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Bleeding Diathesis Inherited & Acquired Causes of Bleeding Disorders

Harry Kopolovich. Bleeding Diathesis Inherited & Acquired Causes of Bleeding Disorders. 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

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Bleeding Diathesis Inherited & Acquired Causes of Bleeding Disorders

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  1. Harry Kopolovich Bleeding DiathesisInherited & Acquired Causes of Bleeding Disorders

  2. 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?

  3. 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?

  4. 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 non-valvular atrial fibrillation Ct-imaging demonstrates a retroperitoneal hematoma with a blush Management?

  5. Disorder of Hemostasis ●Inherited Genetic Mutations • ●Familial ●De Novo Mutations ●Iatrogenic Purposeful Huge Pharmaceutical Market

  6. 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

  7. 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

  8. 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

  9. 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

  10. ●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

  11. 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

  12. 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

  13. Intrinsic Pathway Contact Activation Pathway Initiated by collagen contacting HMWK Monitored by aPTT

  14. Common Pathway Both pathways converge ultimately result in activated thrombin Abnormalities of X, V, II result in elevation of PT & PTT

  15. 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

  16. 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

  17. 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

  18. ● 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

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

  20. 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 • DIC, TTP, HELLP 3)Increased Platelet Sequestration • Splenomegaly, Liver Disease, Malignancy, Myelofibrosis

  21. 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

  22. 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

  23. CongentitalPlatelet 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

  24. Congentital Platelet Dysfunction 2)Disorder of Platelet Granules: Hermansky-Pudlak Syndrome Lack of secondary wave of platelet aggregation due to deficient cytostolic proteins

  25. 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

  26. 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

  27. 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

  28. Coagulation cascade deficiency bleeding differs from platelet dysfunction/absence bleeding

  29. 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

  30. 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 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

  31. 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

  32. Hemophilia B ●Deficiency of Factor IX ●Longer half life then Factor VIII ●Infused every 18-24 hours ●2U/Kg raises factor activity by 2%

  33. 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

  34. 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

  35. Iatrogenic Causes of Bleeding Dysfunction ●Huge Pharmaceutical Market ●Numerous Potential Targets ●Unintended consequence is excessive bleeding ●Unexpected trauma coupled with anti-coagulation is a cofounder for significant morbidity/mortality

  36. Plavix (Cloipodgrel) Normal platelet activation ● Plavix competitively inhibits P2Y12 receptor

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

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

  39. 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

  40. ●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

  41. 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

  42. ●Metabolism -Coumadin undergoes metabolism via Cytochrome P450 system in the liver -92% of metabolites excreted in Urine ●Accidental/Intentional Ingestion -Absorption with activated charcoal

  43. 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

  44. Recommended Management of A Supratherapeutic INR

  45. 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

  46. 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)

  47. 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

  48. ●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

  49. 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

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