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GRAND ROUNDS

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Acquired defects of hemostasis: Vit K deficiency, liver disease, lupus anticoagulant, anticoagulant drugs, DIC, amyloidosis. Child abuse can be a concomitant dx. – PowerPoint PPT presentation

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Title: GRAND ROUNDS


1
  • GRAND ROUNDS
  • 22nd February, 2006
  • Dr. N. Singh
  • Dr. O. Ingaramo
  • Dr. S. Manuel

2
HISTORY OF PRESENT ILLNESS
  • An 8 m old boy was brought to the ER with a
    history of several episodes of epistaxis over the
    last 12 hrs.
  • The mother was also concerned about some
    scattered bruising on her sons forehead,
    occiput, elbows and flanks over the last 10 days.

3
DEVELOPMENT HISTORY
  • Sitting by himself, crawling, in walker.
  • Imm HX Delayed needs 6 mo vaccinations.
  • PM Hx 1. Enterococcal Meningitis _at_ birth
  • 2. ALTE at 1 mo of age
    cyanotic episode at home, ? apneas noticed during
    hospitalization.

4
FAMILY AND SOCIAL HISTORY
  • No h/o bleeding disorders.
  • Single mother, lives with boyfriend in a trailer
    park.
  • No h/o substance abuse.
  • Primary caretaker is mother.
  • Infant also spends time in a daycare and with
    father of boyfriend (esophageal cancer).

5
PHYSICAL EXAM
  • Afebrile, normal vital signs.
  • Wt 5th percentile Length 10th percentile HC
    25th percentile. Alert, interactive and in no
    distress
  • HEENT With some dried blood in nares.
  • Neck No Lymph nodes palpable.
  • Chest CTA B/L
  • CVS-No murmur

6
PHYSICAL EXAM
  • Abd - No HSM (hepatosplenomegaly), No masses.
  • Ext FROM, No swelling in joints.
  • Skin Several areas of green-yellow areas of
    bruising on the forehead, occiput, elbows and
    flanks.

7
SUMMARY
  • An 8 m old boy with epistaxis over the last 12
    hrs.
  • Bruising on forehead, occiput, elbows and flanks
    over the last 10 days.
  • Enterococcal Meningitis _at_ birth
    ALTE at 1 mo of age cyanotic episode at
    home, ? apneas noticed during hospitalization

8
SUMMARY
  • No h/o bleeding disorders
  • Single mother, lives with boyfriend in a trailer
    park.
  • Father of boyfriend (esophageal cancer).
  • Afebrile, normal vital signs
  • Wt 5th percentile Length 10th percentile
    HC 25th percentile. Alert, interactive and in
    no distress.

9
SUMMARY
  • HEENT With some dried blood in nares.
  • Neck No Lymph nodes palpable.
  • Abd - No HSM (hepatosplenomegaly), No masses
  • Ext FROM, No swelling in joints
  • Skin Several areas of green-yellow areas of
    bruising on the forehead, occiput, elbows and
    flanks

10
HEMOSTASIS REQUIRES NORMAL
  • Vessels
  • Platelets
  • Coagulation pathway components.

11
(No Transcript)
12
DIFFERENTIAL DIAGNOSIS OF BLEEDING DISORDERS
  • Platelets
  • petechiae, mucosal bleeding
  • CNS bleeding in severe cases
  • Vascular
  • contusion, ecchymosis, hemorrhage
  • palpable purpura
  • Coagulation disorders
  • Usually cause larger ecchymoses, deep tissue
    hemorrhage, and mucosal bleeding

13
PLATELETS DISORDERS
  • Thrombocytopenias
  • Decreased production.
  • Platelet pooling and splenic sequestration .
  • Increased destruction.
  • Plt lt100 000
  • Spontaneous bleeding uncommmon with plt gt 20,000.
  • Bleeding time prolonged, PT/PTT normal.

14
PLATELETS DISORDERS (cont.)
  • Decreased Production
  • Malignancies (leukemia, lymphoma,
    neuroblastoma).
  • Bone marrow suppression
  • Drug-related (aplastic anemia)
  • Infection
  • Congenital
  • Fanconi anemia
  • TAR syndrome
  • Wiscott-Aldrich
  • Glycogen storage diseases

15
PLATELETS DISORDERS (cont.)
  • Platelet Dysfunction
  • Congenital
  • Glanzmanns thrombasthenia (GP11b/IIIa deficiency)
  • Bernard Soulier (vWF receptor deficiency)
  • Acquired
  • Drugs (ASA/NSAIDs, lasix, nitrofurantoin)
  • Renal disease
  • Liver disease

16
PLATELETS DISORDERS (cont.)
  • Increased Platelet Destruction
  • Immunologic
  • ITP
  • SLE
  • Isoimmunization (post-transfusion, neonatal)
  • Drug related (heparin, quinine, digoxin,
    sulphonamides, phenytoin)
  • Infection
  • Sepsis
  • Mechanical
  • DIC
  • HUS-TTP
  • Giant hemangioma (Kasabach-Merritt)
  • Burns
  • Trauma

17
PLATELETS DISORDERS (cont.)
  • Thrombocytopenia
  • Sequestration
  • Hypersplenism
  • Sickle cell anemia
  • Dilutional
  • Massive transfusion

18
VASCULAR DISORDERS
  • Loss of Vascular Integrity
  • Acquired
  • - Trauma/NAI, Scurvy, Steroid induced,
    Increased intravascular pressure (coughing,
    vomiting, straining).
  • Congenital
  • - Disorders of connective tissue
    Ehlers-Danlos syndrome, Osteogenesis imperfecta,
    Marfans.
  • - Disorders of blood vessels Hemorrhagic
    telangiectasia

19
VASCULAR DISORDERS Vasculitis
  • Drug-related
  • Infection
  • Viral
  • Coxsackie A9, B3
  • Echoviruses 4,9
  • Atypical measles
  • Bacterial
  • Meningococcemia
  • Streptococcal pharyngitis
  • Septic emboli
  • SBE
  • Gonococcus
  • Rickettsial
  • Rocky Mountain spotted fever
  • Immune-mediated
  • HSP
  • SLE
  • Serum sickness
  • Dysgammaglobulinemia

20
COAGULATION FACTOR DISORDERS
  • Clotting factor deficiencies
  • Congenital
  • Von Willebrands disease
  • Hemophilias
  • II, V, X or Fibrinogen deficiency.
  • Acquired
  • Vitamin K deficiency
  • Liver disease
  • Malabsorption
  • Warfarin/superwarfarin
  • Toxin mediated Coumadin
    containing rodenticides.

21
LABS
  • LFTs Bilirubin 0.3 mg/dL
  • Alk PO4 283 u/L (150-420 u/L)
  • Aspartate aminotransferase 83 u/L (20-65 u/L)
  • Protein 5.9 gm/dL (5.6 7.2 gm/dL)
  • Albumin 3.5 gm/dL (3.5 5.5 gm/dL)

22
LABS
  • WBC 9.0. Hb 13, Hct 48.2 Platelets 212.
  • S 56, B 0, L 38, M 5, E 1
  • UA ? Normal
  • PT ? 59.1 (10-13 secs)
  • PTT ? 120 secs (26 37 secs)

23
  • GRAND ROUNDS
  • Februay, 2006
  • Dr. Singh, N.
  • Dr. Manuel, S.
  • Dr. Ingaramo, O.

24
EVALUATIONS OF BLEEDING DISORDERS
  • Require a thorough history and physical exam.
  • Important questions include prolonged bleeding
    following minor trauma, spontaneous bruising, or
    hematoma formation.
  • Drug history is important since many drugs cause
    bleeding. ie Aspirin.
  • Family history and any possible pattern of
    inheritance.

25
PHYSICAL EXAM
  • Petechiae and purpura are signs of platelet
    dysfunction.
  • Large firm bruises with nodular centers are
    commonly seen in congenital factor deficiencies.
  • Icterus and hepatosplenomegaly are indicative of
    liver disease, which may be associated with
    bleeding disorders

26
CLASIFICATION OF BLEEDING DISORDERS
  • Defects of primary hemostasis (platelets,
    vessels, etc.).
  • Defects of secondary hemostasis (coagulation
    cascade and its regulation)

27
DEFECTS OF PRIMARY HEMOSTASIS
  • Vascular disorders
  • -Laboratory tests are characterized by a
    prolonged bleeding time.
  • Platelets Disorders
  • -Quantitative (thrombocytopenia).
  • -Qualitative (poor platelet function)
    Inherited aggregation defect, Drug effect.

28
COAGULATION FACTORS DISORDERS
  • Congenital factor deficiency
  • -Hemophilia A and B
  • -Von Willebrand disease
  • -Other factor deficiencies (rare)
  • Acquired factor deficiency
  • -Vitamin K deficiency
  • -Liver failure
  • -DIC
  • -Drugs Anticoagulants.
  • Antiphospholipid antibody

29
COAGULATION CASCADE
30
LABORATORY OF BLEEDING DISORDERS
  • Most common ordered labs
  • Platelet count.
  • Bleeding time.
  • PT Extrinsic and common coagulation pathway.
  • PTT Intrinsec and common coagulation pathway.

31
LABORATORY OF BLEEDING DISORDERS (cont.)
  • PTT mixing study PTT corrects with factor
    deficiency, but it does not normalize with
    circulating ab/anticoagulants.
  • If positive, determine whether the inhibitor is a
    true antibody to a coagulation protein or an
    antiphospholipid ab.
  • Thrombin time (TT) and reptilase time measure
    conversion of fibrinogen to fibrine and the
    formation of the initial clot by thrombine.
  • Ristocetin, vWF antigen, WF quantity, vWD
    multimeric assay.

32
LABORATORY OF BLEEDING DISORDERS (cont).
  • Assays for fibrinogen, platelet aggregation or
    platelet function assay (e.g. PFA-100), factor
    XIII, dysfibrinogenemia (thrombin time or
    reptilase time)
  • Also assays for factors VIII, IX or XI, even with
    normal PTT
  • More esoteric assays include PAI-1 activity and
    antiplasmin

33
LABORATORY OF BLEEDING DISORDERS (cont).
  • PT is increased in factor deficiency (I, II, V,
    VII, X), liver failure, vitamin K deficiency,
    coumadin, warfarins.
  • aPTT is increased in factor deficiency (XII, XI,
    IX and VIII), vWD, lupus anticoagulant and
    heparin tx. It is less sensitive than the PT to
    deficiencies within the common pathway (X, V, II
    and I). Not affected by VII and XIII.
  • TT is increased in fibrinogen problems and
    heparin tx. Not affected by XIII.

34
LABORATORY OF BLEEDING DISORDERS (cont).
  • Routine screening testing with the platelet
    count, PT, TT, aPTT should allow the clinician to
    more narrowly define the diagnostic
    possibilities.
  • Prolonged PT and aPTT
  • In a bleeding child who is otherwise well
    indicates an inherited disorder within the common
    pathway (I, II, V, X) or an acquired disorder
    involving multiple pathways or anticoagulant
    factor. Other Amyloidosis, coumadin.
  • In a sick child consider DIC, hepatocellular
    dysfunction, severe vit K deficiency, thrombosis,
    hemangioma.
  • Normal TT with normal fibrinogen level will
    exclude abnormal fibrinogen.

35
COAGULATION CASCADE
36
DIFFERENTIAL DX IN PROLONGED PT AND PTT
  • Factor X deficiency rare (1 per 1 million)
  • AR deficiency characterized by asymptomatic
    heterozygotes and by homozygotes with bleeding
    symptoms that correlate with factor activity.
  • May be associated with bruising, epistaxis,
    menorrhagia, GI/GU or umbilical stump bleeding or
    bleeding after surgery, trauma, dental
    procedures, pregnancy or circumcision
  • Severe deficiencies may resemble hemophilia and
    may be associated with intracranial hemorrhage.
  • Treatment fresh frozen plasma Prothrombin
    complex concentrates for serious bleeding.

37
COAGULATION CASCADE
38
DIFFERENTIAL DX IN PROLONGED PT AND PTT
  • Factor V deficiency rare (1 per 1 million)
  • AR deficiency in which asymptomatic heterozygotes
    and homozygotes manifesting platelet-type
    bleeding (easy bruising, epistaxis).
  • Severe deficiencies associated with intracranial
    hemorrhage, although levels do not always
    correlate with severity of symptoms
  • Treatment 10-20 ml fresh frozen plasma/kg
    commercial concentrates of factor V are not
    available

39
COAGULATION CASCADE
40
DIFFERENTIAL DX IN PROLONGED PT AND PTT
  • Factor II deficiency rare (1 per 2 million)
  • AR disorder associated with mucosal and deep
    tissue bleeding.
  • Treatment 10-20 ml fresh frozen plasma/kg
    prothrombin complex concentrates may be used for
    serious bleeding.

41
COAGULATION CASCADE
42
DIFFERENTIAL DX IN PROLONGED PT AND PTT
  • Factor I / fibrinogen deficiency or disorders
  • Rare. Autosomal inheritance most mutations are
    in alpha-fibrinogen chain gene, sparing beta and
    gamma chains
  • Afibrinogenemia homozygous form causes severe
    quantitative deficiency of fibrinogen and
    increased risk of bleeding associated with
    intracranial hemorrhages.
  • Hypofibrinogenemia heterozygous form
    mild/moderate reductions in fibrinogen little/no
    bleeding.

43
DIFFERENTIAL DX IN PROLONGED PT AND PTT
  • Dysfibrinogenemia qualitative fibrinogen.
  • Bleeding due to defective fibrin clot formation
    (impaired release of fibrinopeptides A or B)
  • Thrombosis due to (a) defective thrombin binding
    to fibrin, causing increased thrombin in
    circulation (b) defective binding of tPA or
    plasminogen to fibrin.
  • Labs concentration determined by ELISA. Often
    prolonged TT and reptilase time, PT and PTT
  • Treatment cryoprecipitate fresh frozen plasma
    contains more fibrinogen, but in a much larger
    volume.

44
DIFFERENTIAL DX IN PROLONGED PT AND PTT
  • Combined factor deficiencies are very rare
  • Combined factor V and VIII autosomal recessive.
  • Combined factors II, VII, IX and X deficiency
    due to mutation in gamma-glutamyl carboxylase
    gene, whose protein carboxylates glutamate
    residues in vitamin K-dependent coagulation
    factors
  • Very rare to have bleeding disorders due to
    deficiency in PAI-1 or antiplasmin

45
DIFFERENTIAL DX IN PROLONGED PT AND PTT
  • ACQUIRED DEFECTS OF SECONDARY HEMOSTASIS
  • Vitamin K is needed for the synthesis of factors
    II, VII, IX and X.
  • Vitamin K is vital to the carboxylation of
    glutamic acid residues which is needed for the
    activation of these factors.
  • The most common circumstance in which vitamin K
    deficiency leads to bleeding is hemorrhagic
    disease of the newborn.

46
ACQUIRED DEFECTS OF SECONDARY HEMOSTASIS
  • Vitamin K (cont.)
  • Without vitamin K supplementation, significant GI
    and cutaneous hemorrhage may develop within a few
    days.
  • After the newborn period, vitamin K is absorbed
    from the GI tract. Deficiency may then result
    from nutritional deficits, malabsorption, or
    alteration in intestinal flora.
  • Treatment must be directed at the underlying
    disorder and vitamin K supplementation.

47
DIFFERENTIAL DX IN PROLONGED PT AND PTT
  • ACQUIRED DEFECTS OF SECONDARY HEMOSTASIS (cont.)
  • Decreased synthesis of coagulation proteins
    occurs in severe liver disease.
  • Abnormalities in the liver's capacity to
    synthesize one or more clotting factors may
    result in problems with hemostasis.
  • Treatment involves replacement of the decreased
    factor(s) with fresh frozen plasma.

48
DIFFERENTIAL DX IN PROLONGED PT AND PTT
  • ACQUIRED DEFECTS OF SECONDARY HEMOSTASIS
    (cont.)
  • Acquired factor deficiencies (due to liver
    disease, DIC, lupus anticoagulants, heparin,
    warfarin or other anticoagulants) are more common
    than hereditary factor deficiencies, and should
    be ruled out first

49
ACQUIRED DEFECTS OF SECONDARY HEMOSTASIS (cont.)
  • Acquired inhibitors are antibodies that
    neutralize a specific clotting factor's function
  • The most commonly inhibited factor in clinical
    practice is factor VIII.
  • Autoantibodies to VIIIC are characteristically
    oligoclonal non-complement-fixing IgG.
  • The incidence is 0.2 to 1 per million
    person-years with a higher incidence in older age
    groups.
  • These cause a prolonged PTT which is not
    corrected with 11 dilution with normal plasma.

50
Acquired inhibitors (cont.)
  • Lupus anticoagulant
  • Antibodies against protein-phospholipid
    complexes.
  • May interfere with assays for factors VIII, IX,
    XI and XII without causing a true decrease in
    factor levels
  • In adults, it may be associated with spontaneous
    abortion, and thromboembolism. In the pediatric
    population is transient with rare clinical
    sequelae.
  • Soft-tissue bleeding, gross hematuria, and
    postsurgical hemorrhage can occur fatal bleeds
    may occur in 15 of patients.
  • The treatment is aimed at reducing the antibody
    titer using immunosuppression, IVIG, or
    Plasmapheresis.

51
Acquired Defects of Secondary Hemostasis (cont.)
  • Disseminated intravascular coagulation (DIC)
  • Occurs in patients who are critically ill.
  • Fever, hypotension, acidosis, oliguria, or
    hypoxia may be present. In addition, petechiae,
    purpura, and oozing from wounds and venipuncture
    sites may develop.
  • Microvascular and large vessel thrombosis may
    occur.
  • The platelet count is typically decreased due to
    consumption and platelet destruction.

52
DIC (cont.)
  • The PT and PTT are prolonged from depletion of
    factors V, VIII, IX, and XI.
  • Fibrinogen is decreased. Fibrin degradation
    products and the D-dimer assay are increased.
  • The mainstay of therapy is to treat the
    underlying disease.
  • Additional therapy consists of replacing clotting
    factors and platelets and possibly the use of
    heparin and antifibrinolytic agents.

53
Other Acquired Defects of Secondary Hemostasis
  • Amyloidosis
  • Primary amyloidosis may cause acquired factor X
    deficiency due to the binding of amyloid to
    factor X.
  • Also inhibits fibrinogen conversion to fibrin,
    causing prolongation of thrombin time and
    reptilase time.

54
SUMMARY
  • Possible diagnosis in this patient with prolonged
    PT and PTT
  • Hereditary factor deficiency I, II, V, X,
    antiplasmin and dysfibrinogenemia.
  • Acquired defects of hemostasis Vit K deficiency,
    liver disease, lupus anticoagulant, anticoagulant
    drugs, DIC, amyloidosis.
  • Child abuse can be a concomitant dx.

55
  • Thank you.
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