Pediatric Bleeding Disorders and Thrombocytopenia. David Simon, MD Pediatric Hematology/Oncology Kaiser Permanente Downey Medical Center

Transcription

1 Pediatric Bleeding Disorders and Thrombocytopenia David Simon, MD Pediatric Hematology/Oncology Kaiser Permanente Downey Medical Center 1

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3 Case Presentations Case 1 12 month old male, no personal or family history, presents for WCC to PCP. Just began walking last week. After two days of walking (and falling) family noticed he stopped trying and seemed upset when they would try to make him walk for the video camera. Family upset they have no video of his first steps. PCP notices refusal to put weight on left leg and possibly swollen left ankle/foot 3

4 Case 1 12 month old male, no personal or family history, presents for WCC to PCP. Just began walking last week. After two days of walking (and falling) family noticed he stopped trying and seemed upset when they would try to make him walk for the video camera. Family upset they have no video of his first steps. PCP notices refusal to put weight on left leg and possibly swollen left ankle/foot WBC 5.7 Hgb 13.1 Plt: 344 PT: 10.3 PTT: 78 Fib: 344 Case 2 3 y/o male with no PMH presents to PCP with 2 days of sudden onset bruising and rash. No fever, very active, bouncing off walls (and off the exam table repeatedly). Normal vitals, bruising on the legs, arms, trunk and petechial rash. No bleeding. 4

5 Case 2 3 y/o male with no PMH presents to PCP with 2 days of sudden onset bruising and rash. No fever, very active, bouncing off walls (and off the exam table repeatedly). Normal vitals, bruising on the legs, arms, trunk and petechial rash. No bleeding. WBC 5.3 (nl diff) Hgb 12.1 Platelet 4 PT: 11.1 PT 29 Fibrinogen 278 5

6 Case 3 3 y/o with no past medical history presents to PCP complaining of increased sleeping for 1 week, less playful for 2-3 weeks, fever for 3-4 days and bruises for 2 days. This is 6 th visit to medical care in last 3 weeks, mother is not happy. Case 3 3 y/o with no past medical history presents to PCP complaining of increased sleeping for 1 week, less playful for 2-3 weeks, fever for 3-4 days and bruises for 2 days. This is 6 th visit to medical care in last 3 weeks, mother is not happy. WBC 39 (97% blasts) Hgb: 6.4 Plt: 9 PT: 12 PTT: 28 Fib: 189 6

7 Case 4 13 y/o girl, no past medical history, had menarche 6 months ago. First period 4 days. Then none for 2 months. Now with continuous bleeding for three months. PE: Slightly Pale, mildly fatigued. Mildly tachycardic. BP nl. Case 4 13 y/o girl, no past medical history, had menarche 6 months ago. First period 4 days. Then none for 2 months. Now with continuous bleeding for three months. PE: Pale, fatigued. Mildly tachycardic. BP nl. WBC 6.5 Hgb 6.8 Plt 265 PT: 12.1 PTT: 48 Fibrinogen: 311 7

8 Evaluation of the Patient with Suspected Bleeding Disorder History (Presentation and Past/Surg/Fam) Physical Exam Labs Presentation Presentation Mucous Membrane Bleeding (epistaxis, gingival, menstrual) Von Willebrand Disease (VWD), Thrombocytopenia, Platelet Function Defect Joints/Soft Tissues Hemophilia Umbilical Stump Factor XIII 8

9 Presentation Localized bleeding often not a bleeding disorder (caveats apply family history etc) Unilateral epistaxis in a child nose picking, allergies/congestion, friable superficial vessel Consider ENT first Bleeding after tonsillectomy: surgical trauma >> bleeding disorder Past History Medical Conditions Liver dysfunction, Connective Tissue Disorders, CCHD, Malabsorption Trauma was there excessive bleeding? Surgical was there excessive or unexpected bleeding? Transfusions? 9

10 Family History Abnormal bleeding? Site? Age at onset? Transfusion (esp for something unusual eg. Childbirth)? Get details (family with heavy periods may not realize it if everyone affected) Inheritance Pattern X-linked (hemophilia but up to 30% are spontaneous), Autosomal Dominant (VWD) Rare factor deficiencies tend to be Autosomal Recessive so likely no FHx Lab Workup But first some movies 10

11 INTRINSIC PATHWAY 11

12 Lab Workup CBC with diff Lab Workup CBC with diff PT PTT?von Willebrands 12

13 CBC Platelets Normal vs Low Size (large vs normal or small) WBC Differential PT and PTT A word about specimen collection 13

14 Prothrombin Time (PT) Measurement of Extrinsic Pathway Only clotting factor measured is Factor 7 Clinically significant deficiency is very rare Useful in monitoring of Coumadin (short half life of Factor 7) 14

15 Partial thromboplastin time (PTT) Measures extrinsic pathway Will be prolonged with deficiencies of: Factor 8 (hemophilia A) Factor 9 (hemophilia B) Factor 11 ( hemophilia C ) Factor 12 (NOT a bleeding disorder but very prolonged PTT) Von Willebrand Disease (+/-) heparin contamination Circulating inhibitor mixing study Mixing Study (PTT substituted) Mix normal plasma with patient plasma 1:1 If corrects to normal then there is a factor deficiency If does not correct to normal then there is a circulating inhibitor (Hemophilia with inhibitor, autoimmune disease, viral-induced) 15

16 Evaluation of lab tests in the patient with suspected bleeding disorder Normal Platelets, Normal PT Prolonged PTT Von Willebrand Disease Hemophilia A or B Factor 11 deficiency Factor 12 deficiency (not a bleeding disorder) 16

17 Normal Platelets, Normal PTT Prolonged PT Factor 7 deficiency Wafarin (Coumadin) Ingestion PT, PTT Prolonged Factor 5 or 10 deficiency (very rare) Prolonged exposure to Coumadin Liver dysfunction DIC Many bad things 17

18 Normal PT, PTT and Platelets Von Willebrand Disease Platelet Function Defect Low Platelets LATER 18

19 Factor 8 Von Willebrand Von Willebrand Disease CALL ME ERIK 19

20 Von Willebrand Disease Autosomal Dominant Diagnosed much more frequently in women Platelet plug formation is dependant on von Willebrand binding to exposed subendothelium Von Willebrand also serves as carrier protein for Factor 8 Von Willebrand Disease Prevalence 1:100 Incidence 1:1,000 Very heterogeneous presentation even among family members Type 1 Reduced amount of VW protein Most common Type 2 Qualitative problem with VW Type 3 Near absence very severe and rare 20

21 Tests VW Antigen Quantitative Assay Ristocetin Cofactor measure of activity VW Multimers Measures distribution of multimers present in circulation Factor 8 Activity VW carries Factor 8 in the plasma VW Multimers ADAMTS 13 21

22 Problems with testing Blood Type Group AB may have 60-70% higher VW antigen that Group O Acute Phase Reactant Hyper/Hypothyroidism Maybe as low as in hypo Stress Phlebotomy! 22

23 Type 1 VWD By far most common (~90%) Quantitative decrease in circulating VW Extremely common (up to 1%) Presentation Easy bruising, menorrhagia, post-op hemorrhage and epistaxis. Anemia Type 1 VWD Labs PTT prolonged (+/-) Depends on factor 8 level Ristocetin Cofactor: low VW Antigen: low Factor 8: normal or low Multimers: normal distribution 23

24 Type 1 VWD Treatment Desmopressin IV or Intranasal (Stimate) Aminocaproic Acid (Amicar) Plasma derived vwf/factor VIII (Humate-P) Cryoprecipitate Type 1 VWD Desmopressin ~75% of patients will respond Releases stored VW Antigen into circulation Must give trial dose to assure response IV most effective Intranasal efficacy slightly lower Probably due to variable absorption Good for heavy menses, nosebleeds, minor surgical procedures Must caution about free water restriction DO NOT use enuresis formulation of DDAVP 24

25 Type 1 VWD -Aminocaproic Acid (Amicar) Antifibrinolytic Useful for mucosal bleeding especially in conjunction with Stimate Type 1 VWD Plasma Derived VWF/FVIII (Humate-P) Replacement concentrate Contains normal VW multimer distribution For severe bleeding Surgical Prophylaxis and Post-op Routine Prophylaxis (more common in type 3) Factor VIII concentrates typically lack VW 25

26 Type 1 VWD Cryoprecipitate Plasma component Rich in VW Used in situations where plasma derived concentrate unavailable Much more effective than FFP Type 2 VWD Many types Qualitative problems with VWD Fairly Rare Labs variable depending on type Distinguish from other diseases (eg. hemophilia A vs type 2N) Generally must be treated with plasma derived VWF/FVIII concentrates 26

27 Type 3 VWD Extremely rare Almost complete deficiency of VW (and consequently factor 8) Phenotype similar to severe hemophilia A Severe epistaxis Mucocutaneous hemorrhage Joint/muscle bleeding Treatment/Prophylaxis with plasma derived VWF/FVIII Hemophilia Recognized since biblical times First medical description in 10 th century Scientific Investigation began around turn of 19 th century Effect on history Queen Victoria passed gene for Hemophilia B to two daughters and subsequently to the royal families of Spain, Germany and Russia 27

28 Hemophilia Overall incidence 1:5,000 males Severity proportional to baseline factor level Severe <1% Moderate 1-5% Mild >5% Hemophilia A (Factor 8 deficiency) 80-85% of cases X-Linked Hemophilia B (Factor 9 deficiency) Identical clinical picture to Factor 8 deficiency 28

29 Clinical Presentation Most diagnosed at birth due to family history (~2/3) About 1/3 are due to spontaneous mutations Bleeding with circumcision (~30% will bleed) Without hemostatic challenge most present when crawling/walking with bruises, swollen joints, refusal to walk, oral bleeding (torn frenulum) Clinical presentation Toddler: most common site of bleed is ankle due to pressure from child trying to maintain upright position As child ages elbows and knees become more common 29

30 Lab Workup PT normal PTT prolonged Mixing Study corrects Factor 8 or 9 level low Complications Hemophilic Arthropathy 30

31 Complications Intramuscular Bleeding Very difficult to localize/diagnose High index of suspicion especially with abdominal pain Iliopsoas bleed is life threatening Characteristic hunch gait with pain upon extension of hip despite normal flexion and rotation Diagnose via CT 31

32 Complications Life threatening bleeding CNS Airway Exsanguination Inhibitor Development 14-25% of severe Hemophilia A patient Antibody inactivates Factor 8 Suspect with failure to respond to usual Factor replacement Complications 32

33 Treatment 1930s: Plasma infusions helped 1964: Cryoprecipitate discovered Higher concentration of factor : First plasma derived concentrates First attempts at prophylaxis 1980s: Lost generation Patient mistrust Mid 1980s: improved donor selection, heat inactivation, refined purification 1985: Genes for Factors 8 and 9 cloned 1989: First recombinant products 33

34 Treatment Principles Dose and duration based on: Site of bleed (joint vs muscle vs CNS) target? Patient Weight Product Being Used (factor vs DDAVP) Severity of bleed Surgical Prophylaxis Concomitant Antifibrinolytic (ie. Amicar) 34

35 Prophylaxis vs On-Demand Severe Hemophilia Almost all will benefit from prophylaxis Start when toddling after first bleed Central Venous Catheter needed Moderate Many will require prophylaxis Family History Useful Mild Generally treated with on-demand Thrombocytopenia Peripheral consumption/destruction Poor production ITP HUS Neonatal Alloimmune Thrombocytopenia (NAIT) Neonatal autoimmune thrombocytopenia (like ITP) Cyanotic Congenital Heart Disease Kasabach-Merritt Syndrome TTP Sepsis Acute Leukemia Aplastic Anemia Congenital Thrombocytopenias Drug Induced *Sequestration -hypersplenism -hypothermia -burns *Spurious -EDTA 35

36 Immune Thrombocytopenic Purpura (ITP) Accelerated destruction of antibody sensitized platelets by macrophages (predominantly of the spleen) Incidence: 1:10,000 children Acute: <6 months duration Chronic: >6 months duration Age >10 years and female gender associated with development of chronic Pathogenesis of ITP Autoantibodies to platelet surface glycoproteins (usually GP IIb-IIIa) coat platelets Splenic macrophages clear coated platelets Megakaryocytes are also cleared production is affected Viral infections and immunizations implicated in triggering the process causality is very poorly understood 36

37 Acute Chronic Most will have spontaneous recovery irrespective of therapy 50% by 4-8 weeks 2/3 by 3 months 76%-90% by 6 months Of the remaining 37% eventually had recovery Screen for autoimmune disease especially in teens 37

38 Presentation Abrupt onset of bruising and petechiae in almost every child. Overt bleeding more rare. Peak age 2-6 typically acute. Male:female Infant or Adolescent more often chronic with concomitant autoimmune disorders Female > Male 2:1 in adolescents History of preceeding viral illness or immunization supposedly. Epistaxis or oral mucosal bleeding (blood blisters): < 1/3 Hematuria/Hematochezia/Melena: < 10% Presentation Despite profoundly low platelet counts (<20,000) severe bleeding rare. Particularly compared to thrombocytopenia due to poor production New, large, sticky platelets are more prevalent Malaise, bone pain, adenopathy, fever, hepatosplenomegaly = trouble 38

39 Presentation Platelet count <20,000 in >80%, often less than 10,000 WBC and RBC should be normal Unless severe bleeding Bone marrow is unremarkable Usually only performed if patient fails frontline therapy and requires corticosteroids Treatment (or not) To Treat Americans Risk of ICH (0.9%) (0.1%-0.5%) Trauma ASA use Plt <20,000 Relatively few side effects of treatment Not to treat Europeans No great evidence that treatment prevents ICH Spontaneous remission rates high and unaffected by treatment Cost of treatment Side effects of treatment 39

40 Treatment First Line IVIG Anti Rh o (D) (WinRho) Second Line Corticosteroids Salvage Cytoxan, Cyclosporine, 6MP, Vincristne, Interferon-a, Danazol, Azathioprine Splenectomy New agents (TPO agonists) IVIG Primarily acts by blocking macrophages at the Fc receptor Good efficacy fairly rapid response can be repeated Duration 2-4 weeks Side effects (15-75%): Headaches, nausea, lightheaded, fever, rarely anaphylaxis (IgA deficient patients) Aseptic meningitis (10%) Expensive/Shortage 40

41 Anti-D (WinRho) Rh+ patients only Also acts by blocking macrophages (at the expense of some red cells!) About as effective as IVIG Shorter infusion time (but now longer post infusion observation required) Similar side effect profile Plus acute hemolytic anemic renal failure Corticosteroids Need for bone marrow before therapy? Traditional practice but studies argue against Inhibition of phagocytosis and antibody production Many different regimens: 21 day, pulse then taper, megadose pulse Very effective Side effects related to dose and duration: HTN, hyperglycemia, cushingoid facies, polydipsia/polyuria, weight gain, fluid retention, acne 41

42 Splenectomy Generally reserved for refractory cases in patients with high risk of, or proclivity toward bleeding. Eliminates the major site of both platelet destruction and antibody production Defer in children as long as possible Complete Remission 75%, partial in many more If poor response look for accessory spleen Prophylactic Vaccination Long term risks: Infection Emerging data on pulmonary hypertension, cardiac dysfunction New Agents 42

43 TPO agonists 60-80% effective Concern for rebound thrombocytopenia Marrow reticulin fibrosis Hepatotoxicity 43

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