Bleeding Disorders

Indra Wijaya Internal Medicine Hasan Sadikin Hospital - Medical Faculty Padjadjaran 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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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 bleeding

disorders

Acquired bleeding

disorders

Hemophilia A and B vonWillebrands disease Other factor

Liver disease Vitamin K deficiency/

Warfarin overdose
DIC

deficiencies

e.g: Factor XI deficiency, etc

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Hemofilia

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Hemophilia A and B
Hemophilia A Hemophilia B Factor IX Coagulation factor deficiency Factor VIII Inheritance Incidence Severity X-linked X-linked recessive recessive 1/10,000 males 1/50,000 males

Related to factor level <1% - Severe - spontaneous bleeding 1-5% - Moderate - bleeding with mild injury 5-25% - Mild - bleeding with surgery or trauma Soft tissue bleeding
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Complications

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Hemophilia
Clinical manifestations (hemophilia A & B indistinguishable)
Hemarthrosis (most common)
Fixed joints

Soft tissue hematomas (e.g., muscle)

Muscle atrophy Shortened tendons

Other sites of bleeding

Urinary tract CNS, neck (may be life-threatening)
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Factor VIII concentrate or Recombinant

(Koate/Kogenate)
Dosage based on desired factor VIII increase (%):

Body weight (kg) x 0.5 int. units/kg x desired factor VIII increase (%) = int. units factor VIII required
For example:50 kg x 0.5 int. units/kg x 30 (% increase) = 750 int. units factor VIII

Dosage based on expected factor VIII increase (%):

(# int. units administered x 2%/int. units/kg) divided by body weight (kg) = expected % factor VIII increase
For example: (1400 int. units x 2%/int. units/kg)4/22/12 by 70 divided

General Guidelines F VIII concentrate/recombinant

Minor

hemorrhage: 10-20 int. units/kg as a single dose to achieve FVIII

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Treatment of hemophilia B
Agent
High purity factor IX Recombinant human factor IX

Dose
Initial dose: 100U/kg Subsequent: 50 U/kg every 24 hours

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von Willebrand Disease

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von Willebrand Disease

von Willebrand factor:

Carrier of factor VIII Anchors platelets to subendothelium Bridge between platelets Autosomal dominant (tipe 1 and 2) Autosomal recessive (tipe 3) 1/10,000 Majority of these people do not have symptoms
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Inheritance

Incidence

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von Willebrand Disease

present with varying degrees of bleeding tendency, usually in the form of easy bruising,nosebleedsand bleeding gums. Women may experienceheavy menstrual periods and blood loss duringchildbirth.

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Laboratory evaluation of von Willebrand disease

Classification Type 1 Partial quantitative deficiency Type 2 Qualitative deficiency Type 3 Total quantitative deficiency
Diagnostic tests:
Assay von Willebrand type 1 2 3

vWF antigen

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Treatment of von Willebrand disease Varies by Classification

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 g/kg q 12 hr IV

Factor VIII concentrate (Humate-P)

Virally inactivated product 4/22/12

Bleeding disorder of Sistemic disease

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Liver Disease
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)

Vitamin K (usually ineffective)

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Vitamin K deficiency
Source of vitamin K

Green vegetables Synthesized by intestinal flora Factors II, VII, IX ,X

Required for synthesis

Protein C and S

Causes of deficiency

Biliary obstruction Malabsorption

Malnutrition Antibiotic therapy

Treatment

Fresh frozen plasma

Vitamin K
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Coagulation cascade
Intrinsic system (surface contact) XII XI IX VIII X V II Fibrinogen
Vitamin K dependant factors

Extrinsic system (tissue damage) Tissue factor

XIIa XIa IXa VIIIa Xa Va

VIIa

VII

IIa

(Thrombin) Fibrin

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Vitamin K deficiency due to warfarin overdose

Managing 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 necessary Resume therapy at lower dose when INR therapeutic Chest 2001:119;22-38s
(supplement)

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Vitamin K deficiency due to warfarin overdose

Clinical situation Guidelines

Managing high INR values in bleeding patients

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

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Disseminated Intravascular Coagulation (DIC) Mechanism

Systemic activation of coagulation

Intravascular deposition of fibrin

Depletion of platelets and coagulation factors

Thrombosis of small and midsize vessels with organ failure

Bleeding

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Common clinical conditions associated with DIC

Sepsis Trauma Head injury Fat embolism Malignancy Obstetrical complications Amniotic fluid embolism Abruptio placentae
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Vascular disorders Reaction to toxin (e.g. snake

venom, drugs)

Immunologic disorders Severe allergic reaction Transplant rejection

DIC Treatment approaches

Treatment of underlying disorder Anticoagulation with heparin Platelet transfusion Fresh frozen plasma
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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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Skin and mucous membranes

Petechiae Ecchymosis Hemorrhagic vesicles Gingival bleeding and epistaxis

Sites of bleeding in thrombocytopenia

Menorrhagia Gastrointestinal bleeding Intracranial bleeding

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Petechiae

Do not blanch with pressure (> < angiomas) Not palpable (> < vasculitis)

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Classification of platelet disorders

Quantitative Qualitative disorders
Inherited disorders (rare) Abnormal distribution Dilution effect Decreased production Increased destruction Acquired disorders

disorders

Medications Chronic renal failure

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Acquired thrombocytopenia with shortened platelet survival

Associated with

bleeding

Associated with

thrombosis

Immune-mediated

thrombocytopenia (ITP) Most drug-induced thrombocytopenias Most others

Thrombotic

thrombocytopenic purpura DIC Heparin-associated thrombocytopenia

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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 platelets CBC with peripheral smear Platelet function study
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Platelet transfusions complications

Transfusion reactions
Higher incidence than in RBC transfusions Related to length of storage Bacterial contamination

Platelet transfusion refractoriness

Alloimmune destruction of platelets (HLA antigens) Non-immune refractoriness

Microangiopathic hemolytic anemia Coagulopathy Splenic sequestration Fever and infection Medications (Amphotericin, vancomycin, ATG, Interferons)

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Kebutuhan transfusi trombosit

Penyebab

trombositopenia Derajat trombositopenia Penyakit Penyerta Fungsi trombosit Transfusi akan mampu bertahan empat hari Jenis operasi.
Transfusi trombosit konsentrat pada ITP sebaiknya dihindari
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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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Adjunctive drug therapy for bleeding

Fresh frozen plasma Cryoprecipitate Epsilon-amino-caproic acid (Amicar) DDAVP Recombinant human factor VIIa (Novoseven)

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Fresh frozen plasma

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) 10-15 ml/kg Note Viral screened product ABO compatible

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Cryoprecipitate
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

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Aminocaproic acid (Amicar)

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

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Desmopressin (DDAVP)
Mechanism
Increased release of VWF from endothelium

Dose
0.3g/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

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Tranexamic acid (Kalnex)

MECHANISM OF ACTIONForms a

reversible complex that displaces plasminogen from fibrin resulting in inhibition of fibrinolysis; 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/dose orally 3-4 times/day for 4/22/12

Recombinant human factor VIIa (rhVIIa; Novoseven)

Mechanism Activates coagulation system through extrinsic pathway Approved Use Factor VIII inhibitors in hemophiliacs Dose: (1.2 mg/vial) 90 g/kg q 2 hr Adjust as clinically indicated
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Summary
Identify and correct any specific defect of

hemostasis possible

Use non-transfusional drugs whenever

RBC or blood component transfusion for

surgical procedures or large blood loss

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