Blood Coagulation
Blood Coagulation
Blood Coagulation
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.
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
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
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
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
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
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.
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
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.
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.
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.
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
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
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
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.
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.
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.
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
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
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
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
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
e. Hemolysis Trauma to RBC that are forced through vessels partially occlude by micro vascular thrombi
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
Retaincular Conditions
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.,
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
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
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-
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 -
Bleeding during anticoagulant therapy may be due to over dosage or to a local lesion
Treatment:
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
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:-
Use of prothrombin complex, plasmapheresis high-dose iv gamma globulin are also helpful.
Most commonly seen in disseminated lupus erythematosus, penicillin reactions, pregnancy, rheumatoid disease,
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