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Edward P. Sloan, MD, MPH, FACEP Hemophilia and Rare Bleeding Disorders.

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Presentation on theme: "Edward P. Sloan, MD, MPH, FACEP Hemophilia and Rare Bleeding Disorders."— Presentation transcript:

1 Edward P. Sloan, MD, MPH, FACEP Hemophilia and Rare Bleeding Disorders

2 Edward P. Sloan, MD, MPH, FACEP Atlantic City, NJ September 24, 2007 2007 EMA Advanced Emergency & Acute Care Medicine Conference Atlantic City, NJ September 24, 2007

3 Edward P. Sloan, MD, MPH, FACEP Edward P. Sloan, MD, MPH FACEP Professor Department of Emergency Medicine University of Illinois College of Medicine Chicago, IL

4 Edward P. Sloan, MD, MPH, FACEP Attending Physician Emergency Medicine University of Illinois Hospital Our Lady of the Resurrection Hospital Chicago, IL

5 Edward P. Sloan, MD, MPH, FACEP Disclosures Novo Nordisk grant to conference Novo Nordisk grant to conference FERNE Chairman and President FERNE Chairman and President FERNE grants from Novo Nordisk FERNE grants from Novo Nordisk No financial disclosures No financial disclosures eMedicine source materials eMedicine source materials Slide materials from Novo Nordisk Slide materials from Novo Nordisk

6 Edward P. Sloan, MD, MPH, FACEP www.ferne.org

7 Global Objectives Maximize patient outcome Maximize patient outcome Utilize health care resources well Utilize health care resources well Optimize evidence-based medicine Optimize evidence-based medicine Enhance ED practice Enhance ED practice

8 Edward P. Sloan, MD, MPH, FACEP Sessions Objectives Learn about hemophilia and RBDs Learn about hemophilia and RBDs What are the diseases? What are the diseases? How do patients present? How do patients present? What are management principles? What are management principles? What specific therapies? What specific therapies? How to enhance pt outcomes? How to enhance pt outcomes?

9 Edward P. Sloan, MD, MPH, FACEP Case Presentation 17 year old presents to ED Known hemophilia A Fell off of bicycle Abdominal trauma Hypotensive, tachycardic Abdominal tenderness What do you do?

10 Edward P. Sloan, MD, MPH, FACEP ED Bleeding Disorder Patients: Key Concepts Identify the bleeding disorder Establish if bleeding is present Treat the bleeding Treat the bleeding disorder Establish endpoint for Rx success Disposition based on Dx, Rx, risk

11 Edward P. Sloan, MD, MPH, FACEP Background Rare disorder: Affects fewer than 200,000 Americans (NIH office of Rare Diseases) Hemophilia Other bleeding disorders Rare Bleeding Disorders

12 Edward P. Sloan, MD, MPH, FACEP Disease States

13 Edward P. Sloan, MD, MPH, FACEP Hemophilia Hemophilia A Congenital deficiency of factor VIII (FVIII) Hemophilia B: Christmas Disease Congenital deficiency of factor IX (FIX)

14 Edward P. Sloan, MD, MPH, FACEP Hemophilia Insufficient generation of thrombin by FVIIIa and FIXa complex through the intrinsic pathway of the coagulation cascade

15 Edward P. Sloan, MD, MPH, FACEP Coagulation Cascade

16 Edward P. Sloan, MD, MPH, FACEP Fibrin Clot Structure Hemophilia ANormal Clot Structure

17 Edward P. Sloan, MD, MPH, FACEP Hemophilia Severity Based on procoagulant levels or bleeding severity Severe: <1% clotting factor present Severe: <1% clotting factor present Moderately severe: 1-5% Moderately severe: 1-5% Mild: 5-40% Mild: 5-40% Clinical bleeding severity may not match amount of deficiency Clinical bleeding severity may not match amount of deficiency

18 Edward P. Sloan, MD, MPH, FACEP Other Inherited Bleeding Disorders Congenital factor deficiencies Congenital factor deficiencies von Willebrands Disease von Willebrands Disease Other congenital platelet disorders Other congenital platelet disorders Glanzmanns Thrombasthenia Glanzmanns Thrombasthenia Bernard Soulier Syndrome Bernard Soulier Syndrome

19 Edward P. Sloan, MD, MPH, FACEP von Willebrands Disease Autosomally inherited bleeding disorder, mucocutaneous Deficiency or dysfunction of the protein termed von Willebrand factor (vWF) Primary hemostasis is impaired Defective interaction between platelets and the vessel wall

20 Edward P. Sloan, MD, MPH, FACEP Factor VII Deficiency Fewer than 200 cases of true factor VII deficiency have been reported Fewer than 200 cases of true factor VII deficiency have been reported Gene mutations, protein dysfunction Gene mutations, protein dysfunction Factor VII coagulant activities measured in the laboratory are not well correlated with bleeding manifestations Factor VII coagulant activities measured in the laboratory are not well correlated with bleeding manifestations

21 Edward P. Sloan, MD, MPH, FACEP Acquired Bleeding Disorders Vitamin K Deficiency Severe Liver Disease Factors II, VII, IX and X are decreased Platelets dysfunctional Renal Disease Platelet dysfunction

22 Edward P. Sloan, MD, MPH, FACEP Acquired Bleeding Disorders Oral Anticoagulant Therapy Prolonged Use of Antibiotics Develop anti-platelet antibodies Vitamin K deficiency Acquired Inhibitors (Antibodies) Post malignancy Related to pregnancy Idiopathic Elderly

23 Edward P. Sloan, MD, MPH, FACEP Emergency Department Evaluation

24 Edward P. Sloan, MD, MPH, FACEP Patient Demographics Hemophilia Present in childhood, esp with greater disease severity All races X-linked, recessive males

25 Edward P. Sloan, MD, MPH, FACEP Patient Presentations Mannucci et al. Blood 2004;104:1243-1252

26 Edward P. Sloan, MD, MPH, FACEP History What is the Bleeding Disorder? vWD, Hemophilia A/B, other factor deficiency or platelet disorder

27 Edward P. Sloan, MD, MPH, FACEP History What is the severity of the factor deficiency? Severe - < 1% factor present Bleed spontaneously and often e.g. weekly Moderate – 1-5 % Can have spontaneous bleeding but less frequent e.g. monthly Mild - > 5 % Bleed only when hemostasis is challenged e.g. trauma and surgery

28 Edward P. Sloan, MD, MPH, FACEP 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 Edward P. Sloan, MD, MPH, FACEP 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 Edward P. Sloan, MD, MPH, FACEP Hemorrhage History GI - Hematemesis, melena, frank red blood per rectum, and abdominal pain Genitourinary - Hematuria, renal colic, and postcircumcision bleeding

31 Edward P. Sloan, MD, MPH, FACEP Hemorrhage History Other - Epistaxis, oral mucosal hemorrhage, hemoptysis, dyspnea (hematoma leading to airway obstruction), compartment syndrome symptoms, and contusions; excessive bleeding with routine dental procedures

32 Edward P. Sloan, MD, MPH, FACEP Physical Exam General hemorrhage signs Organ-specific hemorrhage signs Hepatitis signs Infections signs Medic Alert bracelet Wallet the astonis hing results performance improvement

33 Edward P. Sloan, MD, MPH, FACEP Physical Exam General hemorrhage signs Organ-specific hemorrhage signs Hepatitis signs Infections signs Medic Alert bracelet Hemophilia Treatment Center Card) Wallet (Hemophilia Treatment Center Card) the astonis hing results perform ance improve ment

34 Edward P. Sloan, MD, MPH, FACEP Laboratory Testing CBC (Hb, platelets, WBC) PT, aPTT vWF:Ag (Von Willibrand factor antigen) Ristocetin Co-Factor Measures vWF activity to identify qualitative vWF disorder Factor coagulant activity e.g. VIII:C, IX:C in hemophilias Bleeding time?

35 Edward P. Sloan, MD, MPH, FACEP Lab Results for Bleeding Disorders Prolonged PT Prolonged aPTT Prolonged PT and aPTT Inherited Disorders FVII Deficiency FVII Deficiency vWF Type 2&3 vWF Type 2&3 FVIII, FIX, FXI or FXII deficiency FVIII, FIX, FXI or FXII deficiency FII, fibrinogen, FV, X or a combined factor deficiency FII, fibrinogen, FV, X or a combined factor deficiency AcquiredDisorders FVII Inhibitor FVII Inhibitor Vit K deficiency Vit K deficiency Liver disease Liver disease Warfarin use Warfarin use Inhibitor to FVIII, IX, XI, XII, vWF Inhibitor to FVIII, IX, XI, XII, vWF Heparin use Heparin use Direct thrombin inhibitor Direct thrombin inhibitor Inhibitor to FII, fibrinogen or FV or X Inhibitor to FII, fibrinogen or FV or X Liver disease, DIC, combined heparin and warfarin use Liver disease, DIC, combined heparin and warfarin use

36 Edward P. Sloan, MD, MPH, FACEP Laboratory Testing PT: Extrinsic, should be normal unless FVII deficiency or acquired aPTT: Intrinsic, elevated in moderate hemophilia disease severity

37 Edward P. Sloan, MD, MPH, FACEP Other ED Testing Extremity xrays Head CT Abdominal CT Tests for increased compartment pressures Nuclear bleeding studies

38 Edward P. Sloan, MD, MPH, FACEP Emergency Department Management

39 Edward P. Sloan, MD, MPH, FACEP Initial Management Treat the patient ABCs Direct hemorrhage control Hemodynamic support Crystalloids Blood products Specifically assist hemostasis

40 Edward P. Sloan, MD, MPH, FACEP Primary hemostasis: Vasoconstriction Vasoconstriction Platelet adhesion Platelet adhesion Platelet aggregation and contraction Platelet aggregation and contraction Secondary hemostasis: Activation of coagulation factors Activation of coagulation factors Formation of fibrin Formation of fibrinFibrinolysis: Activation of fibrinolysis Activation of fibrinolysis Lysis of the plug Lysis of the plug The 3 Phases of Hemostasis

41 Edward P. Sloan, MD, MPH, FACEP Blood Vessel & Endothelium Hemostasis requires and involves various physiological components: Hemostasis requires and involves various physiological components: The blood vessel wall The blood vessel wall Endothelial cells Endothelial cells Subendothelial tissue Subendothelial tissue Smooth muscle cells Smooth muscle cells The components of blood The components of blood Platelets (thrombocytes) Platelets (thrombocytes) Coagulation (clotting) factors Coagulation (clotting) factors Fibrinolytic/ anticoagulant proteins Fibrinolytic/ anticoagulant proteins

42 Edward P. Sloan, MD, MPH, FACEP 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 injury The first response to endothelial injury is the constriction of the damaged vessel which reduces the blood flow at the site of injury

43 Edward P. Sloan, MD, MPH, FACEP Primary Hemostasis: Formation of a Platelet Plug The exposure of subendothelial components such as collagen promotes platelet adhesion The exposure of subendothelial components such as collagen promotes platelet adhesion The adherence of platelets to the sub- endothelium leads to platelet activation and the formation of platelet aggregates (platelet plug) The adherence of platelets to the sub- endothelium leads to platelet activation and the formation of platelet aggregates (platelet plug)

44 Edward P. Sloan, MD, MPH, FACEP At the site of vascular injury binding of endogenous factor VII/VIIa to tissue factor (TF) leads to the generation of small amounts of thrombin At 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 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 This thrombin burst induces the generation of a haemostatic plug that prevents further blood loss Secondary Hemostasis Adapted from Hoffman M et al., 2001. 1

45 Edward P. Sloan, MD, MPH, FACEP XII XI IX VIIIa X Va IIa (thrombin) II (prothrombin) fibrinogen Fibrin Clot Fibrin Clot TF VIIVIIa/TF X HMWK,PK (factor I) PT PTT How a Blood Clot Forms: Step 2

46 Edward P. Sloan, MD, MPH, FACEP What is Broken? Platelets Clotting factors Coagulation cascade

47 Edward P. Sloan, MD, MPH, FACEP What Can Be Provided? Vitamin K FFP (Fresh frozen plasma) PCC ( prothrombin complex concentrate) Platelets, packed RBCs, whole blood Specific clotting factors Anti-fibrinolytics, anti-hemophilics

48 Edward P. Sloan, MD, MPH, FACEP 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 Edward P. Sloan, MD, MPH, FACEP 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 Edward P. Sloan, MD, MPH, FACEP 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 Edward P. Sloan, MD, MPH, FACEP Hemophilia A: Other Rx FFP: administer 1 mL IV FFP/U factor VIII. Anti-fibrinolytics: Epsilon aminocaproic acid (Amicar) Oral mucosal bleeds, rich fibrinolytic activity 200 mg/kg PO/IV initial dose, 100 mg/kg q6h; not to exceed 5 g Alternatively, 10 g slow IV (over 2 h), followed by 1 g/h continuous infusion

52 Edward P. Sloan, MD, MPH, FACEP Hemophilia A: Other Rx Anti-hemophilic agent: 1-deamino-8-D-arginine vasopressin (desmopressin acetate, DDAVP) 1-deamino-8-D-arginine vasopressin (desmopressin acetate, DDAVP) Increase (up to 4-fold) in FVIII plasma levels Increase (up to 4-fold) in FVIII plasma levels 0.3 mcg/kg in 30-50 mL 0.9% isotonic saline IV over 15-20 min 0.3 mcg/kg in 30-50 mL 0.9% isotonic saline IV over 15-20 min Not indicated in platelet type vWB Not indicated in platelet type vWB

53 Edward P. Sloan, MD, MPH, FACEP Hemophilia B: Factor IX Synthetic recombinant Factor IX Units factor IX =(weight in kg)(100 mL/kg)(1 U factor IX/mL)(desired factor IX level minus the native factor IX level)

54 Edward P. Sloan, MD, MPH, FACEP 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 Edward P. Sloan, MD, MPH, FACEP 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 Edward P. Sloan, MD, MPH, FACEP Hemophilia B: Factor IX Factor IX complex concentrates Coagulation factor IX concentrates, pooled plasma product (high purity)

57 Edward P. Sloan, MD, MPH, FACEP Hemophilia B: Other Rx FFP: administer 1 mL IV FFP/U factor IX. Anti-fibrinolytics: Epsilon aminocaproic acid (Amicar) Oral mucosal bleeds, rich fibrinolytic activity 200 mg/kg PO/IV initial dose, 100 mg/kg q6h; not to exceed 5 g Alternatively, 10 g slow IV (over 2 h), followed by 1 g/h continuous infusion

58 Edward P. Sloan, MD, MPH, FACEP vWDx: Platelet Activation - GPIb IX, V : internalized - GPIIbIIIa : 1) membrane expression increased 2) complex occupied by fibrinogen, vonWillebrand Factor... - P-selectin : translocated to the membrane RESTING ACTIVATED ACTIVATION granules P-selectin GPIV GPIIb-IIIa GPIb/IX/V P-selectin GPIIb-IIIa GPIV GPIb/IX/V Fibrinogen 50,000 25,000 > 500

59 Edward P. Sloan, MD, MPH, FACEP von Willebrands Disease Rx Anti-hemophilic agent: Type 1 vWDx 1-deamino-8-D-arginine vasopressin (desmopressin acetate, DDAVP) 1-deamino-8-D-arginine vasopressin (desmopressin acetate, DDAVP) Up to 3-6 fold increase in FVIII and 2-4 fold increase in vWF plasma levels Up to 3-6 fold increase in FVIII and 2-4 fold increase in vWF plasma levels 300 mcg intranasally produces levels comparable to IV infusion 300 mcg intranasally produces levels comparable to IV infusion Useful for menorrhagia and epistaxis Useful for menorrhagia and epistaxis

60 Edward P. Sloan, MD, MPH, FACEP von Willebrands Disease Rx Platelet transfusions if other Rx not effective, not used widely Cryoprecipitate, FFP contain functional vWF, not used widely

61 Edward P. Sloan, MD, MPH, FACEP Rare Bleeding Disorders Congenital factor deficiency of any of the following: VII XI X II V Combined V and VIII Fibrinogen XIII PAI-1 Congenital Platelet Disorders Glanzmanns Thrombasthenia Bernard Soulier von Willibrands Disease – Types 2 & 3

62 Edward P. Sloan, MD, MPH, FACEP Rare Bleeding Disorders: Rx Stabilize the patient. Call the hematology/oncology consultant.

63 Edward P. Sloan, MD, MPH, FACEP What Can Be Provided? Specific clotting factors PCC, other concentrates Anti-fibrinolytics, anti-hemophilics FFP (1 mL per Unit of clotting factor) Platelets

64 Edward P. Sloan, MD, MPH, FACEP Patient Outcome Low Hb, ruptured spleen IVF, cross-matched blood 10% Factor VIII levels prior Units factor VIII = (70 kg)(50 mL/kg) (1 U factor VIII/mL)(.90) = 3500 Stable to ICU with expectant management

65 Edward P. Sloan, MD, MPH, FACEPConclusions Complex medical problems Lumpers and splitters Treat the patients hemorrhage Identify the disease Treat the disease, as able Consult liberally Admit as indicated

66 Edward P. Sloan, MD, MPH, FACEP Questions? edsloan@uic.edu 312 413 7490 sloan_ema_2007_hemophilia_rbd_092307_final 6/2/2014 3:12 PM


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