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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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Outline l.jpg
Outline

  • 1. Introduction

  • 2. Body

  • Hemostasis

  • Platelet disorder

    - Disorder of Plt function

    - Thrombocytopenia

  • Inherited coagulation disorder

    - Hemophilia

    - Von Willebrand Disease

  • 3. Conclusion


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Introduction

  • All materials from Wintrobe’s Clinical Hematology, 11th edition

    - Ch 51-59


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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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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


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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 >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)


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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I=frbrinogen (120 hr)


Coagulation factor 2 l.jpg
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


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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-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


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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

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


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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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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


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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


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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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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


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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 : < 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


Autosomal dominant macrothrombocytopenia myh9 gene defect l.jpg
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


X linked thrombocytopenia l.jpg

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


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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


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  • 5. checking?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


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ITP checking?

  • By exclusion Dx , no identifiable underlying case

  • 2ndTP


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ITP checking?

  • 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 %


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ITP checking?

  • 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


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ITP checking?

  • 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)



Drugs associated itp l.jpg

Gold persisted for weeks to months checking?

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



Neonatal autoimmune thrombocytopenia l.jpg
Neonatal Autoimmune Thrombocytopenia checking?

  • 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


Neonatal alloimmune thrombocytopenia nait l.jpg
Neonatal Alloimmune Thrombocytopenia ( NAIT) checking?

  • 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


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1. Which of the following statements about ITP is checking?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


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4. Concerning with ITP, which description is checking? 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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Slide44 l.jpg
TTP checking?

  • 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


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TTP checking?

  • 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


Ttp diagnosis hint l.jpg
TTP-Diagnosis Hint checking?

  • 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


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TTP D/D checking?

  • 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


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Hemolytic-Uremic Syndrome normal

  • 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


  • Slide50 l.jpg

    1. normal 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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    3 normal . 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: O157:H7 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

    (E) Transplantation

    Ans : B


    Slide52 l.jpg

    5. Which of the following about TTP is normal 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

    (3) Thrombocytopenia

    (4) Renal failure

    Ans: 1,2,3


    Hemophilia l.jpg
    Hemophilia normal


    Hemophilia55 l.jpg
    Hemophilia normal

    • 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 (>60%) , 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)


    Hemophilia56 l.jpg
    Hemophilia normal

    • 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 > 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


    Hemophilia57 l.jpg
    Hemophilia normal

    • 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


    Hemophilia treatment l.jpg
    Hemophilia Treatment normal

    • 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



    Hemophilia factor viii or ix inhibitor l.jpg
    Hemophilia – Factor VIII (or IX) Inhibitor normal

    • 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 %

      • 1:10 dilution of test plasma has this effect -> 10 Bethesda unit

    • Low responder

      • Ab titer < 5 B.u

      • High-dose factor VIII concentrates and routine inhibitor assay

    • High responder

      • Ab titer > 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)


    Hemophilia factor viii or ix inhibitor63 l.jpg
    Hemophilia – Factor VIII (or IX) Inhibitor normal

    • 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


    Slide64 l.jpg

    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


    Slide65 l.jpg

    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


    Slide66 l.jpg

    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


    Von willebrand disease l.jpg
    Von Willebrand Disease iliopsoas muscle hematoma, which minimal plasma level of FVIII should be kept at the initial treatment stage?

    • 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)


    Von willebrand disease68 l.jpg
    Von Willebrand Disease iliopsoas muscle hematoma, which minimal plasma level of FVIII should be kept at the initial treatment stage?

    • 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)


    Von willebrand disease screen test l.jpg
    Von Willebrand Disease-Screen Test iliopsoas muscle hematoma, which minimal plasma level of FVIII should be kept at the initial treatment stage?

    • 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)

    • Pt’s platelet(ristocetin induced)

    • To DDx of 2B and plt-type from others

  • Multimer studies


  • 1994 classifications of vwd l.jpg
    1994 Classifications of VWD iliopsoas muscle hematoma, which minimal plasma level of FVIII should be kept at the initial treatment stage?


    Management l.jpg
    Management iliopsoas muscle hematoma, which minimal plasma level of FVIII should be kept at the initial treatment stage?

    • 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


    Slide73 l.jpg

    1. iliopsoas muscle hematoma, which minimal plasma level of FVIII should be kept at the initial treatment stage?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 vWF:Ag and vWF:Rco

    (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

    Ans : 2,4


    Slide74 l.jpg

    4. Which of the following about von Willibrand’s 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

    7. Which of the following subtypes of vWD is the most easily mistaken for hemophilia:

    (A) type 1 (B) type 2A (C) type 2B (D) type 2M (E) type 2N

    Ans : E


    Slide75 l.jpg

    8 (vWD) is correct ? .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 %

    Factor VIIIR Ag 20 %

    The most likely diagnosis is :

    (A) Glanzmann’s thrombasthenia (B) Bernard-Soulier syndrome (C) Type I von Willebrand’s disease

    (D) Platelet dysfunction caused by aspirin ingestion (E) vascular purpura

    Ans : C


    Slide76 l.jpg

    10. Which statements about von Willebrand’s 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

    Ans: 1,2,3,4