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EVALUATION OF THE BLEEDING PATIENT
HISTORY (inherited or acquired bleeding tendency?)
• Prior invasive procedures, dental extractions
• Family history
• Medications, alcohol
PHYSICAL EXAM
• 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
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 (do 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 (very rare)
• Fibrinolytic disorders
• Vascular disorders (Ehlers-Danlos, amyloid,
etc)
ACUTE
THROMBOCYTOPENIA
ACUTE THROMBOCYTOPENIA
Immune-mediated platelet consumption
• ITP: Platelets < 10K common, but major bleeding
unusual. Rarely develops during hospitalization
• Drug-induced purpura: Platelets < 10K common,
higher bleeding risk than ITP. Look for recent
changes in drug regimen, quinine exposure
• Heparin-induced thrombocytopenia: Up to 50%
develop thrombosis. Usually not bleeding May occur
after heparin d/c’d. Platelets rarely < 20 K.
• Post-transfusion purpura: Recent blood transfusion,
multiparous woman, sudden severe drop in platelet
count (usually <10K).
DRUGS MOST LIKELY TO CAUSE
THROMBOCYTOPENIA
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Hematology 2009;153
ACUTE THROMBOCYTOPENIA
Other causes
• TTP: Systemic signs and symptoms, high LDH,
schistocytes on blood smear. Platelets may be < 10K.
Rarely develops during hospitalization
• HUS, other microangiopathies: Systemic signs and
symptoms, renal failure, high LDH, schistocytes on
blood smear. Platelets rarely <10K
• DIC: Acute systemic illness, abnormal clotting times,
platelets rarely <10K
• Marrow failure: Other cell lines abnormal. Rarely
presents with isolated severe thrombocytopenia
ACUTE THROMBOCYTOPENIA
Plts <10K?
Bleeding the
predominant
symptom?
Onset during
hospitalization?
ITP
Drug-induced
thrombocytopenia
TTP
Post transfusion
purpura
Marrow failure (if
other counts low)
ITP
Drug-induced
thrombocytopenia
Post transfusion
purpura
DIC
DIC
Heparin-induced
thrombocytopenia
Post-transfusion
purpura
Drug-induced
thrombocytopenia
ACUTE SEVERE THROMBOCYTOPENIA
History
• Recent transfusions, previous pregnancies (posttransfusion purpura)
• Recent drug exposure
• Neuro symptoms (TTP)
• Fever, other systemic symptoms (DIC, TTP)
• Autoimmune disease, CLL (ITP)
ACUTE SEVERE THROMBOCYTOPENIA
Blood smear
•
•
•
•
Platelet clumping (pseudothrombocytopenia)
RBC fragments/schistocytes (TTP, DIC)
Abnormal WBC (marrow dyscrasia)
Large platelets suggest rapid production
ACUTE THROMBOCYTOPENIA
Further diagnostic testing
Drug-dependent antibody panel
Heparin antibody test
HPA-1a antibody testing (post-transfusion purpura)
D-dimer, INR, fibrin monomer (DIC)
LDH, urinalysis, retic count (TTP)
ADAMTS-13 activity (TTP)
Marrow biopsy often unnecessary (for isolated
thrombocytopenia)
• ITP is diagnosis of exclusion
• New onset thrombocytopenia in hospitalized
patient is unlikely to represent ITP or TTP
ACUTE THROMBOCYTOPENIA
Treatment
CONDITION
TREATMENT
ITP
Steroids, IVIG, splenectomy
Drug-induced purpura
Stop drug! IVIG/steroids?
Heparin-induced
thrombocytopenia
TTP
Stop all heparin; alternative
anticoagulant (eg argatroban)
Plasma exchange,
immunosuppression
No platelet transfusions;
washed RBC, IVIG
Post-transfusion purpura
Marrow failure
transfusions
www.ouhsc.edu/platelets
HEMOPHILIA
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 somewhat 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 common
autoimmune factor deficiency)
• Most patients elderly
• Often presents with severe soft tissue or mucosal
bleeding (different bleeding pattern than inherited
hemophilia)
• Laboratory: prolonged aPTT not corrected by
mixing with normal plasma, factor VIII activity
typically < 10%
– Bleeding risk not proportional to factor level
– Normal INR and platelet count
• Treatment: rVIIa, immunosuppression
DISSEMINATED
INTRAVASCULAR
COAGULATION
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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•
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D-dimer (most sensitive)
PT/INR
Fibrinogen
CBC/platelet count
Fibrin monomer (most specific)
TREATMENT OF DIC
• TREAT UNDERLYING DISEASE!
• Clotting factor & inhibitor replacement for
patients with significant bleeding:

Fresh frozen plasma (goal INR ≤ 1.6)

Cryoprecipitate (goal fibrinogen ≥ 100)

Platelets (goal platelet count 50-75K)
• Pharmacologic inhibitors (selected pts with
refractory bleeding)

Heparin (low dose)

Antifibrinolytics (Amicar, tranexamic acid)
THROMBOTIC
THROMBOCYTOPENIC
PURPURA (TTP)
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)
• Hemolytic anemia (high LDH, low
haptoglobin, schistocytes in blood smear)
• Organ dysfunction
– Neurologic symptoms
– Renal dysfunction (hematuria, proteinuria)
– Cardiac (arrhythmia)
• ADAMTS-13 activity low (usually <5%)
TTP - DDX
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Cancer (may be occult)
Pregnancy complications (HELLP, etc)
Hemolytic-uremic syndrome
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
• Do not transfuse platelets unless there is
lifethreatening bleeding
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)
• Side effects usually mild (HA, flushing,
hyponatremia with repeated dosing)
AMICAR
(epsilon aminocaproic acid)
• Antifibrinolytic: inhibits plasmin formation and
binding to fibrin
• Uses
– Treating DIC with hyperfibrinolysis, or bleeding after
thrombolytic drugs
– Prophylaxis in severe thrombocytopenia
– GI tract bleeding
– Menorrhagia
– Prophylaxis after dental extraction in hemophilia
• Short half-life, needs frequent dosing (4-24 grams/d)
• Oral or intravenous administration
• Alternative: tranexamic acid (longer half-life)
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
New anticoagulant drugs:
Dabigatran, rivaroxaban, apixaban
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If PT and aPTT normal overdose is unlikely
No specific antidote
Activated charcoal if drug taken recently
PCC ~ 50 U/kg (rivaroxaban and apixaban)
Consider dialysis (dabigatran only)
FFP likely to be ineffective, risk of volume
overload, TRALI
TRANSFUSION REACTIONS
IMMEDIATE HEMOLYTIC TRANSFUSION REACTION
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•
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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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•
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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,
•
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
•
•
•
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
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