BledingDisorder-MKM.ppt
Transcript of 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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Initial Evaluation of a Bleeding Patient - 2
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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Initial Evaluation of a Bleeding Patient - 3
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
50:50 mix isabnormal
Test for inhibitor activity: Specific: Factor VII (rare) Non-specific: Anti-phospholipid (rare)
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Initial Evaluation of a Bleeding Patient - 4
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
50:50 mix isabnormal
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