1. Coagulation & Hemostasis Part I
臺大醫院 蔡偉醫師

2. Platelet Disorders

3. Classification of Congenital Platelet Disorders
Platelet membrane glycoprotein defects
Glanzmann thrombasthenia (GP IIb-IIIa defect)
Bernard-Soulier syndrome (GP Ib-IX-V defect)
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
Platelet membrane phospholipid, structural or cytoskeletal defects
MYH9-related disorders, Scott syndrome, Wiskott-Aldrich syndrome, X-linked thrombocytopenia, etc.

4. 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.

5. Clot Retraction Clot retraction: Mechanism:
Add thrombin into platelet-rich plasma.
Thrombin induces fibrin formation and platelet activation.
Blood clot reduced to almost 20% of its original volume within 60 min.
Mechanism:
Integrin GP IIb/IIIa ( αIIbβ3) links cytoplasmic actin filaments to surface-bound fibrin polymers.
Platelet activation induces intracellular signals and leads assembly of complex of many actin-binding proteins.
Eventually platelet myosin serves as a motor to drive clot retraction.

6. Euglobulin Lysis Time A test measures overall fibrinolysis.
Plasminogen
Plasmin
Fibrin
Fibrin degradation products
u-PA
t-PA
Plasminogen activator inhibitor-1 (PAI-1)
α2-antiplasmin
A test measures overall fibrinolysis.
Procedures:
Mix platelet-poor plasma with acid in a glass test tube. Acidification causes precipitation, euglobulin fraction.
Euglobulin fraction is resuspended in a borate solution. Clotting is activated by addition of calcium chloride at 37 C.
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

7. 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.

8. Inherited Defects of Receptors & Signaling Pathways
Receptor defects
Collagen receptor defect  α2β1(GP Ia/IIa)
ADP receptor defect  P2Y12, P2Y1, P2X1
Epinephrine receptor defect
Thromboxane A2 receptor defect
Defect of intracellular signaling pathways
G protein activation
Phosphatidyl-inositol metabolism
Arachidonic acid pathways & TXA2 synthesis
Enzyme deficiencies
Cyclo-oxygenase  Lipoxygenase
PG H synthetase  Glycogen-6 synthetase
Thromboxane synthetase  ATP metabolism

9. Platelet Granule Content
Adhesive proteins
vWF
Fibrinogen
Fibronectin
Thrombospondin
Promote coagulation
Factor V
PAI-1
Growth modulators
PDGF
Platelet factor 4
Cell-cell interaction
P-selectin
To recruit additional platelets
ADP, ATP
Serotonin
δ-granule
α-granule
Source: 1. synthesized in megakaryocyte, or
2. endocytosed (absorbed) from plasma

10. Storage Pool Deficiency Syndrome
α-SPD
Abnormal secretion-dependent platelet aggregation
Gray platelet syndrome: rare, autosomal recessive, enlarged platelets (pale, ghost- like platelets), moderate thrombocytopenia, mild myelofibrosis.
Quebec platelet disorder: rare, autosomal dominant. Abnormal proteolysis of α-granule 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.

11. 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)

12. Platelet aggregation Platelet adhesion Fibrinogen Gp IIb/IIIa Gp Ib/IX
vWF

13. Causes of Prolonged Bleeding Time
Thrombocytopenia (platelet < 100K)
Platelet dysfunctions
Congenital
Glanzmann thrombasthenia (GP IIb/IIIa defect)
Bernard-Sőulier syndrome (GP Ib-IX-V defect)
Storage pool disease (δ granule deficiency)
Signal transduction or secretion defects
Acquired
Aspirin, Ticlopidine, NSAID, Carbencillin, etc.
Uremia
Defects of mediators for platelet adhesion and aggregation
von Willebrand disease
Afibrinogenemia
Others: DIC, Hepatic failure, etc

14. 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
Collagen-epinephrine (Col/EPI): primary screening
Collagen-ADP (Col/ADP): differentiation

15. 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
von Willebrand disease (except type 2N)
Glanzmann thrombasthenia or Bernard-Sőulier syndrome
Platelet storage pool and release disorders (slight insensitive)
Aspirin-induced platelet dysfunction (for detection of aspirin resistance)
adequacy of GP IIb/IIIa antagonists during percutaneous coronary intervention.
(Brit. J. Haematol. 2005; 130:3-10)

16. 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 (Semin Thromb Haemost 2006; 32:537)
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.)
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.

17. Bleeding tendency, suspect primary hemostatic disorder
PFA-100 screening
Col/EPI has higher sensitivity and better predict value than Col/ADP.
Col / EPI
Prolonged
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.
Col / ADP
Normal
Prolonged
1. Mild vWD or platelet dysfunction
2. Drug effect
3. False positive
1. Severe vWD or platelet dysfunction
2. Drug effect
3. False positive
Adapted from: Blood Coagul Fibrinolysis 2007; 18:441

18. Platelet Aggregation Tests

19. Normal platelet count, but prolonged bleeding time (PFA-100)
 Drug history
(Herbal medicine)
Stop suspicious drugs
 R/O Uremia
Bleeding time returns normal
 R/O vWD
Platelet aggregation tests
Drug-induced platelet dysfunction
completely absent aggregation responses
absent secondary aggregation wave
impaired ristocetin response only
Glanzmann thrombasthenia
Storage pool deficiency
Signal transduction defects
Defects in AA pathway
vWD
Bernard-Soulier syndrome

20. ADP Collagen Ristocetin
Epinephrine
Collagen
Ristocetin
Bernard-Soulier N
Absent
Epinephrine receptor defect ↓
Collagen receptor defect
ADP, thromboxane receptor defect
δ-SPD
Defect of signal transduction
variable
Glanzmann thrombasthenia
N or↓

21. 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:
Fresh PB (without anticoagulant) smear
Compare platelet count results between heparin-blood and EDTA-blood samples

22. Immune Thrombocytopenic Purpura
Platelet lifespan
Assumption: increased platelet synthetic rate, short platelet lifespan
Increased megakaryocytes in BM
Evidence of increased destruction of platelets in spleen
Platelet antibodies
Truth:
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.

23. Questions about Diagnosis of ITP
Bone marrow examination ?
BM examination is reserved for
Unresponsive to therapy,
Over 50~60 years of age,
R/O MDS (1% presented with isolated thrombocytopenia)
Splenectomy is considered.
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 platelet-associated IgG are neither necessary nor appropriate in evaluation of childhood or adult ITP.

24. 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)

25. Treatment of Patients with Refractory ITP
Eradication of H. pylorie
Dapson
Ritxuimab
Azathioprine
Danazole
Cyclophosphamide
Vincristine
Removal of accessory spleen
Eltrombopag, Romiplostim
Pulse steroid therapy
High-dose cyclophosphamide with autologous stem cell support

26. 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:

27. 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)

28. 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

29. HELLP syndrome
Prevalence: 0.5~0.9% of total pregnancy. A variant of severe pre-eclampsia. 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:
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.

30. Gestational thrombocytopenia
AFLP
HUS
TTP
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.

31. Inherited Thrombocytopenia (1)
Increased platelet size (common)
MYH9-related disease
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)
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)
Macro-thrombocytopenia
Sensori-neural hearing loss
Cataract
Glomerulo-nephritis
Leukocyte inclusions
MHA ＋ －
＋(type 1)
SBS
＋(type 2)
FTNS
＋ (type 2)
EPTS

32. Inherited Thrombocytopenia (2)
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
Reduced platelet size (rare)
Wiskott-Aldrich syndrome (cytoskeleton defect)
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

33. 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, Xp
Immunodeficiency, eczema, lymphoma, small platelets
X-linked thrombocytopenia (XLT)
WAS
Small platelets, no immune problem

34. 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.

35. 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

36. Diagnostic Criteria of type II Heparin-induced Thrombocytopenia
Chong & Isaacs; Thromb Haemost 2009; 101:279
Thrombocytopenia occurs during heparin administration. (Platelet < 100K, or platelet count drop of >50% from baseline, occurring 4th-14th days after initiation of heparin)
Presence of acute arterial or venous thrombosis, but is not essential.
Exclusion of other causes of thrombocytopenia
Resolution of thrombocytopenia after cessation of heparin
( Thrombocytopenia recurs when the patient is rechallenged with heparin )
(The demonstration of a heparin-dependent platelet antibody by an in vitro test)
4T’s score: (Curr Hematol Rep 2003; 2: )
Thrombocytopenia
Time of thrombocytopenia
Thrombosis
Exclusion of other cause of thrombocytopenia

37. IgG antibody reacts with PF4/heparin complex, then they bind to platelet via FcγIIa receptor, and induce strong platelet activation.

38. Clinical Serotonin release assay (platelet activation assay)
Venous thrombosis
>> Pulmonary embolism
> Arterial thrombosis
Clinical
Heparin-induced thrombosis
Platelet counts fall over 50%
Heparin-induced thrombocytopenia
Serotonin release assay (platelet activation assay)
Laboratory
Enzyme immuno-assay (antigen assay)

39. 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

40. Blood Vessel PGI2: prostacyclin
NO: endothelium-derivative relaxing factor, EDRF
ET-1: enothelin-1
TSP1: thrombospondin 1 (anti-angiogenic activity, ect.)

41. Blood Vessel TM: thrombomodulin
EPCR: endothelial cell protein C receptor
TAFI: thrombin-activatable fibrinolysis inhibitor
TFPI: tissue pathway pathway inhibitor

42. 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.

43. Vascular Disorder Macrovascular bleeding Microvascular 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

44. Henoch-Schölein Purpura
Amyloidosis
Henoch-Schölein Purpura
Ehlers-Danlos
syndrome
Cushing syndrome

45. Hereditary Hemorrhagic Telangiectasia

46. 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:
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

47. in Hereditary Hemorrhagic Telaniectasia
Evolution of Cutaneous Telangiectasis
in Hereditary Hemorrhagic Telaniectasia
From: Guttmacher AG et al. N Engl J Med 333:918, 1995

48. Thrmobtic Thrombocytopenic Purpura
Diagnosis
Microangiopathic hemolytic anemia
Thrombocytopenia
Without an alternative causes
Neurological abnormalities (transient confusion, fluctuating focal deficits, seizure, coma, etc.)
Fever
Renal impairment
Exclude alternative causes
Evans syndrome
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

50. ADAMTS13 in TTP Idiopathic TTP Secondary 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.
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

51. Monitoring of ADAMTS13 Activity for Prediction of Therapeutic Response & Prognosis
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.
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

52. NEJM 2006; 354:1927-1934. & Curr Opin Hematol 2008; 15:445-450
Management of TTP (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
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: & Curr Opin Hematol 2008; 15:

53. NEJM 2006; 354:1927-1934. & Curr Opin Hematol 2008; 15:445-450
Management of TTP (2)
Post-diarrheal HUS (Shiga toxin-producing bacteria, typically E. coli O157:H7)
Hemodialysis and supportive care (plasma exchange is not needed.)
Cumulative, dose-dependent drug toxicity: mitomycin, gemcitabine, cyclosporin, tacrolimus.
Mortality is high. Chronic renal failure is common.
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: & Curr Opin Hematol 2008; 15: