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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