Approach to

Bleeding!
Fatima (Fatuma) Khadadah
PGY5 University of Toronto
January 23rd 2020
Disclosures
• No relevant disclosures
• Slide credits to all previous TAAAC residents notably Drs Jiajia Liu and
Abi Vijenthira
Objectives
• Review the mechanisms behind normal and abnormal hemostasis
• Develop an approach to the patient with bleeding
• Discuss specific hemostatic scenarios and challenges
When you think of hemostasis you
think of..

Madne
ss!

Wikipedia.org
Slide from Dr. Michelle Sholzberg
Hemostasis is composed of 4 major
events:
1. Primary hemostasis
2. Secondary hemostasis
3. Fibrin clot formation and stabilization
4. Inhibition of coagulation

Bloody Easy Coagulation Simplified

Primary Hemostasis
Abnormal

• Collagen Vascular Abnormality

• Von Willibrand Disease (VWD)

• Platelet Deficiency
• Quantitative  thrombocytopenia
• Qualitative  platelet dysfunction

• Classic: mucocutaneous bleeding

(petechiae, purpura, gingival bleeding,
menorrhagia)
Normal
Secondary Hemostasis
Abnormal
• Hereditary or acquired
coagulation factor deficiency
• Hemophilia:
• Factor VIII (Hemophilia A)
• Factor IX (Hemophilia B)
• Drugs E.g. DOACs

• Classic: joint, intramuscular

bleeding
Normal
Fibrin Clot Formation and
Stabilization
Abnormal
• Clot stabilizers
• Rare diseases

• Classic: Delayed bleeding

Normal
 Inhibition of Coagulation
• Inhibition of thrombin generation Abnormal
• Hereditary Thrombophilias!
+ • E.g. Factor V Leiden, Protein C and
S deficiency

Normal
Objectives
Review the mechanisms behind normal and abnormal hemostasis
• Develop an approach to the patient with bleeding
• Discuss specific hemostatic scenarios and challenges
What is the most common bleeding
disorder?

Quiroga T, Hematology 2012

 How to approach bleeding NYD?
Location of Bleeding PMHx
• Primary hemostasis defects • Previous hemostatic challenges?
• Mucocutaneous bleeding • Postpartum hemorrhage
• Easy bruising • Circumcision
• Heavy menstrual bleeding • Dental procedures
• Petichiae (low plts) • Surgical procedures

• Secondary hemostasis defects • Comorbidities

• Liver/renal disease
• Hemarthrosis
• Intramuscular bleeding Medications
• Retroperitoneal bleeding • Anticoagulants, Antibiotics, ASA,
• CNS bleeding NSAIDs, valproic acid, SSRI
Onset Family History
• Chronic/recurrent vs. 1st episode? • VWD: predominantly autosomal
• Differentiate congenital vs. acquired dominant (male and female affected)
Severity • Hemophilia A and B: X-linked
(predominately males affected)
• Require blood transfusions?
What is the most important test to
diagnose a bleeding disorder?
• The clinical history!
• The PT/INR and PTT are only 1-2% sensitive for
bleeding disorders
• A bleeding history can be standardised using a Bleeding
Assessment Tool
ISTH Bleeding assessment tool
• Clinician-administered standardized bleeding history and bleeding
severity assessment
• Studied and sensitive in von Willebrand disease, inherited platelet
defects, and mild hemophilia/hemophilia carriers
• Score >4 suggestive of a bleeding disorder
• Sensitivity for vWD 99% - high NPV!
• Specificity 70-80% - > further testing is still needed!
www.isth.org/resource/resmgr/ssc/isth-ssc_bleeding_assessment.pdf
Further testing if ISTH BAT >4 ?
• CBC + differential
• PT/PTT/fibrinogen
• Liver/renal function testing
• Von Willebrand factor antigen level, ristocetin cofactor activity, and
factor VIII level
• Platelet function assay (PFA)
• (Platelet aggregation/Platelet secretion/Platelet flow cytometry)
 DDx: Isolated Prolonged
aPTT
• Heparin or other anticoagulant
• Deficiency or inhibitor of:
• Factor VIII
• Factor IX
• Factor XI
• Factor XII
• Contact factor (XII, PK, HMWK)
• Von Willebrand disease (2nd to low
FVIII)
• Lupus anticoagulant

Which of the above do not confer a bleeding risk?

Lupus anticoagulant + Factor 12 deficiency!
DDx: Isolated
Prolonged PT
• Vitamin K deficiency
• Warfarin therapy
• Liver disease
• Factor VII deficiency/inhibitor
DDx: Prolonged PT &
aPTT
• High dose (heparin or)
warfarin
• Dilutional coagulopathy
• DIC
• Vitamin K deficiency
• Moderate to severe liver
disease
• Common pathway clotting
factor
deficiencies/inhibitors:
Mixing Study
• What is a Mixing study?
• Combine normal plasma + pt plasma 1:1
• Perform PTT afterwards

Two possible outcomes: FACTOR

• PTT fully corrects DEFICIENCY
• PTT does not fully correct
INHIBITOR
Moving on to inpatient
bleeding management and
cases
Principles of Bleed Management
• ABCs
• Ask for help (surgical teams, ICU…)
• Intravenous access
• CBC, PT, PTT, Blood group and screen
• Fluid resuscitation +evaluate need for blood
transfusion
• Tranexamic acid unless contraindicated
• Give targeted hemostatic therapy (factors, etc.) if
appropriate
Tranexamic acid
• Evidence https://doi.org/10.1016/j.transproceed.2015.05.027.

• Trauma (CRASH-2) – improves survival if given <3h from trauma

• TBI (CRASH-3) – treatment <3 hrs reduces head injury related death
• Obstetrics (WOMAN) – reduces death in PPH if given ASAP
• Peri-procedural – decrease blood loss, need for blood transfusions,
mortality benefit
• Elective c-section, TKA, orthognatic surgery, cardiac surgery, spinal surgeries,
TURP, hemophilia and dental extractions
• Menorrhagia – decreased bleeding, improved quality of life
• SAH: decreased rebleeding and mortality
• GI bleeding: trend towards decreased mortality
• Cancer: safe to give and no increased risk of thrombosis or death
(meta-analysis)
Tranexamic acid
• Contraindications:
• Active thrombus (you want the clot to go away!)
• Hematuria (risk of urinary obstruction)
• NOT a contraindication:
• It is not a procoagulant -> multiple large prospective
multicenter trials in high-thrombotic risk populations
(trauma, obstetrics) do not show an increased risk of
thrombosis
• Adverse effects
• Lowers seizure threshold
• Headache, GI effects
 Case 1
50 year old man presents to ER with Investigations
sudden onset severe headache.
• Hemoglobin 9 g/dL
• Platelets 200 x109/L
PMHx
1. Atrial fibrillation
• WBC 9 x109/L
• INR 13
Medications • aPTT 38 s
2. Warfarin 5 mg PO daily • Electrolytes, renal, and liver
function normal
3. Metoprolol 25 mg PO BID
Case Continued…
3 Step Approach to Life-threatening
Bleeding from Warfarin Excess

1. Stabilize
2. Vitamin K 3. Prothrombin Complex
- ABCs (incl. call surgeons)
- 10 mg IV (can repeat in 12h) OR
- Hold warfarin
- Effect in 6-12 h Fresh Frozen Plasma
- Give TXA

Short-term plan
– PCC (lasts 6 hours)
Long-term plan
– Intravenous vitamin K 10mg
Riv,
Apix

Dabi
Why might his INR be elevated?
• Interference with warfarin metabolism
• Heart failure (OR 1.6-3.0)
• Liver dysfunction (OR 2.8)
• Acute illness – infection, diarrhea (OR 12.8!)
• Fever (OR 2.9)

• Large day-to-day variations in Vitamin K intake

• Vitamin K-rich foods: Basil, green leafy vegetables (kale), scallions, chili powder,
asparagus, soybeans (cooked), dried prunes

• Drug Drug Interactions!! – including over-the-counter drugs (paracetamol),

antibiotics
CYP2C9
Warfarin reversal
• Warfarin
• No bleeding: INR > 10, vitamin K 5mg x 1 orally
• Minor bleeding:
• INR > 3 - hold warfarin
• INR 5-10 - oral Vitamin K 1-2.5mg x 1
• INR > 10 – oral vitamin K 5mg x 1
• Life threatening bleeding
• Vitamin K 10mg IV x 1
• PCC = Octaplex/Beriplex or FFP 15cc/kg.
 Prothrombin Complex Fresh Frozen Plasma
(Octaplex, Beriplex)
CONTENTS: CONTENTS
• Factor 2, 7, 9, 10, PrC, PrS, heparin • All clotting factors + fibrinogen
• Specific for warfarin reversal INR of FFP = 1.6
ADVANTAGE OF PCC• OVER FFP
INDICATION INDICATION
• Faster  faster infusion time (mins vs.
• Warfarin reversal or vit K deficiency with • Liver disease and bleeding and INR > 1.5
hrs),
life threatening bleeding and INR does
> 1.5 or not need to be thawed
• Warfarin reversal if no PCC OR patient has hx of HITT
emergency surgery within < 6 hrs
(30mins), does not need**DON’T ABO matching
give plasma for:
***Contraindicated if HITT
(10 min) • Bleeding/procedure & INR < 1.5
***Lasts 6 hours
• Virally inactivated • NOT bleeding and INR > 1.5
DOSE and PRACTICAL TIPS
• DOSE and PRACTICAL TIPS
Less volume
• INR 1.5-2.99: 1000 units over 5 mins
• 15 cc/kg round to nearest 250 mL
• Less
• INR 3-4.99: 2000 units over 10 minstransfusion reactions
• Each unit of 250 mL will increase factor levels by 20%
• INR ≥ 5: 3000 units over15 mins (this is max
dose) • Max. effect only 5-6 hrs corresponding to shortest
half-life (factor VII!)
• If INR unknown and serious bleeding 
2000 units over 10 mins • Beware of transfusion reactions
• TACO, TRALI, AHTR
• Minor urticarial  give anti-histamine, NOT a
contraindication to more plasma
DOACs and bleeding
• General tips
• Local measures
• TXA 1g IV q8h
• When was the last dose and what is their creatinine clearance? It may
already be out of their system!
• Rivaroxaban or Apixaban
• If likely to still have anti-Xa on board: PCC 50 IU/kg or 2000 IU
• (andaxanet alfa)
• DABIGATRAN
• Idarucizumab 5g IV (2 vials)
Case 2
• 19 M presents with weakness in
left leg and flank bruising. No
trauma.
• PMHx:
• History of intermittent joint
swelling and pain since
childhood
• Meds: nil
• FMHx: younger brother had
appendectomy last year and
required +++ blood transfusions
• O/E: HR 110, BP 120/80, T 36.8,
RR 22, O2 100%
Case continued
PTT 50 s INR 1
Mixing study: PTT CORRECTS
Factor VIII level < 1%, Factor XI level 80%
• consistent with Hemophilia A

Overview of treatment
• Factor replacement (recombinant or plasma-derived)
• Cryoprecipitate (or Fresh frozen plasma)
Hemophilia A and B
• Hemophilia A • Classified by severity
• FVIII deficiency Severity Factor
Level
Bleeding Episodes

• Prevalence 1/5 000

Severe < 1% Spontaneous bleeding into joints or muscles,
• X-linked inheritance predominantly in the absence of identifiable
hemostatic challenge
• Hemophilia B
• FIX deficiency Moderate 1-5% Occasional spontaneous bleeding; prolonged
bleeding with minor trauma or surgery
• Prevalence 1/30 000
• X-linked inheritance
Mild 5-40% Severe bleeding with major trauma or surgery.
Spontaneous bleeding is rare.

• World Federation of Hemophilia updated guidelines 2013

Principles of Treating Bleeding
Hemophilia Patient
• Acute bleeds should be treated as soon as possible, preferably within 2
hours. If in doubt, treat.
• In severe bleeding that may be life-threatening, treat with factor
immediately even before diagnostic assessment is completed
• Watch for critical sites that can be life- or limb-threatening (ex.
neurovascular compromise in MSK bleeding) – may still need surgical
opinion
• Tranexamic acid
• Specific factor replacement
• If not available, can use cryoprecipitate or FFP if hemophilia A, and FFP if
hemophilia B
How To Dose Factor Concentrate
Disease Half-Life Yield Products

Hemophilia A 8-12 hours 2% / u / kg Kogenate

(VIII) Advate

Hemophilia B 18-24 hours 0.5-1% / u / kg Benefix

(IX)
How To Dose Factor Concentrate
Bleed Severity Example Treatment Target Dosing (if severe
deficiency)

Major GI Bleed 80-100% HA = 50 u/kg

Retroperit. Bleed HB = 100 u/kg
CNS Bleed

Moderate Hemarthrosis 60-80% HA = 30 u/kg

HB = 60 u/kg

Minor Dental Work 50-60% Consider DDAVP

Tranexamic Acid
If specific factor replacement
unavailable:
• What contains VIII
• Cryoprecipitate (VIII, XIII, FBG, VWF)
• DDAVP (boosts plasma levels of FVIII and VWF) – 0.3 mcg/kg IV or SC can raise FVIII
by 3-6 times

• What contains IX
• Prothrombin Complex Concentrate

• What contains (or helps) both

• FFP – 1 cc FFP contains 1 unit of factor activity, but difficult to achieve FVIII or FIX
levels above 25-30%
• (Tranexamic Acid)
So how much factor does our
patient need?
• Assuming weight is 70 kg

• Assume close to 0% VIII activity

• Factor VIII 70 kg x 2% /u / kg = 70 kg x 50 u / kg = 3500 units IV

How long to treat for?
• Hemarthrosis – 1-2 treatments (40-60%)

• Muscle hemorrhage – 2-3 days, sometimes much longer if at critical site or if

rehabilitation needed

• Throat / neck – 7-14 days

• UGIB – 7-14 days

• CNS – 7-21 days

• World Federation of Hemophilia Recommendations

Case 3
• A 23 F presents to the ER
after experiencing epistaxis
and easy bruising for three
days. She noted petechiae
on her arms and legs

• Exam reveals:
• Wet purpura
• Petechiae, ecchymoses
• Normal spleen size
Investigations:
• CBC: Hg 120, WBC 10, Platelets 2

• Biochemistry: Electrolytes N, Creatinine 80

• Coags: Fibrinogen 2, INR 1, PTT 30

Life-threatening
thrombocytopenia
• Thrombotic microangiopathies (look for anemia, AKI,
blood film!)
• TTP
• aHUS
• DIC (always do PT/PTT/fibrinogen in thrombocytopenic patient)
• HELPP
• Isolated thrombocytopenia
• ITP
• HIT (if recent heparin exposure)
• Malignancy: Acute leukemia
Immune Thrombocytopenia (ITP)
• Diagnosis of exclusion
• An acquired immune-mediated disorder
• Isolated thrombocytopenia
• Platelet count less than 100 * 10 /L, and the absence of any
9

obvious initiating and/or underlying cause

• Clinically: mucocutaneous bleeding. ICH rare
(estimates 1.5%) but fatal
 Investigations
• Exclude other diagnoses
• Look for secondary cause!
• HIV, HCV, H.pylori
• Ancillary
• APLA, ANA
• Quantitative Ig (look for CVID)
• DAT, IAT
• Bone marrow if older, no response to steroids, clinical
concern RE: malignancy
Emergency Management of ITP
1. SUPPORTIVE MEASURES
• Tranexamic acid 500-1000 mg PO TID if bleeding
• Platelet transfusion in life/limb threatening

2. STEROIDS
• Prednisone 1 mg/kg PO OD OR dexamethasone 40 mg PO OD * 4
days

3. IVIG if need a rapid platelet count increase

• IVIG 1 g/kg * 2 days
• NB. Risks of IVIG
• May use Anti-D alternatively (50-75 mcg/kg IV) in RH + non-
splenectomized patients
Transfusion Thresholds for
Thrombocytopenia
• Non active bleeding - nonimmune10
• Active bleeding or going for OR
50
• CNS bleed, eye bleed
100

• For patients in DIC, try to keep counts

> 30-
50

NOT evidence based!!

Objectives
Review the mechanisms behind normal and abnormal hemostasis
Develop an approach to the patient with bleeding
Discuss specific hemostatic scenarios and challenges
 Conclusions
• 3 cases
1. Bleeding on anticoagulants
2. Inherited factor deficiencies
3. Bleeding and thrombocytopenia
• Give tranexamic acid unless contraindicated –
improves outcomes in all studied groups
• Always evaluate for causes and consequences of
bleeding
• History crucial in patients with abnormal bleeding
Thank you!
• You’ve stopped the bleeding!