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Coagulation & Hemostasis
Part I
臺大醫院 蔡偉醫師
Platelet
Disorders
Classification of Congenital Platelet Disorders
1. Platelet membrane glycoprotein defects
Glanzmann thrombasthenia (GP IIb-IIIa defect)
Bernard-Soulier syndrome (GP Ib-IX-V defect)
2. Disorders of storage granules, secretion & signal
transduction
Storage pool deficiencies (α- or δ-granules)
Receptor defects (for TXA2, ADP, collagen)
Impaired arachidonic acid pathways or TXA2 synthesis
Defects in G-protein activation, calcium mobilization, protein
phosphorylation
3. Platelet membrane phospholipid, structural or cytoskeletal
defects
MYH9-related disorders, Scott syndrome, Wiskott-Aldrich syndrome,
X-linked thrombocytopenia, etc.
Glanzmann Thrombasthenia
Autosomal recessive
Symptoms: mild to severe mucocutaneous bleeding
Laboratory evidence:
• Normal platelet count and morphology
• Markedly prolonged bleeding time or PFA-100
• Absent or severely diminished platelet aggregation in response
to ADP, collagen, thrombin, and epinephrine
• Normal but possibly reversible platelet agglutination by
ristocetin and vWF
• Clot retraction, absent to subnormal
Genetics: Defects in GP IIb or GP IIIa gene
Phenotypes:
Type I: GP IIb/IIIa numbers < 5%, absent clot retraction.
Type II: GP IIb/IIIa numbers 5~15%, partial clot retraction.
Treatment: Platelet transfusion. Risk of alloimmunization.
Clot Retraction
Clot retraction:
1. Add thrombin into platelet-rich plasma.
2. Thrombin induces fibrin formation and platelet
activation.
3. Blood clot reduced to almost 20% of its
original volume within 60 min.
Mechanism:
1. Integrin GP IIb/IIIa ( αIIbβ3) links
cytoplasmic actin filaments to surfacebound fibrin polymers.
2. Platelet activation induces intracellular
signals and leads assembly of complex of
many actin-binding proteins.
3. Eventually platelet myosin serves as a
motor to drive clot retraction.
Euglobulin Lysis Time
Plasminogen
u-PA
Plasminogen
activator inhibitor-1
(PAI-1)
t-PA
Plasmin
α2-antiplasmin
Fibrin
Fibrin
degradation
products
A test measures overall fibrinolysis.
Procedures:
1. Mix platelet-poor plasma with acid in a glass test
tube. Acidification causes precipitation, euglobulin
fraction.
2. Euglobulin fraction is resuspended in a borate
solution. Clotting is activated by addition of calcium
chloride at 37 C.
3. Subsequent amount of fibrinolysis is determined
every 10 min until complete lysis. (Normal: within
90 min to 6 hr.)
Euglobulin fraction contains the important fibrinolytic factors (fibrinogen,
PAI-1, tPA, plasminogen, and to a lesser extent α2-antiplasmin).
Increased fibrinolysis (shortened euglobulin lysis time) :
Administration of Streptokinase, urokinase, t-PA, etc.
Cirrhosis (decreased t-PA clearance and antiplasmin production), Shock
Hereditary deficiency of fibrinogen
Leukemia, Prostatic cancer
Obstetric complications (e.g.antepartum hemorrhage, hydatidiform mole, amniotic
embolism)
Extensive vascular (blood vessel) trauma or surgery
Bernard-Söulier Syndrome
Autosomal recessive, BSS is rarer than GT
Symptoms: from very mild to severe mucocutaneous bleeding
Laboratory evidence:
• Moderate to severe thrombocytopenia (20K~120K)
• Large platelets with a heterogeneous size distribution
• Prolonged bleeding time or PFA-100, longer than predict
• Normal platelet aggregation in response to ADP, collagen,
and epinephrine (but not thrombin)
• Absent platelet agglutination by ristocetin and vWF, that is
not corrected by normal plasma
• Normal clot retraction
Genetics: Defects in GP Ibα, GP Ibβ, or GP IX gene
Treatment: Platelet transfusion. Risk of alloimmunization.
Inherited Defects of Receptors & Signaling Pathways
1. Receptor defects




Collagen receptor defect  α2β1(GP Ia/IIa)
ADP receptor defect  P2Y12, P2Y1, P2X1
Epinephrine receptor defect
Thromboxane A2 receptor defect
2. Defect of intracellular signaling pathways



G protein activation
Phosphatidyl-inositol metabolism
Arachidonic acid pathways & TXA2 synthesis
3. Enzyme deficiencies



Cyclo-oxygenase-1
PG H synthetase-1
Thromboxane synthetase
 Lipoxygenase
 Glycogen-6 synthetase
 ATP metabolism
Platelet Granule Content
To recruit additional platelets
ADP, ATP
Serotonin
Adhesive proteins
• vWF
• Fibrinogen
• Fibronectin
• Thrombospondin
Promote coagulation
• Factor V
• PAI-1
δ-granule
α-granule
Growth modulators
• PDGF
• Platelet factor 4
Cell-cell interaction
• P-selectin
Source: 1. synthesized in megakaryocyte, or
2. endocytosed (absorbed) from plasma
Storage Pool Deficiency Syndrome
α-SPD
• Abnormal secretion-dependent platelet aggregation
1. Gray platelet syndrome: rare, autosomal recessive, enlarged platelets (pale,
ghost-like platelets), moderate thrombocytopenia, mild myelofibrosis.
2. Quebec platelet disorder: rare, autosomal dominant. Abnormal proteolysis of αgranule proteins, and abnormal release of large amount of uPA. Bleeding should be
treated with Transamin, rather than platelet transfusion.
δ-SPD (Common. Variant defects)
• Absent ADP or epinephrine-induced 2o wave, although 1o waves are present.
• Some combined form: αδ-SPD
δ-SPD combined other congenital anomalies (rare)
 TAR (thrombocytopenia with absent radius syndrome)
 WAS (Wiskott-Aldrich syndrome): combined eczema, immune deficiency & cancer
 Hermansky-Pudlak syndrome: associated with oculocutaneous albinism, pulmonary
fibrosis, inflammatory bowel syndrome.
 Chédiak-Higashi syndrome: associated with severe immune deficiency and
progressive neurological dysfunction.
Laboratory Tests for Platelet Function
Platelet count
Platelet morphology
• Peripheral blood smear
• Electron microscopy
Template bleeding time
PFA-100
Platelet aggregation tests
Flow cytometry for CD41 (GP IIb), CD61 (GP IIIa)
Fibrinogen
Platelet
aggregation
Gp IIb/IIIa
Gp Ib/IX
Platelet
vWF
Platelet
adhesion
Causes of Prolonged Bleeding Time
1. Thrombocytopenia (platelet < 100K)
2. Platelet dysfunctions
1) Congenital
a) Glanzmann thrombasthenia (GP IIb/IIIa defect)
b) Bernard-Sőulier syndrome (GP Ib-IX-V defect)
c) Storage pool disease (δ granule deficiency)
d) Signal transduction or secretion defects
2) Acquired
a) Aspirin, Ticlopidine, NSAID, Carbencillin, etc.
b) Uremia
3. Defects of mediators for platelet adhesion and aggregation
1) von Willebrand disease
2) Afibrinogenemia
4. Others: DIC, Hepatic failure, etc
In Vitro Bleeding Time
Platelet function
analyzer (PFA-100)
(Dade-Behring, Germany)
a point-of-care assay
Citrated whole blood (0.8 mL), stable for 4 hr at room
temp.
Measure high shear-dependent platelet function
Closure Time
Limitation: Platelet >80K, Hct >30%
Cartridge membrane coated with
1. Collagen-epinephrine (Col/EPI): primary screening
2. Collagen-ADP (Col/ADP): differentiation
Template Bleeding Time better
PFA-100 better
von Willebrand disease
Aspirin ingestion
Congenital platelet receptor disorders
Platelet storage or secretion defects
PFA-100 can detect
1. von Willebrand disease (except type 2N)
2. Glanzmann thrombasthenia or Bernard-Sőulier syndrome
3. Platelet storage pool and release disorders (slight insensitive)
4. Aspirin-induced platelet dysfunction (for detection of aspirin resistance)
5. adequacy of GP IIb/IIIa antagonists during percutaneous coronary
intervention.
(Brit. J. Haematol. 2005; 130:3-10)
High sensitivity to severe vWD and severe platelet dysfunction
•
100% sensitivity for severe vWD (type 2A, 2B, 2M, and type 3 )
•
83.2~91.5% sensitivity for type 1 vWD (C/EPI > C/ADP)
•
Cannot detect type 2N vWD
•
100% sensitivity for severe forms of platelet dysfunction
(Glanzmann thrombasthenia and Bernard-Sőulier syndrome)
30~60% sensitivity for mild forms of platelet dysfunction (storage
pool disease, secretion defect, etc.)
•
(Semin Thromb Haemost 2006; 32:537)
Normal PFA-100 cannot exclude mild vWD or mild platelet dysfunction.
Further investigation is needed, if clinically suspects.
PFA-100 still has false positive results, such as thrombocytopenia, low
hematocrit, anti-platelet drug, some coagulation factor deficiencies, etc.
Bleeding tendency, suspect primary hemostatic disorder
PFA-100 screening
Col/EPI has higher sensitivity and
better predict value than Col/ADP.
Col / EPI
Normal
1. Exclude severe vWD, severe
platelet dysfunction, and
severe drug effect.
2. If initial suspicion low,
no further investigation.
3. If initial suspicion high,
arrange FVIII:C, vWF:Ag,
vWF:RCo, platelet
aggregation test, etc.
Adapted from: Blood Coagul
Fibrinolysis 2007; 18:441
Prolonged
Col / ADP
Normal
Prolonged
1. Mild vWD or
platelet
dysfunction
1. Severe vWD or
platelet
dysfunction
2. Drug effect
2. Drug effect
3. False positive
3. False positive
Platelet Aggregation Tests
Normal platelet count, but
prolonged bleeding time (PFA-100)
 Drug history
(Herbal medicine)
 R/O Uremia
Stop suspicious drugs
Bleeding time
returns normal
 R/O vWD
Platelet aggregation tests
completely absent
aggregation responses
• Glanzmann
thrombasthenia
absent secondary
aggregation wave
• Storage pool deficiency
• Signal transduction defects
• Defects in AA pathway
Drug-induced
platelet dysfunction
impaired ristocetin
response only
• vWD
• Bernard-Soulier
syndrome
ADP
Epinephrine
Collagen
Ristocetin
Bernard-Soulier
N
N
N
Absent
Epinephrine
receptor defect
N
↓
N
N
Collagen receptor
defect
N
N
↓
N
ADP, thromboxane
receptor defect
↓
↓
↓
N
δ-SPD
↓
↓
↓
N
Defect of signal
transduction
variable
variable
variable
N
Glanzmann
thrombasthenia
Absent
Absent
Absent
N or↓
Pseudothrombocytopenia
Incidence: 0.09~0.21%
Falsely low platelet count is caused by in vitro clumping
in EDTA-anticoagulant sample.
Platelet clumping is typically caused by a “naturally
occurring” antibody to GP IIb/IIIa exposed on platelets
by EDTA.
Confirm:
1. Fresh PB (without anticoagulant) smear
2. Compare platelet count results between heparin-blood
and EDTA-blood samples
Immune Thrombocytopenic Purpura
Platelet lifespan
Assumption: increased platelet synthetic rate, short platelet
lifespan
1. Increased megakaryocytes in BM
2. Evidence of increased destruction of platelets in spleen
3. Platelet antibodies
Truth:
1.
2.
3.
111In-label
autologous platelet demonstrated ITP platelets
lifespans are surprisingly long, implying that platelet
turnover is much less than had been assumed.
Evidence of antibodies impaired megakaryocyte
development.
Thrombopoietin levels in ITP patients are similar to that in
normal individuals.
Questions about Diagnosis of ITP
1. Bone marrow examination ?
 BM examination is reserved for
1. Unresponsive to therapy,
2. Over 50~60 years of age,
R/O
MDS (1% presented with isolated thrombocytopenia)
3. Splenectomy is considered.
2. Platelet antibody tests ?
 They could not distinguish between ITP and other
thrombocytopenia. (poor sensitivity and specificity)
 Diagnose ITP remains clinical, and by exclusion.
 (ASH practice guideline) Tests for plateletassociated IgG are neither necessary nor
appropriate in evaluation of childhood or adult ITP.
Questions about Diagnosis of ITP
 Differential diagnosis ?
 Psudothrombocytopenia
 Gestational thrombocytopenia
 SLE, other autoimmune disease (Evans’ syndrome,
Hashimoto’s thyroiditis, Graves’ diseases.)
 Common variable immunodeficiency
 HIV infection, lymhoproliferative disorders, cirrhosis
of liver, sarcoidosis, or Gaucher’s disease.
 More than two first degree relatives in family have
“ITP”. (Hereditary throbocytopenia)
Treatment of Patients with Refractory ITP
1.
Eradication of H. pylorie
2.
Dapson
3.
Ritxuimab
4.
Azathioprine
5.
Danazole
6.
Cyclophosphamide
7.
Vincristine
8.
Removal of accessory spleen
9.
Eltrombopag, Romiplostim
10. Pulse steroid therapy
11. High-dose cyclophosphamide with autologous stem
cell support
ITP and Helicobacter pylorie Eradication
• Molecular minicry of CagA of H.
pylorie to platelet antigen.
• Association of eradication of H.
pylorie and both disappearance
of anti-CagA antibodies and an
increase in platelet count
• The CogA positivity of H pylorie
varies depending upon
geographic location
• In Japan, most H pylorie
strains express CagA;
• In western countries, most
strain do not express CagA
From: Blood 2009; 113:1231-1240
Thrombocytopenia in Pregnancy
Isolated thrombocytopenia
•
Gestational (incidental) thrombocytopenia
incidence: 5% of pregnant women, platelet count >70K,
spontaneous remission
•
Immune thrombocytopenia purpura (ITP)
Associated systemic disorders
•
HELLP (Hemolysis, Elevated Liver function tests, Low
Platelets) syndrome. (a variant form of Pre-eclampsia, always
have hypertension and proteinuria)
•
TTP (thrombotic thrombocytopenic purpura)
 Acute fatty liver of pregnancy (AFLP). (sudden catastrophic
illness; microvesicular fatty infiltration of hepatocytes causes acute
liver failure with coagulopathy and encephalopathy. always without
hypertension or proteinuria)
Management of ITP in Pregnancy
Maternal part:
Indication of treatment: platelet count < 30K in 2nd or 3rd
trimester, or bleeding.
Management:
• Oral steroid,
• IVIG (in 3rd trimester and labor)
• laparoscopic splenectomy (in 2nd trimester)
Safe platelet count for delivery: 50K for vaginal or C/S
C/S does not decrease incidence of fetal intrancranial
hemorrrhage during delivery.
Neonatal part:
Incidence of neonatal thrombocytopenia: 10% below 50K
Cordocentesis or fetal scalp sampling: not necessary
Give platelet transfusion, IVIG, or steroid, if platelet <20K or
hemorrhage
HELLP syndrome
Prevalence: 0.5~0.9% of total pregnancy. A variant of severe preeclampsia. Increased maternal and fetal morbidity and mortality.
Onset: 70% at 3rd trimester, 10% at 2nd trimester, 20% between 37th
gestation weeks and postpartum 48hr.
Clinical symptoms: rapidly develop



Complete form: RUQ pain or epigastralgia, nausea, vomiting,
headache (continuously progress, esp. in nights)
Partial or incomplete form: fewer symptoms
80~90% have hypertension and proteinuria
Triad signs:
1.
2.
3.
Microangiopathic hemolytic anemia (fragmented RBC in
PB, total bilirubin ≧1.2 mg/dL, decreased haptoglobin),
Elevated Liver functions: AST (or ALT) ≧ 70 IU/L,
Low platelet count: ≦ 100K
Immediate delivery is indicated, if after 34th gestation.
AFLP
TTP
HUS
HELLP
Gestational thrombocytopenia
1st trimester
2nd trimester 3rd trimester
• If severe ADAMTS13 deficiency, TTP is diagnosed. If marked elevation
of LDH and modest elevation of AST: more favor TTP than HELLP.
• HUS is rare. It often considered to be primarily a renal disease with
limited systemic complications, while TTP is a systemic disease with a
relatively low frequency of renal disease.
• Serum glucose and ammonia are the most useful tests to help
distinguish AFLP from HELLP syndrome.
• HEELP: no response to plasma exchange. Consider to try high-dose
steroid, or deliver the infant and placenta.
Inherited Thrombocytopenia (1)
1. Increased platelet size (common)
MYH9-related disease

1.
Autosomal dominant, MYH9 gene at 22q12-13, encodes for heavy chain
of non-muscle myosin IIA (NMMHC-IIA) protein which involved in motor
activity of cytoskeleton
May-Hegglin anomaly (MHA)


2.
3.
4.
Mild thrombocytopenia due to ineffective thrombopoiesis, Giant platelets (5-40%)
with under-estimated platelet count, anisocytic or hypergranular platelet
Basophilic inculsions (Döhle’s body) in neutrophils (25~75%) due to aggregation
of MYH9 proteins.
Sebastian syndrome (SBS)
Fechtner syndrome (FTNS)
Epstein syndrome (EPTS)
Macrothrombocytopenia
Sensori-neural
hearing loss
Cataract
Glomerulonephritis
Leukocyte
inclusions
MHA
＋
－
－
－
＋(type 1)
SBS
＋
－
－
－
＋(type 2)
FTNS
＋
＋
＋
＋
＋ (type 2)
EPTS
＋
＋
－
＋
－
Inherited Thrombocytopenia (2)
1. Increased platelet size (continuous)
Grey platelet syndrome (α-storage pool deficiency)
GPIbα gene defects

Bernard-Soulier syndrome

Platelet-type von Willebrand disease

Mediterranean macrothrombocytopenia
Others: Montreal platelet syndrome, Paris-Trousseau / Jacobsen syndrome
2. Reduced platelet size (rare)
Wiskott-Aldrich syndrome (cytoskeleton defect)
3. Normal platelet size (rare)
Congenital amegakaryocytic thrombocytopenia

Defect of c-mpl (TPO receptor), or HOXA11, or large deletion of Iq21.1

Some combined skeletal defect, absent radius, ulna or humerus.
Schulman-Upshow syndrome

Mutations at ADAMTS13 gene, neonatal TTP
Wiskott-Aldrich syndrome
• WASp is a key regulator of actin polymerization in hematopoietic cells;
involved in signal transduction with tyrosine phosphorylation sites & adapter
protein function. Considered as a pathology of cytoskeleton.
• Intermittent bleeding, thrombocytopenia, small platelets
• Classical WAS: Eczema, recurrent bacterial and viral infect defects in
cellular & humoral immunity, increased risk of autoimmunity & malignancy
• Median survival:15 yr. infection (44%), bleeding(23%), malignancy(26%)
• Gene defect:
 Isolate thrombocytopenia (XLT): frequent missense mutation
 WAS syndrome: frequent nonsense or frameshift mutation
Affected Gene
Phenotype
Wiskott-Aldrich syndrome WAS, Xp11.22-23
Immunodeficiency, eczema,
lymphoma, small platelets
X-linked thrombocytopenia
(XLT)
Small platelets, no immune
problem
WAS
Inherited Thrombocytopenia
WAS/XLT: small platelets, poor platelet function
vWD 2B: platelet clumping on smear, varying platelet counts,
exacerbated by pregnancy and other stresses
May-Hegglin anomaly: large platelets, Döhle-like bodies in
neutrophils (other forms of MYH9-related syndromes may have
hearing loss, cataract, or renal disease.)
Bernard-Soulier syndrome: epistaxis, very large platelets
Congenital amegakaryoctyic thrombocytopenia: no
characteristic anomalies; c-mpl (thrombopoietin receptor)
mutation in most patients, may progress to aplastic anemia,
diagnosis usually before age of 2 years.
Heparin-induced Thrombocytopenia
Classical HIT
Non-immune HIT
Incidence
0.01%~2%
10%
Platelet count
10~50K
80~150K
Onset
5th~10th day
1st~2nd day
Symptoms
Venous or arterial
thrombosis
None
Management
DC heparin
Continue heparin
Diagnostic Criteria of type II Heparin-induced
Chong & Isaacs; Thromb Haemost 2009; 101:279
Thrombocytopenia
1. Thrombocytopenia occurs during heparin
administration. (Platelet < 100K, or platelet count drop
of >50% from baseline, occurring 4th-14th days after
initiation of heparin)
2. Presence of acute arterial or venous thrombosis, but is
not essential.
3. Exclusion of other causes of thrombocytopenia
4. Resolution
ofHematol
thrombocytopenia
after cessation of
4T’s
score: (Curr
Rep 2003; 2:148-157)
heparin
1. Thrombocytopenia
5. ( Thrombocytopenia recurs when the patient is
2. Time of thrombocytopenia
rechallenged with heparin )
3. Thrombosis
6. (The demonstration of a heparin-dependent platelet
4.
Exclusion
ofinother
antibody
by an
vitro cause
test) of thrombocytopenia
Venous thrombosis
>> Pulmonary embolism
> Arterial thrombosis
Clinical
Heparininduced
thrombosis
Platelet counts
fall over 50%
Heparin-induced
thrombocytopenia
Serotonin release assay
(platelet activation assay)
Enzyme immuno-assay
(antigen assay)
Laboratory
Summary of HIT with Thrombosis
 Antibody against heparin-PF4(platelet factor 4) complex
 Entire complex binds to platelets through FcRIIA receptor, then
inducing platelet activation, eventually resulting in thrombocytopenia
and/or venous / arterial thrombosis.
 LMW heparins may cross react with these antibodies. (30~50%)
 Warfarin alone is not suitable due to slow action, furthermore, it may
exacerbate thrombosis and precipitate limb gangrene.
 Bridge drugs:
Direct thrombin inhibitors:
• [hepatic excretion]: Argatroban,
• [renal excretion]: Lepirudin (Refludan), Bivulirudin
Danaparoid (20% cross-reactivity with HIT antibody)
Pentasaccharine: Fondaparinux
Blood Vessel
PGI2: prostacyclin
NO: endothelium-derivative relaxing factor, EDRF
ET-1: enothelin-1
TSP1: thrombospondin 1 (anti-angiogenic activity, ect.)
Blood Vessel
TM: thrombomodulin
EPCR: endothelial cell protein C receptor
TAFI: thrombin-activatable fibrinolysis inhibitor
TFPI: tissue pathway pathway inhibitor
Thrombin Activatable Fibrinolysis Inhibitor (TAFI)
TAFI (also called plasma procarboxypeptidase B or U ) removes
carboxy-terminal lysine residues that appear during proteolysis of
the fibrin polymers. This induces hypo-fibrinolysis by decreasing
the fibrin capacity to bind tPA and plasminogen.
Vascular Disorder
Macrovascular bleeding
Ehlers-Danlos syndrome
Hereditary hemorrhagic telangiectasia
Microvascular bleeding
Cutaneous vasculitits, Henoch-Schönlein purpura
Amyloidosis
Scurvy
Cushing syndrome
Senile purpura
Giant cavernous hemangioma
Klippel-Trenaunay syndrome  chronic DIC
Amyloidosis
Ehlers-Danlos
syndrome
Henoch-Schölein
Purpura
Cushing syndrome
Hereditary Hemorrhagic Telangiectasia
Hereditary Hemorrhagic Telangiectasia
Chronic recurrent bleeding
from nose, mucosa (upper or
lower GI bleeding), A-V
malformation (lung, liver,
brain, etc.)
Multiple telangiectasis on lip,
tongue, face, and extremities.
Autosomal dominance, high
penetrance.
Genetic defects:
1.
2.
HHT-1: endoglin, 9q33-34
HHT-2: ALK-1, 12q13
Manifestations
Incidence
Positive family Hx
70-95%
Epistaxis
90-95%
Cutaneous
telangiectasia
70-75%
Visceral
involvement
20-25%
GI bleeding
12-15%
Hepatic AVMs
8-30%
Pulmonary AVMs
5-20%
CNS AVMs
4-10%
J Clin Gastroenterol 2003;36:149
Evolution of Cutaneous Telangiectasis
in Hereditary Hemorrhagic Telaniectasia
From: Guttmacher AG et al. N Engl J Med 333:918, 1995
Thrmobtic Thrombocytopenic Purpura
Diagnosis
Microangiopathic hemolytic anemia
2. Thrombocytopenia
3. Without
Neurological
an alternative
abnormalities
causes
(transient confusion,
fluctuating focal deficits, seizure, coma, etc.)
Exclude
alternative causes
4. Fever
Evans syndrome
5. Renal impairment
1.
SLE
DIC
Sepsis
Eclampsia, preeclampsia, HELLP (hemolysis, elevated liver
function, and low platelet) syndrome
Drug toxicity (e.g. calcineurin inhibitors)
Hematopoietic stem cell transplantation
Malignant hypertension
Cancers
ADAMTS13 in TTP
1.
Idiopathic TTP
Severe deficiency 33~100% (average 75%)
If exclude creat. > 3.5 mg/dL, over 90% of TTP cases have deficiency
of ADMTS13
Idiopathic TTP has good response to plasma exchange.
2.
Secondary TTP
Almost never ADAMTS deficiency in 2o TTP
BMT or CysA-associated TTP: no deficiency of ADAMTS13
Diarrhea-associated HUS: rarely deficiency
“Atypical” HUS (without diarrhea prodrome): seldom have ADAMTS13
deficiency, but common in dysregulation of complement activation
(mutations in complement factor H, factor I, factor B, or membrane
cofactor protein; or autoantibodies of CFH)
Always poor response to plasma exchange
Blood 2008; 112:11-8
Monitoring of ADAMTS13 Activity for
Prediction of Therapeutic Response & Prognosis
1. First attack of TTP
Idiopathic TTP patients whether ADAMTS13 deficiency or not have
similar response rates and short-term survival.
All idiopathic TTP patients should be treated with plasma exchange,
regardless of ADAMTS13 levels.
About one-half of patients with severe ADAMTS deficiency suffer at
least one relapse within 2 years, whereas patients without def. almost
never relapse.
2. After remission
ADAMTS13 levels during TTP remission
Persistent severe def. vs No def. : 60% vs 19%
Autoantibody detectable during remission
Detectable inhibitor vs No inhibitor: 57% vs 4%
Monitoring ADAMTS13 activity and/or its antibodies during remission
might have predictive value of disease relapse.
Blood 2008; 112:11-8
Management of TTP (1)
1. Classical TTP
Acute TTP: Plasma exchange >> plasma infusion (FFP or
cryosupernatant plasma)
RefractoryTTP or Chronic relapsing TTP: Rituximab, Steroid,
IVIG, Immunosupressive agents (vincristine,
cyclophosphamide, etc.), Splenectomy
2. Acute, immune-mediated drug toxicity: Quinine,
ticlopidine, clopidogrel
Plasma exchange is choice (Immunosuppressive treatment is
not needed.)
Chronic renal failure is common.
NEJM 2006; 354:1927-1934.
&
Curr Opin Hematol 2008; 15:445-450
Management of TTP (2)
3. Post-diarrheal HUS (Shiga toxin-producing bacteria, typically E.
coli O157:H7)
Hemodialysis and supportive care (plasma exchange is
not needed.)
4. Cumulative, dose-dependent drug toxicity: mitomycin,
gemcitabine, cyclosporin, tacrolimus.
Mortality is high. Chronic renal failure is common.
5. Allo-BMT or PSCT
Thrombotic microangiopathy limited to the kidney. The
benefit of plasma exchange is unlikely. Mortality is high
because of multiple complication.
NEJM 2006; 354:1927-1934.
&
Curr Opin Hematol 2008; 15:445-450