Approach to Bleeding
Disorders
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? Primary haemostasis involves thebinding of platelets to exposed
collagen in the sub endothelium of
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damaged vessels.
? Secondary haemostasis is the process
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of activation of coagulation factorsleading to the production of
thrombin.
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2
(A) After vascular injury, local neurohumoral
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factors induce a transient vasoconstriction.(B) Platelets bind via glycoprotein Ib (GpIb)
receptors to von Willebrand factor (vWF) on exposed
extracellular matrix (ECM) and are activated,
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undergoing a shape change and granule release.Released ADP & thromboxane A2 (TxA2) induce
additional platelet aggregation through platelet GpIIb
-IIIa receptor binding to fibrinogen, and form the
primary hemostatic plug.
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Platelet adhesion and aggregation-
Von Willebrand factor functions as an
adhesion bridge between subendothelial
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collagen and the glycoprotein Ib (GpIb)platelet receptor. Aggregation occurs by
fibrinogen bridging GpIIb-IIIa receptors on
different platelets.
Congenital deficiencies in the various
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receptors or bridging molecules lead todifferent diseases.
(C) Local activation of the coagulation cascade
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(involving tissue factor and platelet phospholipids) resultsin fibrin polymerization, "cementing" the platelets into a
definitive secondary hemostatic plug.
(D) Counterregulatory mechanisms, mediated by
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tissue plasminogen activator (t-PA, a fibrinolytic product)and thrombomodulin, confine the hemostatic process to
the site of injury
SIMPLIFIED DIAGRAM OF COAGULATION CASCADE:-
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PROCOAGULANT FACTORS :-
PROCOAGULANT FACTORS. Cont'd. :-
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ANTICOAGULANT FACTORS:-
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Bleeding disorder
Bleeding disorders can be due to
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Blood vessel anomaliesPlatelet abnormalities
Coagulation disorders
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DISORDERS OF VESSEL WALL:-
HEREDITARY:-
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1) Hereditary hemorrhagic telangiectasia (Osler?Weber?Rendu disease )
2) Ehler Danlos Syndrome
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ALLERGIC:-1) Henoch?Sch?nlein purpura (HSP)
2) Leucocytoclastic angitis
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ATROPHIC:-
1) Senile purpura
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2) ScurvyMISCELLANEOUS:-
1) Simple easy bruising
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2) Amyloidosis
3) Infections
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PLATELET DISORDERS.. Cont'd:-DISORDERS OF COAGULATION:-
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INHERITEDACQUIRED
HEMOPHILIA A
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DIC
HEMOPHILIA B
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LIVER DISEASEvWD
HDN
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DISORDERS OF FIBRINOGEN-
Nephrotic Syndrome
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HEREDITARY AFIBRINOGENAEMIAHYPOFIBRINOGENAEMIA
DYSFIBRINOGENAEMIA
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FXIII deficiencyAPLS
FV deficiency
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HEPARIN OR ORAL ANTICOAGULANT
THERAPY
VIT K DEFICIENCY
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MASSIVE TRANSFUSION OF STOREDBLOOD
Clinical evaluation.. Cont'd:-
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.
Petechiae <3 mm, Purpura 0.3?1 cm (3?10 mm), ecchymoses >1 cm.
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Clinical evaluation.. Cont'd:-
Hemarthrosis in a case of Hemophilia
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Purpura in a case of ITPVon willebrand Disease
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? One of the Most Common inherited disorders of bleeding
? AD disease with gene located on 12 th chromosome
? vwf synthesize in endothelium, platelet and megakatyocytes
? vwf facilitate platelet adhesion to subendothelial collagen
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C/F ? Spontaneous bleeding from mucus membrane,
Excessive bleeding from wounds / gums
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Menorrhagia
>20 variants reported
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Type1(50% activity) & 3(no activity)Type 2
Reduced vWF
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Qualitative defects
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Lab Findings
? Prolonged BT
? (Normal) platelet count
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? Deficient Ristocetin aggregation? Prolonged PTT
Treatment
? cryoprecipitate
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HEMOPHILIA ? A
(F ? VIII deficiency)
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Most Common hereditary diseaseReduced activity of F ? VIII
X ? linked recessive trait
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30% of patients have no positive family history
<1% of normal F-VIII activity ? Severe disease
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2 ? 5% of normal F-VIII activity ? Moderate disease
6 ? 50% of normal F-VIII activity ? Mild disease
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Clinical /Features:
normal hemostasis require 25% factor VIII activity
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Symptomatic patients mostly have < 5% factor VIII activityEasy bruising
Massive Hemorrhage after mild trauma / operation
Joint bleeding ? Haemarthrosis ? Deformities
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Lab Features
? Bleeding Time - Normal
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? Prothrombin Time - Normal? Platelet Count - Normal
? APTT - Increased
? Diagnosis can be confirmed by F-VIII assay.
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TherapyF-VIII Infusion
15% of severely affected patients ?developed Antibodies against F - VIII
HEMOPHILIA ? B
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Severe Factor - IX deficiencyX ? linked recessive
PT ? Normal
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APTT ? Increased
Factor assay is must to differentiate between Hemophilia A & Hemophilia B
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Screening tests for primary hemostasis are -
I. Bleeding time- Assesses adequate functioning of platelets and blood vessels
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II. Peripheral blood smear examination
III. Platelet count
IV. Mean Platelet volume
V. Reticulated platelets
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VI. Platelet function analysisVII. Tests for Vessel wall disorder
Tests for Vessel wal disorder
HESS` CAPILLARY FRAGILITY TEST:
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Cuff is wrapped in upper arm and pressure is maintained midway b/w systolic anddiastolic BP for 15 minutes, 4 cm below the elbow joint, a circle of 2.5 cm diameter is
drawn on the anterior aspect of forearm.
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Upto 10 new hemorrhagic spots are normal. But >20 new spots are always
pathological.
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This is positive in increased capillary fragility, ITP.Screening tests for secondary hemostasis are -
I. Clotting time
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II. Prothrombin time (PT) and Activated partial thromboplastin time (aPTT)III. Thrombin Time (TT)
Col ection of blood for coagulation studies
The anticoagulant used for coagulation studies is trisodium
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citrate (3.2%), with anticoagulant to blood proportion being 1:9.
Clotting Time
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This is a crude test and is now replaced by activated partial thromboplastin time.Prolongation of clotting time only occurs in severe deficiency of a clotting factor and is
normal in mild or moderate deficiency.
PROTHROMBIN TIME(PT)
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PT assesses coagulation factors in extrinsic pathway (F VII) and
common pathway.
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Principle:- Tissue thromboplastin and calcium are added toplatelet poor plasma and clotting time is determined.
CONCEPT OF INR
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1.The international normalized ratio (INR) was introduced in an attempt to standardize the
PT.
2.Calculation ~ INR = [ PT (patient) / PT (Control) ]ISI
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The INR has no units (it is a ratio)**ISI, or international sensitivity index is a function of the thromboplastin reagent.
** NORMAL RANGE PT 11-16 seconds
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INR 0.9 ? 1.1.
Uses of PT
1. To monitor patients who are on oral anticoagulant
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therapy2. To assess liver function
3. Detection of vitamin K deficiency
4. To screen for hereditary deficiency of coagulation
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factors
Causes of prolongation of PT
1.Treatment with oral anticoagulants
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2.Liver disease3.Vitamin K deficiency
4.Disseminated intravascular coagulation
5.Inherited deficiency of factors in extrinsic and
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commACTI on
V pat
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ATEhwa
D Pys.
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ARTIAL THROMBOPLASTIN TIME (APTT)Significance
Reflects efficiency of Intrinsic and Common pathway.
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PrincipleThe test measures the clotting time of plasma after the activation of contact
factors (Kaolin/Silica/El agic acid) and the addition of phospholipid and
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CaCl2, but without added tissue thromboplastin.So it indicates the overal efficiency of the Intrinsic pathway.
Normal range
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26 to 40 seconds.
Uses of APTT:-
1. Screening for hereditary disorders of
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coagulation
2. To monitor heparin therapy
3. Screening for circulating inhibitors of
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coagulation
aPTT is prolonged in:-
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1.Inherited deficiencies of factor VIII (Hemophilia A) and Factor IX (Hemophilia B)2.Non specific inhibitor antibodies against F VIII e.g. Lupus inhibitor (Don't act directly
but block interaction of FVIII with other clotting factors)
3.DIC
4.Heparin
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( Inhibits factor XII, XI and X through antithrombin III & Heparin therapy is monitoredthrough aPTT)
5. Vit K deficiency
6.Massive transfusion of plasma depleted stored blood.
THROMBIN TIME(TT)
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Significance:-
Asses the final step of coagulation i.e. conversion of fibrinogen to fibrin in presence of
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thrombin.Bypasses Extrinsic & Intrinsic pathway.
Causes of prolonged TT
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1. Disorders of fibrinogen-
i) Afibrinogenaemia
ii) Hypofibrinogenaemia
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3. Chronic liver disease
FXIII Qualitative assay (Urea clot lysis test)
Done when all other tests for hemostasis are normal.
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FXIII provides stability to clot formed.
Method:-
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Summary of Approach to Bleeding Disorders