Coagulation

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Coagulation HemostasisPart I

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Platelet Disorders
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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 (a- or d-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.

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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 lt 5,
  absent clot retraction.
• Type II GP IIb/IIIa numbers 515,
  partial clot retraction.
• Treatment Platelet transfusion. Risk of
  alloimmunization.

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Clot Retraction

• Clot retraction
• 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 ( aIIbß3) 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.

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Euglobulin Lysis Time

• 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
  a2-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

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Bernard-Söulier Syndrome

• Autosomal recessive, BSS is rarer than GT
• Symptoms from very mild to severe mucocutaneous
  bleeding
• Laboratory evidence
• Moderate to severe thrombocytopenia (20K120K)
• 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 Iba, GP Ibß, or GP IX
  gene
• Treatment Platelet transfusion. Risk of
  alloimmunization.

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• Inherited Defects of Receptors Signaling
  Pathways

• Receptor defects
• Collagen receptor defect ? a2ß1(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-1 ?
  Lipoxygenase
• PG H synthetase-1 ? Glycogen-6
  synthetase
• Thromboxane synthetase ? ATP metabolism

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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
d-granule
a-granule
Source 1. synthesized in megakaryocyte, or
2. endocytosed (absorbed) from plasma
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Storage Pool Deficiency Syndrome

• a-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 a-granule
  proteins, and abnormal release of large amount of
  uPA. Bleeding should be treated with Transamin,
  rather than platelet transfusion.

• d-SPD (Common. Variant defects)
• Absent ADP or epinephrine-induced 2o wave,
  although 1o waves are present.
• Some combined form ad-SPD

• d-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.

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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)

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Fibrinogen
Platelet aggregation
Gp IIb/IIIa
Gp Ib/IX
Platelet
Platelet adhesion
vWF
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Causes of Prolonged Bleeding Time

• Thrombocytopenia (platelet lt 100K)
• Platelet dysfunctions
• Congenital
• Glanzmann thrombasthenia (GP IIb/IIIa defect)
• Bernard-Soulier syndrome (GP Ib-IX-V defect)
• Storage pool disease (d 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

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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 gt80K, Hct gt30
• Cartridge membrane coated with
• Collagen-epinephrine (Col/EPI) primary screening
• Collagen-ADP (Col/ADP) differentiation

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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-Soulier
  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 1303-10)

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High sensitivity to severe vWD and severe
platelet dysfunction

• 100 sensitivity for severe vWD (type 2A, 2B, 2M,
  and type 3 )
• 83.291.5 sensitivity for type 1 vWD (C/EPI gt
  C/ADP)
• Cannot detect type 2N vWD (Semin Thromb
  Haemost 2006 32537)

• 100 sensitivity for severe forms of platelet
  dysfunction (Glanzmann thrombasthenia and
  Bernard-Soulier syndrome)
• 3060 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.
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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 FVIIIC, vWFAg, vWFRCo, 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
18441
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Platelet Aggregation Tests
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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

• vWD
• Bernard-Soulier syndrome

• Storage pool deficiency
• Signal transduction defects
• Defects in AA pathway

• Glanzmann thrombasthenia

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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
d-SPD ? ? ? N
Defect of signal transduction variable variable variable N
Glanzmann thrombasthenia Absent Absent Absent N or?
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Pseudothrombocytopenia

• Incidence 0.090.21
• 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

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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.

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Questions about Diagnosis of ITP

• Bone marrow examination ?
• BM examination is reserved for
• Unresponsive to therapy,
• Over 5060 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.

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Questions about Diagnosis of ITP

• Differential diagnosis ?
• Psudothrombocytopenia
• Gestational thrombocytopenia
• SLE, other autoimmune disease (Evans syndrome,
  Hashimotos thyroiditis, Graves diseases.)
• Common variable immunodeficiency
• HIV infection, lymhoproliferative disorders,
  cirrhosis of liver, sarcoidosis, or Gauchers
  disease.
• More than two first degree relatives in family
  have ITP. (Hereditary throbocytopenia)

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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

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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 1131231-1240
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Thrombocytopenia in Pregnancy

• Isolated thrombocytopenia
• Gestational (incidental) thrombocytopenia
• incidence 5 of pregnant women, platelet count
  gt70K, 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)

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Management of ITP in Pregnancy

• Maternal part
• Indication of treatment platelet count lt 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 lt20K or hemorrhage

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HELLP syndrome

• Prevalence 0.50.9 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
• 8090 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.

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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.

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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 (Döhles body) in
  neutrophils (2575) 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 - -
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Inherited Thrombocytopenia (2)

• Increased platelet size (continuous)
• Grey platelet syndrome (a-storage pool
  deficiency)
• GPIba 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

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• 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 survival15 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) WAS Small platelets, no immune problem
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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.

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Heparin-induced Thrombocytopenia
Classical HIT Non-immune HIT
Incidence 0.012 10
Platelet count 1050K 80150K
Onset 5th10th day 1st2nd day
Symptoms Venous or arterial thrombosis None
Management DC heparin Continue heparin
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Diagnostic Criteria of type II Heparin-induced
Thrombocytopenia
Chong Isaacs Thromb Haemost 2009 101279

1. Thrombocytopenia occurs during heparin
   administration. (Platelet lt 100K, or platelet
   count drop of gt50 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 of thrombocytopenia after cessation of
   heparin
5. ( Thrombocytopenia recurs when the patient is
   rechallenged with heparin )
6. (The demonstration of a heparin-dependent
   platelet antibody by an in vitro test)

• 4Ts score (Curr Hematol Rep 2003 2148-157)
• Thrombocytopenia
• Time of thrombocytopenia
• Thrombosis
• Exclusion of other cause of thrombocytopenia

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Venous thrombosis gtgt Pulmonary embolism gt
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)
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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. (3050)
• 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

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Blood Vessel

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

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Blood Vessel

• TM thrombomodulin
• EPCR endothelial cell protein C receptor
• TAFI thrombin-activatable fibrinolysis inhibitor
• TFPI tissue pathway pathway inhibitor

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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.

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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

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Amyloidosis
Henoch-SchöleinPurpura
Ehlers-Danlos syndrome
Cushing syndrome
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Hereditary Hemorrhagic Telangiectasia
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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 200336149
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Evolution of Cutaneous Telangiectasis in
Hereditary Hemorrhagic Telaniectasia
From Guttmacher AG et al. N Engl J Med 333918,
1995
48
Thrmobtic Thrombocytopenic Purpura

• Diagnosis
• Microangiopathic hemolytic anemia
• Thrombocytopenia

1. Neurological abnormalities (transient confusion,
   fluctuating focal deficits, seizure, coma, etc.)
2. Fever
3. Renal impairment

1. Without an alternative causes

• 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

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ADAMTS13 in TTP

• Idiopathic TTP
• Severe deficiency 33100 (average 75)
• If exclude creat. gt 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 11211-8
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 11211-8
52
Management of TTP (1)

• Classical TTP
• Acute TTP Plasma exchange gtgt 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 3541927-1934. Curr Opin
Hematol 2008 15445-450
53
Management of TTP (2)

• Post-diarrheal HUS (Shiga toxin-producing
  bacteria, typically E. coli O157H7)
• 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 3541927-1934. Curr Opin
Hematol 2008 15445-450
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