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Outline. 1. Introduction 2. Body Hemostasis Platelet disorder - Disorder of Plt function - Thrombocytopenia Inherited coagulation disorder - Hemophilia - Von Willebrand Disease 3. Conclusion . Introduction.

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  1. Outline • 1. Introduction • 2. Body • Hemostasis • Platelet disorder - Disorder of Plt function - Thrombocytopenia • Inherited coagulation disorder - Hemophilia - Von Willebrand Disease • 3. Conclusion

  2. Introduction • All materials from Wintrobe’s Clinical Hematology, 11th edition - Ch 51-59

  3. Hemostasis • All component onset at same time and close at different time • Primary(3-5 mins to onset) • Vessel • Platelet • Secondary( 5-10 mins to onset) • Coagulation • Fibrinolysis( need 2-3 days to onset)

  4. How to D/D primary or secondary hemostasis

  5. acquired inherited 一定有answer Drugs: Cpz, fortum, Usually acquired disease Trauma Hx( bone fracture) Also Considermild deficiency of F VIII,IX,XI ( around sen 30-40%) and dysfibinogenemia Pts with mild bleeding disorder and normal aPTT; cause aPTT did not dected the mild deficiecy of F VIII,IX,XI Urea [5M] solubility test

  6. See You Condition with abnormal screening tests but no hemorragic diathesis Factor XII deficiency Prekallikrein deficiency High-molecular-weight kinogen deficiency Mild to moderate factor VII defiency Lupus anticoagulant Exscess citrate anticoagulant (eg with Hct >60%) Symptom(+) Lab (+) and Sym(-) Screen Lab: APTT, PT and PLt (-) (+) • Confirmatory test • mixted aPTT; mixed PT 0 and 2 hour • If corrected (N+P < buffer+normal) • Factor deficiency • Or weak antibody • If not antibody • 1. Anti phospholipid Ab ( no clincal importance) on 0 hr • 2. Factor antibody ex: VIII ab ( delay titier: 2 hr more long) if aPTT,PT,TT and Plt all is normal R/O F XIII problem check urea [5M] solubility test( clot stability test) : if abnormal F XIII resolution in minutes( hydrogen bond  peptide bond by FXIII)

  7. Coagulation Factor (1) • All factor including protein C,S synthesis by liver cells except FVIII( endothelial cells) • Only Hypofibrinogen may rare from deficiency liver biosynthesis • Filling with vit K did not compensate the FII,VII,IX,X prove the hapatocyte cell inj in main cause • Half life • Shortest: VII(4-6 hr) • Longest: XIII 168hrI=frbrinogen (120 hr)

  8. Coagulation Factor (2) • Cofactor • V , VIII, tissue factor, HMWK, protein S, thrombomodulin, EPCR • Protease : others • Not in liver “cell” product: VIII • Vit K dependent : II,VII,IX,X,C,S,Z • Level newborn= adult • Factor I, V, VIII, XIII, vWF • Molecular weight • > 300K : factor I, V, VIII, XIII, vWF • < 50 K : Tissue factor, VII

  9. A Jew patient had minimal bleeding tendency and occasional surgical bleeding since childhood, the most possible factor deficiency is (A) V (B) VIII (C) XI (D) XII (E) X Ans: C 2. Which of the following diagnosis may be compatible with the following coagulation profile: normal prothrombin time and platelet count, prolonged activated partial thromboplastin time ? (1) Deficiency or inhibitor of factor VIII, IX or XI (2) von-Willebrand’s disease (3) Heparin induced (4) Fibrinogen deficiency Ans: 1,2,3 3. Which the following coagulation factors has the longest in-vivo half-life? (A)factor II (B)factor V (C)factor VII (D)factor VIII (E)factor XIII Ans : E

  10. 3. A patient with congenital bleeding tendency, his APTT is normal, but PT is prolonged, which factor deficiency is most likely? (A) XII (B) XIII (C) VII (D) V (E) X Ans : C 4. Which of the following factor deficiencies would be expected to result in prolongation of both the prothrombin time and partial thromboplastin time ? (A) Factor XI (B) Factor X (C) Factor IX (D) Factor VIII (E) None of above Ans : B 5. If a patients has congenital factor XIII deficiency, which screening test is useful for detection? (A) Prothrombin time (B) Activated partial thromboplastin time (C) Urea solubility test (D) Euglobulin lysis test (E) Assay for fibrin degradation products Ans : C

  11. Disorder of Platelet Function Adhension Bernard soulier syndrome Collagen receptor deficiency Plt-type vWD Aggression Galmzman’s thrombobasthenia Secreation αgranule : gray plt syndrome δgranule (dense) : storage pool disease, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Wiskott- Aldrich syndrome, Thrombocytopenia and absent radii Acquired disorder Drug induced : analgesics, antibiotics, cardiovascular drugs, psychotropic drugs Uremia Disorder of hematopoietic system: MDS, MPD, paraproteinemias Platelet procoagulant activity defect Scott syndrome

  12. CD 41,61 CD 42

  13. Bernard Soulier Syndrome • AR, chromosome 17 • Defective Ib-IX complex ( second abundant plt receptor) • Mucocutaneous bleeding • Thrombocytopenia with giant platelet, prolong bleeding time • Platelet aggregation test: • Ristocetin : failure • Other agonists ( ADP, collagen, epi) : normal • Low dose thrombin : may be delayed • Tx: local measure, hormonal management of menses, plt transfusion , DDAVP, factor VIIa, anti-Gp Ib-IX complex alloantibody

  14. Galmzman’s Thrombobasthenia • AR, chromosome 17 • Defective PLT integrin IIb-IIIa complex ( most abundant plt receptor) • Repeated mucocutaneous bleeding at early age • Normal PLT count , bleeding time prolong • Platelet aggregation test: • Ristocetin : normal • Other agonists ( ADP, collagen, epi, thrombin) : absence of secondary aggregation • Tx: PLT transfusion

  15. Hermansky-Pudlak syndrome (HPS) AR, HPS-1 gene (10q) Tyrosinase- positive, severe oculocutaneous albinism associated with photophobia, rotatory nystagmus , and loss of visual acuity Excess accumulation of ceroid –like material in RE cell Mild to moderate bleeding diathesis Major cause of death: pulmonary fibrosis Chediak-Higashi syndrome (CHS) AR(1q) Partial albinism : caused by abnormal large melanosomes Large intracytoplasmic granules in leukocytes, lymphocytes, monocytes and platelets Immune dysfunction : poor mobilization of marrow leukocyte pool, defective chemostaxis and bactericidal activity Often die in first two decades of life : overwhelming infection or lymphoproliferative disorders Storage Pool Disease

  16. Scott Syndrome • Platelet factor 3 activity  • Activated platelets : as once of the principle sites for plasma coagulation reactions • Providing a surface on which coagulation factors complexes assemble, accelerating these reactions • Binding of factors Va-Xa and factors VIIIa-IXa complexes is impaired • Prolong bleeding after dental extractions or surgical procedures, spontaneous retroperitoneal hematoma • No increase bruising or bleeding from superficial cuts • BT, PLT morphology, aggregation and secretion, standard screening for PT and aPTT : normal • Dx : shorten serum prothrombin time due to prothrombin consumption decrease ( decrease thrombin generation) • Tx : PLT transfusion

  17. Thrombocytopenia • Pathophysiology and classification • Inherited platelet disorder : qualitative and quantitative • Immunologic platelet destruction • Nonimmunologic platelet destruction

  18. Pancytopenia (all AR, but DC XR) Fanconi anemia Dyskeratosis congenita (Zinsser-Cole-Engman syndrome) Shwachman-Diamond syndrome Pearson syndrome Reticular dysgenesis Congenital amegakaryocytic thrombocytopenia Congenital thrombocytopenia With megakaryocytic hypoplasia Thrombocytopenia absent radii (TAR) (AR) Thrombocytopenia with radio-ulnar synostosis and HOXA11 gene mutations (AD) Autosomal dominant giant platelet disorder (MYH9 gene defect) May-Hegglin anomaly Sebastian syndrome and variants Fechtner syndrome Epstein syndrome X-linked microthrombocytopenia ( WAS gene mutation) Wiskott-Aldrich syndrome (WAS) X-linked thrombocytopenia (XLT) X-likned macrothrombocytopenia with dyserythropoiesis (GATA1 mutation ) Inherited Platelet Quantitative Disorder

  19. Congenital Amegakaryocytic Thrombocytopenia • AR, c-mpl gene (1p34) • Marked elevated thrombopoietin • Thrombocytopenia in infancy, pancytopenia later • Median age at diagnosis: 1 m/o • S/S : bleeding in skin, mucous membranes or GI tract • PLT count: not improved with age • BM : normal cellularity with absence of megakaryocytes • With or without birth defects • Risk of development of aplastic anemia (40%) • Median survival : 7 y/o • Treatment : SCT

  20. Thrombocytopenia Absent Radii (TAR) • AR • Diagnosis : usually at birth • Bilateral absence of radii with thumbs present(100%) • Hemorrhagic at birth : often petechiae, bloody diarrhea (60 % within first week) • Thrombocytopenia : < 50K/ μL (75%) • Normal BM cellularity, but absence of megakaryocytes • After infancy: very good prognosis • Bleeding in infancy then improvement after the 1st year • > 1 y/o : PLT > 100K/ μL • Spontaneous remission : plateau of 75 % survival by 4 y/o • Major case of death : ICH, GI bleeding • Tx: PLT transfusion

  21. Autosomal-Dominant Macrothrombocytopenia (MYH9 gene defect) • Ineffective thrombopoiesis: PLT 20K- 100k/ μL, Normal PLT survival and BM megakaryocytes. • Easily bruising early in life • MYH9 gene mutation (22q12.3-13.1) for nonmuscle myosin heavy chain

  22. X-linked microthrombocytopenia WASp gene at Xp11.22-p11.23 Thrombocytopenia + small platelet (half size) + eczema + T-cell immunodeficiency Normal or megakaryocyte mass Increase destruction in spleen thrombocytopenia and decrease PLT size Splenectomy definitely improves PLT counts in these pts, which frequently return to normal X-likned macrothrombocytopenia with dyserythropoiesis GATA1 transcriptional activator missense mutation (Xp 11.23) which is necessary for megakaryocyte differentiation Different severities of disease, GATA1 with FOG result in most severe macro-thrombocytopenia and anemia D/D with WAS : normal PLT size, no immune abnormality, severity of bleeding X-Linked Thrombocytopenia

  23. 1. How can we measure the platelet adhesion function by checking? (A) Von Willebrand’s factor (B) ristocetin cofactor assay (C) GPIb/IX (D) fibronectin (E) platelet factor 4 Ans : C 2. Which one is correct in the platelet function disorders? (A) Secretion disorder-- Glanzmann thrombasthenia (B) δ-Granule abnormality -- Gray platelet syndrome (C) Adhesion defect -- Bernard-Soulier syndrome (D) α-Granule abnormality -- Hermansky-Pudlak syndrome Ans: C 3. Thrombocytopenia is least likely to be found in which of the following conditions? (A) Caused by anticoagulant-dependent immunoglobulin (B) Bernard-Soulier syndrome (C) Posttransfusion purpura (D) Glanzmann thrombasthenia (E) Hypothermia Ans: D 4. How dose the vascular system prevent bleeding ? (1) vasoconstraction (2) diversion of blood flow around damaged vasculature (3) initiation of platelet aggregation and fibrin formation (4) secrete hepatan sulfate Ans: 1,2,3,4

  24. 5. Which of the following disease is characterized by giant lysosomes in granulocytes, a picture of partial oculocutaneous albinism, and neuropathy associated with decussation defects at the optic chiasm? • (A) Alder-Reilly anomaly • (B) Chediak Higashi anomaly • (C) Chronic granulomatous disease • (D) Leukocyte adhesion deficiency • (E) May-Hegglin anomaly • Ans : B • 6. Which condition can be associated with prolong bleeding time ? • (1) Thrombocytopenia • (2) Bernard-Soulier syndrome • (3) von Willibrand disease • (4) Sever hypofibrinogenemia • Ans: 1,2,3,4 • 7. Which of the following medical conditions may indicate for the bleeding tendency ? • (1) acute or chronic liver disease • (2) myeloma or paraproteinemia • (3) renal insufficiency • (4) myeloproliferative disorders • Ans: 1,2,3,4 • 8. Which disease(s) will cause platelet adhesion defects? • (1) Bernard-Soulier Syndrome • (2) Storage pool deficiency of platelet • (3) Von Willebrand’s disease • (4) Hemophilia A and B • Ans : 1,3

  25. ITP • By exclusion Dx , no identifiable underlying case • 2ndTP

  26. ITP • Most common antigens: GpIIb/IIIa, Ib/IX • Serum antiplt IgG autoAb : 50-85% • S/S : GU bleeding, GYN menses bleeding • < 50000: even trauma->no bleeding • <10000: spontaneous bleeding • ICH < 1 %

  27. ITP • Childhood is usually benign and self-limited • Plt > 30K and no clinical bleeding : observation only • Plt < 20K + significant mucous membrane bleeding or plt <10K with minor purpura • Steroid increase plt at 1 wk , peak at 2-4 wk • IVIG increase plt at 2 days , peak at 1 wk • Anti-D • Chronic ITP ( > 6 months) : < 20 % • Adult : spontaneous remission <5% , so need long term treatment • <25% after DC prednisolone can long tern PR and CR(Plt>50000) • After prednisolone • response in 1 wk peak in 2-4 wkskep Tx try tapping or DC in week 4 (CR or PR :83% child, 59% adult) • if no response in 1-2 wks try other treatment and splenectomy

  28. ITP • Indication of splenectomy • <10k and Poor response to steroid >6 weeks • <30K and poor response to steroid >3 months • CR to splenectomy : 50- 80% • Accessory spleen : 15-20% ( 50 % relapse) • Immunosuppressive drugs (for refractory case) • Cyclophosphamide (16-55% response) • Vincristine and vinblastine • Anti-CD 20 monoclonal Ab ( 50 % response)

  29. (NEJM 2002;346:995 &2003;349:831&2006;355:1672)

  30. Gold persisted for weeks to months 當懷疑有藥物引起血小板低下時，可藉由受疑藥品的停用來加以証實，通常停用5─7天即可得到証實。一般若想了解究竟是哪些藥物造成病患血小板低下，可參考一些發表過的個案報告，以評估該病患之用藥與血小板低下之間的關係究竟有多大。在報告過的個案中，最常見的是Quinidine、Quinine、RIF以及TMP-SMX。 Drugs Associated ITP

  31. Heparin-Induced Thrombocytopenia

  32. Neonatal Autoimmune Thrombocytopenia • Pathogenesis • Infant of mothers with immune thrombocytopenia ( ITP, SLE, or other autoimmune disorder) • Placental transfer of maternal antoAbs • Clinical features • Less severe than NAIT • Risk of ICH : 1% • Both neonate and mother have thrombocytopenia • Treatment • PLT < 40-50 K • IVIG, steroids

  33. Neonatal Alloimmune Thrombocytopenia ( NAIT) • Incidence : 1/2000 births • Placental transferof maternal alloAbs directed against paternally inherited Ags present on fetal platelets but absent from maternal platelets • Transient , isolated , severe thrombocytopenia • Platelet alloAgs • Human platelet antigen (HPA) 1a, 5b • HLA class I • Blood group ABH • Features • Severe thrombocytopenia (< 10K) on the 1st day • Petechiae (90%), hematoma (66%), GI bleeding (30%) • ICH (15%): prenatal (50%), postnatal • Normal maternal platelet counts • Can occur in both the first and subsequent pregancies • Dx: serologic or genotypic testing • Immunophenotyping of maternal, paternal, and neonatal PLT • Anti-PLT Ab in maternal or fetal serum (< 2/3) • Tx: PLT transfusion • PLT < 30K or clinically significant bleeding • Washed, irradiated, maternal platelets

  34. 1. Which of the following statements about ITP is wrong? It is an autoimmune disease in most adult ITP The effect of IVIG last about 3 weeks Children present with acute ITP and usually with spontaneous remission For chronic ITP, the goal of therapy is to maintain platelet count over 80,000/cmm Splenectomy is indicated in patients with refractory ITP with bleeding problem Ans: D 2. For the first line treatment of a 16 years male suffered from ITP with platelet count < 10,000/mm3, which of the following is not appropriate? (A) close observation (B) corticosteroid (C) IVIG (D) Anti-D (E) Splenectomy Ans : E 3. Which statements about immune thrombocytopenic purpura (ITP) are correct ? (1) Rituximab is effective in certain portion of patients with refractory ITP failing to respond to steroid treatment and splenectomy (2) ITP is caused by autoreactive antibodies that bind to platelets and shorten their life span. However, antiplatelet antibodies are not detected in at least 20% of typical cases of ITP (3) The response rate to prednisolone varies from 60-90 % depending on the intensity and duration of treatment. It is unlikely that additional benefit is achieved by continuing prednisolone beyond 3-4 weeks (4) IVIG is helpful in achieving long term remission of ITP Ans : 1,2,3

  35. 4. Concerning with ITP, which description is wrong? (A) Splenomegaly is a rare manifestation in ITP (B) Oral prednisolone has 10-30 % of response rate to induce long-term remission for adult ITP, and has much higher rate for pediatric ITP (C) Laparoscopic splenectomy has 70-85% of response rate to induce complete remission for adult ITP (D) Rituximab ( anti-CD 20 monoclonal antibody) recently emerges as a new alternativc treatments for refractory ITP (E) IVIG treatment (1g/kg for 1-2 days ) has 50-80% response rate for adult refractory ITP, and its effect usually lasts for more than one month Ans : E 5. Heparin-induce thrombocytopenia (HIT) is a difficult complication while using heparin to treat deep vein thrombosis. Which of the following statement is NOT correct? (A) Approximately 70% of patients will develop thrombocytopenia begins 5 to 10 ays after heparin therapy (B) HIT is dose dependent (C) HIT can be treated with IVIG, plasmapheresis with success (E) LMWH is contraindicated as treatment for HIT Ans: B

  36. Thrombotic microangiopathy • TTP • HUS • DIC

  37. TTP • Incidence: 1-4/ million • Penta: fever, renal , thrombocytopenia, neuro (gray matter and brain stem), hemolytic anemia • 74% with 3( plt, anemia, neuro), 40% with penta • Most common symptom: fever , HA • Reversible aggregation of platelets in microvasculature , brain, abdominal viscera and heart are most common site • F/M=2/1, adult 30-40 y/o • Gene HLA II DR35

  38. TTP • TTP • Vascular abnormality • TTP is a disease due to ADAMTS13 (metaoprotease) deficiency <10% most and increase ULvWF • Point mutation family deficiency(Upshaw-Shulman syn) • Antibody or inhibitor related (居多) • Overproduct (release) of ULvWFthen use off the ADAMTS13 • PAF(platelet aggregation agents) disclosed in blood : PAF37, calpain,3rd?? • FFP ( with protease in FFP) can treatment TTP • DDX: HUS normal protease level

  39. TTP-Diagnosis Hint • PB smear : polychromasia , stippling, nucleated RBC, schistocytes • LDH 400~ more than 1000 • Unconjugated bilirubin  • HgB<10, ret  , hepatoglobin , hemoglobiuria, hemosiderinuria • Plt<100k, most <50,000 • Coagulation : normal ( FDP may slightly ) • Agarose gel : abnormal vWF multimers • Skin, BM, gingiva Bx: hyaline thrombi within arterioles( but also in DIC, HUS, some vasculitis… no specific) • Brain CT : reversible brain edema, ischemic strokes , and frank hematoma • Sensitive indices of the response to therapy : LDH level and platelet count

  40. TTP D/D • HUS • Microangiopathic blood destruction and vascular damage occur principally in kidney • High In child with prodromal infection • Abdominal pain, GI s/s, anuria, several renal failure and hypertension are common in the early course • Neurologic symptom are less common • C’ low, most self remission and relapse is rare • HELLP(pregnant female;eclampsia; hemolysis;elevated liver enzyme; low plt count) • SLE woth immune TTP • Vasculitis • PNH • TTP+AIHA

  41. Plasma exchange should be several days after the plt is normal • and minimal hemolysis • 1/3 relapse after CR in 1 month • No PLT BT ( deterioration renal and neuro status) • Some people with chronic, relapsing TTP have responded to • splenectomy

  42. Hemolytic-Uremic Syndrome • Annual incidence: 1/100,000 • Most often in infants and young children • Most common cause ARF in this age-group • Most common cause : acute infection • Shiga-like toxin ( EHEC O 157: H7) • Capillary thrombosis and ischemic necrosis: kidney ( most severe) , GI, CNS and other organs • Clinical features: • Usually following an acute diarrhea illness • Non-diarrhea HUS ( atypical ) : 10 % • Usually ARF • Hemolytic anemia , thrombocytopenia : less severe than TTP • Laboratory DIC : usually not present • Treatment : supportive

  43. 1. Which statements about thrombotic thrombocytopenic purpura is correct ? (1) Inhibitory antibodies against von Willebrand factor-cleaving protease occur in patients with acute thrombotic thrombocytopenic purpura (2) Detected in the plasma of patients with TTP (3) Deficiency of ADAMTS13 has been reported consistently in patients with TTP. Such defect may be constitutive, due to homozygous or double heterozygous mutations in the corresponding gene, or acquired, due to the presence of circulating inhibitory antibodies (4) ADAMTS13 is an inhibitory antibody against von Willebrand factor-cleaving protease Ans:1,2,3 2. A 72-year-old man, had a flu-like symptoms 2 weeks ago, started to have fluctuation of consciousness, skin ecchymosis, low grade fever, decreased urine amount, was sent to emergent service due to deterioration of consciousness disturbance. On PE: BP 136/82 mmHg, PR 112/min, regular heart beat, consciousness very drowsy, mild fever 37.9 oC, Blood tests: WBC 12300/ul, mild neutrophilia, Hb 8.3 g/dl, MCV 92 fl, Platelet 18000/ul. PB smear: marked thrombocytopenia, apparent RBC fragmentation, no blast. Serum Cr: 3.8 mg/dl, LDH 680 U/dl (high). Normal PT/aPTT. Under this situation, which of the following managements is (are) appropriate (1) Emergent hemodialysis for rapid deterioration of renal function (2) Aggressive transfusion of platelet concentrate to keep platelet count >50000/ul (3) High dose parenteral steroid, e.g. methylprednisolone as pulse therapy (4) Infusion of fresh frozen plasma (FFP), or exchanging plasmaphoresis if available Ans: 4

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