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Bleeding Diathesis
Inherited & Acquired Causes of Bleeding
Harry Kopolovich
Clinical Vignette #1
24 y/o male with a history of
Hemophilia A is playing baseball,
when a line drive strikes him in the
He is immediately brought to your
ER, where he has a GCS of 15,
and a normal neuro exam
He complains of a slight headache
and pain from a bruise that is
developing on his temple
Clinical Vignette #2
●65 y/o woman is brought to
your emergency room
because of epistaxis
Medical history reveals that
she is taking Coumadin for
INR is 7.9
Clinical Vignette #3
55 y/o man is brought to your hospital
after sustaining a frontal crash on I95.
The patient’s abdomen struck the
steering wheel
He is complaining of abdominal pain
Medical history reveals that he is taking
Pradaxa (Dabigatran) for nonvalvular atrial fibrillation
Ct-imaging demonstrates a
retroperitoneal hematoma with a
Disorder of Hemostasis
Genetic Mutations
●De Novo Mutations
Huge Pharmaceutical Market
Normal Hemostasis
●Balance between pro-coagulant and anticoagulant factors
Competing interest between smooth laminar
blood flow and maintenance of structural integrity
of vasculature
Healthy individuals have this occurring constantly
Diseased states lead to hemorrhage or
Arterial V.S. Venous
High flow and high pressure
Small amounts of damage leads to catastrophic losses
Primarily relies on platelets
Slower flow and lower pressure
Coagulation cascade with thrombin generation primary means of
●Thus, ASA to prevent coronary artery
thrombus and heparin/lovenox/coumadin to
prevent DVT
Disorders Of Hemostasis
Following should be considered:
1)Thrombocytopenia or Platelet Dysfunction
2)Low levels of multiple coagulation factors resulting from Vitamin K deficiency
of hepatic dysfunction
3)Single factor deficiency
Inherited or Acquired
4)Consumptive coagulopathies
5)Circulating inhibitors to coagulation factors
Vascular Wall Physiology
●Endothelial Cells
Functions as a barrier to contain
Prevents contact with
thrombogenic sub-endothelial
Intact cells posses strong anticoagulant functions
Prostacyclin, NO, ADPase,
plasminogen activator
●Endothelial Cell Damage
Procoagulant state
Activated endothelial cells
Selectins, β
​ -integrins, vWF
Exposed sub endothelial matrix
Tissue Factor
●End Result
Combination of activated proteins and exposed surfaces
result in:
Platelet Activation
Leukocyte Migration
Initiation of Coagulation Cascade
Initiation of Anti-coagulant systems
Thrombin-thrombomodulin cascade, protein C, S, t-PA
Coagulation Cascade
●Critical for understanding normal hemostasis
●Huge target for Pharmaceutical Companies
●Potential for remediating deficiencies created by
acquired or iatrogenic means
●Liver is the primary site for synthesis of
coagulation factors
Extrinsic Pathway
Vascular injury leads to exposed sub endothelial
Results in exposure of highly thrombogenic
Tissue Factor
Combines with Factor VII--> VIIa
Results in conversion X-->Xa
Monitored using PT/INR
Deficiencies in Vitamin K analogues leads to
Intrinsic Pathway
Contact Activation Pathway
Initiated by collagen contacting HMWK
Monitored by aPTT
Common Pathway
Both pathways converge ultimately result in activated
Abnormalities of X, V, II result in elevation of PT & PTT
Platelet Physiology
●Platelet functions as cellular
based platform for hemostasis
●Adhesion results in
transmembrane signaling
Translocation of receptors to
membrane surface
Receptor transformational
●Pro-coagulant surface of platelet
Serves as assembly point
for coagulation cascade
Amplifies overall
procoagulant response
Produces fibrin-->Leading to
clot stabilization
Platelet Physiology
●Platelets derived from bone marrow
●Survival time 7-10 days
●~7,100 platelets required/day even with no
challenge to vascular integrity
●Normal count is 150,000-450,000
●Qualitative function measure through bleeding
<8 minutes
Prolongation occurs
Plt count <100,000
Abnormal platelet function/vessel adhesion
Normal Platelet Function
● vWF & Collagen
Present in sub endothelium
Damage to endothelial cell lining vasculature causes
exposure to circulating platelets
Leads to binding of GP-Ib binding site on platelet
Extremely rapid/low affinity bond
● Injury leads to tumbling of platelets-->
Conformational change leads to transmembrane
●Exposure of GPIIb/IIIa receptor
Higher affinity bond
Secures platelet firmly to sub endothelium
Bleeding Caused by Platelet
●Can be broadly separated by
Quantitative versus Qualitative Disorders
Quantitative Disorder of Platelets
1)Decreased Platelet Production
B12/Folate Deficiency
Congenital Causes
Alport's Syndrome, Fanconi's anemia, Wiskott-Aldrich Syndrome
Marrow damage
Aplastic anemia, Chemotherapy, Drug Induced, Malignancy
2)Increased Platelet Destruction
Immune Mediated:
ITP, Drug Induced, HIV, SLE, Heparin
Non-Immune Mediated
3)Increased Platelet Sequestration
Splenomegaly, Liver Disease, Malignancy, Myelofibrosis
Qualitative Platelet Defects 1
●Drug Induced
Normal platelet function requires release of Thromboxane
Vasoconstrictor & Platelet Agonist
Generated in cytostol of platelet by cleavage of Arachidonic
acid by COX
ASA irreversibly binds COX for the lifetime of the platelet
Blocks GPIIb/IIIa Receptor
ADP receptor blocker
Qualitative Defects 2
●Uremic Dysfunction
Caused by protein accumulation in renal failure
GSA (Guanidinosuccinic acid): Induces high
levels of NO
Both compounds inhibit platelet function
Can be treated by treating underlying cause
DDAVP, Cryoprecipitate
Platelet transfusion usually futile
Newly transfused platelets rapidly acquire
uremic effect
Congentital Platelet Dysfunction
Inherited platelet disorders can be classified:
1)Disorders of Platelet Receptors
Bernard-Soulier Disorder
▪ Decreased Surface Expression of GPIb
▪ Can manifest even in adulthood
▪ Mild-to-Moderate bleeding disorder
Glanzmann's Thrombasthemia
▪ Absent platelet aggregation in response to Ristocetin
▪ Caused by decreased number/function of GPIIb/IIIa receptors
Congentital Platelet Dysfunction
2)Disorder of Platelet Granules:
Hermansky-Pudlak Syndrome
Lack of secondary wave of platelet aggregation due to deficient
cytostolic proteins
Von Willenbrand Disease
●Disorder of plasma proteins that serve as
ligands for platelet adhesion
Phenotypically identical to platelet dysunction
●vWF is synthesized in vascular endothelial cells
Mediates platelet rolling along damaged vascular
wall with subsequent platelet adhesion
●vWF serves as the carrier protein for Factor VIII
Decreased vWF-VIII binding leads to
elevation of aPTT
Three type of VWD
1)Type I
-Mild to moderate quantitative decrease
Dominant patter of inheritance
Mild bleeding in relation to dental procedures or surgery
Treated with DDAVP 0.3mcg/kg SC
Increases amount of vWF synthesized in EC
2)Type II
-Qualitative defect in vWF
Treatment is with vWF concentrate
3)Type III
-Complete Deficiency of vWF
Inherited two bad copies of genes
Severe bleeding
vWF concentrate
Bleeding Caused by Coagulation
Factor Disorders
●With normal platelet function, primary
hemostasis initiates plugging of vascular lesions
and maintains mucosal integrity
●However, if coagulation factors are not present,
then the initial platelet plug is not solidified by
secondary hemostasis, leading to clot
breakdown and bleeding
Coagulation cascade deficiency
bleeding differs from platelet
dysfunction/absence bleeding
1)Bleeding in
deep tissues &
●X linked deficiencies of Hemophilia A & B are
the most common inherited bleeding disorder
after VWD
●Hemophilia A is six time more common the B
●Both are characterized by their factor levels
Mild: >5% activity
Moderate: 1-5%
Severe: <1%
●Severe forms are evident in childhood
●Mild forms can go undetected into adulthood
Hemophilia A
●Stems from deficiency of Factor VIII
Guide to replacement
1U/Kg of Factor VIII raises activity by 2%
Early joint or muscle bleeding
» Factor Levels to 30-40% of normal
More Severe Muscle Hematoma or undergoing dental
» Factor Levels to 50% of normal
Intracranial/Intra-abdominal Hemorrhage
» Factor Levels 80-100%
Trauma/Bleeding to Face, Neck, Hip
» Factor Level 80-100%
Half life of Human Factor VIII ~8-12 hours
Clinical Vignette #1
24 y/o male with a history of Hemophilia A is playing baseball,
when a line drive strikes him in the head
He is immediately brought to your ER, where he has a
GCS of 15, normal neuro exam
He complains of a slight headache and pain from a bruise that
is developing on his temple
Will need factor correction to 100%
Dose of Factor VIII = (Weight in kg) x (Desired % Increase) x 0.5
Hemophilia B
●Deficiency of Factor IX
●Longer half life then Factor VIII
●Infused every 18-24 hours
●2U/Kg raises factor activity by 2%
Vitamin K Deficiency
1)Biliary tract disease leading to impaired enterohepatic
2)Drugs, Eg. Abx which sterilize gut and reduce bacterial
sources of Vit K
3)Malabsorptive States
Celiac Sprue, Crohn’s
4)Severe Malabsorption
Treatment of Vitamin K Deficiency
●Oral or Paranternal Supplementation
-PO or IV route is preferred
-SC route is no better then placebo
-Supplementation must occur over prolonged duration
Hepatic Synthesis takes ~ 3 days
Iatrogenic Causes of Bleeding
●Huge Pharmaceutical Market
●Numerous Potential Targets
●Unintended consequence is excessive bleeding
●Unexpected trauma coupled with anticoagulation is a cofounder for significant
Plavix (Cloipodgrel)
Normal platelet activation
ADP-P2Y12 Receptor
activation, Calcium
Flux = Platelet
● Plavix competitively inhibits P2Y12 receptor
●Plavix is rapidly absorbed from the gut
Tpeak ~75 minutes
●Metabolized extensively in the liver
~50% urine, 46% stool
-Recovery of platelet function ~3-5 days
-Platelet transfusion
Coumadin (Warfarin)
●Standard Oral Anti-coagulant
●Has been in use since 1950
-Long duration of usage has resulted in protocols for
-Likewise, protocols for reversal of effect have been
developed and validated
-Many drug-drug interaction
-Many food-drug interactions
-Frequent need for monitoring
●Patients on Coumadin frequently become excessively over
anti-coagulated, even those who have been stable for
●In 2001 Penning-Van Beest et al., looked at risks for
becoming over anticoagulated when using coumadin
●Sample size: 17,000 outpatients
INR >6.0 noted on 22.5 per 10,000 treatment day
•Diarrhea: RR 12.8
•Worsened Heart Failure: RR 3.0
•Fever: RR 2.9
•Impaired Liver Function: RR 2.8
●Mechanism of Action
-Blocks gamma-carboxylation of Vitamin K dependent
coagulation factors
-Impairs synthesis of coagulant factors II, VII, IX, X
and anti-coagulant factors protein C & S
-Factor VII has the shortest half life (6 hours)
-Rapidly and completely absorbed from stomach, with peak
concentration occurring within 4 hours
-Coumadin undergoes metabolism via Cytochrome P450
system in the liver
-92% of metabolites excreted in Urine
●Accidental/Intentional Ingestion
-Absorption with activated charcoal
●Need for reversal depends on:
Height of elevation of INR
Seriousness of injury
Need for rapidity of normalization of INR
●2008, Journal Chest Published Pharmacology and
management of the Vitamin K antagonist
Recommended Management of A
Supratherapeutic INR
Bleeding Present
Recommended Action
Lower Warfarin Dose or Omit
a Dose and Resume Warfarin
At A Lower Dose When INR
Is In Therapeutic Range
Omit A Dose And Give Vit K 1
to 2.5mg PO
Hold Warfarin And 2.5 to 5mg
Vit K
Serious or life threatening
Hold Warfarin, Give 10mg Vit
K via Slow IV, Supplement
With FFP or rfVIIa
How to Give Vit K?
●Meta Analysis of 10 randomized and 11 prospective trials to determine
effectiveness of various routes of Vit K supplementation in patients
with pretreatment INR 4.0—10 without signs of bleeding
●Reported as percentages of INR 1.8—4.0 24 hours after stopping
Warfarin and administration of Vitamin K by various routes
-Placebo: 20%
-Subcutaneous: 31%
-IV: 77%
-PO: 82%
●10mg of Vit K temporarily renders pt resistant to Warfarin for
days to weeks
Significant Or Life Threatening
●Rapid reversal must be undertaken at any INR
-Slow IV infusion of Vit K
-FFP: ~2 to 3 Units
▪Dose of FFP = (target INR level [%] - present INR level [%] x kg
▪Eg. 60Kg woman with AVR who has UGIB and INR 7.5 (5% of
normal), target INR 1.5 (40% normal)
(40-5) x 60 = 2100ml FFP
-Recombinant Factor VIIa
-Prothrombin Complex Concentrate (10-80mcg/kg)
ICH on Warfarin
Mortality rates associated with anticoagulant associated ICH at 30 days
Unconscious on Admission – 96%
Unconscious before start of active treatment – 80%
Treatment with Warfarin antagonist while still conscious – 28%
●Factors associated with positive outcome are inversely
proportional to delays in therapy
-Simply put, the longer the delay, the worse off the patient
-Avg 8Units of FFP ~ 2L
-Disadvantage: Large volume load
-Median time to normalization of INR: 30 hours
-Cost: $200-400
-US Has three factor PCC (II, IX, X)
-Disadvantage: Thrombotic events
-Median time to normalization of INR: 30 min
-Cost: $1,000-2,000
●Recombinant factor VIIa
-Initial Dose 62mcg/kg
-Disadvantage: Has to be re-dosed (t1/2 = 2.3 hours)
-Median time to normalization of INR: Immediate
-Cost: $5,000-15,000
Clinical Vignette #2
●65 y/o woman is brought to your emergency room because of
Medical history reveals that she is taking Coumadin for a DVT/PE
INR is 7.9
If you can achieve hemostasis, treat at INR 5.0 – 9.0 with Vit K 2.5 or
If unable to achieve hemostasis and/or bleeding significant, will need
FFP or whatever your facility has
Pradaxa (Dabigtran)
●In 2010, US FDA gave Pradaxa, the first new oral anti-coagulant
in 50 years
●Currently, its approved only for the prevention of embolic stroke
for non-valvular atrial fibrillation
●Reversible, potent, competitive direct thrombin inhibitor.
●Capable of binding both free and already bound thrombin
●Ultimately prevents conversion of fibrinogen to fibrin
-Inhibits platelet aggregation (2o effect of thrombin)
●RE-LY (Randomized Evaluation of Long Term Anti-Coagulation
-Phase 3 Prospective trial
-Head to Head evaluation of Pradaxa vs Coumadin
-Studied 110mg BID, 150mg BID vs. Coumadin
-150mg BID had similar rates of bleeding, but superior
● Dabigatran etexilate is a pro-drug
●After ingestion, it is metabolized to dabigatran, which
produces immediate anti-coagulation
●Time to peak is 2 hours
●Within 4-6 hours post ingestion, 70% drug is metabolized
●80% Eliminated in urine ~12-17 hours
-Dosing Schema
▪Crcl >30ml/min: 150mg/BID
▪CrCl 15-30ml/min 75mg/BID
▪CrCl <15ml/min Not recommended
Monitoring of Anticoagulation
●Currently, there is no simple way of measuring the degree of
●Furthermore, the manufacture does not advocate for routine
monitoring as there are no known drug-drug, drug-food
-Pradaxa-Amiodarone has been implicated in a case
report implicating supratherapeutic dabigatran levels as
contributing to fatal GI hemorrhage
Legrand et al., The use of dabigatran in elderly patients
Monitoring of Anticoagulation
●Typical Measures of clotting time aPTT/PT/INR have limited
clinical utility in assessing the anti-coagulant effect
●aPTT does not respond linearly to the dose or intensity of
●aPTT reaches a plateau and peaks 2-3x control value in the
presence of dabigatran
●aPTT is a qualitative measure to the presence of dabigatran
●If aPTT is normal, excludes presence of dabigatran
●PT/INR also demonstrates linear response
-INR expected to rise no more then 1.2-2.0 in the presence of
Monitoring of anti-coagulation
●Thrombin time
-Not routinely available
-Asses activity of thrombin by measuring rate of conversion of fibrinogen →
●Ecarin Clotting Time (ECT)
-Ecarin is a snake venom
-Converts prothrombin → meizothrombin
-Metabolite inhibited by direct thrombin inhibitors
●Hemoclot Thrombin Inhibitor Kit
-Awaiting FDA approval
Management of Bleeding
●Current recommendation are based on anecdotal reports
●No evidence based recommendations
●2011 AHA/ACC Guidelines recommend dabigatran-associated
hemorrhage be treated with FFP and/or pRBC's
-Theoretical benefit
-FFP contains thrombin, thus potentially competitively inhibiting
dabigatran's effect
-Likely limited effect in cases of supratherapeutic dabigatran
levels in cases of acute renal failure
-Rat studies demonstrate reduced bleeding time
-Even in absence of TF, rfVIIa generates thrombin
-Human experience is limited
-Improved clotting times in animals and humans
-Demonstrated in vitro
-Unfortunately, thrombogenic → Leads to ischemic events
●Dabigatran is renally excreted
-Removes 62 % of dabigatran at 2h and 68% at 4h
-Human experience is lacking
●Activated Charcoal
-Intentional/Accidental overdose
-2-3x serum increase in the setting of normal renal function well
-Admission for prolonged monitoring if ingestion more then that
●”Within 12 weeks of initial marketing approval for the United
States in October 2010, the Institute for Safe Medication
Practices reported that dabigatran was responsible for more
serious adverse events then 98.7% of all medications”
Moore et al., Signals for two newly approved drugs and
2010 annual summary.
●Closed space bleeding is a large concern for ED physicians
-Pericardial, ICH, Intraspinal
-Medical, Surgical management?
●All prior modalities of reversal are theoretical/anecdotal
●75 y/o male with dm, htn, a-fib on Pradaxa.
How often should his renal function be monitored?
d)Some combination of the above
No consensus
Significant implications for lack of monitoring in this age group, that
is likely to have higher likelihood of bleeding as well as less
Clinical Vignette #3
55 y/o man is brought to your hospital after sustaining a frontal crash on
The patient abdomen struck the steering wheel
He is complaining of abdominal pain
Medical history reveals that he is taking Pradaxa (Dabigatran) for nonvalvular atrial fibrillation
Ct-imaging demonstrates a retroperitoneal hematoma with a blush
A, B, C's
PRBC's as needed, IVF
FFP? PCC? Hemodialysis? Prayer?