Transcript Evaluation of the bleeding patient

Evaluation of the
bleeding patient
V. Kinsella M.D.
January,27 2006
MILD bleeding
1.
Platelets secretion disorders
2.
vW deficiency
3.
Platelets dense granules
deficiency
4. Unknown
Hemostasis and thrombosis

Dependent on 3
factors:
1.
Vascular
endothelium
Platelets
Coagulation
system
2.
3.
1.Clinical aspects of bleeding
1.Clinical aspects of bleeding
Evaluation of patients with bleeding is a
multi-step process:

Complete history

Detailed physical exam

Laboratory evaluation
history
1. Is there a personal or family history of
bleeding after surgical procedures, dental
procedures, childbirth, or trauma?
2. When the bleeding episode started?
3. Has the patient received medications that
can cause or make worse a bleeding
problem?
history
Many drugs can contribute to bleeding;
semisynthetic penicillins
cephalosporins
calcium channel blocker
dipyridamole
thiazides
alcohol
quinine, quinidine
chlorpromazine, sulfonamides
INH, rifampin
methyldopa
phenytoin, barbiturates,
warfarin,
heparin, thrombolytic agents
NSAIDs, ASA
allopurinol
TMP/SMX
physical exam
1. Assess volume status (correct shock if
present)
2. Look for hepatosplenomegaly
3. Do a rectal exam for evidence of GI bleeding
4. Examine oropharynx for evidence of
petechiae
Clinical aspects of bleeding
physical exam
5. Look for physical signs and symptoms of diseases
related to capillary fragility:
 Cushing’s syndrome, Marfan syndrome or exogenous
steroids
 "senile purpura”
 Petechiae secondary to coughing, sneezing, Valsalva
maneuver, blood pressure measurement
 vasculitis ("palpable purpura")
 Telangiectasias (Osler-Weber-Rendu syndrome)
(HHT)
petechiae
(typical of platelet disorders)
Do not blanch with
pressure
(angiomas)
Not palpable
(vasculitis)
vasculitis (palpable rash)
2. Hematologic disorders causing
bleeding
– Platelet disorders
– Coagulation factor disorders
Clinical differentiation
Platelets x Coagulation
Defects
Platelets Defects
•
Generally have immediate onset of
bleeding after trauma
•
Bleeding is predominantly in skin,
mucous membranes, nose, GI tract, and
urinary tract
•
Bleeding may be observed as petechiae
(<3 mm) or ecchymoses (>3 mm
Clinical aspects of bleeding
Coagulation Defects

"Deep" bleeding (in the joint spaces,
muscles, and retroperitoneal spaces) is
common. Observed on exam as
hematomas and hemarthroses.
Hematoma
(typical of
coagulation factor
disorders)
Hemarthrosis (acute)
Laboratory Evaluation of Bleeding
CBC and smear
Platelet count
RBC and platelet morphology
Thrombocytopenia
TTP, DIC, etc.
Coagulation
PT
extrinsic/common pathways
PTT
Intrinsic/common pathways
Coag. factor assays
Specific factor deficiencies
50:50 mix
Inhibitors (e.g., antibodies)
Fibrinogen assay
Decreased fibrinogen
Thrombin time
Qualitative/quantitative fibrinogen
defects
D-dimer
Fibrinolysis (DIC)
Laboratory Evaluation of Bleeding
Platelet function
von Willebrand factor
vWD
Bleeding time
In vivo test (non-specific)
Platelet function analyzer (PFA) Qualitative platelet
disorders
Laboratory Evaluation of the
Coagulation Pathways
Partial thromboplastin time
(PTT)
Prothrombin time
(PT)
Surface activating agent
(Ellagic acid, kaolin)
Phospholipid
Calcium
Thromboplastin
Tissue factor
Phospholipid
Calcium
Intrinsic pathway
Extrinsic pathway
Thrombin time Common pathway
Thrombin
Fibrin clot
Coagulation cascade
Intrinsic system (surface contact)
XII
Extrinsic system (tissue damage)
XIIa
Tissue factor
XIa
XI
IX
IXa
VIII
VIIa
VIIIa
X
Vitamin K dependant factors
VII
Xa
V
Va
II
Fibrinogen
IIa
(Thrombin)
Fibrin
Initial Evaluation of a Bleeding Patient
Normal PT
Normal PTT
Consider evaluating for:
Platelet disorder
Mild factor deficiency
Factor XIII
Monoclonal gammopathy
Abnormal fibrinolysis
a2 anti-plasmin deficiency
Vascular disorders
Dysfibrinogenemia
Initial Evaluation of a Bleeding Patient
Elevated PT
Normal PTT
Repeat
with
50:50
mix
50:50 mix is
abnormal
Test for inhibitor activity:
1.Specific: Factor VII (rare)
2.Non-specific: Anti-phospholipid
50:50 mix is
normal
Test for factor deficiency:
1.Multiple factor deficiencies (common)
(Liver disease, vitamin K deficiency, warfarin,
DIC)
2. Deficiency of factor VII (rare)
Initial Evaluation of a Bleeding Patient
Normal PT
Abnormal PTT
Repeat
with
50:50
mix
50:50 mix is
abnormal
Test for inhibitor activity:
Specific factors: VIII, IX, XI
Non-specific (anti-phospholipid)
50:50 mix is
normal
Test for factor deficiency:
Isolated deficiency in intrinsic pathway (factors VIII,
IX, XI)
Multiple factor deficiencies (rare)
Initial Evaluation of a Bleeding Patient
Abnormal PT
Abnormal PTT
Repeat
with
50:50
mix
50:50 mix is
abnormal
Test for inhibitor activity:
Specific : Factors V, X, prothrombin,
fibrinogen (rare)
Non-specific: anti-phospholipid
(common)
50:50 mix is
normal
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)
Bleeding time

5-10% of patients hospitalized patients have
a prolonged bleeding time

Most of the prolonged bleeding times are due to
aspirin or drug ingestion

Prolonged bleeding time does not predict excess
surgical blood loss

Not recommended for routine testing in
preoperative patients
Thrombin Time

Measures rate of fibrinogen conversion to
fibrin

Procedure:
– Add thrombin with patient plasma
– Measure time to clot

Variables:
– Source and quantity of thrombin
Causes of prolonged Thrombin Time






Heparin
Hypofibrinogenemia
Dysfibrinogenemia
Paraprotein
Thrombin inhibitors (Hirudin)
Thrombin antibodies
PLATELETS
Approach to the thrombocytopenic
patient

History
1. Is the patient bleeding?
2. Are there symptoms of a secondary
illness? (neoplasm, infection,
autoimmune disease)
3. Is there a history of medications,
alcohol use, or recent transfusion?
Approach to the thrombocytopenic
patient

History
4. Are there risk factors for viral infection?
5.Is there a family history of thrombocytopenia?
6. Do the sites of bleeding suggest a platelet
defect?
Approach to the thrombocytopenic
patient

Assess the number and function of platelets
– CBC with peripheral smear
– Bleeding time
– Platelet aggregation study
– PFA
Classification of platelet disorders

Quantitative disorders
– Abnormal distribution
– Dilution effect
– Decreased production
– Increased destruction
Classification of platelet disorders

Qualitative disorders
– Inherited disorders (rare)
– Acquired disorders





Immune
Medications
Chronic renal failure
Cardiopulmonary bypass
Liver disease
Inherited platelet disorders
Rare congenital abnormalities on synthesis
or release of secretory granules
Inherited platelet disorders

Gray platelets syndrome:
No alpha granules
Inherited platelet disorders
 May-Hegglin:
Thrombocytopenia
Large platelets
Neutrophils – Dohle bodies
Inherited platelet disorders
 Glazmann’s
thrombasthenia:
Congenital deficiency or abnormality of GP
IIb-IIIa
 Bernard-Solier
syndrome:
Congenital deficiency or abnormality of GP
Ib
Acquired platelet disorders

Decreased production:
Ineffective thrombopoiesis - MDS

Increased destruction:
Immune
Non-immune

Poor aggregation
Increased platelets destruction
1. Immune-mediated
Idiopathic - ITP
Drug-induced
Collagen vascular disease
Lymphoproliferative disease
Sarcoidosis
2.Non-immune mediated
DIC
Microangiopathic hemolytic anemia
ITP is a diagnosis of
exclusion !
Initial Treatment of ITP
Platelet count
Symptoms
>50,000
None
20-50,000
Not bleeding
None
Bleeding
Glucocorticoids
IVIG
Not bleeding
Glucocorticoids
Bleeding
Glucocorticoids
IVIG
Hospitalization
Rituximab
<20,000
Treatment
COAGULATION
FACTOR DEFECTS
Inherited Coagulation factor
bleeding disorders
– vonWillebrand’s disease
– Hemophilia (A and B)
vonWillebrand disease
– Most common hereditary
coagulation disorder
– Autossomal dominant
– Incidence 1:1000
Erik A. vonWillenbrand
M.D.
(1870-1949)
vonWillebrand factor
– Synthesis in endothelium and
megakaryocytes
– Forms large multimers
– Carrier of factor VIII
– Anchors platelets to subendothelium
– Bridge between platelets
vonWillebrand disease

Abnormal synthesis of von Willebrand
factor (vWF) causes decreased
platelet adhesion and decreased
serum levels of factor VIII
vonWillebrand disease
Classification
– Type 1
(“decreased”)
Partial quantitative deficiency
– Type 2
(“abnormal”)
Qualitative deficiency
– Type 3
(“absent”)
Total quantitative deficiency
vonWillebrand disease
Laboratory evaluation:
vonWillebrand type
Assay
1
2
3
vWF antigen

Normal

vWF activity



Normal
Absent
Multimer analysis
Normal
Treatment of von Willebrand
Disease

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
Treatment of von Willebrand
Disease

Cryoprecipitate
– Source of fibrinogen, factor VIII and VWF
– Only plasma fraction that consistently contains
VWF multimers
Factor VIII concentrate (Intermediate purity)
– Virally inactivated product
– Humate-P or Koate-HS
Hemophilia
Clinical manifestations (hemophilia A & B are
indistinguishable)
1. Prolonged bleeding after surgery or dental
extractions
2. Hemarthrosis (most common)
3. Soft tissue hematomas
4. Other sites of bleeding
Urinary tract
CNS, neck (may be life-threatening)
Dosing guidelines for hemophilia A

Mild bleeding:
Hemarthrosis, oropharyngeal or dental, epistaxis, hematuria
Target: 30% dosing q8-12h; 1-2 days (15U/kg)

Major bleeding
–
–
–
–
CNS trauma, hemorrhage, lumbar puncture
Surgery
Retroperitoneal hemorrhage
GI bleeding
Target: 80-100% q8-12h; 7-14 days (50U/kg)

Adjunctive therapy
– -aminocaproic acid (Amicar) or DDAVP (for mild disease only)
Treatment of hemophilia B

Agent
– High purity factor IX
– Recombinant human factor IX

Dose
– Initial dose: 100U/kg
– Subsequent: 50U/kg every 24 hours
Acquired bleeding disorders:
1. Vitamin K deficiency
2. Liver disease
3. Warfarin overdose
4. DIC
5. Inhibitors to CF
Vitamin K deficiency
Vitamin K deficiency

Source of vitamin K :
Green vegetables
Synthesized by intestinal flora

Required for synthesis
Factors II, VII, IX ,X
Protein C and S

Causes of deficiency:
Malnutrition
Billiary obstruction
Malabsorption
Antibiotic therapy
Vitamin K deficiency

Treatment:
Vitamin K replacement
Fresh frozen plasma
DIC
Disseminated Intravascular Coagulation
Activation of both coagulation and fibrinolysis
Triggered by

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
Disseminated Intravascular Coagulation
(DIC)
Mechanism
Systemic activation
of coagulation
Intravascular
deposition of fibrin
Activation of fibrinolysis
Thrombosis of small
and midsize vessels
tissue hypoxia and organ
failure
Depletion of platelets
and coagulation factors
Bleeding
Pathogenesis of DIC
Release of
thromboplastic
material into
circulation
Coagulation
Fibrinolysis
Fibrinogen
Plasmin
Thrombin
Fibrin
Monomers
Fibrin
Clot
(intravascular)
Consumption of
coagulation factors;
presence of FDPs
 aPTT
 PT
 TT
 Fibrinogen
Presence of plasmin
 D-dimer
Fibrin(ogen)
Degradation
Products
Plasmin
Intravascular clot
 Platelets
Schistocytes
Disseminated Intravascular
Coagulation
Treatment approaches

Treatment of underlying disorder

Anticoagulation with heparin

Platelet transfusion

Fresh frozen plasma

Coagulation inhibitor concentrate (ATIII)
Hemostasis in liver disease
Liver Disease and Hemostasis
1.
Decreased synthesis of II, VII, IX, X, XI,
and fibrinogen
2.
Dietary Vitamin K deficiency (Inadequate
intake or malabsortion)
3.
Dysfibrinogenemia
4.
Enhanced fibrinolysis (Decreased alpha2-antiplasmin)
5.
DIC
6.
Thrombocytopenia due to hypersplenism
Management of Hemostatic Defects in
Liver 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
Warfarin Toxicity
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 one or two dose;
Resume therapy when INR is therapeutic
Omit dose and give vitamin K ( 1-2 mg po)
Rapid reversal: vitamin K 2-4 mg po (repeat)
INR >9; no bleeding
Omit dose; vitamin K 10 mg po; repeat as necessary
Resume therapy at lower dose when INR therapeutic
Chest 2004:126; 213 S (supplement)
Warfarin overdose
Managing high INR values in bleeding patients
Clinical situation
Serious bleeding at
Any elevation INR
Guidelines
Omit warfarin
Vitamin K 10 mg slow IV infusion
Omit warfarin
Repeat vitamin K injections every 12 hrs
FFP, PCC or Factor VIIa (depending on urgency)
Any life-threatening
Vitamin K 10 mg slow IV infusion
PCC ( or recombinant human factor VIIa)
Repeat vitamin K injections every 12 hrs
Chest 2004:126; 213 S (supplement)
Approach to Post-operative
bleeding
1.
Is the bleeding local or due to a hemostatic failure?

Local: Single site of bleeding usually rapid with
minimal coagulation test abnormalities

Hemostatic failure: Multiple site or unusual pattern
with abnormal coagulation tests
Approach to Post-operative
bleeding
2.
3.
Evaluate for causes of peri-operative
hemostatic failure

Preexisting abnormality

Special cases (e.g. Cardiopulmonmary bypass)
Diagnosis of hemostatic failure

Review pre-operative testing

Obtain updated testing
Approach to bleeding disorders
Summary

Identify and correct any specific defect of
hemostasis
– Laboratory testing is always needed to establish the cause
of bleeding
– Screening tests (PT,PTT, platelet count) will often allow
placement into one 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
large blood loss
THANK YOU!
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
Drugs and blood products
used for bleeding
Treatment Approaches to
the Bleeding Patient







Red blood cells
Platelet transfusions
Fresh frozen plasma
Cryoprecipitate
Amicar
DDAVP
Recombinant Human factor VIIa
RBC transfusion therapy
Indications

Improve oxygen carrying capacity of blood
– Bleeding
– Chronic anemia that is symptomatic
– Peri-operative management
Red blood cell transfusions
Special preparation
CMV-negative
CMV-negative patients
Prevent CMV
transmission
Irradiated RBCs
Immune deficient recipient
or direct donor
Prevent GVHD
Leukopoor
Previous non-hemolytic
transfusion reaction
CMV negative patients
Prevents reaction
PNH patients
IgA deficient recipient
Prevents hemolysis
Prevents anaphylaxis
Washed RBC
Prevents transmission
Transfusion-transmitted disease
Infectious agent
Risk
HIV
Hepatitis C
Hepatitis B
Hepatitis A
HTLV I/II
CMV
Bacteria
Creutzfeld-Jakob disease
Others
1/500,000
1/600,000
1/500,000
<1/1,000,000
1/640,000
50% donors are sero-positive
1/250 in platelet transfusions
Unknown
Unknown
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)
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

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 drugs
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 drugs
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 drugs
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
Overview
1.
Clinical aspects of bleeding
1.
Hematologic disorders causing bleeding
Coagulation factor disorders
Platelet disorders
Approach to laboratory abnormalities
Diagnosis and management of
thrombocytopenia
2.
3.
Approach to acquired bleeding disorders
Hemostasis in liver disease
Surgical patients
Warfarin toxicity
4.
Drugs and blood products used for bleeding
Clinical Features of Bleeding Disorders
Platelet
disorders
Coagulation
factor disorders
Site of bleeding
Skin
Mucous membranes
(epistaxis, gum,
vaginal, GI tract)
Deep in soft tissues
(joints, muscles)
Petechiae
Yes
No
Ecchymoses (“bruises”)
Small, superficial
Large, deep
Hemarthrosis / muscle bleeding
Extremely rare
Common
Bleeding after cuts & scratches
Yes
No
Bleeding after surgery or trauma
Immediate,
usually mild
Delayed (1-2 days),
often severe
Pre-analytic errors

Problems with blue-top
tube

– Hct ≥55 or ≤15
– Lipemia,
hyperbilirubinemia,
hemolysis
– Partial fill tubes
– Vacuum leak and citrate
evaporation

Problems with phlebotomy
–
–
–
–
–
Heparin contamination
Wrong label
Slow fill
Underfill
Vigorous shaking
Biological effects

Laboratory errors
– Delay in testing
– Prolonged incubation at
37°C
– Freeze/thaw
deterioration
Coagulation factor deficiencies
Sex-linked recessive
 Factors VIII and IX deficiencies cause bleeding
Prolonged PTT; PT normal
Autosomal recessive (rare)
Factors II, V, VII, X, XI
Fibrinogen deficiencies cause bleeding
Prolonged PT and/or PTT
 Factor XIII deficiency is associated with bleeding and
impaired wound healing
PT/ PTT normal; clot solubility abnormal
 Factor XII, prekallikrein, HMWK deficiencies
do not cause bleeding
Classification of platelet disorders

Associated with bleeding
– Immune-mediated (Idiopathic) thrombocytopenic
purpura
– Most others
Classification of platelet disorders

Associated with thrombosis
– Thrombotic thrombocytopenic purpura
– Heparin-induced thrombocytopenia
– Trousseau’s syndrome
– DIC
Hemophilia A and B
Coagulation factor deficiency
Inheritance
Incidence
Severity
Complications
Hemophilia A
Hemophilia B
Factor VIII
Factor IX
X-linked
recessive
X-linked
recessive
1/10,000 males
1/60,000 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
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
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
– Hepatitis C
– HIV
Human parvovirus
Hepatitis A
Other
Features of Acute and Chronic ITP
Features
Acute
Chronic
Peak age
Children (2-6 yrs)
Adults (20-40 yrs)
Female:male
1:1
3:1
Antecedent infection
Common
Rare
Onset of symptoms
Abrupt
indolent
Platelet count at presentation
<20,000
<50,000
Duration
2-6 weeks
Long-term
Spontaneous remission
Common
Uncommon