BY : DR.SHAINA KALRA MODERATOR : DR.VIJAY KUMAR

 Hemophilia A (FVIII),  Hemophilia B (FIX),  Hemophilia C (FXI)  Von Willebrand Disease  Deficiencies of factors X,  Deficiencies of factors V,  Deficiencies of factor VII  Deficiencies Prothrombin  Afibrinogenemia  Dysfibrinogenemia

 Inheritance is X-linked  Deficiency of Factor VIII  Clinical presentation :  90% of bleeding episodes occur into the joints (knees and elbows predominantly)  Intramuscular, intracranial, & gastrointestinal

Mild: activity levels between 5-25% Have significant bleeding after major trauma or surgery but generally go undetected until abnormal APTT is found Moderate: activity levels between 2-5% Bleeding is precipitated by trauma or surgery Severe: less than 1% activity Present with recurrent hemorrhages that occur spontaneously or after minor trauma/surgery

 Severe :  shortly after birth  Extensive cephalhematoma  Profuse bleeding at circumcision  Moderate :  Bleed when they begin to walk or crawl  Mild :  Diagnosed at adult age

 Treatment goal (at present) is to replace FVIII  Since cryoprecipitate (containing FVIII, VWF, & Fibrinogen) is not virally attenuated, it should only be used for urgent replacement.  Plasma-derived concentrates that contain intermediate to high activities of FVIII  Monoclonal antibody purified products that contain extremely high quantities of FVIII  Genetically engineered FVIII

 Mild : DDAVP (desmopressin) increases FVIII level transiently safe causes hyponatremia ppt thrombosis in elderly  Uncomplicated episode of soft tissue bleed one infusion of FVIII concentrate to raise the FVIII level by 15 – 20 %  More extensive hemarthrosis continous infusion of FVIII to keep level of % for atleast 72hours

 Life threatening bleeding into CNS require therapy for 2 weeks to keep the level at 50 % of normal

 Intermediate purity plasma products  Virucidally treated  May contain von Willebrand factor  High purity (monoclonal) plasma products  Virucidally treated  No functional von Willebrand factor  Recombinant factor VIII  Virus free/No apparent risk  No functional von Willebrand factor

 Mild bleeding  Target: 30% dosing q8-12h; 1-2 days (15U/kg)  Hemarthrosis, oropharyngeal or dental, epistaxis, hematuria  Major bleeding  Target: % q8-12h; 7-14 days (50U/kg)  CNS trauma, hemorrhage, lumbar puncture  Surgery  Retroperitoneal hemorrhage  GI bleeding  Adjunctive therapy   amino caproic acid (Amicar) or DDAVP (for mild disease only)

Clinical indication Plasma FVIII target (IU/dl) Dose of FVIII (IU/kg) Early hemarthrosis or muscle bleed 15 – Minor trauma or more severe bleed 35 – Major trauma, surgery or head injury

 Formation of inhibitors (antibodies)  10-15% of severe hemophilia A patients  1-2% of severe hemophilia B patients  Viral infections  Hepatitis BHuman parvovirus  Hepatitis CHepatitis A  HIVOther

 Inheritance is X-linked  Deficiency of Factor IX  Factor IX require vit.K for its biological activity  Treatment :  fresh frozen plasma  plasma enriched in prothrombin complex protein  recombinant Factor IX

 Agent  High purity factor IX  Recombinant human factor IX  Dose  Initial dose: 100U/kg  Subsequent: 50 U/kg every 24 hours

 Autosomal recessive inheritance  Deficiency of Factor XI  Homozygotes : Factor XI conc < 4%  Heterozygotes : Factor XI conc 15 – 65%  Found predominantly in individuals of Ashkenazi Jewish descent  Treatment : FFP  Factor XI concentrates can be given but they are thrombogenic and Factor XI has a v long life

 von Willebrand factorCarrier of factor VWF Anchors platelets to subendothelium. Bridge between platelets  InheritanceAutosomal dominant  Incidence 1/10,000

Mucocutaneous bleeding Epistaxis, menorrhagia, ecchymoses & hematomas, gingival and gastrointestinal bleeding Results from defect in primary hemostasis Soft tissue bleeding (after trauma/injury) Dental extraction, wounds, post-operatively, post-partum Results from defect in secondary hemostasis – VWF is carrier (protector) protein for FVIII

Classification  Type 1 Partial quantitative deficiency  Type 2 Qualitative deficiency  Type 3Total quantitative deficiency  Diagnostic tests: Assay vWF antigen  Normal  vWF activity    Multimer analysisNormalNormal Absent vonWillebrand type Assay vWF antigen  Normal  vWF activity    Multimer analysisNormalNormalAbsent

 APTT (degree of prolongation depends on FVIII levels)  PFA closure time (“in vitro” bleeding time) PFA-100™ instrument measures the time required to stop the flow of blood (by occluding a small hole in a collagen coated membrane) in a high shear environment when exposed to physiologic agonists such as ADP or epinephrine  Platelet count  ABO blood group

 Factor VIII procoagulant activity (FVIII:C) Low plasma levels seen in Hemophilia A and VWD  VWF antigen (VWF:Ag) level  Ristocetin Cofactor (VWF:RCo) activity of VWF Determines VWF function

 Desmopressin (DDAVP) – Synthetic analog of vasopression that releases endogenous stores of VWF from endothelial cells – VWD types 1, 2A, 2M, some 2B  Factor VIII concentrates – Must contain both FVIII and VWF since both defects necessitate correction – Useful in all VWD types

 Cryoprecipitate  Source of fibrinogen, factor VIII and VWF  Only plasma fraction that consistently contains VWF multimers  Correction of bleeding time is variable  DDAVP (Deamino-8-arginine vasopressin)  Increases plasma VWF levels by stimulating secretion from endothelium  Duration of response is variable  Used for type 1 disease  Dosage 0.3 µg/kg q 12 hr IV  Factor VIII concentrate (Humate-P)  Virally inactivated product  Used for type 2 and 3

 Vitamin K deficiency  Liver Disease  Immune coagulopathies  Disseminated intravascular coagulation (DIC)  Pharmacologic overdosing  Acquired platelet defects due to : Uremia, myeloproliferative disorders, antiplatelet antibodies, drugs that inhibit platelet function

 Source of vitamin K Green vegetables Synthesized by intestinal flora  Required for synthesisFactors II, VII, IX,X Protein C and S  Causes of deficiencyMalnutrition Biliary obstruction Malabsorption Antibiotic therapy  TreatmentVitamin K Fresh frozen plasma

Clinical situation Guidelines  INR therapeutic-5 Lower or omit next dose; Resume therapy when INR is therapeutic  INR 5-9; no bleeding Lower or omit next dose; Resume therapy when INR is therapeutic Omit dose and give vitamin K (1-2.5mg po) Rapid reversal: vitamin K 2-4 mg po (repeat)

 INR >9; no bleeding Omit dose; vitamin K 3-5 mg po ; repeat as necessary Resume therapy at lower dose when INR therapeutic  INR > 20; serious bleeding Omit warfarin Any life-threatening bleeding Vitamin K 10 mg slow IV infusion FFP ± factor rhVIIa (depending on urgency) Repeat vitamin K injections every 12 hrs as needed

Systemic activation of coagulation Intravascular deposition of fibrin Thrombosis of small and mid size vessel Organ failure Depletion of platelet and coagulation factor bleeding

 DIC is characterized by excessive deposition of fibrin throughout the vascular tree  Simultaneous depression of inhibitory mechanism of coagulation and impaired fibrin degradation

 Sepsis  Trauma  Head injury  Fat embolism  Malignancy  Obstetrical complications  Amniotic fluid embolism  Abruptio placentae  Vascular disorders  Reaction to toxin (e.g. snake venom, drugs)  Immunologic disorders  Severe allergic reaction  Transplant rejection

 Skin and mucous membrane bleeding.  Hemorrage from Surgical incision Venipuncture less common features :  Peripheral acrocyanosis  Thrombosis  Pregenrenous changes in digits, genitalia and nose

 Thrombocytopenia  Schistiocytes  Prolonged PT and APTT  Prolonged TT  Decreased fibrinogen levels  Raised FDP  d Dimer assay

 Relatively specific test  Tests for the presence of soluble complexes composed of fibrin monomers and FDPs  Addition of protamine desolubilises these complexes resultin in precipitate formation

 Treatment of underlying disorder  Anticoagulation with heparin : if thrombosis is problematic  Cryoprecipitate : hypofibrinogenmeia  Platelet transfusion : if platelet <50,000  Fresh frozen plasma : if factor deficiency  APC(activated protein C) :decreases mortality and organ failure

 Antithrombin III : may reverse the DIC process in septicaemia  Prostacyclin : where platelet activation is the primary cause  Aprotinin : where the primary cause is fibrinolysis

 Decreased synthesis of II, VII, IX, X, XI, and Fibrinogen. Prolongation of PT, aPTT and Thrombin Time  Treatment Fresh-frozen plasma infusion (immediate but temporary effect)

CBC and smearPlatelet countThrombocytopenia RBC and platelet morphologyTTP, DIC, etc. CoagulationProthrombin timeExtrinsic/comm pathways Partial thromboplastin timeIntrinsic/comm pathways Coagulation factor assaysSpecific factor def 50:50 mixInhibitors (e.g., abs) Fibrinogen assayDecreased fibrinogen Thrombin timeQualitative/quantitative fibrinogen defects FDPs or D-dimerFibrinolysis (DIC) Platelet functionvon Willebrand factorvWD In vivo test (non-sp) Platelet function analyzer (PFA)Qualitative plat disorders Bleeding time and vWD Platelet function testsQualitative platelet disorders

 Content - plasma (decreased factor V and VIII)  Indications  Multiple coagulation deficiencies (liver disease, trauma)  DIC  Warfarin reversal  Coagulation deficiency (factor XI or VII)  Dose (225 ml/unit)  ml/kg  Note  Viral screened product  ABO compatible

 Prepared from FFP  Content  Factor VIII, von Willebrand factor, fibrinogen  Indications  Fibrinogen deficiency  Uremia  von Willebrand disease  Dose (1 unit = 1 bag)  1-2 units/10 kg body weight

 Mechanism  Prevent activation plaminogen -> plasmin  Dose  50mg/kg po or IV q 4 hr  Uses  Primary menorrhagia  Oral bleeding  Bleeding in patients with thrombocytopenia  Blood loss during cardiac surgery  Side effects  GI toxicity  Thrombi formation

 Mechanism  Increased release of VWF from endothelium  Dose  0.3µg/kg IV q12 hrs  150mg intranasal q12hrs  Uses  Most patients with von Willebrand disease  Mild hemophilia A  Side effects  Facial flushing and headache  Water retention and hyponatremia

 Mechanism  Activates coagulation system through extrinsic pathway  Approved Use  Factor VIII inhibitors in hemophiliacs  Dose: (1.2 mg/vial)  90 µg/kg q 2 hr  “Adjust as clinically indicated”  Cost (70 kg $1/µg  ~$5,000/dose or $60,000/day

 Surgery or trauma with profuse bleeding  Consider in patients with excessive bleeding without apparent surgical source and no response to other components  Dose: ug/kg for 1-2 doses  Risk of thrombotic complications not well defined  Anticoagulation therapy with bleeding  20ug/kg with FFP if life or limb at risk; repeat if needed for bleeding