Approach to
Bleeding Disorders
Primary haemostasis involves
the binding of platelets to
exposed collagen in the sub
endothelium of damaged
vessels.
Secondary haemostasis is the
process of activation of
coagulation factors leading to
the production of thrombin. 2
(A) After vascular injury, local neurohumoral
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,
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.
Platelet adhesion and aggregation-
Von Willebrand factor functions as an
adhesion bridge between subendothelial
collagen and the glycoprotein Ib (GpIb)
platelet receptor. Aggregation occurs by
fibrinogen bridging GpIIb-IIIa receptors on
different platelets.
Congenital deficiencies in the various
receptors or bridging molecules lead to
different diseases.
(C) Local activation of the coagulation cascade
(involving tissue factor and platelet phospholipids)
results in fibrin polymerization, “cementing” the platelets
into a definitive secondary hemostatic plug.
(D) Counterregulatory mechanisms, mediated by
tissue plasminogen activator (t-PA, a fibrinolytic product)
and thrombomodulin, confine the hemostatic process to
the site of injury
SIMPLIFIED DIAGRAM OF COAGULATION CASCADE:-
PROCOAGULANT FACTORS :-
PROCOAGULANT FACTORS.. Cont’d.. :-
ANTICOAGULANT FACTORS:-
Bleeding disorder
Bleeding disorders can be due to
Blood vessel anomalies Platelet abnormalities Coagulation disorders
DISORDERS OF VESSEL WALL:-
HEREDITARY:-
1) Hereditary hemorrhagic telangiectasia (Osler–Weber–Rendu disease )
2) Ehler Danlos Syndrome
ALLERGIC:-
3) Henoch–Schönlein purpura (HSP)
4) Leucocytoclastic angitis
ATROPHIC:-
5) Senile purpura
6) Scurvy
MISCELLANEOUS:-
7) Simple easy bruising
8) Amyloidosis
9) Infections
PLATELET DISORDERS.. Cont’d:-
DISORDERS OF COAGULATION:-
INHERITED ACQUIRED
HEMOPHILIA A DIC
HEMOPHILIA B LIVER DISEASE
vWD HDN
DISORDERS OF FIBRINOGEN- Nephrotic Syndrome
HEREDITARY AFIBRINOGENAEMIA
HYPOFIBRINOGENAEMIA
DYSFIBRINOGENAEMIA
FXIII deficiency APLS
FV deficiency HEPARIN OR ORAL ANTICOAGULANT
THERAPY
VIT K DEFICIENCY
MASSIVE TRANSFUSION OF STORED
BLOOD
Clinical evaluation.. Cont’d:-
Petechiae <3 mm, Purpura 0.3–1 cm (3–10 mm), ecchymoses >1 cm.
Clinical evaluation.. Cont’d:-
Hemarthrosis in a case of Hemophilia Purpura in a case of ITP
Von willebrand Disease
• 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
C/F – Spontaneous bleeding from mucus membrane,
Excessive bleeding from wounds / gums
Menorrhagia
>20 variants reported
Type1(50% activity) & 3(no activity) Type 2
Reduced vWF Qualitative defects
Lab Findings
• Prolonged BT
• (Normal) platelet count
• Deficient Ristocetin aggregation
• Prolonged PTT
Treatment
• cryoprecipitate
HEMOPHILIA – A
(F – VIII deficiency)
Most Common hereditary disease
Reduced activity of F – VIII
X – linked recessive trait
30% of patients have no positive family history
<1% of normal F-VIII activity – Severe disease
2 – 5% of normal F-VIII activity – Moderate disease
6 – 50% of normal F-VIII activity – Mild disease
Clinical /Features:
normal hemostasis require 25% factor VIII activity
Symptomatic patients mostly have < 5% factor VIII activity
Easy bruising
Massive Hemorrhage after mild trauma / operation
Joint bleeding – Haemarthrosis – Deformities
Lab Features
• Bleeding Time - Normal
• Prothrombin Time - Normal
• Platelet Count - Normal
• APTT - Increased
• Diagnosis can be confirmed by F-VIII assay.
Therapy
F-VIII Infusion
15% of severely affected patients –developed Antibodies against F - VIII
HEMOPHILIA – B
Severe Factor - IX deficiency
X – linked recessive
PT – Normal
APTT – Increased
Factor assay is must to differentiate between Hemophilia A & Hemophilia B
Screening tests for primary
hemostasis are -
I. Bleeding time- Assesses adequate functioning of platelets and blood vessels
II. Peripheral blood smear examination
III. Platelet count
IV. Mean Platelet volume
V. Reticulated platelets
VI. Platelet function analysis
VII. Tests for Vessel wall disorder
Tests for Vessel wall
disorder
HESS` CAPILLARY FRAGILITY TEST:
Cuff is wrapped in upper arm and pressure is maintained midway b/w systolic and
diastolic 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.
Upto 10 new hemorrhagic spots are normal.
But >20 new spots are always
pathological.
This is positive in increased capillary
fragility, ITP.
Screening tests for secondary
hemostasis are -
I. Clotting time
II. Prothrombin time (PT) and Activated partial thromboplastin time (aPTT)
III. Thrombin Time (TT)
Collection of blood for coagulation
studies
The anticoagulant used for coagulation studies is trisodium
citrate (3.2%), with anticoagulant to blood proportion being
1:9.
Clotting
Time
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)
PT assesses coagulation factors in extrinsic pathway (F VII) and
common pathway.
Principle:- Tissue thromboplastin and calcium are added to
platelet poor plasma and clotting time is determined.
CONCEPT OF INR
1.The international normalized ratio (INR) was introduced in an attempt to standardize the
PT.
2.Calculation ~ INR = [ PT (patient) / PT (Control) ]ISI
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 INR 0.9 – 1.1.
Uses of
PT
1. To monitor patients who are on oral anticoagulant
therapy
2. To assess liver function
3. Detection of vitamin K deficiency
4. To screen for hereditary deficiency of coagulation
factors
Causes of prolongation of PT
5.Treatment with oral anticoagulants
6.Liver disease
7.Vitamin K deficiency
8.Disseminated intravascular coagulation
ACTIVATED PARTIAL THROMBOPLASTIN TIME (APTT)
Significance
Reflects efficiency of Intrinsic and Common pathway.
Principle
The test measures the clotting time of plasma after the activation of contact
factors (Kaolin/Silica/Ellagic acid) and the addition of phospholipid and
CaCl2, but without added tissue thromboplastin.
So it indicates the overall efficiency of the Intrinsic pathway.
Normal range
26 to 40 seconds.
Uses of APTT:-
1. Screening for hereditary disorders of
coagulation
2. To monitor heparin therapy
3. Screening for circulating inhibitors of
coagulation
aPTT is prolonged in:-
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
( Inhibits factor XII, XI and X through antithrombin III & Heparin therapy is monitored
through aPTT)
5. Vit K deficiency
6.Massive transfusion of plasma depleted stored blood.
THROMBIN TIME(TT)
Significance:-
Asses the final step of coagulation i.e. conversion of fibrinogen to fibrin in presence of
thrombin.
Bypasses Extrinsic & Intrinsic pathway.
Causes of prolonged
TT
1. Disorders of fibrinogen-
i) Afibrinogenaemia
ii) Hypofibrinogenaemia
3. Chronic liver disease
FXIII Qualitative assay (Urea clot
lysis test)
Done when all other tests for hemostasis are normal.
FXIII provides stability to clot formed.
Method:-
Summary of Approach to Bleeding
Disorders
Thank you..
