Outline

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 Wintrobes 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)

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How to D/D primary or secondary hemostasis
Clinical Distinction between Disorder of Vessels and Platelets and Disorders of Blood Coagulation Clinical Distinction between Disorder of Vessels and Platelets and Disorders of Blood Coagulation Clinical Distinction between Disorder of Vessels and Platelets and Disorders of Blood Coagulation
Finding Disorder of Coagulation Disorder of Platelets or Vessels
Petechiae Deep dissecting hematomas Superficial ecchymoses Hemarthrosis Delayed bleeding Bleeding form superficial cuts and scratches Sex if patient Positive family history Rare Characteristic Common, usually large and solitary Characteristic Common Minimal 80-90 of inherited forms occur only in male patients Common Characteristic Rare Characteristic, usually small and multiple Rare Rare Persistent, often profuse Relative more common in females Rare ( Except vWD and hereditary hemorrhagic telangiectasia)
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acquired
inherited
???answer Drugs Cpz, fortum,
Usually acquired disease
Urea 5M solubility test
Trauma Hx( bone fracture) Also Consider mild
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
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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 gt60)
Symptom()
Lab () and Sym(-)
Screen Lab APTT, PT and PLt
(-)
()

• Confirmatory test
• mixted aPTT mixed PT 0 and 2 hour
• If corrected (NP lt buffernormal)
• 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)
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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?Ifrbrinogen (120 hr)

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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
• gt 300K factor I, V, VIII, XIII, vWF
• lt 50 K Tissue factor, VII

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• 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-Willebrands 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

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• 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

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Disorder of Platelet Function

• Adhension
• Bernard soulier syndrome
• Collagen receptor deficiency
• Plt-type vWD
• Aggression
• Galmzmans thrombobasthenia
• Secreation
• agranule gray plt syndrome
• dgranule (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

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CD 41,61
CD 42
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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

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Galmzmans 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

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Storage Pool Disease

• 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

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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

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Thrombocytopenia

• Pathophysiology and classification
• Inherited platelet disorder qualitative and
  quantitative
• Immunologic platelet destruction
• Nonimmunologic platelet destruction

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Inherited Platelet Quantitative Disorder

• 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 )

• Pancytopenia (all AR, but DC XR)
• Fanconi anemia
• Dyskeratosis congenita (Zinsser-Cole-Engman
  syndrome)
• Shwachman-Diamond syndrome
• Pearson syndrome
• Reticular dysgenesis
• Congenital amegakaryocytic thrombocytopenia

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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

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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 lt 50K/ µL (75)
• Normal BM cellularity, but absence of
  megakaryocytes
• After infancy very good prognosis
• Bleeding in infancy then improvement after the
  1st year
• gt 1 y/o PLT gt 100K/ µL
• Spontaneous remission plateau of 75 survival
  by 4 y/o
• Major case of death ICH, GI bleeding
• Tx PLT transfusion

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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

Syndrome caused by MYH9 gene defects Syndrome caused by MYH9 gene defects Syndrome caused by MYH9 gene defects Syndrome caused by MYH9 gene defects Syndrome caused by MYH9 gene defects Syndrome caused by MYH9 gene defects
Syndrome Macrothrombocytopenia Dohle-like bodies Nephritis Deafness Cataracts
May-Hegglin Sebastian Fechtner Epstein Yes Yes Yes Yes Yes Yes Yes No No No Yes Yes No No Yes Yes No No Yes No
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X-Linked Thrombocytopenia

• 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

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• 1. How can we measure the platelet adhesion
  function by checking?
• (A) Von Willebrands 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) d-Granule abnormality -- Gray platelet
  syndrome
• (C) Adhesion defect -- Bernard-Soulier syndrome
• (D) a-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

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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 Willebrands disease (4)
Hemophilia A and B Ans 1,3
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ITP

• By exclusion Dx , no identifiable underlying case
  
• 2nd TP

Table 53.1. Autoimmune Thrombocytopenia Purpura
Idiopathic (primary) Secondary Infection Collagen vascular diseases Lymphoproliferative disorders Solid tumors Drugs Miscellaneous
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ITP

• Most common antigens GpIIb/IIIa, Ib/IX
• Serum antiplt IgG autoAb 50-85
• S/S GU bleeding, GYN menses bleeding
• lt 50000 even trauma-gtno bleeding
• lt10000 spontaneous bleeding
• ICH lt 1

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ITP

• Childhood is usually benign and self-limited
• Plt gt 30K and no clinical bleeding observation
  only
• Plt lt 20K significant mucous membrane bleeding
  or plt lt10K 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 ( gt 6 months) lt 20
• Adult spontaneous remission lt5 , so need long
  term treatment
• lt25 after DC prednisolone can long tern PR and
  CR(Pltgt50000)
• 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

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ITP

• Indication of splenectomy
• lt10k and Poor response to steroid gt6 weeks
• lt30K and poor response to steroid gt3 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)

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Treatment of ITP in Adults Treatment of ITP in Adults Treatment of ITP in Adults
Approach Treatment Notes
Initial Steroids (prednisone 1-1.5 mg/kg/d po tapered over wks vs.dexamethasone 40 mg po x 4d) Useful acutely, but long term s/e ? Fc receptor on M? ?anti-plt Ab production
Initial Anti-Rh(D) Ig 75µg/kg/d IV For Rh(D) pts Ab-coated RBCs overwhelm M? Fc receptors
Initial IVIG(1g/kg/d IV x 2-3d) If plt lt5000 despite steroids Blacks Fc receptors on M? ?anti-plt Ab production
Refractory Splenectomy ? Plt clearance
Refractory Rituximab (anti-CD20) ? Plt clearance, Ab against B cell
Refractory Danazol, vincristine ? Plt clearance
Refractory Azathioprine, cyclophosphamide Immunosuppressants ? anti-plt Ab production
Refractory AMG531,AKR-501, eltrombopag Thrombopoiesis stim. proteins
Bleeding Aminocaproic acid Inhibits plasmin activation
Bleeding Methylprednisolone 1g/d IV x 3d See above
Bleeding IVIG See above
Chronic refractory Autologous HSCT Investigational
(NEJM 2002346995 200334983120063551672)
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Drugs Associated ITP

• Gold persisted for weeks to months
• ??????????????,???????????????,????5-7????????????
  ??????????????????,?????????????,?????????????????
  ?????????????????,?????Quinidine?Quinine?RIF??TMP-
  SMX?

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Heparin-Induced Thrombocytopenia
Feature Type I Type II
Mechanism Direct effect of heparin Immune(Ab)-mediated IgG vs platelet factor 4-heparin complex
Incidence 20 1-3
Onset After 1-4 d of heparin therapy After 4-10d but can occur early (lt24h)with history of prior exposure within last 100d ( felt to be secondary to persistent Ab) Can occur after heparin discontinue.
Platelet nadir gt 100,000/µl 30-70,000/µl, ? gt50
Sequelae None Thrombotic events (HITT) in 30-50 Rare hemorrhagic complications
Management Can continue heparin and observe Discontinue heparin Alternative anticoagulation (lepirudin or arga)
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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 lt 40-50 K
• IVIG, steroids

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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 (lt 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 (lt 2/3)
• Tx PLT transfusion
• PLT lt 30K or clinically significant bleeding
• Washed, irradiated, maternal platelets

41

• 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 lt
  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

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• 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

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• Thrombotic microangiopathy
• TTP
• HUS
• DIC

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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/M2/1, adult 30-40 y/o
• Gene HLA II DR35

Disease Associated with Thrombotic Thrombocytopenic purpua
Infection HIV, E. coli, Shigella Pancreatitis Drug treatment cyclosporin A, tacrolimus, antineoplastic agents, ticlopidine, clopidogrel, quinine Collagen-vascular disease Pregnancy and the puerperium Cancer Bone marrow transplantation
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TTP

• TTP
• Vascular abnormality
• TTP is a disease due to ADAMTS13 (metaoprotease)
  deficiency lt10 most and increase ULvWF
• Point mutation family deficiency(Upshaw-Shulman
  syn)
• Antibody or inhibitor related (??)
• 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

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TTP-Diagnosis Hint

• PB smear polychromasia , stippling, nucleated
  RBC, schistocytes
• LDH 400 more than 1000
• Unconjugated bilirubin ?
• HgBlt10, ret ? , hepatoglobin ?, hemoglobiuria,
  hemosiderinuria
• Pltlt100k, most lt50,000
• 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

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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 femaleeclampsia
  hemolysiselevated liver enzyme low plt count)
• SLE woth immune TTP
• Vasculitis
• PNH
• TTPAIHA

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Treatment of Thrombotic Thrombocytopenia Purpura
Plasmaphresis with exchange at least one volume of plasma daily Inclusion of antiplatelet agents and corticosteroids is of unproven benefit Salvage therapy Infusion of fresh frozen plasma Plasmapheresis and exchange with cryosupernatant plasma Vincristine IVIG Splenectomy Prostacyclin

• 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

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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

50

• 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
• Ans1,2,3
• 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 gt50000/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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• 3. A 19-year-old female patient is a case
  of systemic lupus erythematosus (SLE) with normal
  renal function before. She suffered from
  abdominal pain and watery diarrhea for a few
  days. Sudden onset of oligouria with black urine
  and exertional dyspnea occurred later. Laboratory
  data showed WBC 1800/ul, Hgb 5.0g/dl, PLT
  30000/ul both direct and indirect Coombs test
  negative haptoglobin very low bilirubin 2.4
  mg/dl BUN/ Creatinin 130/7.0 mg/dl stool
  culture O157H7 E. Coli. Blood smear displaced
  many fragment of erythocytes. What kind of
  disease is most likely?
• (A) Thrombotic thrombocytopenic purpura
• (B) Hemolytic-uremic syndrome
• (C) Disseminated intravascular coagulation
• (D) Autoimmune hemolytic anemia
• (E) Paroxysmal nocturnal hemoglobinuria
• Ans B
• 4. Which of the following laboratory results
  may be presented in patients with
• hemolytic uremic syndrome ?
• (1) Microangiopathic hemolytic anemia
• (2) Renal failure
• (3) Thrombocytopenia
• (4) Abnormal screening test of
  coagulation
• Ans 1,2,3
• 5. The most common cause of idiopathic
  thrombotic thrombocytopenia purpura ( TTP) is
• (A) Drugs such as mitomycin,
  cyclosporin, etc
• (B) Autoantibody to ADAMTS 13
• (C) ADAMTS13 gene mutation
• (D) Shiga toxin

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• 5. Which of the following about TTP is wrong ?
• (A) The best treatment is plasma exchange
• (B) The diagnosis is based on the exclusion of
  other disease that might cause microangiopathic
  hemolytic anemia
• (C) Coagulation studies are usually abnormal
• (D) TTP is due to vascular endothelial injury
  with release of unusually large vWF
• (E) Idiopathic TTP is an immune disorder
• Ans C
• 6. About Hemolytic Uremic Syndrome (HUS) ,
  which of the following statements is (are)
  correct?
• (1) One of the clinical expressions of
  schistocytic hemolytic anemia
• (2) Usually has severe thrombocytopenia
• (3) Most frequently associated with the
  infection by verocytotoxin producing microbes
• (4) The role of plasma therapy in HUS is
  less certain as in patients with TTP ( thrombotic
  
• throbocytopenia purpua)
• Ans 1,2,3,4
• 7. Plasma exchange is the choice of treatment
  for thrombotic thrombocytopenic purpura. If
  patient has response to plasmapheresis, which
  three parameters are the early signs of good
  response?
• (1) Nonfocal neurologic symptoms, such as mental
  status changes
• (2) Serum LDH levels

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Hemophilia
55
Hemophilia

• Incidence 1/5000 male
• 80-85 hemophilia A ( factor VIII deficiency)
• 10-15 hemophilia B ( factor IX deficiency)
• 1/1 million hemophilia C ( factor XI
  deficiency) (Jews 5- 11)
• X-linked recessive ( Xq)
• Hemophilia A gene Xq28, most common intron 22
  inversion ( 45)
• Hemophilia B gene most common missense point
  mutations (gt60) , spontaneous mutation rate is
  low s
• 1/3 new mutations
• 1 unit the amount of factor found in 1 ml of
  normal plasma
• 100 activity (100 unit/dL) the activity of
  factor found in 1 ml normal plasma
• Hemophilia in female
• Skewed lyonization of a carrier female
• Testicular feminization of a genotypic male
• Turner syndrome (XO)
• A daughter of a maternal carrier and a father
  with hemophilia A
• Type 2N VWD ( mutation in factor VIII-binding
  region of VWF protein)

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Hemophilia

• Hemarthrosis
• Major long-term disabling complication
• Most common affected joint ankles (toddler),
  knees and elbows (older child)
• arthropathy
• Synovitis normal ROM, proximal muscle weakness
• Arthritis cartilage erosion , crepitus, ROM ?,
  proximal muscle weakness?
• Chronic hemophilic arthropathy joint fusion and
  narrowing of joint space
• Prophylactic therapy 20-40 unit/kg factor VIII
  qod or three times a week to keep nadir gt 1
• Primary limit the develop of target joint
• Secondary cool down the affected joint
• Intramuscular hematoma often elusive
• Iliopsoas bleeding lift threatening
• D.D. with hip hemarthrosis unable hip extension,
  normal hip joint internal and external rotation
• GI and GU bleeding
• Traumatic bleeding delayed bleeding is common

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Hemophilia

• Hemarthrosis with significant orthopedic
  disability is rare in pt with coagulation
  disorder other than hemophilia A and hemophilia
  B.
• Hemophilia C hemarthrosis is uncommon, often
  delay bleeding after trauma and surgery or
  menorrhagia, associated with Noonan syndrome and
  Gaucher disease.
• Dx PTT prolong, PT normal ( also factor XI,
  factor XII, prekallikrein, HMWH deficiency, but
  latter three not associated with excessive
  clinical bleeding)
• Mild form patient may have normal PTT value.
• Type 2N vWD
• Indistinguishable from mild hemophilia A.
• AR family history
• Confirmatory test for vWD

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Hemophilia Treatment

• Hemophilia A
• Recombinant factor VIII concentrates,
  cryoprecipitate
• Dose(units) desire rise level () x BW (kg) x
  0.5
• Half life 10-12 hrs
• Hemophilia B
• Recombinant factor IX concentrates, FFP
• Dose(units) desire rise level () x BW (kg)
• Half life 18-24 hrs
• DDAVP
• Increase plasma factor VIII and vWF? mild and
  moderate hemophilia A , type 1 vWD
• No effect foe severe hemophilia A , severe vWD,
  any form of hemophilia B, life-threatening
  hemorrhage

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Initial Treatment of Specific Hemorrhages in
Hemophilia
Type of hemorrhage Hemophilia A (units/kg factor VIII concentrate) Hemophilia B (units/kg factor IX concentrate)
Hemarthrosis 20-50 30
Muscle or subcutaneous hematoma 20 30
Tooth extraction 20 30
Epistaxis 20 30
Major surgery, life threatening hemorrhage 50-75 80
Iliopsoas hemorrhage 50 80
Hematouria Bed rest 20 Bed rest 30
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Hemophilia Factor VIII (or IX) Inhibitor

• Severe hemophilia A 14-25 (occur average 9
  days later)
• Bethesda assay
• 1 Bethesda unit the amount of antibody that will
  inactive 50 of the normal factor VIII( or IX) in
  2 hrs when the residual factor VIII( or IX) level
  is between 25-75
• 110 dilution of test plasma has this effect -gt
  10 Bethesda unit
• Low responder
• Ab titer lt 5 B.u
• High-dose factor VIII concentrates and routine
  inhibitor assay
• High responder
• Ab titer gt 5 B.u
• anamnestic response
• Tx
• Continuous factor VIII infusion
• Porcine factor VIII concentrate
• Recombinant factor VIIa
• Prothrombin complex concentrate
• Activated prothrombin complex concentrates (
  Autoplex T, FEIBA)

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Hemophilia Factor VIII (or IX) Inhibitor

• Long-term management
• High dose factor VIII immune tolerance induction
• Intravenous ?-globulin
• Immunosuppressive therapy cyclophosphamide,
  prednisolone
• Remove of antibody by extracorporeal
  immunoadsorption of Staphylococcus protein A
  columns

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• Long term prophylaxis of bleeding in patients
  with severe hemophilia A is important. Which of
  the following is (are) correct?
• (1) Recombinant factor has definite lower
  incidence of inhibitor production
• (2) The dose of coagulation factor should be
  optimal, based on individual requirement.
• (3) Recombinant factor is more effective than
  plasma product
• (4) The prophylaxis period should be
  indefinitely, as long as patient needs
• Ans 2, 4
• A 4-year-old boy with and intramuscular
  hemorrhage that developed 3 days after
  accidentally being hit by his brother with a bat.
  He has never suffered from spontaneous bleeding.
  His maternal uncle dropped out of the army
  because he experienced more bleeding events than
  expected. Physical exam is unremarkable except
  for a swollen, painful right quadriceps muscle.
  The platelet count, PT, and APTT are normal. The
  most likely diagnosis is
• (A) Mild hemophilia B (B) inherited
  platelet defect (C) Mild hemophilia A
• (D) Factor XIII deficiency (E)
  Dysfibrinogenemia
• Ans A

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• 3. About coagulopathy, which of the following
  statement is correct?
• (1) Henophilia A is a disorder of Factor VIII
  deficiency, it is inherited
• by X-linked recessive
• (2) One unit per kilogram factor VIII
  transfusion can raise the plasma
• factor VIII by 1
• (3) The half-life of Factor IX is about 24 hrs
• (4) The half-life of Factor VIII is about 24
  hrs
• Ans 1,3
• 4. Which of the following products may be
  considered as therapeutic agents for the
• patients of hemophilia A with inhibitor ?
• (1) High dose factor VIII concentrates
• (2) Activated prothrombin complex
  concentrates
• (3) Porcine factor VIII
• (4) Recombinant factor VIIa
• Ans 1,2,3,4

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• 5. For a case of severe hemophilia A complicated
  with iliopsoas muscle hematoma, which minimal
  plasma level of FVIII should be kept at the
  initial treatment stage?
• (A)15 (B)40 (C)60 (D)80 (E) 120
• Ans D
• 6. A 11 y/o girl had easy nasal bleeding before.
  She had life-
• threatening bleeding at her menarche.
  Laboratory data
• revealed PT 45.2, aPTT 32.0 and platelet
  count
• 374,000/cumm. Which of the following
  treatments is
• relatively suitable for this patient?
• (A)cryoprecipitate (B)Promthrombin complex
  concentrate
• (C)Recombinant factor VIII (D)Recombinant
  factor IX
• (E)DDAVP
• Ans B

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Von Willebrand Disease

• Large , multimeric glycoprotein
• Act in coagulation
• Bridges together plt with vascular subendothelium
  (Gp Ib-IX)
• FVIII carrier protein
• Synthesis in megakaryocytes and endothelial cells
• Stored in Weibel-Palade body (endothelial cell)
  and ? granule (platelet)

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Von Willebrand Disease

• The most common bleeding disorder
• Incidence 1
• Genetic chromosome 12 (p13.3) ,usually AD, AR (
  2N, 3 and rare 2A )
• Blood group O vWF( 30 lower than other group)
• vWF elevated in stress, pregnancy and trauma
• Clinical presentation
• Excessive bruising , menorrhagia, trauma induced
  mild to moderate bleeding , hemarthrosis ( type 3)

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Von Willebrand Disease-Screen Test

• BT, aPTT
• vWF immunoassay(Ag)
• quantitative immunoelectrophoretic assay
• Ristocetin cofactor activity
• single most sensitive and specific test
• binding of VWF to Gp Ib receptor on platelet
• discrepancy between vWF function and vWF ag
  provide qualitative disorder
• F VIIIc
• If VWF ok and decrease FVIIIc?2N
• Plt aggression test ( LD-RIAP)
• Pts platelet(ristocetin induced)
• To DDx of 2B and plt-type from others
• Multimer studies

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1994 Classifications of VWD
1994 Term 1994 Definition Genetics, Comment
Type 1 Partial quantitative deficiency Dominant with variable expression phenotype influenced by multiple genes
Type 2 Qualitative defect
Type 2A Decreased platelet-dependent function with absence of largest multimers Dominant
Type 2B Increased VWF affinity for platelet GPIb Dominant. May be associated with thrombocytopenia, especially after DDAVP
Type 2M Decreased platelet-dependent function with presence of largest multimers Dominant
Type 2N Decreased VWF affinity for FVIII Recessive, often mistaken for mild-moderate hemophilia A
Type 3 Virtually complete deficiency Recessive homozygous or doubly heterozygous
Platelet-type (pseudo-VWD) Not a defect of VWF, not to be considered a form of VWD Dominant. A platelet disorders increased affinity of platelet GPIb for VWF. Thrombocytopeinia may be present.
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normal Type 1 Type 3 Type 2A Type 2B Type 2N Type 2 M PT-VWD BSS
VWFAg N ? absent ? ? N or ? ? or N ? N
VWFRco N ? absent ? ? ? ? N or ? ? ? ? ? N
FVIII N ? or N 1-3 N or ? N or ? ? ? N N N
RIAP N often normal absent ? often normal N ? N absent
LD-RIAP absent absent absent absent ??? absent absent ??? absent
Platelet count N N N N ? N N ? ?
Usual Tx DDAVP VWF con VWF conc VWF conc (DDAVP) VWF conc VWF conc (DDAVP) VWF conc platelets platelets
Response DDAVP good none poor decrease platelets poor poor decrease platelets none or poor
Response to VWF conc good good good good good good decrease platelets none
Frequency 1-2 very rare 1250,000 rare rare rare rare rare rare
Multimers N N variable abnormal, presence of small multimers or absent multimers absence of large and intermediated- size multimers absence of large multimers N N reduced, caused by consumption by platelet normal
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Management

• Education
• Cryoprocipitate
• (dose desired rise level BW 0.75)
• BT with vWF and F VIII at same time ( or need
  8-12 hr to work)
• DDAVP for type 1
• not for type 3, not for 2A, 2B
• Amicar (antifibrinolytic agent) for mucosal
  bleeds
• Humate-P (factor 8 and vWF) for surgery, trauma
• Platelet for pseudo-vWD
• Recombinant factor 7a, correct underlying
  disorder (hypothyroidism) for acquired vWD

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• 1. A patient suspected with von Willebrand
  disease (vWD and) had a normal level of
• vWF antigen but reduced vWF activity. Which
  of the following subtype is matched
• the above pattern of test results?
• (a)Type 1 vWD (b) Type 2A vWD (c) Type 2N vWD (d
  ) Type 3 vWD (e) Platelet-type
• vWD
  
  
• Ans b
• 2. Which of the following statements about von
  Willebrand disease (vWD) are correct?
• (1) Patients with blood group O have vWF levels
  that are on average 30 lower than patients with
  blood group A, B, or AB
• (2) Patients with pseudo-vWD have a genetic
  defect resulting in increased affinity of
  GpIIb-IIIa
• (3) Patients with type 1 vWD have concordant
  reduction of vWFAg and vWFRco
• (4) Patients with type IIb vWD have best
  response to DDAVP
• Ans 1,3
• 3. Which of the following laboratory results
  would be useful for the diagnosis of vWD?
• (1) Prothrombin time
• (2) Assay for factor VIIIc and vWF
• (3) Clot retraction time
• (4) Ristocetin cofactor activity

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• 4. Which of the following about von Willibrands
  disease (vWD) is correct ?
• (A) in type I vWD, the level if von
  Willebrand factor ( vWF) is decreased
• (B) the coagulation defect cannot be
  corrected by DDAVP infusion
• (C) the levels of vWF in a normal woman
  always remain constant and are not
• affected by menstrual cycle
• (D) in type III vWD, the level of von
  Willebrand factor is normal but the functional
• activity is reduced
• (E) the most common presentation of vWD is
  the unexplained thrombocytopenia
• Ans A
• 5. The response to DDAVP is usually predicted to
  be effective in the following
• subtypes of vWD
• (1) type 3 (2) type 2B (3) type 2M
  (4) type 1
• Ans 4
• 6. Which of the following factors can affect vWF
  level ?
• (1) sex (2) age (3) ABO blood type
  (4) exercise
• Ans 1,2,3,4

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• 8. The statements are true, except
• von Willebrand factor (vWF) is a large multimeric
  plasma protein composed of subunit polypeptides
• vWF has no known enzyme activity
• vWF functions as a carrier protein for factor
  VIII
• vWF is not necessary for normal factor VIII
  survival in vivo
• The normal function of vWF in platelet plug is
  apparently dependent on the assembly of this
  protein into large multimers
• Ans D
• 9. A 22-year old woman is referred for the
  evaluation of menorrhagia. She has frequent
  problems
• with heavy mens and nosebleeds, and also has
  gun bleeding after minor dental surgery. She
• uses no medications regularly, but dose take
  aspirin for menstrual cramps. She states that her
  
• mother and two maternal aunts have similar
  problems, and one aunt had a hysterectomy at age
• 30 to control her menorrhagia. The laboratory
  tests show
• Platelet count
  345,000/uL
• Platelet aggregation normal to
  ADP, epinephrine and collagen, absent with
  ristocetin
• Bleeding time(Ivy) 21 minutes
• Partial thromboplastin time 39 seconds
• Prothrombin time 10 sec.(
  control 10.5)
• Factor VIII coagulant activity 43

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• 10. Which statements about von Willebrands
  disease (vWD) are correct ?
• (1) vWD is inherited in an autosomal manner
• (2) The diagnosis is established by finding
  reduced plasma levels of vWF activity,
• vWF Ag, or factor VIII, or a
  prolonged bleeding time
• (3) Partial thromboplastin time is often
  normal in vWD
• (4) Analysis of the multimeric composition
  of vWF is required for subtyping of vWF
• but is not helpful in choosing optimal
  therapeutic agents
• Ans 1, 2, 3
• 11. The response to DDAVP is usually predicted to
  be effective in the following subtypes of vWD?
• (1) type 3 (2) type 2B (3) type 2M (4)
  type 1
• Ans 4
• 12. If a reproductive-age women with menorrhagia
  of unknown cause, the percentage of inherited
  bleeding disorder will be
• (A) 5-10 (B) 10-25 (C) 20-30 (D) 30-40
  (E) 40-50
• Ans B
• 13. von Willebrand factor is normally found in
• (1) plasma (2) endothelial cells (3)
  subendothelial space (4) megakaryocytes