BledingDisorder-MKM.ppt

8/21/2019 BledingDisorder-MKM.ppt

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Bleeding Disorders

Bahan dari Slides: Morey A. Blinder, MDDivision of HematologyDivision of Laboratory Medicine

Dairion Gatot

Divisi Hematologi & Onkologi Medik Bagian Penyakit Dalam

FK USU RSUP H Adam Malik/ RS Pirngadi Medan


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Objectives

I. Clinical aspects of bleedingII. Hematologic disorders causing bleeding

• Coagulation factor disorders

• Platelet disorders

III. Approach to acquired bleeding disorders• Hemostasis in liver disease

• Surgical patients•

Warfarin toxicityIV. Approach to laboratory abnormalities

• Diagnosis and management of thrombocytopenia

V. Drugs and blood products used for bleeding


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Objectives - I

Clinical aspects of bleeding


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Clinical Features of Bleeding Disorders

Platelet oag!lationdisorders "a#tor disorders

Site o" $leeding Skin Dee% in so"t tiss!es

M!#o!s mem$ranes 'oints( m!s#les)

e%ista*is( g!m(

vaginal( G+ tra#t)Pete#,iae -es .o

##,ymoses 0$r!ises1) Small( s!%er"i#ial 2arge( dee%

Hemart,rosis / m!s#le $leeding *tremely rare ommon

Bleeding a"ter #!ts & s#rat#,es -es .o

Bleeding a"ter s!rgery or tra!ma +mmediate( Delayed 345 days)(

!s!ally mild o"ten severe


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Petechiae

Do not blanch with pressure

(cf. angiomas)Not palpable (cf. vasculitis)

(typical of platelet disorders)


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Ecchymoses

(typical of coagulation

factor disorders)


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Objectives - II

Hematologic disorders causing bleeding–Coagulation factor disorders

–Platelet disorders


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Coagulation factor disorders

Inherited bleedingdisorders

–Hemophilia A and B

–vonWillebrands disease

–Other factor deficiencies

Acquired bleedingdisorders

–Liver disease

–Vitamin K

deficiency/warfarinoverdose

–DIC


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Hemophilia A and B

Hemophilia 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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Hemo%,ilia

Clinical manifestations(hemophilia A & B areindistinguishable)

Hemarthrosis (most common)Fixed joints

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

Other sites of bleedingUrinary tract

CNS, neck (may be life-threatening)Prolonged bleeding after surgery or dental extractions


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Hemart,rosis a#!te)


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Treatment of hemophilia A

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


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Dosing guidelines for hemophilia A

Mild bleeding–Target: 30% dosing q8-12h; 1-2 days (15U/kg)–Hemarthrosis, oropharyngeal or dental, epistaxis, hematuria

Major bleeding–Target: 80-100% q8-12h; 7-14 days (50U/kg)

–CNS trauma, hemorrhage, lumbar puncture–Surgery

–Retroperitoneal hemorrhage

–GI bleeding

Adjunctive therapy

– ε-aminocaproic acid (Amicar) or DDAVP (for mild disease only)


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Complications of therapy

Formation of inhibitors (antibodies)–10-15% of severe hemophilia A patients

–1-2% of severe hemophilia B patients

Viral infections

–Hepatitis B Human parvovirus

–Hepatitis C Hepatitis A

–HIV Other


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Viral infections in hemophiliacs

HIV -positive HIV-negative (n=382) (n=345) 53% 47%

Hepatitis serology % positive % negative

Negative 1 20Hepatitis B virus only 1 1Hepatitis C virus only 24 45Hepatitis B and C 74 34

Blood 1993:81;412-418


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Treatment of hemophilia B

Agent–High purity factor IX

–Recombinant human factor IX

Dose

–Initial dose: 100U/kg

–Subsequent: 50U/kg every 24 hours


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von 6ille$rand Disease7 lini#al Feat!res

von Willebrand factor–Synthesis in endothelium and megakaryocytes

–Forms large multimer

–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 ofvon Willebrand disease

Classification–Type 1 Partial quantitative deficiency

–Type 2 Qualitative deficiency

–Type 3 Total quantitative deficiency

Diagnostic tests:

vonWillebrand type

Assay 1 2 3

vWF antigen Normal⇓

vWF activity ⇓Multimer analysis Normal Normal Absent


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8reatment o" von 6ille$rand Disease

Cryoprecipitate–Source of fibrinogen, factor VIII and VWF

–Only plasma fraction that consistently contains VWF multimers

DDAVP (deamino-8-arginine vasopressin)

↑ plasma VWF levels by stimulating secretion from endothelium

–Duration of response is variable

–Not generally used in type 2 disease

–Dosage 0.3 µg/kg q 12 hr IV

Factor VIII concentrate (Intermediate purity)–Virally inactivated product


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Vitamin K deficiency

Source of vitamin K Green vegetables Synthesized by intestinaflora

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

Causes of deficiency Malnutrition Biliary obstructionMalabsorption Antibiotic therapy

TreatmentVitamin K Fresh frozen plasma


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Common clinical conditions associated withDisseminated Intravascular Coagulation

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

Activation of both coagulation and fibrinolysisTriggered by


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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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Pat,ogenesis o" D+

Coagulation Fibrinolysis

Fibrinogen

FibrinMonomers

FibrinClot

(intravascular)

Fibrin(ogen)Degradation

Products

Plasmin

Thrombin Plasmin

Release ofthromboplasticmaterial intocirculation

Consumption ofcoagulation factors;presence of FDPs

aPTT PT

TT

Fibrinogen

Presence of plasmin

FDP

Intravascular clot

PlateletsSchistocytes


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Disseminated Intravascular CoagulationTreatment approaches

Treatment of underlying disorder

Anticoagulation with heparin

Platelet transfusion

Fresh frozen plasma

Coagulation inhibitor concentrate (ATIII)


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Classification of platelet disorders

Quantitative disorders

–Abnormal distribution

–Dilution effect

–Decreased production

–Increased destruction

Qualitative disorders

–Inherited disorders(rare)

–Acquired disorders

»Medications

»Chronic renal failure

»Cardiopulmonary bypass


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Thrombocytopenia

Immune-mediatedIdioapthicDrug-induced

Collagen vascular diseaseLymphoproliferative diseaseSarcoidosis

Non-immune mediatedDICMicroangiopathic hemolytic anemia


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Features of Acute and Chronic ITP

Features AcuteITP Chronic ITP

Peak age Children (2-6 yrs) Adults (20-40 yrsFemale:male 1:1 3:1

Antecedent infection Common RareOnset of symptoms Abrupt Abrupt-indolentPlatelet count at presentation


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Incidence of adult ITP increases with age

Incidence (per 105/ year)

Age (yrs) Female Male Total

15-! "# 1# #$%0-5! #" 1#1 %#

$0& %#$ %#% !#0

Total #" "#0 "#$

Frederiksen and Schmidt, Blood 1999:94;909


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Initial Treatment of ITP

Platelet count Symptoms Treatment (per µl)

>50,000 None

20-50,000 Not bleeding NoneBleeding Glucocorticoids

IVIG


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Summary of case seriesAdults with ITP

'ariale o#/total (*)

+omplete response

,ith glcocorticoids .0/1%%. ("$*)

,ith splenectomy 51/5 ($$*)

eath rom hemorrhage ./1.$1 (%*)

2ealthy at last oser3ation 10"./1$0$ ($%*)

George, JN. N Engl J Med: 1994;331; 1207


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Long-term morbidity and mortalityin adults with ITP

1% patients 4ith se3ere ITP stdied or mean o 10#5 yrs

+6 and P6 patients (5*)

7 o increased mortality compared to control poplation

on-responders/maintenance therapy

7 Increased moridity de to ITP-related hospitali8ations

7 Increased mortality related e9ally to leeding and inection

Portielje JE et al. Blood 2001:97;2549


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Objectives - III

Approach to acquired bleeding disorders–Hemostasis in liver disease

–Surgical patients

–Warfarin toxicity


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2iver Disease and Hemostasis

1.

Decreased synthesis ofII, VII, IX, X, XI, and fibrinogen2. Dietary Vitamin K deficiency (Inadequate intake or malabsortion)

3. Dysfibrinogenemia

4. Enhanced fibrinolysis (Decreased alpha-2-antiplasmin)

5. DIC

6. Thrombocytoepnia due to hypersplenism

Management o" Hemostati#


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Management o" Hemostati#

De"e#ts in 2iver Disease

Treatment for prolonged PT/PTT Vitamin K 10 mg SQ x 3 days - usually ineffective

Fresh-frozen plasma infusion 25-30% of plasma volume (1200-1500 ml) immediate but temporary effect

Treatment for low fibrinogen Cryoprecipitate (1 unit/10kg body weight)

Treatment for DIC (Elevated D-dimer, low factor VIII, thrombocytopenia Replacement therapy

VitaminKdeficiencyduetowarfarinoverdose


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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 (1-2.5 mg 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)

Vi iKdfii d fi d


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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 warfarinVitamin K 10 mg slow IV infusionFFP or PCC (depending on urgency)Repeat vitamin K injections every 12 hrs as needed

Any life-threatening bleeding Omit warfarinVitamin K 10 mg slow IV infusionPCC ( or recombinant human factor VIIa)Repeat vitamin K injections every 12 hrs as needed

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

A , t P t ti $l di


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A%%roa#, to Post4o%erative $leeding

1. Is the bleeding local or due to a hemostatic failure?1. Local: Single site of bleeding usually rapid with minimal coagulation test

abnormalities2. Hemostatic failure: Multiple site or unusual pattern with abnormal coagulation tests

2. Evaluate for causes of peri-operative hemostatic failure1. Preexisting abnormality2. Special cases (e.g. Cardiopulmonmary bypass)

3. Diagnosis of hemostatic failure

1. Review pre-operative testing2. Obtain updated testing


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Objectives - IV

Approach to laboratory abnormalities–Diagnosis and management of thrombocytopenia

Laboratory Evaluation of Bleeding


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aboatoy auato o eed gOverview

CBC and smear Platelet count Thrombocytopenia

RBC and platelet morphology TTP, DIC, etc.

Coagulation Prothrombin time Extrinsic/common pathwaysPartial thromboplastin time Intrinsic/common pathwaysCoagulation factor assays Specific factor deficiencies50:50 mix Inhibitors (e.g., antibodies)Fibrinogen assay Decreased fibrinogenThrombin time Qualitative/quantitative

fibrinogen defects

FDPs or D-dimer Fibrinolysis (DIC)

Platelet function von Willebrand factor vWDBleeding time In vivo test (non-specific)

Platelet function analyzer (PFA)Qualitative platelet disordersand vWD

Platelet function tests Qualitative platelet disorders

C li d


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XIIaXIIa

Coagulation cascade

IIa

Intrinsic systemIntrinsic system s!r"a#e #onta#t)s!r"a#e #onta#t)

XIIXII

XIXI XIa

Tissue factor Tissue factor

IXIX IXa VIIa VIVI

VIIIVIII VIIIaVIIIa

Extrinsic systemExtrinsic system tiss!e damtiss!e dam

XX

VV VaVa

IIII

FibrinogenFibrinogen FibrinFibrin

(Thromb(ThrombIIa

Vitamin K dependant factorsVitamin K dependant factors

Xa

LaboratoryEvaluationofthe


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Laboratory Evaluation of theCoagulation PathwaysPartial thromboplastin time

(PTT)

Prothrombin time

(PT)

Intrinsic pathway Extrinsic pathway

Common pathwayThrombin timeThrombin

Surface activating agent (Ellagic acid, kaolin)PhospholipidCalcium

Thromboplastin Tissue factor PhospholipidCalcium

Fibrin clot


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Pre-analytic errors

Problems with blue-top tube

–Partial fill tubes

–Vacuum leak and citrateevaporation

Problems with phlebotomy

–Heparin contamination

–Wrong label

–Slow fill

–Underfill

–Vigorous shaking

Biological effects

–Hct ≥55 or ≤15

–Lipemia, hyperbilirubinemia,hemolysis

Laboratory errors–Delay in testing

–Prolonged incubation at 37°C

–Freeze/thaw deterioration


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Initial Evaluation of a Bleeding Patient - 1

Normal PTNormal PTT

Consider evaluating for: Mild factor deficiency Monoclonal gammopathy Abnormal fibrinolysis Platelet disorder (α2 anti-plasmin def) Vascular disorder Elevated FDPs

Ureasolubility

Normal

Abnormal

Factor XIII deficiency


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Normal PTAbnormal PTT

Test for factor deficiency: Isolated deficiency in intrinsic pathway (factors VIII, IX, XI) Multiple factor deficiencies (rare)

Repeatwith50:50mix

50:50 mix is normal

50:50 mix isabnormal

Test for inhibitor activity: Specific factors: VIII,IX, XI Non-specific (anti-phospholipid Ab


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Abnormal PTNormal PTT

Test for factor deficiency: Isolated deficiency of factor VII (rare) Multiple factor deficiencies (common) (Liver disease, vitamin K deficiency, warfarin, DIC)

Repeatwith50:50mix

50:50 mix is normal


Test for inhibitor activity: Specific: Factor VII (rare) Non-specific: Anti-phospholipid (rare)


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Abnormal PTAbnormal PTT

Test for factor deficiency: Isolated deficiency in common pathway: Factors V, X,Prothrombin, Fibrinogen

Multiple factor deficiencies (common) (Liver disease, vitamin K deficiency, warfarin, DIC)

Repeatwith50:50mix

50:50 mix is normal


Test for inhibitor activity: Specific : Factors V, X, Prothrombin,fibrinogen (rare) Non-specific: anti-phospholipid (com

Coagulation factor deficiencies


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Summary

Sex-linked recessive Factors VIII and IX deficiencies cause bleeding

ProlongedPTT;PT normal

Autosomal recessive(rare) Factors II, V, VII, X, XI, fibrinogen deficiencies cause bleeding

ProlongedPT and/orPTT

Factor XIII deficiency is associated with bleeding andimpaired wound healingPT/ PTT normal;clot solubility abnormal

Factor XII, prekallikrein, HMWK deficienciesdo not cause bleeding


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Thrombin Time

Bypasses factors II-XII

Measures rate of fibrinogen conversion to fibrin

Procedure:

–Add thrombin with patient plasma

–Measure time to clot

Variables:

–Source and quantity of thrombin


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Causes of prolonged Thrombin Time

Heparin Hypofibrinogenemia

Dysfibrinogenemia

Elevated FDPs or paraprotein Thrombin inhibitors (Hirudin)

Thrombin antibodies

C


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Classification of thrombocytopenia

Associated 4ith leeding Immne-mediated

thromocytopenia (ITP)

Most others

Associated 4ith thromosis Thromotic thromocytopenic

prpra

2eparin-associated

thromocytopenia

Trossea:s syndrome

I+


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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

–Bleeding time or platelet aggregation study


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Bl di ti dbl di


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Bleeding time and bleeding

5-10% of patients have a prolonged bleeding time Most of the prolonged bleeding times are due toaspirin or drug ingestion

Prolonged bleeding time does not predict excesssurgical blood loss

Not recommended for routine testing inpreoperative patients

Objecties V


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Objectives - V

Drugs and blood products used for bleeding

Treatment Approaches to


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the Bleeding Patient

Red blood cells Platelet transfusions

Fresh frozen plasma

Cryoprecipitate

Amicar

DDAVP

Recombinant Human factor VIIa

RBC transfusion therapy


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Indications

Improve oxygen carrying capacity of blood

–Bleeding

–Chronic anemia that is symptomatic

–Peri-operative management

Red blood cell transfusions


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Special preparation

CMV-negative CMV-negative patients Prevent CMVtransmission

Irradiated RBCs Immune deficient recipient Prevent GVHD

or direct donor

Leukopoor Previous non-hemolytic Prevents reaction transfusion reactionCMV negative patients Prevents transmission

Washed RBC PNH patients Prevents hemolysisIgA deficient recipient Prevents anaphylaxis

Red blood cell transfusionsAd


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Adverse reactions

Immunologic reactionsHemolysis RBC incompatibilityAnaphylaxis Usually unknown; rarely against IgAFebrile reaction Antibody to neutrophils

Urticaria Antibody to donor plasma proteinsNon-cardiogenic Donor antibody to leukocytes pulmonary edema

Red blood cell transfusionsAd i


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Adverse reactions

Non-immunologic reactions

Congestive heart failure Volume overload

Fever and shock Bacterial contamination

Hypocalcemia Massive transfusion

Transfusiontransmitteddisease


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Transfusion-transmitted disease

Infectious agent RiskHIV ~1/500,000Hepatitis C 1/600,000Hepatitis B 1/500,000

Hepatitis A


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Platelet transfusions

Source–Platelet concentrate (Random donor)–Pheresis platelets (Single donor)

Target level–Bone marrow suppressed patient (>10-20,000/µl)–Bleeding/surgical patient (>50,000/µl)

Platelettransfusions complications


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Platelet transfusions - complications Transfusion reactions

–Higher incidence than in RBC transfusions–Related to length of storage/leukocytes/RBC mismatch

–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)

Freshfrozenplasma


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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

Cryoprecipitate


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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

Hemostatic drugsA i i id(A i )


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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

Hemostatic drugsD i(DDAVP)


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Desmopressin (DDAVP) 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

RecombinanthumanfactorVIIa(rhVIIa;Novoseven


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Recombinant human factor VIIa (rhVIIa;Novoseven

Mechanism–Direct activation of common pathway

Use–Factor VIII inhibitors

–Bleeding with other clotting disorders

–Warfarin overdose with bleeding

–CNS bleeding with or without warfarin

–Dose

–90 µg/kg IV q 2 hr

–“Adjust as clinically indicated”

Cost (70 kg person) - $1 per µg–~$5,000/dose or $60,000/day

Approach to bleeding disordersSummary


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Summary

Identify and correct any specific defect of hemostasis–Laboratory testing is almost always needed to establish the cause ofbleeding

–Screening tests (PT,PTT, platelet count) will often allow placement intoone of the broad categories

–Specialized testing is usually necessary to establish a specific diagnosis Use non-transfusional drugs whenever possible

RBC transfusions for surgical procedures or largeblood loss

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