GRAND ROUNDS 22nd February, 2006 Dr. N. Singh Dr. O. Ingaramo Dr. S. Manuel

1. GRAND ROUNDS 22nd February, 2006 Dr. N. Singh Dr. O. Ingaramo Dr. S. Manuel

2. HISTORY OF PRESENT ILLNESS An 8 m old boy was brought to the ER with a history of several episodes of epistaxis over the last 12 hrs. The mother was also concerned about some scattered bruising on her son’s forehead, occiput, elbows and flanks over the last 10 days.

3. DEVELOPMENT HISTORY Sitting by himself, crawling, in walker. Imm HX: Delayed – needs 6 mo vaccinations. PM Hx: 1. Enterococcal Meningitis @ birth 2. ALTE at 1 mo of age – cyanotic episode at home, ? apneas noticed during hospitalization.

4. FAMILY AND SOCIAL HISTORY No h/o bleeding disorders. Single mother, lives with boyfriend in a trailer park. No h/o substance abuse. Primary caretaker is mother. Infant also spends time in a daycare and with father of boyfriend (esophageal cancer).

5. PHYSICAL EXAM Afebrile, normal vital signs. Wt: 5th percentile; Length: 10th percentile; HC: 25th percentile. Alert, interactive and in no distress HEENT: With some dried blood in nares. Neck: No Lymph nodes palpable. Chest: CTA B/L CVS-No murmur

6. PHYSICAL EXAM Abd - No HSM (hepatosplenomegaly), No masses. Ext: FROM, No swelling in joints. Skin: Several areas of green-yellow areas of bruising on the forehead, occiput, elbows and flanks.

7. SUMMARY An 8 m old boy with epistaxis over the last 12 hrs. Bruising on forehead, occiput, elbows and flanks over the last 10 days. Enterococcal Meningitis @ birth ALTE at 1 mo of age – cyanotic episode at home, ? apneas noticed during hospitalization

8. SUMMARY No h/o bleeding disorders Single mother, lives with boyfriend in a trailer park. Father of boyfriend (esophageal cancer). Afebrile, normal vital signs Wt: 5th percentile ; Length: 10th percentile; HC: 25th percentile. Alert, interactive and in no distress.

9. SUMMARY HEENT: With some dried blood in nares. Neck: No Lymph nodes palpable. Abd - No HSM (hepatosplenomegaly), No masses Ext: FROM, No swelling in joints Skin: Several areas of green-yellow areas of bruising on the forehead, occiput, elbows and flanks

10. HEMOSTASIS REQUIRES NORMAL: Vessels Platelets Coagulation pathway components.

13. PLATELETS DISORDERS Thrombocytopenias: Decreased production. Platelet pooling and splenic sequestration . Increased destruction. Plt <100 000 Spontaneous bleeding uncommmon with plt > 20,000. Bleeding time prolonged, PT/PTT normal.

14. PLATELETS DISORDERS (cont.) Decreased Production: Malignancies (leukemia, lymphoma, neuroblastoma). Bone marrow suppression Drug-related (aplastic anemia) Infection Congenital Fanconi anemia TAR syndrome Wiscott-Aldrich Glycogen storage diseases

15. PLATELETS DISORDERS (cont.) Platelet Dysfunction: Congenital Glanzmanns thrombasthenia (GP11b/IIIa deficiency) Bernard Soulier (vWF receptor deficiency) Acquired Drugs (ASA/NSAIDs, lasix, nitrofurantoin) Renal disease Liver disease

16. PLATELETS DISORDERS (cont.) Increased Platelet Destruction: Immunologic ITP SLE Isoimmunization (post-transfusion, neonatal) Drug related (heparin, quinine, digoxin, sulphonamides, phenytoin) Infection Sepsis Mechanical DIC HUS-TTP Giant hemangioma (Kasabach-Merritt) Burns Trauma

17. PLATELETS DISORDERS (cont.) Thrombocytopenia: Sequestration Hypersplenism Sickle cell anemia Dilutional Massive transfusion

18. VASCULAR DISORDERS Loss of Vascular Integrity: Acquired: - Trauma/NAI, Scurvy, Steroid induced, Increased intravascular pressure (coughing, vomiting, straining). Congenital: - Disorders of connective tissue: Ehlers-Danlos syndrome, Osteogenesis imperfecta, Marfan’s. - Disorders of blood vessels: Hemorrhagic telangiectasia

19. VASCULAR DISORDERS: Vasculitis Drug-related Infection Viral Coxsackie A9, B3 Echoviruses 4,9 Atypical measles Bacterial Meningococcemia Streptococcal pharyngitis Septic emboli SBE Gonococcus Rickettsial Rocky Mountain spotted fever Immune-mediated HSP SLE Serum sickness Dysgammaglobulinemia

20. COAGULATION FACTOR DISORDERS Clotting factor deficiencies Congenital Von Willebrand’s disease Hemophilias II, V, X or Fibrinogen deficiency. Acquired Vitamin K deficiency Liver disease Malabsorption Warfarin/superwarfarin Toxin mediated: Coumadin containing rodenticides.

21. LABS LFTs – Bilirubin 0.3 mg/dL Alk PO4 283 u/L (150-420 u/L) Aspartate aminotransferase 83 u/L (20-65 u/L) Protein 5.9 gm/dL (5.6 – 7.2 gm/dL) Albumin 3.5 gm/dL (3.5 – 5.5 gm/dL)

22. LABS WBC 9.0. Hb 13, Hct 48.2 Platelets 212. S 56, B 0, L 38, M 5, E 1 UA ? Normal PT ? 59.1 (10-13 secs) PTT ? 120 secs (26 – 37 secs)

23. GRAND ROUNDS Februay, 2006 Dr. Singh, N. Dr. Manuel, S. Dr. Ingaramo, O.

24. EVALUATIONS OF BLEEDING DISORDERS Require a thorough history and physical exam. Important questions include prolonged bleeding following minor trauma, spontaneous bruising, or hematoma formation. Drug history is important since many drugs cause bleeding. ie Aspirin. Family history and any possible pattern of inheritance.

25. PHYSICAL EXAM Petechiae and purpura are signs of platelet dysfunction. Large firm bruises with nodular centers are commonly seen in congenital factor deficiencies. Icterus and hepatosplenomegaly are indicative of liver disease, which may be associated with bleeding disorders

26. CLASIFICATION OF BLEEDING DISORDERS Defects of primary hemostasis (platelets, vessels, etc.). Defects of secondary hemostasis (coagulation cascade and its regulation)

27. DEFECTS OF PRIMARY HEMOSTASIS Vascular disorders: -Laboratory tests are characterized by a prolonged bleeding time. Platelets Disorders: -Quantitative (thrombocytopenia). -Qualitative (poor platelet function): Inherited aggregation defect, Drug effect.

28. COAGULATION FACTORS DISORDERS Congenital factor deficiency -Hemophilia A and B -Von Willebrand disease -Other factor deficiencies (rare) Acquired factor deficiency -Vitamin K deficiency -Liver failure -DIC -Drugs: Anticoagulants. Antiphospholipid antibody

29. COAGULATION CASCADE

30. LABORATORY OF BLEEDING DISORDERS Most common ordered labs: Platelet count. Bleeding time. PT: Extrinsic and common coagulation pathway. PTT: Intrinsec and common coagulation pathway.

31. LABORATORY OF BLEEDING DISORDERS (cont.) PTT mixing study: PTT corrects with factor deficiency, but it does not normalize with circulating ab/anticoagulants. If positive, determine whether the inhibitor is a true antibody to a coagulation protein or an antiphospholipid ab. Thrombin time (TT) and reptilase time measure conversion of fibrinogen to fibrine and the formation of the initial clot by thrombine. Ristocetin, vWF antigen, WF quantity, vWD multimeric assay.

32. LABORATORY OF BLEEDING DISORDERS (cont). Assays for fibrinogen, platelet aggregation or platelet function assay (e.g. PFA-100), factor XIII, dysfibrinogenemia (thrombin time or reptilase time) Also assays for factors VIII, IX or XI, even with normal PTT More esoteric assays include PAI-1 activity and antiplasmin

33. LABORATORY OF BLEEDING DISORDERS (cont). PT is increased in factor deficiency (I, II, V, VII, X), liver failure, vitamin K deficiency, coumadin, warfarins. aPTT is increased in factor deficiency (XII, XI, IX and VIII), vWD, lupus anticoagulant and heparin tx. It is less sensitive than the PT to deficiencies within the common pathway (X, V, II and I). Not affected by VII and XIII. TT is increased in fibrinogen problems and heparin tx. Not affected by XIII.

34. LABORATORY OF BLEEDING DISORDERS (cont). Routine screening testing with the platelet count, PT, TT, aPTT should allow the clinician to more narrowly define the diagnostic possibilities. Prolonged PT and aPTT: In a bleeding child who is otherwise well indicates an inherited disorder within the common pathway (I, II, V, X) or an acquired disorder involving multiple pathways or anticoagulant factor. Other: Amyloidosis, coumadin. In a sick child consider DIC, hepatocellular dysfunction, severe vit K deficiency, thrombosis, hemangioma. Normal TT with normal fibrinogen level will exclude abnormal fibrinogen.

35. COAGULATION CASCADE

36. DIFFERENTIAL DX IN PROLONGED PT AND PTT Factor X deficiency: rare (1 per 1 million) AR deficiency characterized by asymptomatic heterozygotes and by homozygotes with bleeding symptoms that correlate with factor activity. May be associated with bruising, epistaxis, menorrhagia, GI/GU or umbilical stump bleeding or bleeding after surgery, trauma, dental procedures, pregnancy or circumcision Severe deficiencies may resemble hemophilia and may be associated with intracranial hemorrhage. Treatment: fresh frozen plasma; Prothrombin complex concentrates for serious bleeding.

37. COAGULATION CASCADE

38. DIFFERENTIAL DX IN PROLONGED PT AND PTT Factor V deficiency: rare (1 per 1 million) AR deficiency in which asymptomatic heterozygotes and homozygotes manifesting platelet-type bleeding (easy bruising, epistaxis). Severe deficiencies associated with intracranial hemorrhage, although levels do not always correlate with severity of symptoms Treatment: 10-20 ml fresh frozen plasma/kg; commercial concentrates of factor V are not available

39. COAGULATION CASCADE

40. DIFFERENTIAL DX IN PROLONGED PT AND PTT Factor II deficiency: rare (1 per 2 million) AR disorder associated with mucosal and deep tissue bleeding. Treatment: 10-20 ml fresh frozen plasma/kg; prothrombin complex concentrates may be used for serious bleeding.

41. COAGULATION CASCADE

42. DIFFERENTIAL DX IN PROLONGED PT AND PTT Factor I / fibrinogen deficiency or disorders Rare. Autosomal inheritance; most mutations are in alpha-fibrinogen chain gene, sparing beta and gamma chains Afibrinogenemia: homozygous form; causes severe quantitative deficiency of fibrinogen and increased risk of bleeding; associated with intracranial hemorrhages. Hypofibrinogenemia: heterozygous form; mild/moderate reductions in fibrinogen; little/no bleeding.

43. DIFFERENTIAL DX IN PROLONGED PT AND PTT Dysfibrinogenemia: qualitative fibrinogen. Bleeding due to defective fibrin clot formation (impaired release of fibrinopeptides A or B) Thrombosis due to (a) defective thrombin binding to fibrin, causing increased thrombin in circulation; (b) defective binding of tPA or plasminogen to fibrin. Labs: concentration determined by ELISA. Often prolonged TT and reptilase time, PT and PTT Treatment: cryoprecipitate; fresh frozen plasma contains more fibrinogen, but in a much larger volume.

44. DIFFERENTIAL DX IN PROLONGED PT AND PTT Combined factor deficiencies are very rare Combined factor V and VIII: autosomal recessive. Combined factors II, VII, IX and X deficiency: due to mutation in gamma-glutamyl carboxylase gene, whose protein carboxylates glutamate residues in vitamin K-dependent coagulation factors Very rare to have bleeding disorders due to deficiency in PAI-1 or antiplasmin

45. DIFFERENTIAL DX IN PROLONGED PT AND PTT ACQUIRED DEFECTS OF SECONDARY HEMOSTASIS: Vitamin K is needed for the synthesis of factors II, VII, IX and X. Vitamin K is vital to the carboxylation of glutamic acid residues which is needed for the activation of these factors. The most common circumstance in which vitamin K deficiency leads to bleeding is hemorrhagic disease of the newborn.

46. ACQUIRED DEFECTS OF SECONDARY HEMOSTASIS:  Vitamin K (cont.) Without vitamin K supplementation, significant GI and cutaneous hemorrhage may develop within a few days. After the newborn period, vitamin K is absorbed from the GI tract. Deficiency may then result from nutritional deficits, malabsorption, or alteration in intestinal flora. Treatment must be directed at the underlying disorder and vitamin K supplementation.

47. DIFFERENTIAL DX IN PROLONGED PT AND PTT ACQUIRED DEFECTS OF SECONDARY HEMOSTASIS (cont.) Decreased synthesis of coagulation proteins occurs in severe liver disease. Abnormalities in the liver's capacity to synthesize one or more clotting factors may result in problems with hemostasis. Treatment involves replacement of the decreased factor(s) with fresh frozen plasma.

48. DIFFERENTIAL DX IN PROLONGED PT AND PTT ACQUIRED DEFECTS OF SECONDARY HEMOSTASIS (cont.): Acquired factor deficiencies (due to liver disease, DIC, lupus anticoagulants, heparin, warfarin or other anticoagulants) are more common than hereditary factor deficiencies, and should be ruled out first

49. ACQUIRED DEFECTS OF SECONDARY HEMOSTASIS (cont.): Acquired inhibitors are antibodies that neutralize a specific clotting factor's function The most commonly inhibited factor in clinical practice is factor VIII. Autoantibodies to VIII:C are characteristically oligoclonal non-complement-fixing IgG. The incidence is 0.2 to 1 per million person-years with a higher incidence in older age groups. These cause a prolonged PTT which is not corrected with 1:1 dilution with normal plasma.

50. Acquired inhibitors (cont.) Lupus anticoagulant: Antibodies against protein-phospholipid complexes. May interfere with assays for factors VIII, IX, XI and XII without causing a true decrease in factor levels In adults, it may be associated with spontaneous abortion, and thromboembolism. In the pediatric population is transient with rare clinical sequelae. Soft-tissue bleeding, gross hematuria, and postsurgical hemorrhage can occur; fatal bleeds may occur in 15% of patients. The treatment is aimed at reducing the antibody titer using immunosuppression, IVIG, or Plasmapheresis.

51. Acquired Defects of Secondary Hemostasis (cont.) Disseminated intravascular coagulation (DIC) Occurs in patients who are critically ill. Fever, hypotension, acidosis, oliguria, or hypoxia may be present. In addition, petechiae, purpura, and oozing from wounds and venipuncture sites may develop. Microvascular and large vessel thrombosis may occur. The platelet count is typically decreased due to consumption and platelet destruction.

52. DIC (cont.) The PT and PTT are prolonged from depletion of factors V, VIII, IX, and XI. Fibrinogen is decreased. Fibrin degradation products and the D-dimer assay are increased. The mainstay of therapy is to treat the underlying disease. Additional therapy consists of replacing clotting factors and platelets and possibly the use of heparin and antifibrinolytic agents.

53. Other Acquired Defects of Secondary Hemostasis Amyloidosis: Primary amyloidosis may cause acquired factor X deficiency due to the binding of amyloid to factor X. Also inhibits fibrinogen conversion to fibrin, causing prolongation of thrombin time and reptilase time.

54. SUMMARY Possible diagnosis in this patient with prolonged PT and PTT: Hereditary factor deficiency: I, II, V, X, antiplasmin and dysfibrinogenemia. Acquired defects of hemostasis: Vit K deficiency, liver disease, lupus anticoagulant, anticoagulant drugs, DIC, amyloidosis. Child abuse can be a concomitant dx.

55. Thank you.