Transcript 投影片 1

Outline
• 1. Introduction
• 2. Body
•
Hemostasis
•
Platelet disorder
- Disorder of Plt function
- Thrombocytopenia
•
Inherited coagulation disorder
- Hemophilia
- Von Willebrand Disease
• 3. Conclusion
Introduction
• All materials from Wintrobe’s Clinical
Hematology, 11th edition
- Ch 51-59
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)
How to D/D primary or secondary hemostasis
Clinical Distinction between Disorder of Vessels and Platelets and Disorders of Blood Coagulation
Finding
Petechiae
Deep dissecting hematomas
Superficial ecchymoses
Hemarthrosis
Delayed bleeding
Bleeding form superficial cuts and
scratches
Sex if patient
Positive family history
Disorder of Coagulation
Rare
Characteristic
Common, usually large and solitary
Characteristic
Common
Minimal
80-90% of inherited forms occur
only in male patients
Common
Disorder of Platelets or Vessels
Characteristic
Rare
Characteristic, usually small and
multiple
Rare
Rare
Persistent, often profuse
Relative more common in females
Rare ( Except vWD and hereditary
hemorrhagic telangiectasia)
acquired
inherited
一定有
answer
Drugs: Cpz,
fortum,
Usually
acquired
disease
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
Urea [5M]
solubility
test
See You
Symptom(+)
Lab (+) and
Sym(-)
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%)
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)
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)
• 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
1. 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
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
Disorder of Platelet Function
1.
2.
3.
4.
5.
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
CD
41,61
CD 42
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
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
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
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
Thrombocytopenia
• Pathophysiology and classification
• Inherited platelet disorder : qualitative and
quantitative
• Immunologic platelet destruction
• Nonimmunologic platelet destruction
Inherited Platelet Quantitative Disorder
• 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 radioulnar 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 )
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
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)
• 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
May-Hegglin
Sebastian
Fechtner
Epstein
Macrothrombocytopenia
Dohle-like bodies
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Nephritis
No
No
Yes
Yes
Deafness
No
No
Yes
Yes
Cataracts
No
No
Yes
No
X-Linked Thrombocytopenia
• X-linked
microthrombocytopenia
– WASp gene at Xp11.22p11.23
– 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 macrothrombocytopenia and anemia
– D/D with WAS : normal PLT
size, no immune abnormality,
severity of bleeding
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
5. Which of the following disease is characterized by giant lysosomes in granulocytes, a picture
of partial oculocutaneous albinism, and neuropathy associated with decussation defects at the
optic chiasm?
(A) Alder-Reilly anomaly
(B) Chediak Higashi anomaly
(C) Chronic granulomatous disease
(D) Leukocyte adhesion deficiency
(E) May-Hegglin anomaly
Ans : B
6. Which condition can be associated with prolong bleeding time ?
(1) Thrombocytopenia
(2) Bernard-Soulier syndrome
(3) von Willibrand disease
(4) Sever hypofibrinogenemia
Ans: 1,2,3,4
7. Which of the following medical conditions may indicate for the bleeding tendency ?
(1) acute or chronic liver disease
(2) myeloma or paraproteinemia
(3) renal insufficiency
(4) myeloproliferative disorders
Ans: 1,2,3,4
8. Which disease(s) will cause platelet adhesion defects?
(1) Bernard-Soulier Syndrome
(2) Storage pool deficiency of platelet
(3) Von Willebrand’s disease
(4) Hemophilia A and B
Ans : 1,3
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
ITP
•
•
•
•
•
•
Most common antigens: GpIIb/IIIa, Ib/IX
Serum antiplt IgG autoAb : 50-85%
S/S : GU bleeding, GYN menses bleeding
< 50000: even trauma->no bleeding
<10000: spontaneous bleeding
ICH < 1 %
ITP
•
Childhood is usually benign and self-limited
–
Plt > 30K and no clinical bleeding : observation only
–
Plt < 20K + significant mucous membrane bleeding or plt <10K with
minor purpura
–
•
•
•
•
•
Steroid increase plt at 1 wk , peak at 2-4 wk
IVIG increase plt at 2 days , peak at 1 wk
•
Anti-D
Chronic ITP ( > 6 months) : < 20 %
Adult : spontaneous remission <5% , so need long term treatment
<25% after DC prednisolone can long tern PR and CR(Plt>50000)
After prednisolone
–
response in 1 wk peak in 2-4 wkskep Tx try tapping or DC in
week 4 (CR or PR :83% child, 59% adult)
–
if no response in 1-2 wks try other treatment and splenectomy
ITP
• Indication of splenectomy
– <10k and Poor response to steroid >6 weeks
– <30K and poor response to steroid >3 months
• CR to splenectomy : 50- 80%
– Accessory spleen : 15-20% ( 50 % relapse)
• Immunosuppressive drugs (for refractory case)
– Cyclophosphamide (16-55% response)
– Vincristine and vinblastine
– Anti-CD 20 monoclonal Ab ( 50 % response)
Treatment of ITP in Adults
Approach
Initial
Refractory
Bleeding
Chronic refractory
Treatment
Notes
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 Mɸ
anti-plt Ab production
Anti-Rh(D) Ig 75μg/kg/d IV
For Rh(D) +pts
Ab-coated RBCs overwhelm Mɸ
Fc receptors
IVIG(1g/kg/d IV x 2-3d)
If plt <5000 despite steroids
Blacks Fc receptors on Mɸ
anti-plt Ab production
Splenectomy
 Plt clearance
Rituximab (anti-CD20)
 Plt clearance, Ab against B cell
Danazol, vincristine
 Plt clearance
Azathioprine, cyclophosphamide
Immunosuppressants
 anti-plt Ab production
AMG531,AKR-501, eltrombopag
Thrombopoiesis stim. proteins
Aminocaproic acid
Inhibits plasmin activation
Methylprednisolone 1g/d IV x 3d
See above
IVIG
See above
Autologous HSCT
Investigational
(NEJM 2002;346:995 &2003;349:831&2006;355:1672)
Drugs Associated ITP
•
•
Gold persisted for weeks to months
當懷疑有藥物引起血小板低下時，可藉由受疑藥品的停用
來加以証實，通常停用5─7天即可得到証實。一般若想了解
究竟是哪些藥物造成病患血小板低下，可參考一些發表過
的個案報告，以評估該病患之用藥與血小板低下之間的關
係究竟有多大。在報告過的個案中，最常見的是Quinidine、
Quinine、RIF以及TMP-SMX。
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
(<24h)with history of prior
exposure within last 100d ( felt
to be secondary to persistent Ab)
Can occur after heparin
discontinue.
Platelet nadir
> 100,000/μl
30-70,000/μl,  >50%
Sequelae
None
Thrombotic events (HITT) in 3050%
Rare hemorrhagic complications
Management
Can continue heparin and
observe
Discontinue heparin
Alternative anticoagulation
(lepirudin or arga)
Neonatal Autoimmune Thrombocytopenia
• Pathogenesis
– Infant of mothers with immune thrombocytopenia ( ITP,
SLE, or other autoimmune disorder)
– Placental transfer of maternal antoAbs
• Clinical features
– Less severe than NAIT
– Risk of ICH : 1%
– Both neonate and mother have thrombocytopenia
• Treatment
– PLT < 40-50 K
– IVIG, steroids
•
•
Neonatal Alloimmune Thrombocytopenia
( NAIT)
Incidence : 1/2000 births
Placental transferof maternal alloAbs directed against paternally inherited Ags
present on fetal platelets but absent from maternal platelets
– Transient , isolated , severe thrombocytopenia
– Platelet alloAgs
• Human platelet antigen (HPA) 1a, 5b
• HLA class I
• Blood group ABH
•
Features
–
–
–
–
–
•
Severe thrombocytopenia (< 10K) on the 1st day
Petechiae (90%), hematoma (66%), GI bleeding (30%)
ICH (15%): prenatal (50%), postnatal
Normal maternal platelet counts
Can occur in both the first and subsequent pregancies
Dx: serologic or genotypic testing
– Immunophenotyping of maternal, paternal, and neonatal PLT
– Anti-PLT Ab in maternal or fetal serum (< 2/3)
•
Tx: PLT transfusion
• PLT < 30K or clinically significant bleeding
• Washed, irradiated, maternal platelets
1. Which of the following statements about ITP is wrong?
(A) It is an autoimmune disease in most adult ITP
(B) The effect of IVIG last about 3 weeks
(C) Children present with acute ITP and usually with spontaneous remission
(D) For chronic ITP, the goal of therapy is to maintain platelet count over 80,000/cmm
(E) 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
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
•Thrombotic
microangiopathy
•TTP
•HUS
•DIC
TTP
•
•
•
•
•
•
•
Incidence: 1-4/ million
Penta: fever, renal , thrombocytopenia, neuro (gray matter and brain stem),
hemolytic anemia
74% with 3( plt, anemia, neuro), 40% with penta
Most common symptom: fever , HA
Reversible aggregation of platelets in microvasculature , brain, abdominal viscera
and heart are most common site
F/M=2/1, adult 30-40 y/o
Gene HLA II DR35
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
TTP
• TTP
• Vascular abnormality
– TTP is a disease due to ADAMTS13 (metaoprotease) deficiency <10%
most and increase ULvWF
• Point mutation family deficiency(Upshaw-Shulman syn)
• Antibody or inhibitor related (居多)
– Overproduct (release) of ULvWFthen use off the ADAMTS13
– PAF(platelet aggregation agents) disclosed in blood : PAF37,
calpain,3rd??
• FFP ( with protease in FFP) can treatment TTP
• DDX: HUS normal protease level
TTP-Diagnosis Hint
•
•
•
•
•
•
•
•
PB smear : polychromasia , stippling, nucleated RBC, schistocytes
LDH 400~ more than 1000
Unconjugated bilirubin 
HgB<10, ret  , hepatoglobin , hemoglobiuria, hemosiderinuria
Plt<100k, most <50,000
Coagulation : normal ( FDP may slightly )
Agarose gel : abnormal vWF multimers
Skin, BM, gingiva Bx: hyaline thrombi within arterioles( but also in DIC,
HUS, some vasculitis… no specific)
• Brain CT : reversible brain edema, ischemic strokes , and frank hematoma
• Sensitive indices of the response to therapy : LDH level and platelet
count
TTP D/D
• HUS
– Microangiopathic blood destruction and vascular damage occur
principally in kidney
– High In child with prodromal infection
– Abdominal pain, GI s/s, anuria, several renal failure and hypertension
are common in the early course
– Neurologic symptom are less common
– C’ low, most self remission and relapse is rare
• HELLP(pregnant female;eclampsia; hemolysis;elevated liver
enzyme; low plt count)
• SLE woth immune TTP
• Vasculitis
• PNH
• TTP+AIHA
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
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
1. Which statements about thrombotic thrombocytopenic purpura is correct ?
(1) Inhibitory antibodies against von Willebrand factor-cleaving protease occur in patients with acute
thrombotic thrombocytopenic purpura
(2) Detected in the plasma of patients with TTP
(3) Deficiency of ADAMTS13 has been reported consistently in patients with TTP. Such defect may
be constitutive, due to homozygous or double heterozygous mutations in the corresponding gene,
or acquired, due to the presence of circulating inhibitory antibodies
(4) ADAMTS13 is an inhibitory antibody against von Willebrand factor-cleaving protease
Ans:1,2,3
2. A 72-year-old man, had a flu-like symptoms 2 weeks ago, started to have fluctuation of
consciousness, skin ecchymosis, low grade fever, decreased urine amount, was sent to
emergent service due to deterioration of consciousness disturbance. On PE: BP 136/82 mmHg,
PR 112/min, regular heart beat, consciousness very drowsy, mild fever 37.9 oC, Blood tests:
WBC 12300/ul, mild neutrophilia, Hb 8.3 g/dl, MCV 92 fl, Platelet 18000/ul. PB smear:
marked thrombocytopenia, apparent RBC fragmentation, no blast. Serum Cr: 3.8 mg/dl, LDH
680 U/dl (high). Normal PT/aPTT. Under this situation, which of the following managements
is (are) appropriate
(1) Emergent hemodialysis for rapid deterioration of renal function
(2) Aggressive transfusion of platelet concentrate to keep platelet count >50000/ul
(3) High dose parenteral steroid, e.g. methylprednisolone as pulse therapy
(4) Infusion of fresh frozen plasma (FFP), or exchanging plasmaphoresis if available
Ans: 4
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: 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
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
(3) Thrombocytopenia
(4) Renal failure
Ans: 1,2,3
Hemophilia
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 (>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)
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 > 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
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
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
Initial Treatment of Specific
Hemorrhages in Hemophilia
Type of hemorrhage
Hemophilia A
(units/kg factor VIII
concentrate)
Hemophilia B
(units/kg factor IX
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
concentrate)
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 %
– 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) 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
1.
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
2.
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
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
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 lifethreatening 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
• Large , multimeric glycoprotein
• Act in coagulation
– Bridges together plt with vascular subendothelium (Gp IbIX)
– FVIII carrier protein
• Synthesis in megakaryocytes and endothelial cells
• Stored in Weibel-Palade body (endothelial cell) and  granule
(platelet)
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)
Von Willebrand Disease-Screen Test
•
•
BT, aPTT
“vWF immunoassay(Ag)”
•
•
“Ristocetin cofactor activity”
•
•
•
•
If VWF ok and decrease FVIIIc2N
Plt aggression test ( LD-RIAP)
•
•
•
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”
•
•
quantitative immunoelectrophoretic assay
Pt’s platelet(ristocetin induced)
To DDx of 2B and plt-type from others
Multimer studies
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.
normal
Type 1
Type 3
Type 2A
Type 2B
Type 2N
Type 2
M
PT-VWD
BSS
VWF:Ag
N

absent


N or 
 or N

N
VWF:Rco
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


DDAVP
VWF
con
VWF conc
VWF
conc
VWF
conc
VWF
conc
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
1:250,000
rare
rare
rare
rare
rare
rare
N
variable
abnormal,
presence of
small
multimers or
absent
multimers
absence
of large
and
intermedi
ated- size
multimers
absence of
large
multimers
N
N
reduced,
caused by
“consumpti
on” by
platelet
normal
Usual Tx
Multimers
N
(DDAVP)
(DDAVP)
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
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 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
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
Ans : 4
(2) type 2B
(3) type 2M
(4) type 1
6. Which of the following factors can affect vWF level ?
(1) sex (2) age
Ans : 1,2,3,4
(3) ABO blood type (4) exercise
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
8. The statements are true, except
(A) von Willebrand factor (vWF) is a large multimeric plasma protein composed of subunit
polypeptides
(B) vWF has no known enzyme activity
(C) vWF functions as a carrier protein for factor VIII
(D) vWF is not necessary for normal factor VIII survival in vivo
(E) 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
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