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APPROACH TO A CASE OF COAGULATION DISORDER
Injury to vessel wall
Exposure to tissue factor on Endothelial cell
TF + VII
TF + VIIaXI XIa
IX IXa
X Xa
Extrinsic Pathway
Intrinsic Pathway
Ca / PL
Ca / PL
Ca / PLVIII VIIIa
Ca / PL
CommonPathway
X Xa
Prothrombin Thrombin
Fibrinogen Fibrin Monomer + Fibrinopeptides
Fibrin PolymerStable FibrinXIII
Ca
Ca / PL
Coagulation Factor1) Factor - I Fibrinogen :-
Level is high 200-400mg/dl
Consist of 3 pair of polypeptide chain
Cleaved by thrombin leaving monomer
2) Factor-II Prothrombin :-
Prothrombin converted to Thrombin by enzyme complex Xa-V-phospholipid-Ca.
3) Factor - III (Thromboplastin) :-
Require for activation of Factor VII in Extrinsic pathway.
4) Factor IV - Calcium,
5) Factor V (Proaccelerin) :-
- Act as a co-factor in conversion of Prothrombin to Thrombin by Prothrombinase complex.
6) Factor VI :-
Activated form of Factor V.
7) Factor VII (Stable factor) :-
Initiate Extrinsic pathway.
8) Factor VIII ( Anti-Haemophilic factor ) :-
- Complex of 2 compound :
a) F VIIIc :- Low Mol. Wt.,
- Pro-coagulant Activity,
b) Von-Willebrand Factor :-
- High Mol. Wt.,
9) Factor IX (Christmas Factor) :-
- Vit. K depending Glycoprotein.
- Activated by F XIa or by F VIIa -
tissue factor complex
10) Factor X (Stuart Prower factor) :-
- Vit. K dependant protein,
- Activated by both, Extrinsic & Intrinsic pathway.
11) Factor XI (Plasma Thromboplastin Antecedent) :-
- Activated by F XIIa in +nce of HMW kininogen,
12) Factor XII (Hageman Factor) :-
- Activated when comes in contact with Collagen,
Glass, Celite,
13) Factor XIII (Fibrin Stabilizing Factor) :-
- Stabilize Fibrin clot by formong intermolecular cross linkage bet. Glutamine & Lysine residue
Primary tests
• Bleeding Time :-
1) Duke’s Method :- Normal range 1 - 5 min.
2) Ivy’s Method :- Normal range 2 - 7 min.
- Sensitive method
3) Standardized Template Method :
- Normal range 2.5 - 9.5 min.
• Coagulation Time :-
1) Dale & Laidlaw’s Method (Capillary Tube Method) :-
• Normal range 4 - 8 mins,
• Insensitive & Nonspecific,
• Clot Retraction Test :-
– Volume of Serum (Blood clotted at 37O C) measured &
expressed as % of Whole blood,
– Normal range 45 - 65 %,
Primary tests
Prothrombin Time
• Principle :-
when the mixture of plasma and tissue
extract (thromboplastin ) are recalcified fibrin
form at normal rate if the factor involved in
extrinsic and common pathway are present in
normal amount.
• Normal Range :- 11-17 sec
Prolonged PT :-
1. Administration of oral anticoagulant drug.
2. Obstructive liver disease.
3. Vit-k deficiency
4. DIC
Prothrombin Time
Activated Partial Thromboplastin Time
• Principle :-
When mixture of plasma ,phospholipid and plate substitute are calcified fibrin form at normal rate only if factor involved in intrinsic and common pathway are present in normal amount.
• Normal Range :- 30- 40 sec
Prolonged aPTT :-1. DIC
2. Liver disease
3. Massive transfusion with stored blood
4. Circulating anticoagulant
5. Administration of heparin.
Activated Partial Thromboplastin Time
Thrombin time
• Thrombin added to plasma & clotting time
measure.
• Affected by
i) Concentration and reaction of fibrinogen.
ii) Presence OF Inhibitory substance.
• RANGE :- 15 – 19 sec
Prolonged in
1. Hypofibrinogenemia found in DIC
2. Raised concentration of FDP found in
DIC or liver disease.
3. Dysfibrinogenemia inherited or acquired
4. hypofibrinogenemia
Thrombin time
Classification of Coagulation Disorder
Inherited coagulation disorder
Acquired coagulation disorder
Inherited Coagulation Disorder
X- linked recessive :- Hemophilia - A Hemophilia - B
Autosomal dominant :- Von-willebrand disease Dysfibrinogenemia
Autosomal recessive :- Factor XI deficiency Prothrombin deficiency Factor v deficiency Factor vii deficiency Factor x deficiency Factor xiideficiency Factor xiii deficiency Afibrinogenemia
Acquired Coagulation Disorder
1. Vitamin k deficiency
2. Liver disease
3. Disseminated intravascular coagulation
4. Anticoagulant drug
5. Acute primary fibrinolysis
6. Massive transfusion of store blood
7. Circulating inhibitor of coagulation
Hemophilia - A
Occur in 1:10000 individual Caused by hereditary deficiency of or
dysfuction of factor viii X- linked recessive The abnormal gene located on x chromosome The disease manifest in only in male. Female are carrier but do not manifest the
disease.
Clinical feature
Fa viii /fa ix level (U/dl)
c/f Hemophilia-A
Hemophilia
B
<1 severe spontaneous
bleeding
70% 50%
1-5 Moderate bleeding with minimal trauma or surgery
15% 30%
6-40 Mild bleeding with mild trauma or surgery
15% 20%
Clinical Features :- Haemarthrosis
- commonly affected joint are knee ankle,
hip & elbow. Subcutaneous & intramuscular hematoma. Gastrointestinal ,genitourinary bleeding Hemorrhage from mouth ,gum ,lip & tongue Traumatic bleeding.
Hemophilia - A
Lab Diagnosis of Hemophilia - A
• PS examination show +nce or -nce of features of anemia.
• BM reflects response to Blood loss,
• Platelet count usually Normal or Elevated,
• aPTT prolonged,
• F VIIIc assays,– Done by :-
• 2 stage method,• One stage method,• Micromethod,
• F VIII Ag assay :-– Highly Specific but, Complicated,– Immunoradiometric method & ELISA technique,
Lab Diagnosis of Hemophilia - A
Hemophilia-B
• Also known as Christmas disease,
• Incidence in 1:60000 population,
• X - linked recessive,
• Less common than hemophilia A,
• Deficiency of factor IX,
• Sign / symptom similar to hemophilia A,
• Specific factor assay necessary to distinguish between Haemophilia A & B
Von-Willebrand Disease
• Van Willebrand factor – synthesized by :-
1) Endothelial cell
2) Megakaryocytes
– Mediate adhesion of platelet to Subendothelium by binding to platelet glycoprotein receptor GpIb & Subendothelium.
– Forms non-covalent complex with F VIII in circulation & prevent degradation and rapid removal of F VIII from circulation.
• Types of bleeding– Mucocutaneous bleeding
– Epistaxis, Menorrhagia, Ecchymoses &
hematomas, gingival &
– GI bleeding
– Soft tissue bleeding (after trauma/injury)
– Dental extraction, wounds, post-operatively,
post-partum
– Results from defect in secondary hemostasis
• Type 1: partial quantitative deficiency of VWF• Of patients with VWD, 73% have Type 1 • Type 2: qualitative deficiency of VWF (21% of VWD patients)• Type 2 variants• VWD Type 2A (synthesis or stability defect)• Decreased platelet dependent function due to loss of large,
functional polymeric forms • high molecular weight multimers [HMWM])• VWD Type 2B (gain of function defect)• Increased affinity for platelet GPIb• VWD Type 2M (“multimer”)• Qualitative defects with decreased platelet dependent function
not caused by• loss of HMWM• VWD Type 2N (FVIII binding defect)• Decreased affinity for FVIII • Type 3: total deficiency of VWF (6% of VWD patients)
Lab Diagnosis in VWD
• Bleeding time - May be Normal in many pts.,• aPTT is prolonged,• F VIIIc assay - Specific,• VWF Immunoassay :
– VWF Ag - measured by Laurell Immunoelectrophoresis method,
– Other Methods - Radioimmunoassay & ELISA,
• Ristocetin Co-factor activity :-– Quantitative Technique for estimating Functional
property of VWF in plasma,
– Most Sensitive & Specific assay,
• Ristocetin Induced Platelet Aggregation :-– Qualitative test,
– Ristocetin + Pts Platelet rich palsma = Aggregation response observed,
Lab Diagnosis in VWD
Disorder of fibrinogen
Quantitative Qualitative
1) Complete absence -afibrinogenemia 1)
2) Low level -Hypofibrinogenemia
Abnormal fibrinogen molecule -Dysfibrinogenemia
Afibrinogenemia
• Autosomal recessive disorder
• Complete absence of fibrinogen in plasma.
• In neonatal period there may be bleeding from umbilical cord.
• Intracranial hemorrhage are common cause of death.
Hypofibrinogenemia
• Autosomal recessive or dominant.• Fibrinogen concentration in plasma less than
100mg/dl.• The condition may be asymptomatic or may
manifest as mild bleeding disorder.•
Dysfibrinogenemia
• Impair fibrin polymerisation
• Impair formation of fibrin clot by interfering in formation of fibrin monomer.
Lab Diagnosis of Afibrinogenemia / Hypofibrinogenemia
• PT, • aPTT, Increased• Thrombin Time,
• Fibrinogen estimation Total absence or
Trace amount
Factor XIII Deficiency
• Inherited as Autosomal Recessive Trait,
• Bleeding occur shortly after birth from Umbilical cord,
• Most life threatening event - Spontaneous Intracranial
Hemorrhage (25 % cases),
• Soft tissue haemorrhages, Hemarthrosis, Hematoma may
occur.
Lab Diagnosis
• PT• aPTT, Normal• Bleeding time,• Platelet count
• Urea Solubility Test (Clot Solubility Test) :- – Clot formed In -nce of F XIII dissolve in urea within min,
– Most useful screening test for F XIII deficiency,
• Quantitative Measurement of F XIIIa • Immunological based assay by ELISA.
Prothrombin Deficiency
• Autosomal Recessive
• Spontaneous hemorrhages - Uncommon,
• Post-traumatic bleeding - MC complaint,
• Bleeding from Umbilical Stump - Common in
infants,
• Specific factor assay used for diagnosis.
Factor V Deficiency
• Autosomal Recessive,• Uncommon,• Epistaxis, Menorrhagia, GIT bleeding,• Inherited form - distinguished from comb. def. of
F V & VII,• Diagnosed by specific assay,
Factor VII deficiency
• Autosomal Recessive,
• F VII level not completely correlate with severity of symptom,
• Pts with level 5 - 10 U / dl,
• Mild symptoms such as epistaxis, GI bleed
• Diagnosis suspected in prolonged PT & normal aPTT,
• Diagnosis by specific Factor assay,
Factor X Deficiency
• Autosomal Recessive,
• Clinical features resembles those of F VII def.,
• Prolongation of PT & aPTT,
• Diagnosed by specific assay
Factor XI Deficiency
• Autosomal Dominant,
• Spontaneous bleeding - Rare,
• Bleeding after Trauma or Surgical procedure,
• aPTT prolonged,
• Diagnosed by Specific assay.
Acquired Coagulation Disorders
Vitamin-K Deficiency
• Fat soluble vitamin
• Required for gamma carboxylation of glutamic acid residues of four vitamin- k dependant factors ii, vii, ix, x
• Post translational modification is essential for binding of these coagulation factor to phospholipid in the presence of calcium.
1. Cause of vitamin k deficiency
2. Haemorrhagic disease of new born.
3. Poor dietary intake.
4. Malabsorption syndrome
5. Obstructive jaundice
DIC
• Characterised by
• 1) Widespread systemic activation coagulation with formation of microthrombi in blood vessels.
• 2)Bleeding diasthesis secondary to depletion of coagulation factor and platelet.
Cause of DIC
1. Obstetric complication
- Abruptio plasenta
septic abortion
IUD
Amniotic fluid embolism
2)Infection
viral-herpes,rubela
bagterial-septicemia
protozoal-malaria
Pathophysiology of DIC
3)neoplasm
prostatic carsinoma
breast carsinoma
lung carsinoma
4)disorder of hemopoietic system
Acut promyelocytic leukaemia
Intravascular hemolysis
5)vascular disorder
Collagen vascular disorder
6)Massive tissue injury
Burn
7)Miscellaneous
Head trauma
snake bite
Clinical featureAcute DIC
Sudden onset of spontaneous bleeding
from multiple site.
Skin - petechiae,ecchymosis
Gastrointestinal bleeding
Hematuria
Epistaxis
Oozing from venepuncture site
Intracranial hemorrhages
Chronic DIC
Manifest usually as venous thrombosis
Laboratory feature
1)P.S. Examination
Fragmented red cells (schistocytes,helmet cells)
Thrombocytopenia
2)coagulation profile
PT
APTT
TT
Level of fibrinogen decreases
Test for fibrinolysis
1)Fibrin degradation product
Acquired Inhibitor Of coagulation
1)Specific
Impair the coagulation by inactivating specific coagulation factor
2)Nonspecific
Interfering with coagulation reaction
Specific
These are antibodies inhibit the activity of specific coagulation factor .
Antibodies against F VII, FIX,FV, FVII,Fbrinogen,von willibrand factor,prothrombin
NonspecificNonspecific
Lupus anticoagulant :-
• Antiphospholipid antibodies that inhibit
coagulation reactions requiring phospholipid.
• These are IgG,IgM
• Interfere with binding of prothrombin and
F Xa to phospholipid
• Prevent the formation of prothrombinase
complex.
These occur in
SLE
Autoimmuno disease
Viral infection (HIV)
Lymphoproliferativ disorder
Drug
C/F
1) Recurrent arterial and venous thrombosis
2)Recurrent spontaneous abortion
3)Intrauterine foetal death
Lab Diagnosis of Lupus Anticoagulant
• ISTH criteria :-– Prolongation of at least one Phospholipid dependant
coagulation test, (e.g. aPTT, Dilute PT, Dilute Russell’s Viper venom time, Kaolin clotting time),
– failure to correct prolonged coagulation time by mixing pts & normal plasma,
– Confirmation of Lupus Anticoagulant by demonstrating correction of prolonged CT by addition excess Phospholipids,
– Exclusion of alternative coagulopathies using specific assay
Other Acquired Coagulative Disorders
• Renal Disease :-– Nephrotic Syndrome:-
• Excessive urinary loss of coagulation factor IX & Antithrombin III,
– Uremia :-
• Haemostatic abn. - defective Platelet function &
- Impairement of Fibrin monomer
polymerisation.
• Amylodosis :-– Deposits in tissue binds F X & causes sec. def.
• Massive Transfusion of Stored blood :-
– Transfusion Pt’s blood volume within 24 hr.
– Usually Deficient in Platelets & coagulation
factors V & VII,
– Dilution of Platelets & coagulation factor.
Other Acquired Coagulative Disorders
Clinical diff between vascular & coagulatio disorder
Parameter Vascular disorder Coagulation disorder
Commonly affected sex
Female Male
Family history Offen negative Offen positive
Petechiae bleeding gum epistaxsis
Common Rare
Deep hematoma & haemarthrosis
Not seen Common
Delayed bleeding Not seen Characteristic
Previous h/o bleeding Not present Present early childhood
Suspected Bleeding Disorder (Repeated bleeding episodes, bleeding from > 1 site, Spontaneous bleeding,)
See nature of Bleeding disorder (Whether Hereditary orAcquired, and Vascular/platelet or coagulation)
Perform screening test (PS, BT, PT, aPTT)
Perform Specific test depending result of screening tests
Specific Diagnosis
aPTT prolonged + PT prolonged
Common Pathway
Thrombin TimeFibrinogen Level
NormalAbnormal
• Common Drugs,• Liver Disease,• Vit. K Deficiency
• Heparin, • Liver disease,• DIC
Reptilase TimeAbnormal Normal
Other Causes Heparin
Acquired Coagulation Disorders