Bleeding Diathesis Inherited & Acquired Causes of Bleeding
Disorders Harry Kopolovich
Slide 3
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, and a
normal neuro exam He complains of a slight headache and pain from a
bruise that is developing on his temple Imaging? Management?
Slide 4
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 a DVT/PE INR is 7.9 Treatment?
Slide 5
Clinical Vignette #3 55 y/o man is brought to your hospital
after sustaining a frontal crash on I- 95. The patients abdomen
struck the steering wheel He is complaining of abdominal pain
Medical history reveals that he is taking Pradaxa (Dabigatran) for
non- valvular atrial fibrillation Ct-imaging demonstrates a
retroperitoneal hematoma with a blush Management?
Slide 6
Disorder of Hemostasis Inherited Genetic Mutations Familial De
Novo Mutations Iatrogenic Purposeful Huge Pharmaceutical
Market
Slide 7
Normal Hemostasis Balance between pro-coagulant and anti-
coagulant 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 thromboembolism
Slide 8
Arterial V.S. Venous Arterial High flow and high pressure Small
amounts of damage leads to catastrophic losses Primarily relies on
platelets Venous Slower flow and lower pressure Coagulation cascade
with thrombin generation primary means of hemostasis Thus, ASA to
prevent coronary artery thrombus and heparin/lovenox/coumadin to
prevent DVT
Slide 9
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 Eg. DIC 5)Circulating inhibitors to
coagulation factors
Slide 10
Vascular Wall Physiology Endothelial Cells Functions as a
barrier to contain blood Prevents contact with thrombogenic
sub-endothelial contents Intact cells posses strong anti- coagulant
functions Prostacyclin, NO, ADPase, plasminogen activator
Slide 11
Endothelial Cell Damage Procoagulant state Activated
endothelial cells Selectins, -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
Slide 12
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
Slide 13
Slide 14
Extrinsic Pathway Vascular injury leads to exposed sub
endothelial matrix 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 elevations
Slide 15
Intrinsic Pathway Contact Activation Pathway Initiated by
collagen contacting HMWK Monitored by aPTT
Slide 16
Common Pathway Both pathways converge ultimately result in
activated thrombin Abnormalities of X, V, II result in elevation of
PT & PTT
Slide 17
Platelet Physiology Platelet functions as cellular based
platform for hemostasis Adhesion results in transmembrane signaling
Translocation of receptors to membrane surface Receptor
transformational changes Degranulation Pro-coagulant surface of
platelet Serves as assembly point for coagulation cascade Amplifies
overall procoagulant response Produces fibrin-->Leading to clot
stabilization
Slide 18
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 time
Injury leads to tumbling of platelets--> Conformational
change leads to transmembrane signaling Exposure of GPIIb/IIIa
receptor Higher affinity bond Secures platelet firmly to sub
endothelium
Slide 21
Bleeding Caused by Platelet Disorder Can be broadly separated
by Quantitative versus Qualitative Disorders
Qualitative Platelet Defects 1 Drug Induced Aspirin Normal
platelet function requires release of Thromboxane A2
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 Aggrenox Blocks
GPIIb/IIIa Receptor Plavix ADP receptor blocker
Slide 24
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
Slide 25
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
Slide 26
2)Disorder of Platelet Granules: Hermansky-Pudlak Syndrome Lack
of secondary wave of platelet aggregation due to deficient
cytostolic proteins Congentital Platelet Dysfunction
Slide 27
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
Slide 28
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 Dominant/Recessive Treatment is with vWF concentrate
3)Type III -Complete Deficiency of vWF Inherited two bad copies of
genes Severe bleeding vWF concentrate
Slide 29
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
Slide 30
Coagulation cascade deficiency bleeding differs from platelet
dysfunction/absence bleeding Etiology Platelet Abnormality
Coagulation Factor Deficiency Phenotype 1)Mucosal bleeding
2)Petechiae 1)Bleeding in deep tissues & joints 2)Delayed
bleeding
Slide 31
Hemophilia 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:
Patients on Coumadin frequently become excessively over
anti-coagulated, even those who have been stable for months 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
Slide 43
Coumadin 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)
Absorption -Rapidly and completely absorbed from stomach, with peak
concentration occurring within 4 hours
Slide 44
Metabolism -Coumadin undergoes metabolism via Cytochrome P450
system in the liver -92% of metabolites excreted in Urine
Accidental/Intentional Ingestion -Absorption with activated
charcoal
Slide 45
Reversal 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
Slide 46
Recommended Management of A Supratherapeutic INR INRBleeding
PresentRecommended Action >Ther5.0NoLower Warfarin Dose or Omit
a Dose and Resume Warfarin At A Lower Dose When INR Is In
Therapeutic Range >59.0NoOmit A Dose And Give Vit K 1 to 2.5mg
PO >9.0NoHold Warfarin And 2.5 to 5mg Vit K AnySerious or life
threateningHold Warfarin, Give 10mg Vit K via Slow IV, Supplement
With FFP or rfVIIa
Slide 47
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 4.010
without signs of bleeding Reported as percentages of INR 1.84.0 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
Slide 48
Significant Or Life Threatening Bleeding 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)
Slide 49
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
Slide 50
FFP - Avg 8Units of FFP ~ 2L -Disadvantage: Large volume load
-Median time to normalization of INR: 30 hours -Cost: $200-400 PCC
- 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
Slide 51
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 a DVT/PE INR is 7.9 Treatment? Depends If you
can achieve hemostasis, treat at INR 5.0 9.0 with Vit K 2.5 or 5mg
If unable to achieve hemostasis and/or bleeding significant, will
need FFP or whatever your facility has
Slide 52
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 (2 o effect of thrombin)
Slide 53
Background RE-LY (Randomized Evaluation of Long Term
Anti-Coagulation Therapy) -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
efficacy
Slide 54
Pharmacokinetics 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
Slide 55
Monitoring of Anticoagulation Currently, there is no simple way
of measuring the degree of anti- coagulation Furthermore, the
manufacture does not advocate for routine monitoring as there are
no known drug-drug, drug-food interactions* -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
Slide 56
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 dabigatran 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
dabigatran
Slide 57
Monitoring of anti-coagulation Thrombin time - Not routinely
available -Asses activity of thrombin by measuring rate of
conversion of fibrinogen fibrin Ec arin Clotting Time (ECT) -
Ecarin is a snake venom -Converts prothrombin meizothrombin
-Metabolite inhibited by direct thrombin inhibitors Hemoclot
Thrombin Inhibitor Kit - Awaiting FDA approval
Slide 58
Management of Bleeding Complications 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
Slide 59
Reversal? rfVIIa -Rat studies demonstrate reduced bleeding time
-Even in absence of TF, rfVIIa generates thrombin -Human experience
is limited aPCC -Improved clotting times in animals and humans
-Demonstrated in vitro -Unfortunately, thrombogenic Leads to
ischemic events
Slide 60
Dabigatran is renally excreted -Hemodialysis -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 tolerated
-Admission for prolonged monitoring if ingestion more then that
amount
Slide 61
Retrospective 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
Slide 62
Monitoring 75 y/o male with dm, htn, a-fib on Pradaxa. How
often should his renal function be monitored? a)Always b)Sometimes
c)Never 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
reserve
Slide 63
Clinical Vignette #3 55 y/o man is brought to your hospital
after sustaining a frontal crash on I-95. The patient abdomen
struck the steering wheel He is complaining of abdominal pain
Medical history reveals that he is taking Pradaxa (Dabigatran) for
non- valvular atrial fibrillation Ct-imaging demonstrates a
retroperitoneal hematoma with a blush Management? A, B, C's PRBC's
as needed, IVF IR FFP? PCC? Hemodialysis? Prayer?