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

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

2  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

3  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

4 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

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

6  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

7  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

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

9  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

10  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)

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12 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

13  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

14  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

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

16  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

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

18 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

19 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

20  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

21  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

22  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

23  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

24  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

25  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

26 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)

27  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

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

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

30  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

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

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

33  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

34  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

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

36  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)

37 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

38  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

39  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

40  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

41  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

42  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

43  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


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