Ecchymosis, Epistaxis, and Bleeding
Brandon M. Hardesty, MD
The Indiana Hemophilia & Thrombosis Center
Indianapolis, IN
1-877-CLOTTER
DISCLOSURES
CATEGORY
CONFLICT
Employment
No conflict of interest to disclose
Research support
No conflict of interest to disclose
Scientific advisory board No conflict of interest to disclose
Consultancy
NovoNordisk, Biogen
Speakers bureau
No conflict of interest to disclose
Major stockholder
No conflict of interest to disclose
Patents
No conflict of interest to disclose
Honoraria
NovoNordisk, Biogen
Travel support
No conflict of interest to disclose
Other
No conflict of interest to disclose
Objectives
▪ Discuss one approach to evaluation of patients with bleeding symptoms
• Quantify to differentiate normal from abnormal
▪ Review interpretation of screening laboratory tests to guide further
evaluation
▪ Urgent evaluation and management of the bleeding patient
Common Consultations
▪ Easy bruising
• Present in 24% of “healthy” women and 7% of “healthy” men
▪ Subcutaneous hematoma without obvious cause
• 7%
▪ Menorrhagia
• Reported by 47% of women; only 23% required treatment
▪ Surgical bleeding
• <1 to 3%
▪ Peripartum/postpartum bleeding
• 6-7%
1. Mauer AC et al. J Thromb Haemost 2011;9(1):100-8.
Overview of Evaluation
▪ Personal History
• Search for hemostatic challenge (i.e. surgery, dental extraction, trauma,
childbirth, etc.)
❖ Timing of bleeding relative to insult may be significant
❖ What did it take to stop bleeding
•
•
•
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Spontaneous hematomas
Menorrhagia
History of blood transfusion or iron deficiency
Poor wound healing
Evaluation Continued
▪
Medications and herbs
• Potential antiplatelet properties
❖ Ginkgo, garlic, bilberry, ginger, dong quai, feverfew, ginseng, turmeric,
•
▪
meadowsweet, willow
Coumarin containing herbs
❖ Motherwort, chamomile, horse chestnut, red clover, fenugreek
Family History
• Miscarriage, peripartum hemorrhage, transfusion, iron deficiency anemia,
•
aspirin intolerance
Hemophilia, von Willebrand disease, platelet problems, ultra flexible joints
Bleeding Scores
▪ ISTH Bleeding Assessment Tool (BAT)1 or MCMDM-1vWD2 (Vicenza) score
• http://c.ymcdn.com/sites/www.isth.org/resource/resmgr/ssc/isthssc_bleeding_assessment.pdf
▪ Both scores assess similar dimensions with similar grading
• Grade from 0-4 with higher scores indicating greater severity
▪ Established that BAT score >3 in men or >5 in women is abnormal3
▪ MCMDM-1vWD score >10 was associated with need for DDAVP or factor
replacement4
1. Rodeghiero F et al. J Thromb Haemost 2010;8(9):2063-5.
2. Tosetto A et al. J Thromb Haemost 2006;4(4):766-73.
3. Elbatarny M et al. Haemophilia 2014;10.1111/hae.12503. [Epub ahead of print].
4. Federici AB et al. Blood 2014;123(26):4037-44.
A Case of Abnormal Bruising – Case #1
▪ 72-year-old woman with COPD notes worsening bruising over the last 6 months.
Bruises are predominantly located on forearms and measure 1-3 cm. No
hematomas and no injury. Bruises slow to resolve. Rare bruises located on shin;
none involving torso. No epistaxis, h/o menorrhagia; 2 full term SVDs without
complications. Had excessive bleeding with dental extraction in 2009 without
requiring further intervention.
▪ H/o cholecystectomy, breast biopsy, and hysterectomy (for abnormal PAP). No h/o
transfusion. H/o iron deficiency anemia after second child, resolved with PO iron
for 6 months.
▪ Multivitamin daily, inhaled fluticasone/salmeterol, metoprolol. Taking ASA for 5
years; stopped 3 months ago without change in bruising. Quit smoking in 2002, no
EtOH or IVDU. No FHx bleeding disorder.
Examination
▪ Elderly Caucasian woman in NAD
▪ Afebrile, VSS
▪ Skin: 6 separate ecchymoses on extensor surface of bilateral forearms
with irregular border. Varying stages of healing. Skin quite thin. No
scars. Two 2 cm ecchymoses on shins. No lesions on torso, CCX scar
faint and well healed.
▪ HEENT: Normal, no macroglossia, no telangiectasias
▪ Remainder of examination normal
Laboratory Assessment
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▪
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CBC normal with normal appearance of platelets
PT/aPTT/TT/Fib WNL
PFA-100 WNL
Ristocetin cofactor 70%; vWF:Ag 86%; FVIII 93%
Assessment
▪ History / Physical examination / Laboratory assessment
• Multiple non-palpable ecchymoses on extensor surface of arm
• Has h/o iron deficiency anemia after childbirth and mild bleeding after dental extraction, but
no other convincing history despite multiple challenges
• Tolerated ASA for years without difficulty
• Initial laboratory assessment normal
▪ Senile Purpura
• Results from loss of subcutaneous connective tissue in elderly persons
• Exacerbated/accelerated by sun exposure and use of corticosteroids (including inhaled)
• Typical findings include ecchymoses limited to extensor surfaces and notably thin skin
Primary vs. Secondary Hemostatic Defect
▪ Primary
• Characterized most prominently by mucocutaneous bleeding and
intraoperative or immediate postoperative hemorrhage
• Generally a manifestation of defects in vWF or platelets
▪ Secondary
• Characterized most prominently by bleeding into tissues
• Bleeding after surgical provocation tends to be delayed by several
days
• Generally a manifestation of defects in humoral clotting factors,
vessel/connective tissue, or hyperfibrinolysis
Goals of History Taking & Physical Examination
▪ Determine the pretest probability of an actual bleeding disorder
• Definite bleeding disorder
• Possible bleeding disorder
• Bleeding disorder unlikely
▪ If present, is it a disorder of primary or secondary hemostasis?
▪ Is this most likely to be hereditary or acquired?
LABORATORY EVALUATION OF HEMOSTASIS
Screening Tests
▪ Primary hemostasis
• CBC with manual review of smear
❖ Assess for platelet size, granules, clumping, neutrophil inclusions, other
abnormalities
• PFA-100
▪ Secondary hemostasis
• PT, aPTT, fibrinogen, and TT
▪ None of these screening tests adequately predict bleeding risk
• Risk of bleeding is best predicted by patient history and/or identification of the
underlying defect
Bleeding Disorder Unlikely
▪ Reassurance is all that is needed
▪ If high-risk procedure in critical location (CNS, complicated
cardiac, or Bx liver/kidney) is planned it may be beneficial to
perform screening tests
Possible Bleeding Disorder
▪ Screening laboratory testing performed
▪ If completely normal, bleeding disorder unlikely
▪ If high-risk procedure is planned a more detailed evaluation
of the suspected hemostatic defect may be beneficial
Definite Bleeding Disorder
▪ Routine studies for screening
▪ More specific studies based on screening results and
suspicion for primary versus secondary defect of hemostasis
to elucidate actual disorder
▪ If screening studies are negative then referral to a specialist
in hemostasis recommended
• Cost of further testing has the potential to increase exponentially
with very low yield without an expert guiding evaluation
Historical background
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William Shakespeare 1564-1616
Birthplace: Stratford-upon-Avon
Education: Stratford Grammar School
Celebrated actor and playwright
Published references to experimental coagulation
Incubation of procoagulants and thromboplastins……
Second witch:
Fillet of a fenny snake,
In the cauldron boil and bake;
Eye of newt and toe of frog,
Wool of bat and tongue of dog,
Adder's fork and blind-worm's sting,
Lizard's leg and owlet's wing,
For a charm of powerful trouble,
Like a hell-broth boil and bubble.
Macbeth Act IV Scene 1
PFA-100
Coagulation pathways
Case Presentation – Case #2
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42 year old woman with a history of nosebleeds once or twice a week
Oozing with dental cleaning
Menorrhagia – changing pads every 30 mins on heaviest days
Prolonged bleeding after childbirth
On Yaz for control of her menstrual cycle
Laboratory results – Case 2
▪ FACTOR VIII ACTIVITY 117 % (50-149)
▪ RISTOCETIN COFACTOR 50 % (50-158)
▪ VON WILLEBRAND FACTOR ANTIGEN
73 % (50-160)
▪ VON WILLEBRAND MULTIMERS – all multimers present
Plasma VWF Multimers
Case Presentation – Case #3
▪ 52 year old WM had two teeth extracted (December), and had
bleeding for 3 weeks post-procedure
▪ Taking testosterone replacement q2wks
▪ Decided to “get healthy” (January)
• ASA 81 mg daily
• Joined gym
Case Presentation
▪ Developed symptoms of “muscle strain” in R. leg after jogging on
treadmill
▪ Progressed to severe pain and swelling
▪ Diagnosed with compartment syndrome
▪ Underwent fasciotomy
▪ Transferred to St. Vincent Hospital with uncontrolled dripping of blood
from incisions
Physical Examination
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Pale, diaphoretic
No gingival lesions
No lymphadenopathy
No hepatosplenomegaly
No hemarthroses
Upper extremity bruising
RLE swollen, compression dressing, blood dripping from incisions
Laboratory results
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▪
▪
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PTT 69 secs
INR 1.02
Hgb 13.1 g/dL, platelet count 412 K/uL
Total bilirubin 1.5 mg/dL
Incubated mix (aPTT)
▪ The patient’s plasma is mixed with an equal volume of pooled normal
plasma
▪ The aPTT is repeated immediately and after an incubation period (e.g. 60
minutes at 37°C)
▪ Pooled normal plasma is assayed concurrently
▪ Only approx 40% of an individual factor is necessary to yield a normal aPTT
▪ A severe clotting factor deficiency should correct completely
Patient Sample #3
Test
Result
N/Abn
APTT
N = <42.1 seconds
APTT
84.2
Abnormal
APTT 1:1
Mix
68.6
Uncorrected
PT
N = <14.1 seconds
PT
13.2
Normal
Severe Factor VIII Deficiency
with inhibitor
Acquired hemophilia - characteristics
 Incidence 0.2-1.0 case per million per year – is
incidence increasing???
 80-90% present with major hemorrhages
 10-22% mortality attributed to inhibitor
 Biphasic age distribution
• Small peak in young postpartum women
• Major peak in 60-80 years of age
Case Presentation – Case #4
▪ A 31 year old wm presented with hematuria and bruising for 2 days.
▪ No prior history of bleeding problems.
▪ Past history of testicular seminoma treated about 6 months earlier
with orchiectomy and abdominal radiotherapy.
▪ 1 month before presentation he had a normal follow up abdominal CT
scan.
Medications
▪ Aspirin, 650 mg taken 24hrs before presentation, for pain
Family history
▪ Lung cancer in father and paternal grandfather
Social history
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▪
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Worked in a lumberyard for past 16 yrs
Married, 2 children
No alcohol, smoking, illicit drug use
No travel
Review of systems
▪
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No fever, chills or weight loss
No headaches
No gum bleeding or hematochezia
No joint pain or swelling
Physical examination – Case #4
▪ 31 year old wm, sitting comfortably, in good general health, slightly
pale
▪ Bruising over R. eyelid, L. hand, both knees, L. flank, R. neck
▪ No adenopathy or hepatosplenomegaly
▪ No joint tenderness or swelling
▪ Stool hemoccult negative
Labs from OSH
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Na 134, K 3.2, Cl 96, HCO3 27, Bun 9, Cr 1.0
Hb 11.9, WBC 8.4, Plts 203, MCV 87
76 segs, 9 lymphs, 10 monos
Alb 4.4, Tbili 0.7, alk phos 48, AST 21, ALT 34
PT >200 secs, INR unable to calculate
PTT 137.8 secs
Hospital course
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He was given 1 unit of FFP, and 5 mg vitamin K IM!!!, then transferred
Repeat labs
Hb 8.0
PT 65.2, INR 7.86
PTT 63.3
TCT <9 (9-13)
Fibrinogen 607 mg/dL
Labs
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D-dimer 745 ng/mL (0-499)
LDH 145
AFP 1.8
Β HCG 0.7
Conclusions
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Markedly prolonged PT and aPTT
No heparin contamination of sample
Suspect inhibitor or Coagulation factor deficiency
• II
• V
• X
Coagulation studies
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Mixing studies consistent with factor deficiency
Factor VII <2% (50-175)
Factor V 114 % (65-162)
Factor X 5 % (68-145)
He was transfused with 2 units of packed RBCs and 2 units of FFP
Coagulation screen
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CBC with review of peripheral smear
Prothrombin time (PT)
Activated partial thromboplastin time (aPTT)
Fibrinogen
Thrombin clotting time (TCT)
D-dimer
Platelet function screening test (PFA- 100)
Additional laboratory tests
▪ Prothrombin time >200 secs
▪ aPTT 137.8 secs
Coagulation screen results
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After 1 unit of FFP and 5 mg vitamin K (IM) given
PT 65.2 secs; INR 7.86
PTT 63.3 secs
TCT < 9 secs (9 -13)
Fibrinogen 607mg/dL
D-dimer 745 ng/mL
Differential diagnosis
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Liver disease
Vitamin K antagonist
Gastro-intestinal malabsorption
Dysproteinemia
Familial multiple factor deficiencies
Warfarin level
▪ Chromatographic assay
▪ Therapeutic concentration 2.0-5.0 ug/mL
▪ Toxic concentration > 10.0 ug/mL
The “Superwarfarins”
▪ Long-acting anticoagulant type rodenticides
▪ First described in 1975
▪ Developed as rodenticides for warfarin resistant rats
• 4-hydroxycoumarins
❖Brodifacoum
❖Difenacoum
❖Bromadiolone
• Coumatetryls
• Andanediones
▪ All inhibit γ-carboxylation of vitamin K dependent clotting factors
Brodifacoum vs warfarin
▪ Half-life
• Warfarin 37 +/- 15 hours
• Brodifacoum 20 – 63 days (av, 437 hours)
▪ Side chains
• 4-hydroxycoumarin
• Brodifacoum has a large lipophilic side chain, enhance affinity for
receptor and longer half-life
Initial presentation
▪ PT/INR and aPTT prolonged 24-72 hours after ingestion
▪ Clues to superwarfarin ingestion
• Mixing study shows factor deficiency
• Warfarin assay negative
• Lack of sustained response to vitamin K and FFP
• Brodifacoum assay if available
URGENT EVALUATION AND MANAGEMENT OF BLEEDING
Case Presentation - Case #5
▪ 68 yo male brought to hospital after MVA which occurred while
intoxicated. Combative at scene with GCS 13; progressively more
somnolent deteriorating to GCS 11 upon arrival to ER. Head CT
indicates right frontal intraparenchymal hemorrhage with extension
into lateral ventricle.
▪ CBC indicates mild anemia with Hgb 12 and normal plt count. PT and
aPTT normal. AST 75 with ALT 32. Creatinine 1.1. Chemistry panel
otherwise normal.
▪ CT chest/abd/pelvis with trivial injuries
▪ Intubated and transferred to trauma center.
At Trauma Center
▪ Neurosurgery places ICP monitor
▪ Head CT indicates progression of hemorrhage
▪ Family updated on status and mentions that patient’s
brother was diagnosed with vWD (unknown type) and
patient has long been suspected of having vWD due to
bleeding symptoms, but never got testing.
▪ Hematology consult requested
What is the next best step?
a.
b.
c.
d.
Obtain records from brother’s hematologist
Send ristocetin cofactor, vWF:Ag, and factor VIII STAT
Send above laboratory testing, and infuse DDAVP at 0.3 mcg/kg IV
once
Send above laboratory testing and infuse vWF containing blood
product at 60 RCoF units/kg
Laboratory Results
▪ Coagulation studies and CBC unchanged
▪ FVIII level 140%
▪ Ristocetin cofactor takes 48h
▪ Continue dosing vWF containing blood product?
Outcome
▪ vWF containing blood product was continued and infusion
rate had to be increased after 3 days to maintain ristocetin
cofactor levels around 100%
▪ Prolonged hospitalization, but ultimately discharged to
subacute rehabilitation facility in fair condition
Summary
▪ The bleeding history is far more useful when objective quantitative
information is included
▪ Patient pretest probability for a bleeding disorder should be stratified
into likely, possible, and unlikely
▪ Dividing bleeding manifestations into disorders of primary or
secondary hemostasis can be useful
▪ Management of urgent bleeding is still driven by focused patient
history
What, will these hands ne'er be clean?—
Here's the smell of the blood still: all the perfumes of Arabia will not
sweeten this little hand.
Lady Macbeth, Macbeth, Act V, scene 1
- Yet
who would have thought the old man
to have had so much blood in him?
Lady Macbeth, Macbeth, Act V, scene 1
Questions?
Fibrin Clot
IIa
II
IIa
TF
VIIa
TF
Fibrinogen
IIa
Xa Va
Xa
X
V
X
Activated
Platelet
Amplification
IXa VIIIa
IIa
II
PAR
VIII
IX
Initiation
IIa
VII