Kelainan Perdarahan.ppt

8/11/2019 Kelainan Perdarahan.ppt

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Bleeding Disorders

Indra Wijaya

Internal MedicineHasan Sadikin Hospital - Medical FacultyPadjadjaran University


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Objectives

Coagulation factor disorders and treatment

Disorders of platelets and platelet transfusion Adjunctive drug therapy for bleeding


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Coagulation factor disorders

Inherited bleedingdisorders

Hemophilia A and B

vonWillebrands diseaseOther factor deficiencies

Acquired bleedingdisorders

Liver disease

Vitamin K deficiency/warfarinoverdoseDIC


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Hemophilia A and BHemophilia A Hemophilia B

Coagulation factor deficiency Factor VIII Factor IX

Inheritance X-linked X-linkedrecessive recessive

Incidence 1/10,000 males 1/50,000 males

Severity Related to factor level


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Hemophilia

Clinical manifestations (hemophilia A & Bindistinguishable)

Hemarthrosis (most common) Fixed joints

Soft tissue hematomas (e.g., muscle)Muscle atrophyShortened tendons

Other sites of bleeding Urinary tractCNS, neck (may be life-threatening)

Prolonged bleeding after surgery or dental extractions


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Treatment of hemophilia A

Intermediate purity plasma productsVirucidally treatedMay contain von Willebrand factor

High purity (monoclonal) plasma productsVirucidally treatedNo functional von Willebrand factor

Recombinant factor VIIIVirus free/No apparent riskNo functional von Willebrand factor


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Treatment of hemophilia B

AgentHigh purity factor IXRecombinant human factor IX

DoseInitial dose: 100U/kgSubsequent: 50 U/kg every 24 hours


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von Willebrand Disease Clinical features

von Willebrand factor Carrier of factor VIII Anchors platelets to subendothelium

Bridge between platelets

Inheritance Autosomal dominant

Incidence 1/10,000

Clinical features Mucocutaneous bleeding


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Laboratory evaluation of von Willebrand disease

ClassificationType 1 Partial quantitative deficiencyType 2 Qualitative deficiencyType 3 Total quantitative deficiency

Diagnostic tests:von Willebrand type

Assay 1 2 3

vWF antigen Normal

vWF activityMultimer analysis Normal Normal Absent


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Treatment of von Willebrand diseaseVaries by Classification

Cryoprecipitate Source of fibrinogen, factor VIII and VWFOnly plasma fraction that consistently contains VWF multimersCorrection of bleeding time is variable

DDAVP (Deamino-8-arginine vasopressin) Increases plasma VWF levels by stimulating secretion fromendotheliumDuration of response is variableUsed for type 1 diseaseDosage 0.3 g/kg q 12 hr IV

Factor VIII concentrate (Humate-P) Virally inactivated productUsed for type 2 and 3


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Vitamin K deficiencySource of vitamin K Green vegetables

Synthesized by intestinal flora

Required for synthesis Factors II, VII, IX ,XProtein C and S

Causes of deficiency MalnutritionBiliary obstructionMalabsorption

Antibiotic therapy

Treatment Vitamin KFresh frozen plasma


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Vitamin K deficiency due to warfarin overdoseManaging high INR values

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 necessaryResume therapy at lower dose when INR therapeutic

Chest 2001:119;22-38s (supplement)


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Vitamin K deficiency due to warfarin overdoseManaging high INR values in bleeding patients

Clinical situation Guidelines

INR > 20; serious bleeding Omit warfarinAny 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


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Disseminated Intravascular Coagulation (DIC)Mechanism

Systemic activationof coagulation

Intravasculardeposition of fibrin Depletion of plateletsand coagulation factors

BleedingThrombosis of smalland midsize vesselswith organ failure


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Common clinical conditionsassociated with DIC

Sepsis

TraumaHead injury

Fat embolism

Malignancy

Obstetrical complications

Amniotic fluid embolism Abruptio placentae

Vascular disorders

Reaction to toxin (e.g. snakevenom, drugs)

Immunologic disordersSevere allergic reactionTransplant rejection


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DICTreatment approaches

Treatment of underlying disorder

Anticoagulation with heparin

Platelet transfusion

Fresh frozen plasma


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Liver Disease

Decreased synthesis of II, VII, IX, X, XI, and fibrinogenProlongation of PT, aPTT and Thrombin Time

Treatment

Fresh-frozen plasma infusion (immediate but temporaryeffect)

Vitamin K (usually ineffective)


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Coagulation cascade

Vitamin K dependant factors

XIIa

IIa

Intrinsic system (surface contact)

XII

XI XIa

Tissue factor

IX IXa VIIa VII

VIII VIIIa

Extrinsic system (tissue damage)

X

V Va

II

Fibrinogen Fibrin

(Thrombin)IIa

Xa


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Disorders of Platelets and PlateletTransfusion


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Sites of bleeding in thrombocytopeniaSkin and mucous membranes

PetechiaeEcchymosisHemorrhagic vesiclesGingival bleeding and epistaxis

MenorrhagiaGastrointestinal bleedingIntracranial bleeding


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Petechiae

Do not blanch with pressure(> < angiomas)

Not palpable(> < vasculitis)


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Classification of platelet disorders

Quantitative disorders

Abnormal distributionDilution effect

Decreased productionIncreased destruction

Qualitative disorders

Inherited disorders (rare) Acquired disorders

MedicationsChronic renal failure


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Acquired thrombocytopenia withshortened platelet survival

Associated withbleeding

Immune-mediatedthrombocytopenia (ITP)Most drug-inducedthrombocytopeniasMost others

Associated withthrombosis

Thromboticthrombocytopenic purpuraDICHeparin-associatedthrombocytopenia


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Approach to the thrombocytopenic patient

History Is the patient bleeding?

Are there symptoms of a secondary illness? (neoplasm, infection,autoimmune disease)Is there a history of medications, alcohol use, or recent transfusion?

Are there risk factors for HIV infection?Is there a family history of thrombocytopenia?Do the sites of bleeding suggest a platelet defect?

Assess the number and function of plateletsCBC with peripheral smearPlatelet function study


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Platelet transfusions - complicationsTransfusion reactions

Higher incidence than in RBC transfusionsRelated to length of storageBacterial contamination

Platelet transfusion refractoriness Alloimmune destruction of platelets (HLA antigens)

Non-immune refractorinessMicroangiopathic hemolytic anemiaCoagulopathySplenic sequestrationFever and infection

Medications (Amphotericin, vancomycin, ATG, Interferons)


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Adjunctive therapy forbleeding disorders


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Adjunctive drug therapy for bleeding

Fresh frozen plasmaCryoprecipitateEpsilon-amino-caproic acid (Amicar )DDAVPRecombinant human factor VIIa (Novoseven)


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Fresh frozen plasma

Content - plasma (decreased factor V and VIII)IndicationsMultiple coagulation deficiencies (liver disease, trauma)DICWarfarin reversalCoagulation deficiency (factor XI or VII)

Dose (225 ml/unit)10-15 ml/kg

NoteViral screened product

ABO compatible

Cryoprecipitate


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Cryoprecipitate

Prepared from FFPContent

Factor VIII, von Willebrand factor, fibrinogen

IndicationsFibrinogen deficiency

Uremiavon Willebrand disease

Dose (1 unit = 1 bag)1-2 units/10 kg body weight


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Aminocaproic acid (Amicar)

MechanismPrevent activation plaminogen -> plasmin

Dose50mg/kg po or IV q 4 hr

UsesPrimary menorrhagiaOral bleedingBleeding in patients with thrombocytopeniaBlood loss during cardiac surgery

Side effectsGI toxicityThrombi formation


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Desmopressin (DDAVP)

Mechanism

Increased release of VWF from endothelium

Dose0.3g/kg IV q12 hrs150mg intranasal q12hrs

UsesMost patients with von Willebrand diseaseMild hemophilia A

Side effectsFacial flushing and headacheWater retention and hyponatremia


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Tranexamic acid (Kalnex)

MECHANISM OF ACTION Forms a reversible complex thatdisplaces plasminogen from fibrin resulting in inhibition offibrinolysis; it also inhibits the proteolytic activity of plasmin

Hemophilia patient:

during and following tooth extraction:I.V.: 10 mg/kg immediately before surgery, then 25 mg/kg/doseorally 3-4 times/day for 2-8 days

Alternatively:Oral: 25 mg/kg 3-4 times/day beginning 1 day prior to surgeryI.V.: 10 mg/kg 3-4 times/day in patients who are unable to take oral


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Recombinant human factor VIIa(rhVIIa; Novoseven )

Mechanism Activates coagulation system through extrinsic pathway

Approved UseFactor VIII inhibitors in hemophiliacs

Dose: (1.2 mg/vial)90 g/kg q 2 hrAdjust as clinically indicated


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Approach to bleeding:Summary

Identify and correct any specific defect ofhemostasis

Use non-transfusional drugs whenever possible

RBC or blood component transfusion forsurgical procedures or large blood loss

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Kelainan Perdarahan.ppt