Evaluation of Bleeding in the Pediatric Patient

1. Evaluation of Bleeding in the Pediatric Patient Thomas C Newton, MD Major, MC, USAF Fellow - Pediatric Hematology/Oncology Uniformed Services University of the Health Sciences

2. Objectives • Understand the different laboratory testing available for evaluation of bleeding • Understand the available options for treatment • Determine appropriate laboratory work-up based on history and physical exam • Determine most likely diagnosis and appropriate treatment options based on relevant clinical and laboratory data

3. Hemostasis: An Overview • Vasoconstriction • Formation of the platelet plug • Formation of the fibrin clot

7. Clot Lysis

8. Defects of Primary Hemostasis • Thrombocytopenia • decreased production • increased destruction • abnormal distribution • Platelet function defects • Receptor/membrane defects • storage granule defects • Inhibition (meds, toxins) • Vascular/connective tissue disorders

9. Defects of Secondary Hemostasis • Inherited factor deficiencies • Hemophilia A and B • Rare: fibrinogen, FV, FVII, FX, FXI, FXIII • Acquired factor deficiencies • Vitamin K deficiency • Liver dysfunction • DIC • Acquired inhibitory antibodies

10. Coagulation Testing Plasma

11. Coagulation Testing – Abnormal APTT • Factor VIII • ?? vWD • Factor IX • Factor XI • Heparin • Intended • Line draw • Other

12. APTT Curve: Factor XI

13. Coagulation Testing – Abnormal Protime • Factor VII • Coumadin • Occ. Liver Disease • Occ. DIC • rVIIa Effect

14. Coagulatin Testing – Abnormal PT and APTT • Common Pathway Factors • II, V, X • Fibrinogen • Liver Disease • Vitamin K Deficiency • Coumadin • DIC

15. Normal Patient with Abnormal Coagulation Labs • Lupus Anticoagulant • Mild Factor Deficiency • High Pathway Factor Deficiency • HMWK, PK, Factor XII • Lab Error

16. Bleeding Patient with Normal Coagulation Labs • Lab Error • Platelet Disorder • Mild vWD • Connective Tissue Disorder • Factor XIII • Factitious (ie – Suture deficiency)

18. Special Coagulation Testing • Mixing Study • vWF Testing • PFA-100 • Platelet Aggregation Studies • Lupus Anticoagulant Studies

19. Mixing Study

20. Von Willebrand Factor Assay • vWF Antigen • vWF Activity (Ristocetin CoFactor) • Factor VIII Activity • vW Multimers • Blood Type O+ decreases vWF • Stress/Menses increases vWF

21. Clinically Relevant Factor Levels

22. Hemostatic Agents • Systemic – Nonspecific • Blood Products • Platelet Concentrates • Fresh Frozen Plasma (FFP) • Cryoprecipitate (Cryo) • Medications • Desmopression (Stimate) • Aminocaproic Acid (Amicar) • Tranexamic Acid (only IV) • Aprotinin

23. Hemostatic Agents • Systemic – Specific • Factor Concentrates (Plasma Derived) • FVIII and FIX • Activated Prothrombin Complex Concentrates (APCC) • FII, FVII, FIX, FX • Prothrombin Complex Concentrates • FXIII • vWF (Humate-P) • Factor Concentrates (Recombinant) • rFVIII and rFIX • rFVIIa • rFXIII

24. Hemostatic Agents - Topical • Mammalian Factor Based • Topical Thrombin (Bovine) • Fibrin Sealant (Human ± Bovine) • Platelet Gel • Collagen Based • Cellulose Based • Gelatin Based • Antifibrinolytics • Amicar

25. Pros Contains all hemostatic factors Not thrombogenic Easily available Cons Too dilute to increase majority of individual factors to hemostatic levels Hypersensitivity Potential infectious agent transmission Fresh Frozen Plasma

26. Pros Enriched with vWF, FVIII, FXIII, fibrinogen Treatment of choice for fibrinogen and FXIII deficiencies Cons Potential transmission of infectious agents Transfusion reactions Cryoprecipitate

27. Pros Increases vWF and FVIII vWD and mild hemophilia A Enhances platelet function Platelet Dysfunction IV and intranasal Cons Flushing, hypotension, headache, SIADH Not useful for severe bleeding or type 2 & 3 vWD Not all patients respond Desmopressin (Stimate)

28. Pros Enhances clot stability (prevents rebleeding) PO and IV Few side effects Cons Potentially thrombogenic Not effective at stopping bleeding in areas without increased fibrinolytic activity, if bleeding brisk, or liver clot present Aminocaproic Acid (Amicar)

29. Specific Factor Concentrates • FVIII • Recombinate – rFVIII: contains human albumin, viral inactivation • Advate – rFVIII: no added human/animal protein, viral inactivation • FIX • Benefix – rFIX: no added human/animal protein, larger volume of distribution than pd-FIX

30. Dosing Recommendations for Clotting Factor Replacement Therapy

31. Specific Factor Concentrates • pd-vWF (Humate-P) • 2 doses on vial – vWD and Hemophilia A • rFVIIa • Hemophilia with inhibitors • FVII deficiency • pd-FXIII (compassionate basis in USA)

32. Evaluation - History • Type of bleeding • Mucosal bleeding vs joint/soft tissue bleeding • Medications • Age of onset • Newborn/infant vs older • Surgeries/trauma • Patient and family • Circumcision

33. Evaluation - History • Transfusions • Especially if required after child birth or surgery • Recent/current illness or underlying medical problem • Family history of bleeding • Be specific • Gynecology history of family members

34. Evaluation • Physical exam • Ecchymoses, petechiae • Telangiectasias, hemangiomas • Joint deformities, hypermobility • Organomegaly

35. Primary Evaluation • Initial laboratory evaluation • PT, APTT, CBC with diff • Consider adding fibrinogen and TT for sepsis/infection, DIC, liver failure in differential diagnosis

36. Secondary Evaluation • ?vWD – consider panel • Abnormal PT or APTT • Mixing study to determine deficiency versus inhibitor • Specific Factor activity levels • Lupus anticoagulants

37. Case 1 • Called to nursery to see newborn male infant with bleeding from circumcision • History reveals the infant had prolonged oozing from heel stick • History of maternal uncle who died at age 2 from bleeding after surgery • Circumcision bleed is now stopped

38. Case 1 • Initial Labs: • 8.6 >15/48<210 • APTT 75 seconds, PT 15 seconds, fibrinogen 347, TT 17 seconds • What tests to order next?

39. Case 1 • APTT 1 to 1 mix corrects prolongation • What does this indicate? • Do you want to order any further testing? • Do you want to give a Hemostatic Product?

40. Case 1 • FVIII 2%, FIX 27%, FXI 58% • vWF antigen < 10% • Diagnosis – Type 3 vWD • What product is appropriate to use if circumcision starts to bleed again?

41. Case 2 10y/o female with bleeding from an extracted tooth that has been on and off for 2 days FH: paternal aunt “heavy cycles”, father also with frequent nosebleeds PE: normal, scattered ecchymoses on anterior tibia and knees/elbows, gelatinous material in tooth socket

42. Case 2 Laboratory data: 7.5>12/35<280 PT 12 sec APTT 35 sec Do you want to order additional laboratory testing? Do you want to institute any therapies?

43. Case 2 • vWF Panel • vW Antigen 18% • Ristocetin Cofactor 12% • Factor VIII Activity 55% • Multimers – normal • Diagnosis: Type I vWD • What would be the next testing/procedure that you would want to pursue for this patient?

44. von Willebrand Disease • Most common inherited bleeding d/o • Autosomal dominant • Mucocutaneous and post-trauma/surgical bleeding • Quantitative or qualitative defect in vWF • Adherence of platelets to endothelium • Stored by platelets and endothelial cells • Circulates bound to FVIII

45. Case 3 15m/o male with swollen, painful elbow Fell on the lawn this am without any significant trauma, no recent illness Bruises easily No prior surgeries, not circumcised FH: unknown, patient adopted

47. Case 3 PE: swollen, tender left elbow, scattered ecchymoses Laboratory data: CBC 11> 12/36 <750 PT 14 sec APTT 60 sec Do you want any additional laboratory testing? Do you want to give any treatment and if so what do you want to treat with?

48. Case 3 • Mixing Study 1:1 for APTT • 0 min 60 min • Patient 30 31 • Normal 28 29 • After 25units/kg rFVIII and 60units/kg rFIX given there appears to be no additional swelling of the joint

49. Case 3 • FVIIIa 89%, FIXa 2%, FXIa 98% • Diagnosis: Hemophilia B

50. Hemophilia • Inherited deficiency of FVIII (hemophilia A) or IX (hemophilia B) • X-linked recessive • Spontaneous bleeds, hemarthroses and deep tissue bleeding