7 Global Objectives Maximize patient outcome Utilize health care resources wellOptimize evidence-based medicineEnhance ED practice54254
8 Sessions Objectives Learn about hemophilia and RBDs What are the diseases?How do patients present?What are management principles?What specific therapies?How to enhance pt outcomes?54254
9 Case Presentation 17 year old presents to ED Known hemophilia A Fell off of bicycleAbdominal traumaHypotensive, tachycardicAbdominal tendernessWhat do you do?
10 ED Bleeding Disorder Patients: Key Concepts Identify the bleeding disorderEstablish if bleeding is presentTreat the bleedingTreat the bleeding disorderEstablish endpoint for Rx successDisposition based on Dx, Rx, risk
11 Background Rare disorder: Affects fewer than 200,000 Americans (NIH office of Rare Diseases)HemophiliaOther bleeding disordersRare Bleeding Disorders
17 Hemophilia Severity Based on procoagulant levels or bleeding severity Severe: <1% clotting factor presentModerately severe: 1-5%Mild: 5-40%Clinical bleeding severity may not match amount of deficiency
19 von Willebrand’s Disease Autosomally inherited bleeding disorder, mucocutaneousDeficiency or dysfunction of the protein termed von Willebrand factor (vWF)Primary hemostasis is impairedDefective interaction between platelets and the vessel wall
20 Factor VII DeficiencyFewer than 200 cases of true factor VII deficiency have been reportedGene mutations, protein dysfunctionFactor VII coagulant activities measured in the laboratory are not well correlated with bleeding manifestations
21 Acquired Bleeding Disorders Vitamin K DeficiencySevere Liver DiseaseFactors II, VII, IX and X are decreasedPlatelets dysfunctionalRenal DiseasePlatelet dysfunction
22 Acquired Bleeding Disorders Oral Anticoagulant TherapyProlonged Use of AntibioticsDevelop anti-platelet antibodiesVitamin K deficiencyAcquired Inhibitors (Antibodies)Post malignancyRelated to pregnancyIdiopathicElderly
24 Patient Demographics Hemophilia Present in childhood, esp with greater disease severityAll racesX-linked, recessive males
25 Patient Presentations Mannucci et al. Blood 2004;104:
26 History What is the Bleeding Disorder? vWD, Hemophilia A/B, other factor deficiency or platelet disorder
27 History What is the severity of the factor deficiency? Severe - < 1% factor presentBleed spontaneously and often e.g. weeklyModerate – 1-5 %Can have spontaneous bleeding but less frequent e.g. monthlyMild - > 5 %Bleed only when hemostasis is challenged e.g. trauma and surgery
28 History Do they have a inhibitor (assoc with congenital factor def)? What is their HIV/Hepatitis Status?How is the bleeding disorder being treated?When was your most recent treatment or infusion?Are you taking other medications?
29 Hemorrhage History General - Weakness and orthostasis Musculoskeletal (joints) - Tingling, cracking, warmth, pain, stiffness, and refusal to use joint (children)CNS - Headache, stiff neck, vomiting, lethargy, irritability, and spinal cord syndromes
30 Hemorrhage HistoryGI - Hematemesis, melena, frank red blood per rectum, and abdominal painGenitourinary - Hematuria, renal colic, and postcircumcision bleeding
31 Hemorrhage HistoryOther - Epistaxis, oral mucosal hemorrhage, hemoptysis, dyspnea (hematoma leading to airway obstruction), compartment syndrome symptoms, and contusions; excessive bleeding with routine dental procedures
35 Lab Results for Bleeding Disorders Prolonged PTProlonged aPTTProlonged PT and aPTTInherited DisordersFVII DeficiencyvWF Type 2&3FVIII, FIX, FXI or FXII deficiencyFII, fibrinogen, FV, X or a combined factor deficiencyAcquiredDisordersFVII InhibitorVit K deficiencyLiver diseaseWarfarin useInhibitor to FVIII, IX, XI, XII, vWFHeparin useDirect thrombin inhibitorInhibitor to FII, fibrinogen or FV or XLiver disease, DIC, combined heparin and warfarin use
36 Laboratory TestingPT: Extrinsic, should be normal unless FVII deficiency or acquiredaPTT: Intrinsic, elevated in moderate hemophilia disease severity
37 Other ED Testing Extremity xrays Head CT Abdominal CT Tests for increased compartment pressuresNuclear bleeding studies
39 Initial Management Treat the patient ABCs Direct hemorrhage control Hemodynamic supportCrystalloidsBlood productsSpecifically assist hemostasis
40 The 3 Phases of Hemostasis Primary hemostasis:VasoconstrictionPlatelet adhesionPlatelet aggregation and contractionSecondary hemostasis:Activation of coagulation factorsFormation of fibrinFibrinolysis:Activation of fibrinolysisLysis of the plug
41 Blood Vessel & Endothelium Hemostasis requires and involves various physiological components:The blood vessel wallEndothelial cellsSubendothelial tissueSmooth muscle cellsThe components of bloodPlatelets (thrombocytes)Coagulation (clotting) factorsFibrinolytic/ anticoagulant proteins
42 Primary Hemostasis: Vasoconstriction The first response to endothelial injury is the constriction of the damaged vessel which reduces the blood flow at the site of injuryColman RW, et al. Overview of haemostasis. In: Colman RW, Hirsh J, Marder VJ, Clowes AW, George JN, eds. Haemostasis and Thrombosis: Basic Principles and Clinical Practice. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001: 3–16.
43 Primary Hemostasis: Formation of a Platelet Plug The exposure of subendothelial components such as collagen promotes platelet adhesionThe adherence of platelets to the sub-endothelium leads to platelet activation and the formation of platelet aggregates (platelet plug)Colman RW, et al. Overview of haemostasis. In: Colman RW, Hirsh J, Marder VJ, Clowes AW, George JN, eds. Haemostasis and Thrombosis: Basic Principles and Clinical Practice. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001: 3–16.Monroe DM, Hoffman M. Arterioscler Thromb Vasc Biol 2006; 26(1): 41–48.
44 Secondary HemostasisAt the site of vascular injury binding of endogenous factor VII/VIIa to tissue factor (TF) leads to the generation of small amounts of thrombin Thrombin activates platelets and additional coagulation factors which subsequently generate large amounts of thrombin This “thrombin burst” induces the generation of a haemostatic plug that prevents further blood loss Hoffman M, Monroe DM. Thromb Haemost 2001; 85(6): 958–965.Monroe DM, et al. Blood Coagul Fibrinolysis 1998; 9(Suppl 1): S15–20.Monroe DM, Hoffman M. Arterioscler Thromb Vasc Biol 2006; 26(1): 41–48.Adapted from Hoffman M et al.,
45 How a Blood Clot Forms: Step 2 PTTHMWK,PKPTXIIXITFIXVIIa/TFVIIVIIIaXXVaIIa(thrombin)II (prothrombin)fibrinogenFibrinClot(factor I)
46 Platelets Clotting factors Coagulation cascade What is Broken?PlateletsClotting factorsCoagulation cascade
47 What Can Be Provided? Vitamin K FFP (Fresh frozen plasma) PCC (prothrombin complex concentrate)Platelets, packed RBCs, whole bloodSpecific clotting factorsAnti-fibrinolytics, anti-hemophilics
48 Hemophilia A: Factor VIII Recombinant factor VIII concentrate is the preferred source of factor VIII. The factor VIII activity level should be corrected to 100% of normal for potentially serious hemorrhage.Units factor VIII=(weight in kg)(50 mL plasma/kg)(1 U factor VIII/mL plasma)(desired factor VIII level minus the native factor VIII level)
49 Hemophilia A: Factor VIII As an example, an 80-kg individual diagnosed with hemophilia with known 1% factor VIII activity level presents to the ED with a severe upper GI bleed.Units factor VIII = (80 kg)(50 mL/kg)(1 U factor VIII/mL)(.99) = 3960
50 Hemophilia A: Factor VIII Next dose: 12 hours later, 1/2 initial dose.Minor hemorrhage: 1-3 doses factor VIII.Major hemorrhage: many doses, continued factor VIII activity monitoring.Goal: trough activity level at least 50%.
51 Hemophilia A: Other Rx FFP: administer 1 mL IV FFP/U factor VIII. Anti-fibrinolytics:Epsilon aminocaproic acid (Amicar)Oral mucosal bleeds, rich fibrinolytic activity200 mg/kg PO/IV initial dose, 100 mg/kg q6h; not to exceed 5 gAlternatively, 10 g slow IV (over 2 h), followed by 1 g/h continuous infusion
52 Hemophilia A: Other Rx Anti-hemophilic agent: 1-deamino-8-D-arginine vasopressin (desmopressin acetate, DDAVP)Increase (up to 4-fold) in FVIII plasma levels0.3 mcg/kg in mL 0.9% isotonic saline IV over minNot indicated in platelet type vWB
53 Hemophilia B: Factor IX Synthetic recombinant Factor IXUnits factor IX =(weight in kg)(100 mL/kg)(1 U factor IX/mL)(desired factor IX level minus the native factor IX level)
54 Hemophilia B: Factor IX As an example, an 80-kg individual diagnosed with hemophilia with known 1% factor IX activity level presents to the ED with a severe CNS bleed.Units factor IX = (80 kg)(100 mL/kg) (1 U factor IX/mL)(.99) = 7920
55 Hemophilia B: Factor IX Next dose: 12 hours later, 1/2 initial dose.Minor hemorrhage: 1-3 doses factor IX.Major hemorrhage: many doses, continued factor IX activity monitoring.Goal: trough activity level at least 50%.
56 Hemophilia B: Factor IX Factor IX complex concentratesCoagulation factor IX concentrates, pooled plasma product (high purity)
57 Hemophilia B: Other Rx FFP: administer 1 mL IV FFP/U factor IX. Anti-fibrinolytics:Epsilon aminocaproic acid (Amicar)Oral mucosal bleeds, rich fibrinolytic activity200 mg/kg PO/IV initial dose, 100 mg/kg q6h; not to exceed 5 gAlternatively, 10 g slow IV (over 2 h), followed by 1 g/h continuous infusion
58 vWDx: Platelet Activation RESTINGACTIVATED50,000> 500Fibrinogen granulesP-selectinGPIIb-IIIaGPIIb-IIIaP-selectinGPIVGPIb/IX/VGPIb/IX/VGPIVACTIVATION25,000- GPIb IX, V : internalized- GPIIbIIIa : 1) membrane expression increased2) complex occupied by fibrinogen, vonWillebrand Factor ...- P-selectin : translocated to the membrane
59 von Willebrand’s Disease Rx Anti-hemophilic agent:Type 1 vWDx1-deamino-8-D-arginine vasopressin (desmopressin acetate, DDAVP)Up to 3-6 fold increase in FVIII and 2-4 fold increase in vWF plasma levels300 mcg intranasally produces levels comparable to IV infusionUseful for menorrhagia and epistaxis
60 von Willebrand’s Disease Rx Platelet transfusions if other Rx not effectiveCryoprecipitate, FFP contain functional vWF, not used widely
61 Rare Bleeding Disorders Congenital factor deficiency of any of the following:VIIXIXIIVCombined V and VIIIFibrinogenXIIIPAI-1Congenital Platelet DisordersGlanzmann’s ThrombastheniaBernard Souliervon Willibrands Disease – Types 2 & 3
62 Rare Bleeding Disorders: Rx Stabilize the patient.Call the hematology/oncology consultant.
63 What Can Be Provided? Specific clotting factors PCC, other concentratesAnti-fibrinolytics, anti-hemophilicsFFP (1 mL per Unit of clotting factor)Platelets
64 Patient Outcome Low Hb, ruptured spleen IVF, cross-matched blood 10% Factor VIII levels priorUnits factor VIII = (70 kg)(50 mL/kg) (1 U factor VIII/mL)(.90) = 3500Stable to ICU with expectant management
65 Conclusions Complex medical problems Lumpers and splitters Treat the patient’s hemorrhageIdentify the diseaseTreat the disease, as ableConsult liberallyAdmit as indicated