Good Morning
SEMINAR
Presented by:
Dr.Prashant Munde ( MDS- I )
Guided by : Dr. Mrs. SHUBHANGI KHANDEKAR
( PROFESSOR & GUIDE )
Dr. Mrs. ALKA DIVE( PROFESSOR & H.O.D)
INVESTIGATIONS FOR HAEMORRHEGIC DISORDERS
Hemorrhagic Disorders
Hemorrhagic or Bleeding disorders are a group of
conditions in which there is a problem with the body's
blood clotting process.
These disorders can lead to heavy and prolonged bleeding
after an injury. Bleeding can also begin on its own.
Defects in blood coagulation usually give abnormal
coagulation tests and C.T.
CausesNormal blood clotting involves coagulation
factors which act together with other
chemicals to form fibrin that stops bleeding.
Problems can occur when certain coagulation
factors are low or missing.
Bleeding disorders can also result from having
poorly working or too few platelets.
Some bleeding disorders are present at birth
and are passed through families (inherited).
Others develop from:
Illnesses such as vitamin K deficiency or severe
liver disease.
Treatments such as the use of drugs to stop
blood clots (anticoagulants) or the long-term
use of antibiotics.
Diagnosis of Hemorrhagic Disorders
Present history: Rash following infection, abdominal and joint pain.
Family History: For evidence of inheritance of any bleeding tendencies.
Past History: Excessive, prolonged bleeding of the surgical interventions as tonsillectomy, circumcision or tooth extraction.
Physical Examination: General condition, type and distribution of the rash, fever, organ enlargement, lymph glands.
Hemorrhagic disorders
Excessive bleeding can result from
(1) Increased fragility of vessels,
(2) Platelet deficiency or dysfunction, and
(3) Derangement of coagulation, alone or in combination.
Common laboratory tests used in the evaluation of a
bleeding disorders are the following:
Screening tests: Bleeding Time
Complete blood count (CBC)
Prothrombin Time
Activated partial thromboplastin time
Thrombin Time
Fibrinogen activity test
Tests of Hemorrhagic Disorders
BLEEDING TIME
Bleeding time
oBleeding time - The time when the incision is made until
all bleeding has stopped is measured and is called the
bleeding time.
o Used to assess platelet function.
oA prolonged bleeding time may be a result from decreased
number of thrombocytes or impaired blood vessels.
o However, the depth of the puncture or incision may be the
source of error.
Methods
Duke Methodo With the Duke method, the patient is pricked with a needle
or lancet, on fingertip, after swabbed with alcohol.
o The prick is about 3–4 mm deep.
o Every 30 seconds, filter paper or a paper towel is used to
wipes the blood .
o Normal values- is about 2–5 minutes.
Ivy method
In the Ivy method, the blood pressure cuff is placed on
upper arm and inflated to 40 mmHg.
A lancet is used to make a shallow incision on the
underside of the forearm.
Every 30 seconds, filter paper or a paper towel is used
to draw off the blood.
Normal values - 3 – 10 minutes
Interpretation
Bleeding time is affected by platelet function, certain vascular
disorders and von Willebrand Disease—not by other coagulation
factors such as hemophilia.
Diseases that cause prolonged bleeding time include
Thrombocytopenia,
Disorders of platelet function
Disseminated intravascular coagulation (DIC),
Acute Leukemia
Aplastic anemia
Liver diseases
Aspirin and other cyclooxygenase inhibitors can
prolong bleeding time significantly.
While warfarin and heparin have their major effects on
coagulation factors, an increased bleeding time.
People with von Willebrand disease usually experience
increased bleeding time, as von Willebrand factor is a
platelet adhesion protein, but this is not considered an
effective diagnostic test for this condition.
Complete blood count (CBC)
Complete blood count (CBC)RBC count
WBC count
The total amount of hemoglobin in the blood
The fraction of the blood composed of red blood cells
(hematocrit)
The platelet count.
The CBC test also provides information about:
Average red blood cell size (MCV)
Hemoglobin amount per red blood cell (MCH)
The amount of hemoglobin relative to the size of cell
(hemoglobin concentration) per red blood cell (MCHC).
A complete blood count (CBC) is used to detect or monitor
many different health conditions.
Diagnose infections or allergies
Detect blood clotting problems or blood disorders, including
anemia.
Evaluate red blood cell production or destruction.
The CBC interpretation are useful in the diagnosis of
various types of anemias.
It can reflect acute or chronic infection, allergies, and
problems with blood clotting.
Normal Results
Blood counts may vary with altitude. In general, normal results are:
RBC count:
Male: 4.7 to 6.1 million cells/mcLFemale: 4.2 to 5.4 million cells/mcL
WBC count: 4,500 to 10,000 cells/mcL
Hematocrit: Male: 40.7 to 50.3%Female: 36.1 to 44.3%
Hemoglobin:
Male: 13.8 to 17.2 gm/dL
Female: 12.1 to 15.1 gm/dL
Red blood cell indices:
MCV: 80 to 95 femtoliter
MCH: 27 to 31 pg/cell
MCHC: 32 to 36 gm/dL
Abnormal Results
A high RBC or hematocrit may be due to:
Dehydration (such as from severe diarrhea)
Kidney disease with high erythropoietin production
Low oxygen level in the blood for a long time due to
heart or lung disease.
Polycythemia vera
A low RBC or hematacrit is a sign of anemia, which can result
from:
Autoimmune diseases ( lupus erythematosus or rheumatoid
arthritis)
Blood loss (hemorrhage)
Bone marrow failure ( from radiation, infection, or tumor)
Chronic kidney disease
Hemolysis (red blood cell destruction)
Leukemia and other blood cancers
Long-term infections such as hepatitis
Poor diet and nutrition, causing too little iron, folate, vitamin
B12, or vitamin B6
A lower than normal white blood cell count is called
leucopenia.
A decreased WBC count may be due to:
Autoimmune diseases (such as systemic lupus
erythematosus)
Bone marrow failure (for example, due to
infection, tumor, radiation, or fibrosis)
Disease of the liver or spleen
High numbers of WBCs is called leukocytosis.
It can result from:
Infectious diseases
Inflammatory disease (such as rheumatoid
arthritis or allergy)
Leukemia
Severe emotional or physical stress
Tissue damage (such as burns)
A complete blood count with differential WBC Count
will also include:
Neutrophil — May indicate bacterial infection.
May also be raised in acute viral infections.
Eosinophilic — Increased in parasitic infections,
asthma, or allergic reaction.
Basophil — May be increased in bone marrow related
conditions such as leukemia or lymphoma.
Lymphocytes — Higher with some viral infections such as
glandular fever and raised in chronic lymphocytic leukemia
(CLL). Can be decreased by HIV infection.
Monocytes — May be raised in bacterial infection,
tuberculosis, malaria, Rocky Mountain spotted fever, monocytic
leukemia, chronic ulcerative colitis and regional enteritis .
Platelet counts
These are obtained on anticoagulated blood using an
electronic particle counter.
The reference range is 1.5 to 4 lac platelets/mm3.
Bleeding resulting from thrombocytopenia is associated
with a normal PT and PTT.
NORMAL 100,000 - 400,000 Cells/mm3
< 100,000 Thrombocytopenia
50,000 - 100,000 Mild Thrombocytopenia
< 20,000 SevereThrombocytopeniaSpontaneous bleeding
Bleed after major trauma
Bleed after minor trauma
Counts well outside this range should be confirmed
by a visual inspection of a peripheral blood smear,
since clumping of platelets can cause
“thrombocytopenia” during automated counting,
and high counts may be indicative of a
myeloproliferative disorder, such as essential
thrombocythemia.
Increase platelet counts can be due to :
Essential (primary)
Essential thrombocytosis (a form of myeloproliferative
disease)
Other myeloproliferative disorders such as chronic
myelogenous leukemia, polycythemia vera, myelofibrosis
It manifests clinically with elevated platelet counts and is
separated from PCV and primary myelofibrosis based on the
absence of polycythemia and marrow fibrosis, respectively. In
those cases without tyrosine kinase mutations, causes of
reactive
thrombocytosis, such as inflammatory disorders and iron
deficiency, must be excluded before the diagnosis can be
established.
Reactive (secondary)
Inflammation
Surgery (which leads to an inflammatory state)
Hyposplenism (decreased breakdown due to
decreased function of the spleen)
Splenectomy
Iron deficiency anemia or hemorrhage
Decreased platelet counts can be due to
Idiopathic thrombocytopenic purpura
Thrombotic thrombocytopenic purpura
Disseminated intravascular coagulation
Systemic lupus erythematosus
Vitamin B12 or folic acid deficiency
Leukemia or myelodysplastic syndrome
Sepsis, systemic viral or bacterial infection
chemotherapy drugs
Valproic acid, Methotrexate, Interferon,Isotretinoin
Tests of platelet functionAt present, no single test provides an adequate
assessment of the complex functions of platelets.
One older test, the bleeding time, which measures the
time taken for a standardized skin puncture to stop
bleeding, has some value but is time-consuming,
difficult to perform well, and not a good predictor of
bleeding during haemostatic stresses such as surgery.
As a result of these limitations, the use of the bleeding
time has declined considerably in recent years.
Newer instrument-based assays designed to measure platelet
function under conditions of high shear stress show promise
but at present are also less than ideal screening tests.
Other specialized tests that can be useful in particular clinical
settings include
Tests of platelet aggregation, which measure the ability
of platelets to aggregate in response to agonists like
thrombin; and quantitative and qualitative tests of von
Willebrand factor, which play an important role in platelet
adhesion to the extracellular matrix.
More specialized tests are available to measure the levels of specific clotting factors, fibrinogen, fibrin split products, and the presence of circulating anticoagulants.
Tests of blood coagulation
Routine tests of blood coagulation, such as the
Prothrombin time (PT),
Activated partial thromboplastin time (aPTT), and
Thrombin time (TT)
are frequently ordered to assess clotting function in
patients.
Prothrombin time (PT)
oThe prothrombin time is the time it takes plasma to clot
after addition of tissue factor.
oThis measures the quality of the extrinsic pathway (as well
as the common pathway) of coagulation.
oThey are used to determine the clotting tendency of blood,
in the measure of warfarin dosage, liver damage, and
vitamin K status.
Prothrombin time (PT)
oPT measures factors I (fibrinogen), II (prothrombin),
V, VII, and X.
o It is used in conjunction with the activated partial
thromboplastin time (aPTT) which measures the
intrinsic pathway.
oNormal range
oThe reference range for prothrombin time is usually
around 12-13 seconds, and the INR in absence of
anticoagulation therapy is 0.8-1.2.
Interpretation
•The prothrombin time can be prolonged as a result
of Deficiencies in vitamin K,
• warfarin therapy,
•Malabsorption, or lack of intestinal colonization by
bacteria (such as in newborns).
•Poor factor VII synthesis (due to liver disease) or
•Increased consumption (in disseminated
intravascular coagulation) may prolong the PT.
•The INR is typically used to monitor patients on
warfarin or related oral anticoagulant therapy.
•The normal range of INR for a healthy person not
using warfarin is 0.8–1.2 sec., and for people on
warfarin therapy 2 –3 sec.
•High INR indicates a higher risk of bleeding, while a low
INR suggests a higher risk of developing a clot.
Activated partial
thromboplastin time (APTT)
oThe partial thromboplastin time (PTT) or activated
partial thromboplastin time (aPTT or APTT) test
assesses both the intrinsic and common clotting
pathways.
The clotting of plasma after addition of kaolin, cephalin, and
Ca [2] + ions is measured in seconds.
Kaolin activates the contact dependent factor XII, and
cephalin substitutes for platelet phospholipids.
ACTIVATED PARTIAL THROMBOPLASTIN TIME
oApart from detecting abnormalities in blood clotting,it is
also used to monitor the treatment effects with heparin,
a major anticoagulant. It is used in conjunction with the
prothrombin time (PT) which measures the extrinsic
pathway.
o Prolongation of the PTT can be due to deficiency or
dysfunction of factors V, VIII, IX, X, XI, or XII,
prothrombin, or fibrinogen.
•Interpretation
•The typical reference range is between 30 seconds and 50
s.
•Shortening of the PTT is considered to have little clinical
relevance, but it might increase risk of thromboembolism.
•Normal PTT times require the presence of coagulation
factors:
• I, II, V, VIII, IX, X, XI, & XII.
•Deficiencies in factors VII or XIII will not be detected with
PTT test.
•Prolonged APTT may indicate:
•use of heparin (or contamination of the sample)
•Antiphospholipid antibody (especially lupus
anticoagulant, which paradoxically increases propensity
to thrombosis)
•coagulation factor deficiency (e.g. hemophilia)
•Sepsis - coagulation factor consumption
•Presence of antibodies against coagulation factors
(Factor inhibitors)
Mixing testPatient plasma
Normal plasma
PTT
Correctable PTT Factor deficiency
• If the abnormality does not disappear, the sample is said to
contain an "inhibitor" (either heparin, antiphospholipid
antibodies or coagulation factor specific inhibitors), while if it
does correct a factor deficiency is more likely.
THROMBIN TIME
•The thrombin time (TT), measures the time it takes
for a clot to form in the plasma of a blood sample
containing anticoagulant, after an excess of thrombin
has been added.
•It is used to diagnose blood coagulation disorders and
to assess the effectiveness of fibrinolytic therapy.
•This test is repeated with pooled plasma from normal
patients.
Thrombin time
•The difference in time between the test and the
'normal' indicates an abnormality in the conversion of
fibrinogen to fibrin.
•Normal values for thrombin time are 12 to 14 seconds.
•Thrombin time can be prolonged by heparin, fibrin
degradation products, factor XIII deficiency, and
fibrinogen deficiency or abnormality.
FIBRINOGEN ACTIVITY
TEST
A fibrinogen activity test is ordered as part of an
investigation of a possible bleeding disorder or
thrombotic episode.
It may be ordered as a follow-up to an abnormal
Prothrombin Time (PT) or Partial Thromboplastin Time
(PTT) and/or an episode of prolonged or unexplained
bleeding.
FIBRINOGEN ACTIVITY TEST
•It may be measured, along with tests such as PT, PTT,
platelet function tests, fibrin degradation products (FDP),
and D-dimer to help diagnose disseminated intravascular
coagulation (DIC) or abnormal fibrinolysis.
•Fibrinogen activity test is ordered to help monitor the
status of a progressive disease (such as liver disease) over
time.
•Sometimes this test is ordered, along with other cardiac
risk markers such as C-reactive protein (CRP), to help
determine a person's overall risk of developing
cardiovascular disease.
• Fibrinogen levels can be measured in venous blood.
• Normal levels are about 1.5-3 g/L, depending on the
method used.
• Higher levels are, amongst others, associated with
cardiovascular disease (>3.43 g/L).
• It may be elevated in any form of inflammation, as it is
an acute-phase protein; for example, it is especially
apparent in human gingival tissue during the initial
phase of periodontal disease.
•Low levels of fibrinogen can indicate a systemic
activation of the clotting system, with consumption of
clotting factors faster than synthesis.
• This excessive clotting factor consumption condition
is known as disseminated intravascular coagulation or
"DIC.“
• In DIC low fibrinogen levels with prolonged clotting
times (PT or aPTT), in the context of acute critical
illness such as sepsis or trauma.
Fibrinogen levels are increased in:
Increasing age
Female sex, pregnancy, oral contraception
In post-menopausal women
Acute phase reaction
Disseminated malignancy
Fibrinogen levels are reduced in:
DIC due the the consumption of clotting factors.
Liver disease due to decreased synthesis.
Massive transfusion
Inherited deficiencies e.g. Hypofibrinogenaemia,
afibrinogenaemia and dysfibrinogenaemia
Following thrombolytic therapy
In some patients following treatment with asparaginase
FACTOR ASSAYS TESTS
Clotting Factor Tests
Clotting factor tests, also called factor assays, are required to diagnose a bleeding disorder.
This blood test shows the type of hemophilia and the severity.
It is important to know the type and severity in order to create the best treatment plan.
Haemophilia A and Haemophilia B:
Activated partial thromboplastin time (APTT); prolongation depends on the severity of the factor deficiency.
Prolonged APTT plus prolonged bleeding suggests von Willebrand's disease
factor VIII clotting assay - low levels in Haemophilia A
factor IX clotting assay - low levels in Haemophilia B
In severe cases of Haemophilia B whole blood coagulation time is increased
The severity of vWD varies and many patients will never
be diagnosed, as their disorder may never come to light.
In practice - both primary and secondary - the patients
with more severe forms of the disorder will present with
abnormal bleeding.
Following this, basic blood tests including FBC, clotting
screen and liver function should be performed and
patients should be referred for a specialist opinion and
other more specialised investigations such as plasma
levels of vWf.
Plasma levels of vWF – Deficiency can be quantitative
or qualitative.
Quantitative deficiency - detected by vWF antigen
assay.
Qualitative deficiency - detected by a number of
methods including glycoprotein binding assay,
ristocetin cofactor activity, ristocetin-induced platelet
agglutination.
Factor VIII measurement:
Factor VIII binds to vWF which in turn prevents the rapid
breakdown of factor VIII; thus, a deficiency of vWF can
also lead to deficiency of factor VIII.
In type 2 vWF - factor VIII levels are normal; studies of
platelet aggregation with sub-endothelium are
necessary.
Oestrogens, vasopressin and growth hormone all
elevate levels.
These include assays of factor VIII, von Willebrand factor
antigen, von Willebrand factor activity (measured by the
ristocetin cofactor assay), and template bleeding time. In
von Willebrand disease the defect is in von Willebrand
factor.
The affected individual may have subnormal levels of
structurally and functionally normal von Willebrand factor
(this is called "classic" or type I von Willebrand disease) or
may produce von Willebrand factor that is structurally and
functionally abnormal (von Willebrand disease type 2).
Individuals who inherit a gene for von Willebrand disease from both parents have severe (type 3) von Willebrand disease and will have extremely low levels (< 3%) of von Willebrand factor and factor VIII and will have a very prolonged bleeding time.
In most populations type I disease is the most common form, whereas type 3 is the least commonly encountered form.
It should be noted that levels of von Willebrand factor can be influenced by the patient's blood type (persons who have blood type AB have 60% to 70% higher levels than do persons who have blood type O) and can be elevated during pregnancy, stress, and hyperthyroidism.
Disseminated intravascular coagulation
Diagnosis is usually suggested by-
Severe cases with hemorrhage:
The PT and APTT are usually very prolonged and the
fibrinogen level markedly reduced.
High levels of fibrin degradation products, including D-dimer.
There is severe thrombocytopenia.
The blood film may show fragmented red blood cells
(schistocytes).
Mild cases without bleeding:
There is increased synthesis of coagulation factors
and platelets.
PT, APTT, and platelet counts are normal.
Fibrin degradation products are raised.
Clinical assessment, pertinent history, and family
history are good indicators for determining
patient's bleeding tendencies.
The most appropriate laboratory tests performed
are Routine screening tests include a complete
blood cell count, platelet count, and evaluation of a
peripheral blood sample, a prothrombin time, and
an activated partial thromboplastin time.
Summary
References Kumar, V., & Robbins, S. L. 1. (2007). Robbins basic pathology (8th
ed.). Philadelphia, PA: Saunders/Elsevier.
Hoffman Hematology: Basic Principles and Practice. 5th ed. Philadelphia, Pa: Churchill Livingstone Elsevier; 2008:chap 121.
Kessler C. Hemorrhagic disorders: Coagulation factor deficiencies. In: Goldman L, Ausiello D, eds. Cecil Medicine. 23rd ed. Philadelphia, Pa: Saunders Elsevier;2007:chap 180.
Hoffbrand AV, Pettitt JE (1999). Essential Haematology. Blackwell Scientific Publications, Oxford.
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