Title: Outline
1Outline
- 1. Introduction
- 2. Body
- Hemostasis
- Platelet disorder
- - Disorder of Plt function
- - Thrombocytopenia
- Inherited coagulation disorder
- - Hemophilia
- - Von Willebrand Disease
- 3. Conclusion
2Introduction
- All materials from Wintrobes Clinical
Hematology, 11th edition - - Ch 51-59
3Hemostasis
- 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)
4How 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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6acquired
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
7See 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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9Coagulation 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)
10Coagulation 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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12- 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
13- 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
14Disorder 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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16CD 41,61
CD 42
17Bernard 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
18Galmzmans 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
19Storage 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
20Scott 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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22Thrombocytopenia
- Pathophysiology and classification
- Inherited platelet disorder qualitative and
quantitative - Immunologic platelet destruction
- Nonimmunologic platelet destruction
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24Inherited 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
25Congenital 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
26Thrombocytopenia 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
27Autosomal-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
28X-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
29- 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
305. 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
31ITP
- 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
32ITP
- 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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34ITP
- 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
35ITP
- 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)
36Treatment 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)
37Drugs Associated ITP
- Gold persisted for weeks to months
- ??????????????,???????????????,????5-7????????????
??????????????????,?????????????,?????????????????
?????????????????,?????Quinidine?Quinine?RIF??TMP-
SMX?
38Heparin-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)
39Neonatal 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
40Neonatal 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
42- 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
43- Thrombotic microangiopathy
- TTP
- HUS
- DIC
44TTP
- 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
45TTP
- 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
46TTP-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
47TTP 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
48Treatment 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
49Hemolytic-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
51- 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
52- 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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54Hemophilia
55Hemophilia
- 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)
56Hemophilia
- 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
57Hemophilia
- 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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60Hemophilia 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
61Initial 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
62Hemophilia 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)
63Hemophilia 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
64- 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
65- 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
66- 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
67Von 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)
68Von 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)
69Von 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
701994 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.
71 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
72Management
- 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
73- 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
74- 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
75- 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
76- 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