APPROACH TO A CASE OF COAGULATION DISORDER

Injury to vessel wall Exposure to tissue factor on Endothelial cell

Intrinsic Pathway XI XIa

Ca / PL

TF + VII TF + VIIa

Extrinsic Pathway

IX

IXa
VIII VIIIa
Ca / PL

Ca / PL

X
Ca / PL

Xa

Common Pathway X Xa
Ca / PL

Prothrombin Fibrinogen

Thrombin Fibrin Monomer + Fibrinopeptides

XIII Ca

Stable Fibrin

Fibrin Polymer

Coagulation Factor
1) 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) Dukes Method :- Normal range 1 - 5 min. 2) Ivys Method :- Normal range 2 - 7 min. - Sensitive method 3) Standardized Template Method : - Normal range 2.5 - 9.5 min.

Primary tests
Coagulation Time :1) Dale & Laidlaws 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 %,

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

Prothrombin Time

Prolonged PT :1. Administration of oral anticoagulant drug. 2. Obstructive liver disease. 3. Vit-k deficiency

4. DIC

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

Activated Partial Thromboplastin Time

Prolonged aPTT :1. DIC 2. Liver disease 3. Massive transfusion with stored blood 4. Circulating anticoagulant 5. Administration of heparin.

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

Thrombin time

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

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. 2. 3.

Vitamin k deficiency Liver disease Disseminated intravascular coagulation

4.
5. 6. 7.

Anticoagulant drug
Acute primary fibrinolysis Massive transfusion of store blood 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 c/f level (U/dl) Hemophilia Hemophilia -A B

<1
1-5

severe spontaneous
bleeding Moderate bleeding with minimal trauma or surgery Mild bleeding with mild trauma or surgery

70%
15%

50%
30%

6-40

15%

20%

Hemophilia - A

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.

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,

Lab Diagnosis of Hemophilia - A

F VIIIc assays, Done by : 2 stage method, One stage method, Micromethod, F VIII Ag assay : Highly Specific but, Complicated, Immunoradiometric method & ELISA technique,

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,

Lab Diagnosis in VWD

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,

Disorder of fibrinogen
Qualitative Abnormal fibrinogen molecule -Dysfibrinogenemia

Quantitative 1) Complete absence -afibrinogenemia 1)

2) Low level -Hypofibrinogenemia

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, Thrombin Time,

Increased

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, Bleeding time, Platelet count

Normal

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. 2. 3. 4.

Cause of vitamin k deficiency Haemorrhagic disease of new born. Poor dietary intake. Malabsorption syndrome 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 feature
Acute 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

Nonspecific
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 Russells 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.

Other Acquired Coagulative Disorders

Massive Transfusion of Stored blood : Transfusion Pts blood volume within 24 hr.

Usually Deficient in Platelets & coagulation

factors V & VII,

Dilution of Platelets & coagulation factor.

Clinical diff between vascular & coagulatio disorder

Parameter Commonly affected sex Family history Petechiae bleeding gum epistaxsis Deep hematoma & haemarthrosis Delayed bleeding Previous h/o bleeding Vascular disorder Female Offen negative Common Not seen Not seen Not present Coagulation disorder Male Offen positive Rare Common Characteristic Present early childhood

Suspected Bleeding Disorder (Repeated bleeding episodes, bleeding from > 1 site, Spontaneous bleeding,) See nature of Bleeding disorder (Whether Hereditary or Acquired, and Vascular/platelet or coagulation) Perform screening test (PS, BT, PT, aPTT)

Perform Specific test depending result of screening tests

Specific Diagnosis

Acquired Coagulation Disorders

aPTT prolonged + PT prolonged

Common Pathway
Abnormal Heparin, Liver disease, DIC Abnormal Reptilase Time Thrombin Time Fibrinogen Level Normal Common Drugs, Liver Disease, Vit. K Deficiency Normal Heparin

Other Causes