Transcript Heme emergencies (bleeding, transfusion)

EVALUATION OF THE BLEEDING PATIENT
HISTORY (inherited or acquired bleeding tendency?)
• Prior invasive procedures, dental extractions
• Family history
• Medications, alcohol
PHYSICAL EXAM (platelet/VWD defect vs clotting
factor deficiency vs vessel injury or defect?)
• Mucosal/skin vs soft tissue bleeding?
• Bleeding from one or multiple sites?
• Mucosal hemangiomas, skin/joint laxity, etc
Platelet defects and vessel disorders: immediate bleeding from
skin and mucosal surfaces, petechiae
Coagulation factor deficiency: delayed bleeding into soft
tissues
Hereditary hemorrhagic telangiectasia
Researchgate.net
Ehlers-Danlos Syndrome
Lifewitheds.com
Morphopedics.wikdot.com
Amyloidosis
Bleeding confined to an operative site
is usually due to a severed vessel
Initial laboratory evaluation
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Platelet count
PT/INR
aPTT
Fibrinogen
Platelet function screen
Prothrombin time/INR
Long PT/INR
– Liver disease
– Vitamin K deficiency
– Warfarin or warfarin analogs (rat poison)
– DIC
– Inherited conditions rare
– Won’t detect hemophilia, factor VIII inhibitor,
heparin at therapeutic concentrations
Magnitude of test abnormality usually
proportional to clinical severity
aPTT
Long aPTT
– Heparin (therapeutic or contaminant)
– Hemophilia A or B
– von Willebrand disease (low VIII – but PTT may be
normal)
– Factor XI deficiency
– Factor VIII inhibitor
– Contact factor deficiency (does not cause bleeding)
– Lupus anticoagulant (does not cause bleeding)
– Less sensitive than PT/INR to liver disease, DIC,
warfarin
Magnitude of test abnormality not necessarily
proportional to clinical severity
Platelet function screen
• Replaces the bleeding time
• Advantages
– Ex vivo test (no skin incision)
– Better standardized
– Better sensitivity and specificity
PFA-100
Platelet function screen
Sensitive to:
 Defective platelet adhesion in von Willebrand
disease
 Platelet dysfunction due to many drugs
 Inherited platelet disorders
 Not useful in patients with moderate or severe
Thrombocytopenia
 Rarely the only abnormal test in an acute bleeding
disorder
Conditions that may cause bleeding with
normal or near-normal screening tests
• Mild hemophilia (factor level 20-30% of
normal)
• Von Willebrand disease
• Factor XIII deficiency (rare)
• Fibrinolytic disorders
• Vascular disorders (Ehlers-Danlos, amyloid,
etc)
IMMUNE THROMBOCYTOPENIA
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ITP
Drug-induced purpura
Heparin-induced thrombocytopenia
Post-transfusion purpura
ITP
• Autoimmune platelet destruction
• Mild to severe thrombocytopenia
– Other blood counts, coag tests typically normal
• A diagnosis of exclusion
• Bleeding risk low to moderate in most cases
– Hospitalization not always needed
• Rarely begins in hospital
• Few symptoms other than bruising &
petechiae
ITP: initial treatment
• Corticosteroids: prednisone 1 mg/kg or
pulse high dose dexamethasone
• IVIG (high dose)
• Platelet transfusion sometimes
effective
• Splenectomy (refractory/severe
disease)
Drug-induced thrombocytopenia
• Thrombocytopenia may be severe (<5K)
• Often begins in hospital, precipitous drop in
platelet count
• Bleeding risk moderate to high
• Typically occurs within days of starting a
drug
DRUGS MOST LIKELY TO CAUSE
THROMBOCYTOPENIA
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Hematology 2009;153
Drug-induced thrombocytopenia
management
• Stop any potentially offending drug
– Resolution may take days to weeks
• Steroids less effective than in ITP
• IVIG in selected cases
Heparin-induced thrombocytopenia
• Mild to moderate thrombocytopenia with onset
4-7 days after initial heparin exposure (UFH >
LMWH)
• Recent surgery, infection, inflammation
increase risk
 Bleeding risk low, thrombosis risk high
• Heparin Ab test very sensitive – HIT can be
ruled out if negative
• Serotonin release assay predicts thrombotic
risk
• Rx: Stop heparin (any form), consider
alternative anticoagulant (not warfarin)
Post-transfusion purpura
• Severe, precipitous drop in platelet count, usually a
few days after blood product exposure (FFP, RBC
most common)
• Most patients are multigravid women
– Prior exposure to platelet antigen during
pregnancy, recall reaction after transfusion
• Most affected patients lack a common platelet
alloantigen called HPA-1 (~ 2% of population)
• Antibodies directed against HPA-1 on transfused
“passenger” platelets, patient’s own platelets are
destroyed as “innocent bystanders”
Post-transfusion purpura
• If suspected notify blood bank to arrange
for appropriate testing and transfusion
therapy
• Test for HPA-1 antibodies in patient serum
• Do NOT give platelet transfusion
• If RBC transfusion needed give washed
RBC
• High dose IVIG
• Steroids generally not helpful
www.ouhsc.edu/platelets
DISSEMINATED INTRAVASCULAR COAGULATION
• Rapid formation & lysis of intravascular fibrin
• Consumption of clotting factors, platelets,
inhibitors
• Life-threatening underlying disease
• Bleeding due to uncontrolled fibrinolysis,
thrombocytopenia, clotting factor consumption
and tissue injury from underlying disease
• Tissue injury/necrosis due to microvascular
occlusion, hypotension, cytokine-mediated
endothelial damage
• Most deaths due to underlying disease
PUPURA FULMINANS
Pneumococcal sepsis in splenectomized patient
NEJM 2001;344:1593
DIAGNOSIS OF DIC
1. Underlying disease capable of causing
DIC?
2. Evidence of accelerated clotting factor and
platelet consumption, and increased
fibrinolysis?
If both present DIC is likely
SCREENING FOR DIC
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D-dimer (most sensitive)
PT/INR (PTT less helpful)
Fibrinogen
CBC/platelet count
Fibrin monomer (most specific)
TREATMENT OF DIC
• TREAT UNDERLYING DISEASE!
• Clotting factor & inhibitor replacement if there is
significant bleeding:
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Fresh frozen plasma (goal INR ≤ 1.6)
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Cryoprecipitate (goal fibrinogen ≥ 100)
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Platelets (goal platelet count 50-75K)
• Pharmacologic inhibitors (selected pts with
refractory bleeding)
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Heparin (low dose)
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Antifibrinolytics (Amicar, tranexamic acid)
TTP
• Microangiopathic hemolytic anemia
• Thrombocytopenia
• Organ dysfunction (CNS, renal, other) due
to small vessel occlusion
• Untreated mortality rate >90%
• With treatment mortality < 20%
• 1-2 cases/yr @ UWHC
TTP
• Caused by autoimmune destruction of
ADAMTS-13 protease that modulates von
Willebrand factor multimer size
• Very large multimers clump platelets
• Microthrombi damage RBC and block
vessels
TTP
• Thrombocytopenia (may be severe)
• Intravascular hemolysis (high LDH, low
haptoglobin, schistocytes in blood smear)
• INR, PTT, fibrinogen usually normal
• Organ dysfunction
– Neurologic symptoms
– Renal dysfunction (hematuria, proteinuria)
– Cardiac (arrhythmia)
• ADAMTS-13 activity low (usually <5%)
TTP - DDX
• Occult cancer
• Pregnancy complications (HELLP, etc)
• Hemolytic-uremic syndrome (kidney main target
organ)
– Shiga toxin, GI prodrome
– “Atypical” HUS: genetic component, complementmediated, no GI prodrome
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Vasculitis (SLE, scleroderma)
HIV infection
DIC
Drugs (calcineurin inhibitors, mitomycin C,
interferon, clopidogrel, ticlopidine)
TTP
• Urgent plasma exchange
– Plasma infusion if PE not immediately available
• Immunosuppression
– Corticosteroids
– Rituximab for patients with resistant, refractory
or relapsed disease (or upfront?)
• Do not transfuse platelets unless there is
lifethreatening bleeding
HEMOPHILIA
• Inherited deficiency of factor VIII (hemophilia A) or
factor IX (hemophilia B)
• Sex-linked inheritance; almost all patients male
• Most bleeding into joints, muscles; mucosal and
CNS bleeding uncommon
• Severity inversely proportional to factor level:
< 1%: severe, bleeding after minimal injury
1-5%: moderate, bleeding after mild injury
> 5%: mild, bleeding after significant trauma or surgery
(may not be diagnosed until adulthood)
HEMOPHILIA
Treatment of bleeding episodes
• Unexplained pain in a hemophilia should be
considered due to bleeding unless proven
otherwise
• External signs of bleeding may be absent
• Treatment: factor replacement, pain control
– Most adult patients self-administer factor
• Test for inhibitor (antibody vs factor) if
unexpectedly low response to factor
replacement
– Most inhibitors occur in children
TREATMENT OF BLEEDS IN HEMOPHILIA
• Administer appropriate clotting factor concentrate
– 20-40 U/kg for minor bleeds, repeat daily for 2-3 days
– 40-50 U/kg for major bleeds, repeat daily for 4-7 days
– 50 U/kg q 12 hours for life-threatening bleeds
• 1 U/kg should increase plasma level of factor by
about 2%
– Initial dose higher with factor IX concentrate (greater
volume of distribution, but longer half-life)
TREATMENT OF HEMOPHILIACS WITH
INHIBITORS
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Call a hematologist
Recombinant factor VIIa
High dose factor VIII (if low titer inhibitor)
Induce tolerance with daily factor infusion ±
immunosuppression
ACQUIRED FACTOR VIII DEFICIENCY
• Autoantibody to factor VIII
• Most patients elderly
• Extensive soft tissue or mucosal bleeding
(different bleeding pattern than inherited
hemophilia)
• Laboratory: prolonged aPTT with normal INR,
platelets
• aPTT not corrected by mixing with normal plasma
• Factor VIII activity typically < 10%
– Bleeding risk not proportional to factor level
• Treatment: rVIIa, immunosuppression
BLOOD PRODUCTS AND
DRUGS IN THE TREATMENT OF
BLEEDING DISORDERS
BLOOD COMPONENT TRANSFUSION TO
TREAT OR PREVENT BLEEDING
• Platelets:
– Active bleeding: if platelet count < 50K
– Prophylaxis: when platelets <10-20K
– Patient having surgery: if platelets < 50-100K
• FFP (active bleeding):
– When INR > 1.6
• Cryoprecipitate (active bleeding):
– Goal fibrinogen level 100
DDAVP
(Desmopressin)
• Vasopressin analogue, stimulates VWF/factor VIII
release from endothelium
• Intravenous or intranasal administration
• Increases plasma VWF/factor VIII levels for 18-24h,
enhances platelet adhesion
• Effective in
– Type I VWD (usually not in type 2, never in type 3)
– Mild hemophilia A
– Platelet dysfunction (variably effective)
• HA, flushing, hyponatremia with repeated dosing
Antifibrinolytic drugs
• Amicar (IV or PO, requires frequent dosing)
• Tranexamic acid (longer half-life)
• Uses
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DIC with hyperfibrinolysis
Bleeding after thrombolytic drug administration
Prophylaxis in severe thrombocytopenia
GI tract bleeding
Menorrhagia
Prophylaxis after dental extraction in hemophilia
Decrease bleeding after major trauma
Recombinant Factor VIIa (rFVIIa)
• Augments tissue factor-induced coagulation
• FDA approved for treatment of Factor VIII
inhibitor w/bleeding
• Off-label use is common, efficacy unclear:
– Other coagulation inhibitors (including drugs)
w/bleeding
– Emergency reversal of coagulopathy (eg,
warfarin) in patients with lifethreatening
bleeding
• Potent procoagulant → risk of thrombosis
• Very expensive!
Prothrombin complex concentrate (PCC)
• Mixture of vitamin K dependent
procoagulant factors: II, IX, X ,VII
• Used to rapidly correct warfarin effect (or
severe vitamin K deficiency) in acutely
bleeding patient or prior to urgent surgical
procedure
• Advantages vs FFP:
– Less volume
– No risk of TRALI, low risk of allergic rxn
– Less risk of virus transmission
VITAMIN K
Indications:
1. Correction of vitamin K deficiency
2. Treatment of warfarin or superwarfarin
overdose
3. Prophylaxis in patients at risk for vitamin K
deficiency
Oral or IV administration (unreliable
absorption with subcutaneous injection)
ANTICOAGULANT-RELATED
BLEEDING
Bleeding events/100 patient-yr
BLEEDING RISK VS INR
200
150
100
50
0
<2
2.0-2.9
3-4.4
INR
4.5-6.9
>7
Lancet 1996; 348:423
Treatment of warfarin-induced coagulopathy in the
non-bleeding patient
Dentali et al, J Thrombos Haemost 2006;4:1853
Treatment of warfarin-induced coagulopathy in the
bleeding patient
Dentali et al, J Thrombos Haemost 2006;4:1853
Reversal of heparin and LMWH
• Heparin:
– FFP won’t help
– Protamine sulfate: 1 mg/100U heparin
– Neutralizes 80% of heparin
• LMWH
– FFP won’t help
– Protamine neutralizes 40% of LMWH
– Andexanet (FDA approval pending) reverses
anti-Xa effect
Direct oral anticoagulant drugs:
Dabigatran, rivaroxaban, apixaban, edoxaban
• Specific antidote (idarucizumab) now
available for dabigatran
• Andexanet (antidote for Xa inhibitors)
awaiting FDA approval
• Activated charcoal if drug taken recently
• PCC ~ 50 U/kg (rivaroxaban, apixaban,
edoxaban)
• FFP likely to be ineffective, risk of volume
overload, TRALI
TRANSFUSION REACTIONS
IMMEDIATE HEMOLYTIC TRANSFUSION REACTION
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Intravascular lysis of transfused rbcs by complement, IgM
Causes:
 Transfusion of ABO-incompatible blood
 Transfusion of ABO-incompatible plasma
 Non-ABO antibodies
Clinical manifestations:
 Fever (but most febrile reactions not hemolytic)
 Back pain
 Dark or red urine (hemoglobinuria)
 Bronchospasm
 Shock
 DIC
 Organ failure (esp kidneys)
 Death
IMMEDIATE HEMOLYTIC TRANSFUSION REACTION
Evaluation of suspected cases
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Check blood product/paperwork to ensure correct
product given
Notify blood bank/transfusion service
Obtain blood and urine samples:
 Plasma and urine hemoglobin
 Direct Coombs test
 Repeat crossmatch/antibody screen
 Repeat ABO/Rh typing
IMMEDIATE HEMOLYTIC TRANSFUSION REACTION
Management
• Stop transfusion immediately
• IV crystalloid or colloid
• Maintain BP, heart rate
• Maintain airway
• Diuresis
 fluid,
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loop diuretic (mannitol may cause
volume overload)
Monitor renal and coagulation status
DELAYED HEMOLYTIC TRANSFUSION REACTION
• IgG-mediated lysis of transfused red cells
(usually extravascular, non-ABO)
• Usually begins 5-10 days after transfusion
• Jaundice, falling Hct, positive direct Coombs
test, fever
• Not generally life-threatening
FEBRILE, NONHEMOLYTIC TRANSFUSION
REACTION
• Cause: cytokines released by leukocytes during
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storage; antibodies to HLA antigens on transfused
or donor PMNS
Incidence: ≤0.5% of units transfused
More common in multiply transfused recipients
Fever, chills, respiratory distress in severe
reactions
Reduced incidence/severity with leukocyte-poor
product
TRANSFUSION-RELATED ACUTE LUNG INJURY
(TRALI)
• Hypoxemia with bilateral pulmonary infiltrates
• No increase in central venous or pulmonary artery
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pressures
Usually begins acutely within 6 hours of
transfusion
Clinical: acute respiratory distress, fever, chills
Pathophysiology:
1. Underlying lung injury (eg, sepsis, pneumonia) causes
PMNs to adhere to pulmonary capillaries
2. Mediators in transfused blood product (neutrophil
antibodies, cytokines) activate PMNs with resultant
capillary injury
TRANSFUSION-RELATED ACUTE LUNG INJURY
TRANSFUSION-RELATED ACUTE LUNG INJURY
(TRALI)
• Risk: FFP > platelets > RBC
• Treatment: stop transfusion (if still in progress);
oxygen; ventilatory support if necessary; pulse
corticosteroids
OTHER ACUTE NON-INFECTIOUS
COMPLICATIONS OF TRANSFUSION
• Allergic reactions
• Anaphylaxis (IgA-deficient recipient)
• Lung damage from microaggregates (massive
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transfusion)
Transfusion-associated circulatory overload
(“TACO”)
Bacterial infection (mainly with platelet transfusion)
Hypothermia (rapid infusion of refrigerated blood)
Citrate toxicity/hypocalcemia (massive transfusion
or apheresis)
Graft-vs-host disease
Air embolism
Transfusion-related deaths 2005-2010
TRALI
TACO
HTR
(non-ABO)
HTR
(ABO)
Bacterial
Infection
Anaphylaxis
2005
29
1
16
6
8
0
2006
35
8
9
3
7
1
2007
34
5
2
3
6
2
2008
16
3
7
10
7
3
2009
13
12
8
4
6
1
2010
18
8
2
2
2
4
• TRALI – Transfusion-associated lung injury
• TACO – Transfusion-associated circulatory overload
• HTR – Hemolytic transfusion reaction