Bleeding Diathesis Inherited Acquired Causes of Bleeding Disorders

Bleeding Diathesis Inherited & Acquired Causes of Bleeding Disorders 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 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?

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?

Clinical Vignette #3 55 y/o man is brought to your hospital after sustaining a frontal crash on I 95. 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 blush Management?

Disorder of Hemostasis ●Inherited Genetic Mutations ●Familial ●De Novo Mutations ●Iatrogenic Purposeful 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 thromboembolism

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

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

Vascular Wall Physiology ●Endothelial Cells Functions as a barrier to contain blood Prevents contact with thrombogenic sub-endothelial contents Intact cells posses strong anticoagulant functions Prostacyclin, NO, ADPase, plasminogen activator

●Endothelial Cell Damage Procoagulant state • Activated endothelial cells – • Selectins, β-integrins, v. WF 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 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

Intrinsic Pathway Contact Activation Pathway Initiated by collagen contacting HMWK Monitored by a. PTT

Common Pathway Both pathways converge ultimately result in activated thrombin 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 changes • Degranulation ●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 time • • <8 minutes Prolongation occurs – – Plt count <100, 000 Abnormal platelet function/vessel adhesion

Normal Platelet Function ● v. WF & 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 signaling ●Exposure of GPIIb/IIIa receptor – – Higher affinity bond Secures platelet firmly to sub endothelium

Bleeding Caused by Platelet Disorder ●Can be broadly separated by Quantitative versus Qualitative Disorders

Quantitative Disorder of Platelets 1)Decreased Platelet Production • B 12/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 – DIC, TTP, HELLP 3)Increased Platelet Sequestration • Splenomegaly, Liver Disease, Malignancy, Myelofibrosis

Qualitative Platelet Defects 1 ●Drug Induced Aspirin • Normal platelet function requires release of Thromboxane A 2 • 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 Aggrenox Plavix

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 ●v. WF is synthesized in vascular endothelial cells • Mediates platelet rolling along damaged vascular wall with subsequent platelet adhesion ●v. WF serves as the carrier protein for Factor VIII • Decreased v. WF-VIII binding leads to elevation of a. PTT

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. 3 mcg/kg SC • Increases amount of v. WF synthesized in EC 2)Type II -Qualitative defect in v. WF • Dominant/Recessive • Treatment is with v. WF concentrate 3)Type III -Complete Deficiency of v. WF • Inherited two bad copies of genes • Severe bleeding • v. WF 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 Etiology Platelet Abnormality Coagulation Factor Deficiency Phenotype 1)Mucosal bleeding 2)Petechiae 1)Bleeding in deep tissues & joints 2)Delayed bleeding

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: <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 1 U/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 procedures » 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 Management? 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 ● 2 U/Kg raises factor activity by 2%

Vitamin K Deficiency ●Etiology 1)Biliary tract disease leading to impaired enterohepatic circulation 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 Dysfunction ●Huge Pharmaceutical Market ●Numerous Potential Targets ●Unintended consequence is excessive bleeding ●Unexpected trauma coupled with anticoagulation is a cofounder for significant morbidity/mortality

Plavix (Cloipodgrel) Normal platelet activation ADP-P 2 Y 12 Receptor Platelet Conformational Change Gp IIb/IIIA/Phospholipase activation, Calcium Flux = Platelet Activation ● Plavix competitively inhibits P 2 Y 12 receptor

●Plavix is rapidly absorbed from the gut Tpeak ~75 minutes ●Metabolized extensively in the liver ●Eliminated ~50% urine, 46% stool

Reversal ●Discontinuation -Recovery of platelet function ~3 -5 days ●Reversal -Platelet transfusion

Coumadin (Warfarin) ●Standard Oral Anti-coagulant ●Has been in use since 1950 ●Advantages -Long duration of usage has resulted in protocols for dosing -Likewise, protocols for reversal of effect have been developed and validated ●Disadvantages -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 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

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

●Metabolism -Coumadin undergoes metabolism via Cytochrome P 450 system in the liver -92% of metabolites excreted in Urine ●Accidental/Intentional Ingestion -Absorption with activated charcoal

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

Recommended Management of A Supratherapeutic INR Bleeding Present Recommended Action >Ther— 5. 0 No Lower Warfarin Dose or Omit a Dose and Resume Warfarin At A Lower Dose When INR Is In Therapeutic Range >5— 9. 0 No Omit A Dose And Give Vit K 1 to 2. 5 mg PO >9. 0 No Hold Warfarin And 2. 5 to 5 mg Vit K Any Serious or life threatening Hold Warfarin, Give 10 mg Vit K via Slow IV, Supplement With FFP or rf. VIIa

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% ● 10 mg of Vit K temporarily renders pt resistant to Warfarin for days to weeks

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. 60 Kg woman with AVR who has UGIB and INR 7. 5 (5% of normal), target INR 1. 5 (40% normal) (40 -5) x 60 = 2100 ml FFP -Recombinant Factor VIIa -Prothrombin Complex Concentrate (10 -80 mcg/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

●FFP -Avg 8 Units of FFP ~ 2 L -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 62 mcg/kg -Disadvantage: Has to be re-dosed (t 1/2 = 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 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 5 mg 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 (2 o effect of thrombin)

Background ●RE-LY (Randomized Evaluation of Long Term Anti-Coagulation Therapy) -Phase 3 Prospective trial -Head to Head evaluation of Pradaxa vs Coumadin -Studied 110 mg BID, 150 mg BID vs. Coumadin -150 mg BID had similar rates of bleeding, but superior efficacy

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 >30 ml/min: 150 mg/BID ▪Cr. Cl 15 -30 ml/min 75 mg/BID ▪Cr. Cl <15 ml/min Not recommended

Monitoring of Anticoagulation ●Currently, there is no simple way of measuring the degree of anticoagulation ●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

Monitoring of Anticoagulation ●Typical Measures of clotting time a. PTT/PT/INR have limited clinical utility in assessing the anti-coagulant effect ●a. PTT does not respond linearly to the dose or intensity of dabigatran ●a. PTT reaches a plateau and peaks 2 -3 x control value in the presence of dabigatran ●a. PTT is a qualitative measure to the presence of dabigatran ●If a. PTT 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

Monitoring of anti-coagulation ●Thrombin time -Not routinely available -Asses activity of thrombin by measuring rate of conversion of fibrinogen → fibrin ●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 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 p. RBC'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

Reversal? ●rf. VIIa -Rat studies demonstrate reduced bleeding time -Even in absence of TF, rf. VIIa generates thrombin -Human experience is limited ●a. PCC -Improved clotting times in animals and humans -Demonstrated in vitro -Unfortunately, thrombogenic → Leads to ischemic events

●Dabigatran is renally excreted -Hemodialysis -Removes 62 % of dabigatran at 2 h and 68% at 4 h -Human experience is lacking ●Activated Charcoal -Intentional/Accidental overdose -2 -3 x serum increase in the setting of normal renal function well tolerated -Admission for prolonged monitoring if ingestion more then that amount

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

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

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 nonvalvular 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?