, antihistamine or even hydrocortisone .and adrenaline may
be required. Potentially more sinister is the very high incidence of laboratory evidence of hepatitis in patients
receiving regular component therapy. The majority of severely hemophilic patients have antibody to
hepatitis B surface antigen and a smaller proportion (about 10 per cent) are hepatitis Bantigen positive. Most
have persistently elevated liver enzyme concentrations, and biopsy evidence of live disease is frequently
present in the comparatively small numbers of patients studied. The long-term significance of these
abnormalities is not known, but clearly administration of concentrates prepared from massive donor pools
should be avoided where possible in the mildly affected patient, and vaccine should be undertaken. This
clearly leaves patients exposed to non-A, non-B hepatitis.
Finally, cases of acquired immunodeficiency syndrome have occurred in hemophilic patients who have been
infected with the causative virus (HIV) in contaminated plasma fractions. Most hemophilic patients
receiving replacement therapy have laboratory abnormalities associated with immunodeficiency, and
circulating antibodies to HIV. With donor screening for HIV and heat tretreatment of factor concentrates, the
risks of seroconversion are now very small.
Because of the risks of infection and the expense of preparing coagulation factor concentrates, the recent
successful cloning of the gene for factor VIII is an exciting advance. Its expression in mammalian cells
indicates the possibility of recombinant DNA-factor VIII becoming available for therapeutic use in the near
future.
CONGENITAL HEMORRHAGIC DISORDERS

A) Haemophilia A ("Factor VIII Deficiency) And Hemophilia B (Factor IX Deficiency)

Pathophysiology
a. The genes for factor VII and for factor IX both reside on the X Chromosome. As a result hemophilia can
only occurs in males who have inherited the abnormal gene, whereas females who inherit the gene are
carriers
b. It is now know that the genetic defects that result in hemophilia are actually quite heterogeneous.
i) Mild disease. Patients with mild disease (factor levels >0.05 u/ml) usually are symptomatic except
when stressed by trauma or surgery. Serious bleeding after a relatively minor surgical procedure (e.g., a
dental extraction)
ii) Moderate disease. Patients with moderate disease (factor levels between 0.02 and 0.05 U/ml) often are
asymptomatic, but occasional bleeding can occur without a defined trauma, most commonly bleeding is
associated with minor trauma, some patients experience, spontaneous episodes of soft tissue bleeding
and even hemarthrosis.
iii) Severe disease-;:
1 Patients with severe disease (factor levels <0.01 u/ml) experience frequent spontaneous bleeding, most
commonly hemarthrosis in large joints
2 Soft tissue bleeding can result in nerve compression syndromes, and central nervous system (CNS)
bleeding has been estimated to occur in as many as 1 % of hemophiliacs each year.
3 Bleeding associated with trauma or surgery is life-threatening unless properly, treated

Diagnosis
a) Screening tests of the intrinsic system namely the PTT or APT , are
abnormal in patients with hemophilia, although he prolongation of these test s may be minimal in patients
with very, mild disease. The bleeding time and PT are unaffected
b) Specific factor assay provides a definitive diagnosis Factor levels range
from less than 0.01 U/ml (<1 % of normal) in patient with severe disease to as high as 0.40 U/ml (40 % of
normal) in those with very mild disease, unless an inhibitor develops, the factor level for an individual
patient remains essentially constant throughout the course of the disease
Therapy:-
The goal, of therapy is to raise the deficient factor to a level that will control bleeding.
Pharmacologic therapy
i. Hemophilia A. The vasopressin analog desmopressin (1 -desamino-8-0 arginine vasopressin
dDAVP) stimulates the release of body stores of factor VIII, effectively increasing the factor VIII
level by three to four times the baseline level.
ii. Hemophilia B has no effective pharmacologic therapy.
Replacement therapy
1. General principles a. All blood products used for replacement therapy have potentially adverse effects
ranging from allergic reactions to the transmission of vital disease. The technology of blood product
preparation has changed dramatically in response to the acquired immune deficiency syndrome (AIDS).
2. Dosage calculation
The increase in factor level that can be achieved by a given close of the factor depends on the plasma volume
in which the factor is distributed. Normal factor levels are, by definition 1 u/ml (100 %) and the normal
plasma volume can be estimated to be 40 ml/KG 3.
3. Treatment options
Fresh frozen plasma (FFP) contains all the clotting factors and can be used for the treatment of mild
hemophilia B.
(i). Advantages. Each unit of FFO comes from a single donor; thus, FFP is statistically less likely to contain
undetected viral contaminants.
(it) Disadvantages. The major limitations in its usefulness are the relatively large and the possibility of viral
contamination
b. Cryoprecipitate is prepared by thawing FFP at 4"C which results in the precipitation of a large percentage
of factor VII, vWF, and fibrinogen from the plasma. Cryoprecipitation does not concentrate factor IX, and
thus, is not used for the treatment of hemophilia B.
Advantages include its small volume and the fact that is prepared from a relatively small number of donors.
Disadvantages include the risk of viral infection inherent in any fresh blood product
C. Factor concentrates. Lyophilized, highly purified concentrates of factor
VIII and factor IX are made commercially from plasma pooled from
thousands of donors.
Advantages. These preparations are ideal for home therapy and for chronic treatment when high closes are
necessary for extended periods of time
Disadvantages. In the past, transmission of hepatitis and human immunodeficiency in product preparation

Complications of hemophilia and its treatment

Arthropathy
Repeated bleeding into the joints (hemarthrosis) results in an inflammatory reaction and eventual destruction
of cartilage, narrowing of the joint space, and bony spur formation
Inhibitors
From 10 % to 15% of patients with severe hemophilia A and approximately 5 % of those with severe
hemophilia B develops antibodies that acts as inhibitors of the missing factor, thus greatly complicating the
treatment of these patients
Liver disease is among the most frequent cause of death in patients with hemophilia
HIV infection. HIV transmission from pooled blood products has
resulted in the seroconversion of as many as 90% of patients with severe hemophilia

Interdisciplinary care.
The development of hemophilia centers has made such a comprehensive approach possible
a. Medical care.
Patients with hemophilia need access not only to physicians with experience in replacement therapy
(including home care ) but also to specialists in orthopedics physical medicine, and dentistry who are
experienced in treating patients with bleeding disorders,
b. Psychosocial care.
c. Genetic counseling. Carrier testing and prenatal diagnosis have become an integral part of the care of
the hemophiliac and his family

C. Von Willebrand's disease,

The most common inherited bleeding disorder, should be considered in the diagnosis of patients with a
lifelong history of bruising or excessive bleeding, Von Willebrands disease is now recognized to be a
heterogeneous disorder, with variability in the severity of the bleeding manifestations among the
different subtypes as well as in the same patient over time
Clinical features
Mucous membrane bleeding predominates; epitasis and menorrhagia are common problems. Except in
severe disease, bruising and bleeding are usually mild unless induced by trauma

Diagnosis
Classically, the combination of a prolonged bleeding time and a decreased VIIIa level is considered the
hallmark of von Willebrand's disease. Bleeding time is not a test of VWF along. It also depends on normal
platelet numbers and function. Nonetheless, it is an important screening test of the ability of the patient's
vWF to support the platelet sub endothelium interaction at the time of vessel disruption
Differentiation of subtypes.
Patients with von Willebrand's disease should be typed because of the therapeutic implications of these
classifications
Type I. The plasma is severely depleted of all multimers, but the platelets form these patients contain all the
normal multimers
Type IIA. Both plasma and platelets have decreased amounts of high- and intermediate molecular weight
multimers
Type IIB . High molecular weight multimers decreased in plasma, but not in platelets from these parents

Therapy
a.) DAVP. Patients with mild von Willebrand's disease will respond to dDAVP with a several-fold
increase in vWF - factor VIII-related activities. This increase represents a relief of stores.
b.) Cryopreopitate. Because it contains large amounts of vWF, cryoprecipitate has traditionally been the
treatment of choice for the patient with severe disease or with type HB disease
c) Factor VTII concentrates. Some of the newer lyophilized factor VII concentrates contains some
VWF; these are now used in some circumstances because they have undergone extensive purification.

Other congenital disorders

Congenital Fibrinogen (factorI) deficiency
In this rare disorder there is almost complete absence of fibrinogen in the plasma. It affects both sexes, and is
inherited as an autosomal recessive character. The hemorrhagic tendency resembles that of moderate
hemophilia. Bleeding most commonly follows trauma, especially severe trauma, but may occur
spontaneously. Small lacerations frequently do not bleed excessively. In women, menstruation is usually
normal. The characteristic laboratory finding is the failure of a clot to appear in the whole blood clotting
time, the one-stage prothrombin time, and activated partial thromboplastin time and the thrombin time tests;
the thromboplastin generation test is normal, and assay tests show that only fibrinogen is deficient. By
biochemical methods, it appears that fibrinogen is completely absent, but immunological methods may reveal trace amounts of
fibrinogen, Partial deficiency of fibrinogen, hypofibrinogenaemia also occurs, probably representing the heterozygous state, and
does not cause a haemostatic defect.
The general treatment is along the lines described on accessible bleeding points usually respond to vasoconstrictor drags, pressure,
and, if necessary, suture. Blood transfusion may be required if blood loss had been great.
Inherited dysfibrinogenaemia A steadily increasing number of families with functionally abnormal described. Only a
proportion bleed excessively some show a tendency to wound breakdown, and a very few are reported to have a thrombotic
tendency
Congenital deficiency of factor II (prothrombin), factor V ,factor VII, factor X

Prothrombin deficiency

Congenital deficiency of this factor is very rare. The bleeding tendency usually commences in infancy or childhood. The disorders

affect both sexes, and appear to be inherited as autosomal recessive characters. The hemorrhagic symptoms are similar to those of

moderate hemophilia. Several variants of prothrombin deficiency have been described, and all have been due to the presence of a
 defective coagulant protein. Combined deficiency of factors V and VHI have been reported (Selicsohn & Ramot 1969). This defect

may result from an underlying lack of protein C inhibitor, allowing activated protein C to destroy circulating factors Va and
a (Marlar & Griffin 1980), although this notion has not been confirmed. Other combined deficiency diseases
are reviewed by soff & Levin (1981)

Factor XI deficiency
This congenital disorder resembles moderate to mild hemophilia. It is transferred as an autosomal recessive
character and affects both sexes; it is rare, and has been found most commonly in Jews. The laboratory
findings include an abnormal activated partial thromboplastin time, and the deficiency is problem in a
specific assay for factors XI. Without this step, the abnormality may be difficult to distinguish in the
laboratory from factor XII deficiency. Bleeding is usually not severe, but may be controlled by transfusion of
plasma or of the supernatant from cryoprecipitate.

Factor XII (Hageman factor) deficiency

Congenital deficiency of Hageman factor is characterized by the absence of a clinical hemorrhagic tendency
despite prolongation of the whole blood coagulation time and the activated partial thromboplastin time. Most
patients with this disorder have been discovered on routine laboratory testing. No treatment is required, and
the patients may safely undergo surgical operations without special precautions. Fletcher factor and
Fitzgerald factor deficiencies produce similar laboratory abnormalities without clinical significance, and are
extremely rare.
Factor XIII (fibrin-stabilizing factor) deficiency
Congenital deficiency of fibrin-stabilizing factor causes hemorrhagic symptoms similar to mild and moderate
grades of hemophilia. The congenital defect has been observed in a number of families, and bleeding from the
umbilical stump after birth is a characteristic feature. The healing of wounds has been stated to be less
satisfactory man in other coagulation defects. The bleeding time, platelet count, and the usual coagulation tests
are normal. The diagnosis is established by demonstrating that the patient's blood clot dissolves in solutions of
urea or monochloracetic acid. Bleeding is treated by local measures and the transfusion of fresh frozen plasma.
Factor XIII has a long plasma half-life, and plasma transfusion corrects the
bleeding tendency for several days.

ACQUIRED HEMORRHAGIC DISORDERS

A. Vitamin k deficiency. Vitamin K is fact-soluble vitamin that is necessary for the functional integrity of
factors II (prothrombin), VII, IX and X. The major source of vitamin K is dietary especially leafy green
vegetables, but some intestinal bacteria also produce a form of vitamin K.

Etiology
a. Dietary deficiency. Vitamin K reserves can be depleted over a period of several weeks. Such dietary
deficiency is not uncommon in chronically ill severely malnourished patients.
b. Malabsorption. Because vit-K fat -soluble, its absorption depends on biliary and pancreatic secretions.
Cholestasis, therapy with bile acid-binding resigns, or any fat-losing enteropathy can result in
malabsorption of vitamin K.
 c. Antibiotic therapy. although the amount of vitamin k that intestinal bacteria normally contribute is
unknown, alteration of this flora with broad-spectrum antibiotics appears to enhance the likelihood of
development of vitamin k deficiency.
d. Vitamin K antagonists. Oral anticoagulants (e.g. warfarin) act by Interfering with the reduction of
vitamin k, thus depleting the active form of the vitamin.

e. Hemorrhagic disease of the newborn.

2. Clinical features. Patients may present with severe bruising or excessive bleeding following a surgical
procedure, or they may be asymptomatic

3. Diagnosis. Severe vitamin K deficiency prolongs both the PT and PTT. The PT alone may be
prolonged in early or milder deficiencies, such as that induced by administration of therapeutic doses of
warfarin.

4. Therapy: a. parenteral vitamin K therapy should result in normalization of the PT WITHIN 12- 24
hours and such a response confirms the etiology of the abnormality

FFP can be used for immediate replacement of vitamin K- dependent factors, but this is only justified
when severe deficiency is accompanied by life-threatening bleeding
B. Liver disease.
A
The coagulopathy associated with liver disease is complex and multifactorial.
1. Etiology

a. Decreased synthesis of coagulation factors is the primary cause of coagulation abnormalities in sever lever disease,

since all the coagulation factors except vWF are made by hepatocytes

b. Cholestatic liver disease can cause vitamin K deficiency mat may only be distinguished from decreased synthesis of

coagulation factors after a successful trail of vitamin K replacement

c. Functionally abnormal fibrinogens

d. Clearance of activated coagulation factors

2 . Clinical features vary with the course of the patient's liver disease, but, in general evidence for decreased synthesis of
coagulation factor is an ominous prognostic sign.
3. Diagnosis. Laboratory findings also are variable
a. Early in the course of liver disease, the PT is most commonly prolonged, caused the liver synthesizes all coagulation
factors except vWF.
4. Therapy

a Because vitamin k deficiency in liver disease can be hard to distinguish from decreased synthesis of coagulation factors, an

initial trial of parenteral vitamin k therapy is appropriate not only for diagnostic assessment but also for its potential therapeutic

benefit if an element of vitamin k deficiency exists

C. Disseminated Intravascular Coagulation (DIC)

 Probably is the most common thrombohemorrhagic disorder. DIC should be viewed as a secondary

phenomenon; thus, the underlying and precipitating condition should be sought.

1. Pathphysiology.

Various underlying conditions can precipitate DIC. Once initiated, the balance among coagulant, anticoagulant,

and fibrinolytic processes determines the clinical features of DIC in a given patient,

a. Initiation.

DIC is initiated by pathologic activation of the coagulation cascade, which can occur by a variety of

mechanisms at different points in the cascade. For example, endotoxin produced during septicemia can

activate factor XII directly. It also can damage endothelial cells causing the release of tissue factor and the

destruction of thrombomodulin,

b. Thrombosis. If the stimulus persists, normal control mechanisms are overwhelmed and there is diffuse

micro thrombus formation.

c. Consumption, Continuation of the process leads to depletion of all elements of the coagulation system and

development of hemorrhagic characteristics. At III also seems to decrease, which may further enhance the

thrombotic component of the disorder,

d. Fibrinolysis occurs soon after unitization of fibrin deposition. FSPS begin to be detectable and may be

present in high titers. These products further aggravate the hemorrhagic component of the disorder by inhibiting

platelet function and by interfering with normal fibrin polymerization .

e. Hemolysis Trauma to RBC that are forced through vessels partially occlude by micro vascular thrombi

causes a microangiopathic hemolytic process.

X CLINICAL FEATURES

The clinical picture of DIC varies widely over time and different situation The disorder may be so subtle that abnormal

laboratory findings are the only signs. Conversely, life threatening bleeding may occur .The balance among patho physiological

processes and the resulting tempo of consumption determine the severity of manifestation

a) The presence of DIC often is heralded by the appearance of diffuse bleeding from multiple sites
b) Careful evaluation usually reveals thromobotic nature of these lesions initially may not be apparent ,as bleeding may

supervene at these compromised sites

Condition that Commonly Precipitate DIC

Infectious Conditions- Gram negative septicemia

Other endotoxin related condition

Obstetric Condition – Abruptio placentae

Amniotic fluid embolism

Retaincular Conditions

Vascular condition Aneurysm

Giant Cavernous Hemangioma

Hematologic conditions Massive hemolysis

Snake venom

Trauma

Diagonosis- Laboratory, findings vary with time and circumstances. In severe DIG, all of the following are

present,
a. Thrombocytopenia. The platelet count almost invariably is less than 100,000/ul, and, in severe DIC,
commonly is less than 50,0007ul.
b. Prolonged PT often is the result of motor VII depletion and consumption of factors in the common
pathway. Prolongation may be severe, and vitamin K deficiency should be excluded, especially in patients
in whom both DIC and vitamin K deficiency are likely,
c. Prolonged PTT. PTT may be markedly prolonged, especially when most factors have been consumed by
massive DIC. Prolonged PTT in combination with the other findings and with appropriate clinical features
strongly suggests DIC.
d. Prolonged thrombin time is a highly suffocative finding, which may be the result of decreased fibrinogen.
However, thrombin time may be disproportionately long due to the anticoagulant effects of FSPs or to the
inadvertent use of small amounts of heparin (e.g., to flush intravenous catheters).

e. Decreased fibrinogen. Fibrinogen may be severely depressed but can also be normal or only mildly

depressed because of a high fibrinogen level that may have existed prior to the onset of consumption (e.g.,

in an infected or ill patient).

f. FSPs. The presence of FSPs strongly suggests DIC in the absence of other explanations (e.g., recent

surgery). The absence of FSPs makes the diagnosis of DIC highly unlikely

g.. Microangiopathic hemolytic anemia. Review of the peripheral smear is extremely important to confirm the

suspected traumatic effect of small vessel thrombi on red cells. Findings such as schistocytes or helmet

cells are supportive evidence.

4. Therapy. Foremost in treatment is elimination of the precipitating cause of DIC. This usually means

treatment of sepsis or, in obstetric patients, emptying the uterus.. Unfortunately, some situations are not

immediately reversible. The need for additional treatment in these cases is determined by the tempo and clinical

consequences of the coagulopathy. ,

a. In low-grade DIC without clinical evidence of bleeding or clinically significant thrombosis, treatment
may not be necessary, especially if the underlying cause is reversible.
b. For clinically significant bleeding, replacement of depleted coagulation factors and cells with
appropriate blood products (FFP, cryoprecipitate, platelets, red cells) is useful until treatment of the
underlying process is successful.
c. When thrombosis is a major manifestation, heparin therapy may be required. Rarely, heparin may be
used to interrupt the cycle of consumption when the precipitating cause cannot be readily treated. The added
risk of bleeding, however, demands careful risk-benefit assessment before such a decision to give heparin is
made.
Anticoagulation Drugs:-

These are heparin and the vit-k antagonists

Heparin inhibits the formation of thromboplastin and the action of thrombin. Has an immediate

anticoagulant effect which lasts from 1 to 6 hours after iv inj depending on the dose given

vit—k antagonists: Include coumarin and indanedione derivative. These drugs suppress an essential step in the

synthesis of active vitamin k~ dependent clotting factors, (factors II,XII, JX, &X) by the liver. The anticoagulant effect is

therefore delayed until the existing circulating factors are cleared from the blood stream. & the delay is approximately 36-

48 hours with warfarin (coumarin, Marevan)

Control of anticoagulant therapy:-

When heparin is given by continuous iv infusion, the whole blood clotting time should be maintained at 2-3 time, the

normal value, and the corresponding prolongation of PTT is 1.5 -2.5 time, the normal value.

During oral anticoagulant therapy -the therapeutic range for the one-stage PT is a ratio of patient to control of 2.0 -

4.0(based on INR) and For the Thrombotent is 6-15% of normal.

Bleeding during anticoagulant therapy may be due to over dosage or to a local lesion
Treatment:

Bleeding during heparin therapy:

Protamine sulphate; I mg to 100 units of heparin (1 mg of protamine neutralizes approx (100 units) of heparin
 Bleeding during oral anticoagulant therapy: If bleeding is severe Vit-k - 25 mg iv at a rate not exceeding
5mg / min,. inj
If there is no bleeding but the PT is below the accepted safe level and reversal is indicated
5 mg of vit-k1 orally or 1-2 mg i.m. inj

Hemorrhage and Blood Transfusion

Hemorrhage resulting from blood transfusion may be caused by

1. The administration of large amounts of stored blood

2. Haemolytic transfusion reactions

3. Transfusion thrombocytopenia due to platelet allo-antibodies

Treatment:- ^
2 units of fresh blood or 3-5 units of fresh frozen plasma are given with every 10 units of packed red cells
that is rapidly transferred. Established bleeding due to large volume can be treated by fresh frozen plasma,
platelet concentrates or fresh whole blood; In addition, hypocalcemia can be prevented by the inj of
calcium gluconate.
Haemorrhagic Disorders Due To Circulating Inhibitors of Coagulation
Hemorrhagic Disorders Due To Circulating Inhibitors of Coagulation

Circulating inhibitors are antibodies almost always of the IgG heavy chain class, with activity directed against a

coagulation protein.
Two types:-

1. Those occurring in the course of hemophilia or other congenital coagulation disorders

Some are less potent and become undetectable later periods without treatment and others are very active and
persist indefinitely
Treatment: -
Massive doses of factor concentrates may be required

Temporary good response is obtained with porcine bovine factor VIII

Immune suppressive treatment combined with massive factor replacement

Use of prothrombin complex, plasmapheresis high-dose iv gamma globulin are also helpful.

2. Those acquired spontaneously or in the course of some other disease state:-

Most commonly seen in disseminated lupus erythematosus, penicillin reactions, pregnancy, rheumatoid disease,

Treatment: is often unsatisfactory

When bleeding occurs, blood transfusion and large doses of a concentrate of the appropriate factor,
together with immunosuppressive may control hemorrhage.

APPROACHES TO PATIENTS WITH COAGULATION DISORDERS

A. History
1 Bleeding history it is very useful to know if the bleeding disorder is
been lifelong, although this may be difficult to ascertain .
 a) Clues to a congenital bleeding disorder
1. Specific questioning may uncover a history of excessive bleeding initiated by common
childhood traumas or after dental extractions, which suggests that the disorder is lifelong.
2. A history of bleeding disorders in family members is extremely useful and when the mode of
inheritance can be determined, may even suggest a specific diagnosis
a. Hemophilia (a r B) is suggested when the inheritance is X-linked
b. Von willebrand's disease is suggested in a patient with a low level of factor VIII and a
family history consistent with an autosomal inheritance
b) Clues to an acquired bleeding disorder
1. A patient who presents with a bleeding disorder and who gives a
history of tolerating stress to the coagulation system usually can be assumed to have an acquired
disorder

2 The time between exposure to potentially causative factors and the onset of the bleeding disorder may
provide clues to the etiology and particulary in medication-related disorders, the treatment of the
bleeding problem
Nature of Bleeding
1. Sites of bleeding may suggest where in the lagulation process the defect may be
a. Mucous membrane bleeding and petechiae are often seen in platlet-related disorders
b. He marthroses are common in hemophilia
c. Soft tissue hemotomas without petechiae or mucous membrane bleeding suggest a defect in the
coagulation cascade
2. Severity of the bleeding disorder influences therapeutic decisions and may be deduced from the degree of
trauma necessary to induce excessive bleeding
a. Spontaneous bleeding usually occurs only in the most severe disorders.
b. History of bleeding only after major trauma or surgery suggests a mild bleeding are normal, because
very mild decreases in factor levels may not prolong the prothrombin time (PT) or partial
thromboplastin time (PTT)
3. Timing of episodes. Bleeding that is uncontrolled form the onset suggests a defect in primary homeostasis,
whereas a history of bleeding after initial apparent homeostasis is event is sometimes seen in factor XII
deficiency.
2. Medical history. A review of all medical conditions, and their treatment, can provide insight into the
possible nature of the bleeding disorder.
a. Malnourished,-hospitalized patients who have been treated with multiple
antibiotics are highly prone to vitamin k deficiency
b.Systemic lupus erythematosus and human immunodeficiency virus (HIV
infection are associated with syndromes of immune mediated
(idiopathic) thrombocytopenic purpura (ITP)
c. Septicemia is the most common underlying cause of disseminated
intravascular coagulation (DIC)
3. Medications
Careful review of all medications is critical in evaluating a patient with a coagulation abnormality
a. Aspirin is a common cause of altered platelet function
b.Incidental heparin, which often is used for flushing intravenous access lines, can cause thrombocytopenia,
and inadvertent anticoagulation
c.An extensive number of the drugs are known to induce thrombocytopenia
d. Acquired factor inhibitors have been associated with medications (e g. penicillin)
 B. Physical examination may provide valuable clues as to where in the coagulation system the abnormality is
likely to be found
1. Petechiae usually indicate bleeding at the level of the microvasculature and are associated with abnormalities
of platelet number and function
2. Mucous membrane bleeding can result from any defect in coagulation, but when mucous membranes are
the only bleeding sites, thrombocytopenia, platelet function disorders, or von willebrands it-disease is likely.
3. Hemarthrosis or evidence of recurrent joint bleeding is almost always associated with a severe form of
hemophilia, although this type of bleeding can occur in severe acquired factor deficiencies as well.
4. Diffuse bleeding form multiple sites, both mucous membrane and sites of trauma such as vein puncture sites,
is often seen with severe combined coagulation defects such as DIC, or severe liver disease
5. Other physical findings may suggest underlying medical conditions that could predispose to the bleeding
disorder, such as splenomegaly in a patient with SLE and thrombocytopenia or fever and evidence of sepsis
in a patient with DIC
D.Laboratory studies . Ideally the choice of laboratory studies guided by the history and physical
examination of the patient.

BIBLIOGRAPHY >
Text book of hematology- Jeffrey.A.Kant
De Gruchy's clinical hematology in medical practice- Firkin&Rush
Davidson's principles & practice of medicine.
Text book of physiology- Ganong
Oral maxillofacial surgery clinics of North America- Management of medica--Orrett. E.Ogle(August
1998)
Clinical diagnosis & management by laboratory method- Todd & Davidsohn