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					  Bleeding Disorders
Vascular and Platelet Disorders



                 Ahmad Shihada Silmi
                      Msc,FIBMS
                          IUG
                Medical Technology Dept
    Bleeding Disorder Terms

   Petechiae-pinpoint size/pinhead size hemorrhagic spots in skin
   Purpura-hemorrhage under the skin, varying in color and duration
   Ecchymosis-purplish patch caused by extravasation of blood into
    skin, larger than petechiae
   Epistaxis-nosebleed
   Menorrhagia-excessive menses
   Hematuria-blood in urine
   Hemarthrosis-bleeding into joint
   Hematemesis-vomiting blood
   Hemoptysis-spitting blood
   Melena-blood in stool (occult blood)
                             Bleeding
                             disorders




  Vascular                           Clotting factor
                Platelet disorders                     DIC
abnormalities                        abnormalities
    Vessel Defects Causing Bleeding


   Begins with bleeding episode in presence of normal
    lab tests for coagulation function
   Types divided into hereditary and acquired
   Symptoms are usually of the superficial ones.
   Usually these diseases are diagnosed by exclusion.
    After ruling out PLT disorders, coagulation or
    fibrinolytic disorders in a patient who has bleeding
    symptoms.
       Vascular Diseases


   PLT count and screening tests for coagulation
    factors are usually normal.

   PLT function tests such as bleeding time and
    other PLT function tests are also normal, but
    BT may be prolonged in some vascular
    diseases.
    Inherited vascular disorders


   They are very rare, and while bleeding is a
    common symptom, hemostasis tests are NOT
    necessary for diagnosis.
Hereditary Connective Tissue Defects

   Defect affects ability to support vessel walls
   Examples
     – Ehlers-Danlos Syndrome
           Lack of structural tissue support (collagen disorders)
           Skin elasticity and fragility.
           Hypermobility of joints
           Evidenced by bleeding/bruising
           Recurrent joint problems & scarring of the face.
           The most serious is deficient of type III collagen (blood
            vessel type). Which leads to Acute & sever Internal bleeding
            & sudden death.
Hereditary Connective Tissue Defects

   Pseudoxanthoma Elasticum
    –   Autosomal recessive trait
    –   Lack of skin elasticity
    –   Some connective tissue calcified
    –   Bleeding and bruising evident
Hereditary Vessel Disease

   Hereditary Haemorrhagic telangiectasia (HHT)
       Inherited as autosomal dominant trait
       Defect of angiogenesis
       Involves bleeding from abnormally dilated vessels
        “telangiectasias”
       Vessels involved do not contract normally and collapse easily
       Patient has pinpoint lesions (tiny areas of bleeding)
       Lesions occur on face, hands and feet
       May develop at all ages
       Blood loss may cause anemia
       Diagnosis based on physical appearance
Hereditary Vessel Disease

   Kasabach-Merritt syndrome (Hemangioma)

   Benign tumour of vascular tissue
   Grow rapidly to giant proportion.
   Threaten the function of neighbouring tissues.
   Mechanical injury may result in sever bleeding.
   May trigger a localized DIC with thrombocytopeia &
    consumption coagulopathy, thereby worsening
    bleeding.
   Tumor composed of many blood vessels (blood-filled)
Hereditary Vessel Disease

   HHT or also called Cavernous Hemangioma
     Lesion  may swell and bleed
     Tumor site may form clots, hemolyzed RBCs and
      vessel obstruction
     Present at birth
     Treatment is by surgical removal, if possible,or
      localized radiotherapy with injection of fibrinolytic
      inhibitors.
Acquired Vascular Disorders

   Are seen quite often.

   Are characterized by bruising and petechiae
Acquired Connective Tissue Defects

   Vitamin C Deficiency (Scurvy)
     Caused  deficient Vitamin C
     Vitamin C required for vessel collagen integrity
     Acts as “cement” holding endothelial cells together
     Lack of Vitamin C prevents proper collagen formation
     Result: bleed and vessel fragility
     Symptoms include gum bleeding, petechiae and
      bleeding into tissues and muscles
     Treated with Vitamin C
Acquired Connective Tissue Defects

   Senile Purpura
     Occurs  in elderly population
     Usually benign
     Collagen degradation/loss affects vessel
      integrity
     Bruising on arms/hands
     No treatment/therapy available
    Purpura due to Paraproteins

   Due to abnormal proteins in the vascular system

   Paraproteins are monoclonal Ig produced by a
    single clone of plasma cells.

   Also called M component.

   These paraproteins occur in MM, WM, and
    lymphoproliferative disorders.
                                                       Cont’d




    Purpura due to Paraproteins

   Symptoms: purpura, bleeding and thrombosis.
   The defect is related to multifactors:
     – Qualitative PLT defects.
     – Acquired inhibitors.
     – Deficiency in coagulation factors.
     – Paraproteins binds Ca, Ca either will not be
       available for coagulation or the Ca bounded
       paraproteins will interfere with coagulation.
     – Thrombocytopenia.
                                  Cont’d




    Purpura due to Paraproteins


   Bleeding symptoms include:
    –   Epistaxis
    –   Petechiae,
    –   Purpura, and
    –   Retinal bleeding.
Purpura due to Paraproteins


   Amyloidosis
   Occur as primary disease or is associated
    with paraproteinemias.
   Deposition of amyloid on skin and
    vascular walls.
   Leads to fragility of vessel walls.
Other Vascular Disorders

   Self-produced “autoantibodies” damage to vessels
      Caused by drugs resulting in purpura
      Caused by allergic/immune disturbance
           Evidenced by swelling, ulcers, purpura and lesions and other
            symptoms
           Affects children
     Other allergic purpura-Hemoch-Schonlein variety
        Accompanied by joint and abdominal pain

        Avoidance of allergen aids recovery
Other Vascular Disorders

   Infectious purpura
      Observe petechiae and purpura
      Results from
           Inflammatory response to agent
           Autoimmune/autoantibody response
           Bacterial products or toxins
           Injury caused by agent
     Low platelets observed and      DIC
     Cure is to treat infection
                             Bleeding
                             disorders




  Vascular              ***          Clotting factor
                                                       DIC
abnormalities   Platelet disorders   abnormalities
Platelet Disorders Classification:
            Quantitative PLT Disorders


 Thrombocytopenia                Thrombocytosis


       PLT Reference Range = 150 - 450 x109/L




               Thrombocytopathy

             Qualitative PLT Disorders
    Thrombocytosis

   Thrombocytosis resulting from myeloproliferation
     –   essential thrombocythemia
     –   polycythemia vera
     –   chronic myelogenous leukemia
     –   myeloid metaplasia
   Secondary (reactive) thrombocytosis
     –   systemic inflammation
     –   malignancy
     –   iron deficiency
     –   hemorrhage
     –   postsplenectomy
    Thrombocytopenia

   Reduced platelet count.

   The most common cause of excess or abnormal
    bleeding.

   As anemia is a symptom of a disease as we
    have seen in Hematology #1, thrombocytopenia
    is also a symptom of a disease!
Do not forget to assure that the case
you have is a real thrombocytopenia
 and not Pseudothrombocytopenia
Platelet clumping, or             Platelet
    aggregation                  Satelltism




            Pseudothrombocytopenia
 Thrombocytopenia

Platelet count   Symptoms

50-100 X109/L    Prolonged bleeding following trauma


< 50X109/L       Easy bruising
                 Purpura following minor trauma

< 20 X109/L      Spontaneous bleeding
                 Petechiae
                 May suffer spontaneous internal and
                 intracranial bleeding
Hemostatic Level

   Hemostatic Platelet count level is more
    than 50 x109/L.

   This means that normal hemostasis may
    occur ≥ 50 x109/L
Classification: platelet disorders
        Thrombocytopenia
                                                 Causes




               Impaired or Decreased       Distribution/Dilution       Increased
                    Production                   Disorders             Destruction




Megakaryocyte aplasia                                         Immune                 Non-Immune




                BM Replacement




                                Ineffective poiesis
    General characteristics of platelet
    disorders

   characterized by variable mucocutaneous
    bleeding manifestations.
   excessive hemorrhage may follow surgical
    procedures or trauma.
   Platelet counts and morphology are normal.
   prolonged bleeding time,
   Abnormal Platelet aggregation and secretion
    studies
Thrombocytopenia

   Usually mucosal bleeding
   Epistaxis, menorrhagia, and GI bleeding is
    common
   Trauma does not usually cause bleeding
Thrombocytopenia

   Three mechanisms of Thrombocytopenia
    –   Decreased production
            Usually chemotherapy, myelophthisic disease, or BM
             effects of alcohol or thiazides
    –   Splenic Sequesteration
            Rare
            Results from malignancy, portal hypertension, or
             increased Splenic RBC destruction ( hereditary
             spherocytosis, autoimmune hemolytic anemia)
    –   Increased Destruction
Thrombocytopenia

   Immune thrombocytopenia
     – Multiple causes including drugs, lymphoma, leukemia,
       collagen vascular disease
     – Drugs Include
          Digitoxin, sulfonamindes, phenytoin, heparin, ASA,
           cocaine, Quinine, quinidine, glycoprotein IIb-IIa
           antagonists
     – After stopping drugs platelet counts usually improve over 3
       to 7 days
     – Prednisone (1mg/kg) with rapid taper can shorten course
Thrombocytopenia

   HIT
    –   Important Immunologic Thrombocytopenia
    –   Usually within 5-7 days of Initiation of Heparin
        Therapy but late onset cases are 14-40 days
    –   Occurrence 1-5% with unfractionated heparin
        and less than 1% with low molecular-weight
        heparin
    –   Thrombotic complications in up to 50% of HIT
        with loss of limb in 20% and mortality up to 30%
ITP

   Diagnosis of exclusion
   Associated with IgG anti-platelet antibody
   Platelet count falls to less that 20,000
ITP

   Acute Form
    –   Most common in children 2 to 6 years
    –   Viral Prodrome common in the 3 weeks prior
    –   Self Limited and > 90% remission rate
    –   Supportive Treatment
    –   Steroids are not helpful
ITP

   Chronic Form
    –   Adult disease primarily
    –   Women more often than men
    –   Insidious onset with no prodrome
    –   Symptoms include: easy bruising, prolonged
        menses, mucosal bleeding
    –   Bleeding complications are unpredictable
    –   Mortality is 1%
    –   Spontaneous remission is rare
ITP

   Chronic Form
    –   Hospitalization common because of a complex
        differential diagnosis
    –   Multiple treatments
    –   Platelet transfusions are used only for life
        threatening bleeding
    –   Life threatening bleeding is treated with IV
        Immune globulin (1g/kg)
TTPHUS

   Exist on a continuum and are likely the same
    disease
   Diagnosed by a common pentad
    –   Microangiopathic Hemolytic Anemia: Schistocytes
        membranes are sheared passing through microthrombi
    –   Thrombocytopenia: More sever in TTP
    –   Fever
    –   Renal Abnormalities: More prominent in HUS: include Renal
        insufficiency, azotemia, proteinuria, hematuria, and renal
        failure
    –   Neurologic Abnormalities: hallmark of TTP 1/3 of HUS: Sx
        of HA, confusion, CN palsies, seizure,coma
TTPHUS

   Labs
    –   PT, PTT, and fibrinogen are within reference
        range
    –   Helmet Cells (Shistocytes) are common
TTPHUS

   HUS
    –   Most common in infants and children 6mo - 4
        years
    –   Often associated with a prodromal diarrhea
    –   Strongest association to E. coli O157:H7 but also
        associated with SSYC as well as multiple virus
    –   Prognosis
            Mortality 5-15%
            Younger patients do better
TTPHUS

   HUS
    –   Treatment
          Mostly supportive
          Plasma exchange reserved for sever cases
          Treat hyperkalemia
          Avoid antibiotics with Ecoli
             – May actually increase verotoxin production.
             – May be helpful with cases of Shigella dysenteriae
TTPHUS

   TTP
    –   More common in adults
    –   Untreated mortality rate of 80% 1 to 3 months
        after diagnosis
    –   Aggressive plasma exchange has dropped the
        mortality to 17%
    –   Splenectomy, immune globulin, vincristine all play
        a role in therapy
TTPHUS

   AVOID PLATELET TRANSFUSION
    –   May lead to additional microthrombi in circulation
    –   Transfuse only with life threatening bleeding
Dilutional Thrombocytopenia

   PRBC are platelet poor
   Monitor platelet count with every 10 u PRBC
   (for each 8-10 units of PRBC, 2 units of FFP
    & 5 units of platelet concentrate are given)
   Transfuse when count below 50,000
   Get them upstairs before you transfuse 10
    units PRBC
Bleeding
Clinical Correlation - PLT Numbers

    PLT Count           Spontaneous Bleed         Post Trauma Bleed



    >50K/ml                     No                      Rare

  30 – 50K/ml                  Rare                 Occasional

  10 – 30K/ml              Occasional                 Always

     10K/ml                 Frequent                  Always
 BT prolongation proportional to PLT count IF no complicating factors.
Significant Lab Data in Defects of
Primary Hemostasis
  Test      Vascular Disorder   Thrombocytopenia   PLT Dysfunction



PLT Count          N                   D                 N


   PT              N                   N                 N


  APTT             N                   N                 N


   BT          N or ABN              ABN             N or ABN
Hereditary Platelet Function Defects
 Petechiae
 typical of platelet abnormality




Do not blanch with pressure

Not palpable
Bernard-Soulier Syndrome

   First described in 1948 by Jean Bernard and Jean-
    Pierre Soulier; French hematologists
           Bernard J, Soulier JP: Sur une nouvelle variete de dystrophie
            thrombocytaire hemarroagipare congenitale. Sem Hop Paris
            24:3217, 1948
   AR; characterized by moderate to severe
    thrombocytopenia, giant platelets, and
    perfuse/spontaneous bleeding
   Basis for the disease is deficiency or dysfunction of
    the GP Ib-V-IX complex
Bernard-Soulier Syndrome

   Decreased GP Ib-V-IX leads to decreased platelet
    adhesion to the subendothelium via decreased binding of
    vWF
   Approximately 20,000 copies of GP Ib-V-IX per platelet
   GP 1b: heterodimer with an alpha and beta subunit
   The gene for GP Ib alpha is located on chromosome 17;
    GP Ib beta: chromosome 22; GPIX and V: chromosome 3
   Most mutations are missense or frameshifts resulting in
    premature stop codons
   Most mutations involve GP Ib expression (rare GP IX
    mutations have been described; no mutations in GP V)
Diagnosis

   Prolonged bleeding time, thrombocytopenia
    (plt<20 K), peripheral smear shows large
    platelets (mean diameter >3.5 microns)
Diagnosis

   Platelet aggregation studies show normal
    aggregation in response to all agonists
    except Ristocetin (opposite pattern than
    thrombasthenia)
   Flow cytometry: decreased expression of
    mAbs to CD 42b (GPIb), CD42a(GPIX),
    CD42d(GPV)
Platelet Aggregometer
   Light focused on sample cuvette
    contained PRP


   PRP stirred and recorder identified
    baseline – 0% transmittance
   Agonist added
   Transmitted light changes
    proportionally in response to degree
    PLT shape changes
   Change in light transmission
    continuously monitored and recorded
   As PLT aggregates form, recorder
    moves towards 100% transmittance
   Abnormalities
     – Diminished or absent shape
       change
     – Diminished aggregation                         Platelet-rich plasma in an optical aggregometer.
                                                      Platelet count is approximately 200 × 109/L, and
                                                      platelets are maintained in suspension by a
                                                      magnetic stir bar turning at 1000 rpm. (Courtesy
                                                      of Kathy Jacobs, Chronolog, Inc., Havertown,
                                                      Penn.)
     Graphic accessed URL http://evolvels.elsevier.com/section/default.asp?id=1138_ccalvo7_0001, 2008.
Differentiation between vWD & BSD

   Measuring the platelet aggregation response
    to ristocetin following the addition of PPP.
   A normal aggregation response suggests the
    plasma defect, which is typical of vWD.
   The persistence of defective response
    suggests the presence of a platelet defect
    which is typical of BSD.
Glanzmann’s Thrombasthenia

Eduard Glanzmann (1887-1959), Swiss
  pediatrician
Reported a case of a bleeding disorder starting
  immediately after birth
W. E. Glanzmann:Hereditäre hämorrhägische
  Thrombasthenie. Ein Beitrag zur Pathologie
  der Blutplättchen.
  Jahrbuch für Kinderheilkunde, 1918; 88: 1-
  42, 113-141.
Glanzmann’s

   IIbIIIa most abundant platelet surface
    receptor (80,000 per platelet)
   IIbIIIa complex is a Ca++ dependent
    heterodimer
   Genes for both subunits are found on
    Chromosome 17
   Disease is caused by mutations (substitution,
    insertion, deletion, splicing abnormalities) in
    genes encoding for IIb or IIIa resulting in
    qualitative or quantitative abnormalities of the
    proteins
Glanzmann’s

   Fundamental defect of thrombasthenic
    patients is the inability of the platelets to
    aggregate
   Other problems: platelets do not spread
    normally on the subendothelial matrix (due to
    lack of IIbIIIa – vWF/fibronectin interaction)
   Also, alpha granule fibrinogen is decreased
    to absent
Glanzmann’s

   AR inheritance
   Patients present with wide spectrum of
    disease
   Like thrombocytopenic bleeding: skin,
    mucous membrane (petichiae, echymoses),
    recurrent epistaxis, GI hemorrhage,
    menorrhagia, and immediate bleeding after
    trauma/surgery
   ICH, joint, muscle bleeding uncommon
   Glanzmann’s patients are stratified into
    three groups based on complex expression:
    –   Type I less than 5 percent GPIIbIIIa, absent alpha
        granule fibrinogen
          Usually   as a result of IIb gene mutation
    –   Type II <20 percent, fibrinogen present
    –   Type III >50 percent; “variant” thrombasthenia;
        qualitative disorder
Diagnosis

   Platelet count and morphology are normal
   Bleeding time prolonged
   The hallmark of the disease is severely
    reduced or absent platelet aggregation in
    response to multiple agonists ie ADP,
    thrombin, or collagen (except Ristocetin)
   Flow cytometry: decreased mAb
    expression of CD41 (GPIIb) and CD61
    (GPIIIa)
Platelet Aggregation Studies

   Platelet-rich plasma (PRP) is prepared from citrated
    whole blood by centrifugation
   Inactive platelets impart a characteristic turbidity to
    PRP
   When platelets aggregate after injection of an
    agonist, the turbidity falls, and light transmission
    through the sample increases proportionally
   The change in light transmission can be recorded on
    an aggregometer
Agonists

   Different concentrations of each agonist are
    used
   ADP: biphasic pattern:
          First wave: low concentration, reversible
          Second wave: high concentration, irreversible
Other agonists

   Epinephrine: triphasic (resting platelets,
    primary aggregation, secondary aggregation)
Other agonists

   Collagen, arachidonic acid, Calcium
    ionophore, PAF are potent agonists and
    induce a single wave of irreversible
    aggregation
   Ristocetin (antibiotic): aggregation can be
    reproduced with metabolically inert, formalin-
    fixed platelets
         Defective risto-induced aggregation is
          characteristic of Bernard-Soulier
Problems with platelet aggregation
studies

   Numerous variables affect aggregation:
        Anticoagulant (sodium citrate best)
        Plt count in PRP
        Plt size distribution
        Time of day
        Temporal relation to meals and physical
         activity
Storage Pool Defects

   Classified by type of granular deficiency or
    secretion defect.
   Dense body deficiency, alpha granule
    deficiency (gray platelet syndrome), mixed
    deficiency, Factor V Quebec
 Defects in secondary aggregation
 Deficiency of contents of one of granules
 Inheritance is variable (heterogeneous group)
 Bleeding is usually mild to moderate but can
  be exacerbated by aspirin
 Clinical: easy bruising, menorrhagia, and
  excessive postpartum or postoperative
  bleeding
Dense body deficiency

   decreased dense
    bodies (ADP, ATP,
    calcium,
    pyrophosphate, 5HT)
   Normal platelet
    contains 3-6, 300
    micron dense bodies
   Described in inherited disorders ie
    Hermansky-Pudlak syndrome, Wiskott-
    Aldrich syndrome, Chediak-Higashi
    syndrome, and Thrombocytopenia with
    absent radius (TAR) syndrome
Wiskott-Aldrich

   X-linked, genetic defect in WASp (protein
    responsible for actin cytoskeleton formation
    in hematopoetic cells)
   characterized by thrombocytopenia (with
    platelet storage pool defect), eczema, and
    recurrent infections
Hermansky-Pudlak

   Described in 1959 by Hermansky and Pudlak
   AR, tyrosinase-positive oculocutaneous
    albinism, ceroid-like deposition in lysosomes of
    the RES and marrow
   Highest prevalence in Puerto Rico
   May be associated with pulmonary fibrosis, and
    recurrent infections
   quantitative deficiency of dense granules leading
    to mild-moderate bleeding diathesis
Chediak-Higashi

   described by Beguez Cesar in 1943, Steinbrinck in
    1948, Chédiak in 1952, and Higashi in 1954
   AR; abnormal microtubule formation and giant
    lysozomal granules are present in phagocytes and
    melanocytes
   No degranulation/chemotaxis = recurrent bacterial
    infections
   Partial oculocutaneous albinism
   Dense-body granules decreased/absent
Thrombocytopenia with absent radius
(TAR)

   First described in 1951
   AR, characterized by absent radii,
    thrombocytopenia (with storage pool defect),
    and other abnormalities of the skeletal, GI,
    cardiovascular system
   Etiology unclear
   Hemorrhage is the major cause of mortality
   PX is good if survive the two years
   Typical Lab Findings            Diagnosis
     – Usually normal platelet
       count                          – Measure the whole platelet
     – Morphology is variable           ATP/ADP ratio
     – Platelet aggregation              Normal: 2.5:1
       shows primary wave but            ADP storage pool deficiency
       absence of secondary
       wave when stimulated               increased >3:1
       with ADP, epinephrine,         – Often associated with disorders
       arrachidonic acid
                                        affecting granules in other cells
     – Platelet aggregation with
       thrombin is usually normal        Chediak-Higashi Syndrome
       (overrides need for               Hermansky-Pudlak Syndrome
       granule release)
     – Ristocetin agglutination is       Wiskott-Aldrich Syndrome
       normal                             – Platelets are small with
                                            decreased number of both
                                            alpha and dense granules
Diagnosis

   Platelet aggregation studies may show
    diminished response to low concentration
    collagen
   ADP and epinephrine show diminished
    second wave response
   Ristocetin shows normal aggregation
   EM: lack of dense bodies
   Increased ATP:ADP ratio within platelets
Alpha granule deficiency

   Alpha storage pool deficiency, Gray Platelet
    Syndrome
   First described by Raccuglia in 1971
   Normal platelets contain approximately 50
    granules (PF4, beta-thromboglobulin, PDGF,
    fibrinogen, vWF, Factor V, fibronectin)
   Patients lack granules, present with lifelong, mild
    to moderate mucocutaneous bleeding
Diagnosis

   Prolonged bleeding time, mild
    thrombocytopenia
   A granular, large “gray” platelets on
    peripheral smear
   Aggregation studies: decreased to absent
    response to collagen
Summary

   Morphology and role of the platelet in primary
    hemostasis
   Adhesion: GP1b-V-IX; Bernard-Soulier;
    aggregates with everything but Ristocetin
   Activation (Secretion): dense body deficiency
    (associated syndromes), alpha granule
    deficiency
   Aggregation: GPIIb-IIIa; Glanzmann’s; no
    aggregation except for Ristocetin
Differential diagnosis
Table. The clinical distinction between disorders of vessels and platelets and disorders of
blood coagulation




  Fingdings                      Disorders of platelet or     Disorders of coagulation
                                 vessels
  Petechiae                      Characteristic               Rare

  Deep dissecting                Rare                         Characteristic
  hematomas
  Superficial ecchymoses         Characteristic; usually      Common; uaually large
                                 small and multiple           and solitary
  Hemarthrosis                   Rare                         Characteristic

  Delayed bleeding               Rare                         Common

  Bleeding from                  Persistent; often            Minimal
  superficial cuts and           profuse
  scratches
  Sex of patient                 Relatively more              80-90% of hereditary
                                 common in females            forms occur only in
                                                              males
  Positive family history        Rare                         Common
Clinical Cases
Nail bed - Hematoma


                      •Red
                      •Blue/Gr
                      •Brown
Contusion - Hematoma
Laceration - Trauma
Petechiae & Echymoses -Plt
Petechiae & Echymoses -Plt
Bleeding-Coagulation disorder


                    •Deep bleeding
                    •Haematoma
                    •Joint bleeds
                    •Haemophilia
Leptospirosis - Weil’s disease:
             Jaundice
Sub Conjuctival Haemorrhage
            Low PLT
Dengue – Hemorrhagic fever Plt
                             Bleeding
                             disorders




  Vascular                           Clotting factor
                Platelet disorders                     DIC
abnormalities                        abnormalities
Hereditary Type

   The genetic defect can either be the failure of
    synthesis of one of the proteins or the production
    of a malfunctioning or abnormal molecule.
          Quantitative vs Qualitative
   But in both of these genetic defects they will
    result in slowing down and ineffective production
    of fibrin.
LAB Screening Tests

   Lab screening tests are based on the length
    of time that it takes a clot to form in plasma.

   So screening tests does not differentiate
    between qualitative or quantitative defects!
                    CRM + Vs CRM-

   CRM is the abbreviation of Cross-Reacting Material
   Any protein has a functional activity and an immunologic
    characteristics.
   Abnormal protein is functionally ineffective, but is
    recognized immunologically.
         Is called CRM +
   No protein (deficient) has no function and also will not be
    recognized immunologically.
         Is called CRM -
Types of Bleeding Disorders

   Hemophilia A (factor VIII deficiency)

   Hemophilia B (factor IX deficiency)

   von Willebrand Disease (vWD)

   Other
Platelet               Coagulation




Petechiae, Purpura   Hematoma, Joint bl.
What is Hemophilia?

 Hemophilia   is an inherited
 bleeding disorder in which
 there is a deficiency or lack of
 factor VIII (hemophilia A) or
 factor IX (hemophilia B)
      Hemophilia A and B
                                Hemophilia A               Hemophilia B

Coagulation factor deficiency          Factor VIII                  Factor IX

  Inheritance                          X-linked                     X-linked
                                       recessive                    recessive

  Incidence                      1/10,000 males                 1/50,000 males

  Severity                                     Related to factor level
                                       <1% - Severe - spontaneous bleeding
                                  1-5% - Moderate - bleeding with mild injury
                                5-25% - Mild - bleeding with surgery or trauma

  Complications                                    Soft tissue bleeding
Inheritance of Hemophilia
   Hemophilia A and B are X-linked recessive
    disorders
   Hemophilia is typically expressed in males
    and carried by females
   Severity level is consistent between family
    members
   ~30 % of cases of hemophilia are new
    mutations
Genetics of Hemophilia A

   The gene F8 is located in the X chromosome, at
    Xq28, near telomeric region.
   It consists of 26 exons, and 25 introns.
   The F8 gene spans 186 Kb.
   Mature RNA is 8.8 Kb.
   The F8 protein is 2351 amino acid.
   The leader sequence is 19 a.a.
   So the real protein= 2351-19= 2332 aa.
    Genetics of Hemophilia A

   Half of hemophilia A patients have no detectable
    factor VIII;
    about 5% have normal levels of dysfunctional
    factor VIII as protein and are termed CRM+
   whereas the rest (45%) have plasma factor VIII
    Ag protein reduced to an extent roughly
    comparable to the level of factor VIII:C activity
    and are designated CRM-.
Detection of Hemophilia
   Family history
   Symptoms
    –   Bruising
    –   Bleeding with circumcision
    –   Muscle, joint, or soft tissue bleeding
   Hemostatic challenges
    –   Surgery
    –   Dental work
    –   Trauma, accidents

   Laboratory testing
Screening Tests
in Secondary Hemostasis Defects

   PT is prolonged or (test extrinsic pathway)
   APTT is prolonged or (test intrinsic pathway)
   Both are prolonged.
   Platelets are normal in count and function.
   TT (thrombin time): prolonged in disorders of
    fibrinogen.
   If any test is abnormal of these screening tests,
    additional testing may resolve the disorder>>>>
Additional Testing

   Specific Factor Assays.
   Fibrinogen Level
   D-Dimer
   FDP’s
   Antithrombin Level
   The list continues to expand………….
Degrees of Severity of Hemophilia

   Normal factor VIII or IX level = 50-150%
   Mild hemophilia
    –   factor VIII or IX level = 6-50%

   Moderate hemophilia
    –   factor VIII or IX level = 1-5%

   Severe hemophilia
    –   factor VIII or IX level = <1%
Hemophilia Prevalence

   Hemophilia A; 1 in 5000 population
    – coagulation factor VIII deficiency

   Hemophilia B; 1 in 30000 population
    – coagulation factor IX deficiency

   Hemophilia A is six-fold more prevalent than
    hemophilia B.
Types of Bleeds

   Joint bleeding - hemarthrosis
   Muscle hemorrhage
   Soft tissue
   Life threatening-bleeding
   Other
Hemarthrosis
Joint or Muscle Bleeding

 Symptoms
 –   Tingling or bubbling sensation
 –   Stiffness
 –   Warmth
 –   Pain
 –   Unusual limb position
Life-Threatening Bleeding
   Head / Intracranial
    –   Nausea, vomiting, headache, drowsiness, confusion, visual
        changes, loss of consciousness
   Neck and Throat
    –   Pain, swelling, difficulty breathing/swallowing
   Abdominal / GI
    –   Pain, tenderness, swelling, blood in the stools
   Iliopsoas Muscle
    –   Back pain, abdominal pain, thigh tingling/numbness,
        decreased hip range of motion
Other Bleeding Episodes

   Mouth bleeding
   Nose bleeding
   Scrapes and/or minor cuts
   Menorrhagia
Complications of Bleeding

   Flexion contractures
   Joint arthritis / arthropathy
   Chronic pain
   Muscle atrophy
   Compartment syndrome
   Neurologic impairment
     Hemophilia “General Consideration”

   There is a strong correlation between residual clotting factor
    level and severity of bleeding symptoms.

   Spontaneous bleeding is only seen in severe disease.

   Affected males with severe disease are generally diagnosed by
    the age of one year.

    Even where there is no prior family history of hemophilia,
    sporadic cases caused by new mutations, which are responsible
    for 1/3 of cases.

   In males with mild hemophilia, it is not unusual for the disorder
    to not be diagnosed until middle age, possibly following
    prolonged bleeding at surgery.
Treatment of Hemophilia
   Replacement of missing clotting protein
    –   On demand
    –   Prophylaxis
   DDAVP / Stimate
   Antifibrinolytic Agents
    –   Amicar
   Supportive measures
    –   Icing
    –   Immobilization
    –   Rest
Factor VIII Concentrate

   Intravenous infusion
    –   IV push
    –   Continuous infusion
   Dose varies depending on type of bleeding
    –   Ranges from 20-50+ units/kg. body weight
   Half-life 8-12 hours
   Each unit infused raises serum factor VIII
    level by 2 %
Factor IX Concentrate

   Intravenous infusion
    –   IV push
    –   Continuous infusion
   Dose varies depending on type of bleeding
    –   Ranges from 20-100+ units/kg. body weight
   Half-life 12-24 hours
   Each unit infused raises serum factor IX level
    by 1%
History of Clotting Factor
Concentrates

Prior to 1950: whole blood
1952: Hemophilia A distinguished from B
1950-1960: FFP and Cryoprecipitate
Early 1970s: Commercial plasma-derived factor
  concentrates
Mid-late 1970’s: Home infusion practices
1981: First AIDS death in the Hemophilia
  community
History of Clotting Factor
Concentrates (cont’d)

Mid-1983: Factor concentrates heat treated for
  hepatitis
1985: All products heat treated for viral
  inactivation
1987: Monoclonal factor concentrates
1992: Recombinant factor VIII
1994: Recombinant factor IX-albumin free
2001: 2nd generation recombinant factor VIII
Infusions of Factor Concentrates

   Verify product with physician order.
   Dose may be +/- 10% ordered.
   Do not waste factor even if the dose is not
    exactly what is ordered.
   Reconstitute factor per package insert.
   Infusion rate per package insert or pharmacy
    instructions.
   Document lot number, expiration date, time
    of infusion, and exact dose given in units.
Prophylaxis

   Scheduled infusions of factor concentrates to
    prevent most bleeding
   Frequency: 2 to 3 times weekly to keep
    trough factor VIII or IX levels at 2-3%
   Types
    –   primary prophylaxis
    –   secondary prophylaxis
   Use of IVAD necessary in some patients
DDAVP (Desmopressin acetate)
 Syntheticvasopressin
 Method of action -
  –   release of stores from endothelial cells raising factor VIII
      and vWD serum levels

 Administration              -
  –   Intravenous
  –   Subcutaneously
  –   Nasally (Stimate)

 Side      effects
Stimate

   How supplied
    –   1.5 mg./ ml (NOT to be confused with DDAVP nasal spray
        for nocturnal enuresis)
    –   2.5 ml bottle - delivers 25 doses of 150 mcg.
   Dosing
    –    Every 24-48 hours prn
    –   <50 kg. body weight - 1 spray (150 mcg.)
    –   >50 kg. body weight - 2 sprays (300 mcg.)
Amicar
(epsilon amino caproic acid)


   Antifibrinolytic
   Uses
    –   Mucocutaneous bleeding

   Dosing: 50 - 100 mg./kg. q. 6 hours
   Side effects
   Contraindications
    –   Hematuria
Complications of Treatment

   Inhibitors/Antibody development
   Hepatitis A
   Hepatitis B
   Hepatitis C
   HIV
Inhibitors

   Definition
    –   IgG antibody to infused factor VIII or IX
        concentrates, which occurs after exposure to the
        extraneous VIII or IX protein.
   Prevalence
    –   20-30% of patients with severe hemophilia A
    –   1-4% of patients with severe hemophilia B
Hepatitis

   Hepatitis A- small risk of transmission
    –   Vaccination recommended

   Hepatitis B - no transmissions since 1985
    –   Vaccination recommended

   Hepatitis C - no transmissions since 1990
    –   ~90% of patients receiving factor concentrates prior to 1985
        are HCV antibody positive
Human Immunodeficiency Virus

   No transmissions of HIV through factor
    concentrates since 1985 due to viral
    inactivation procedures
 HIV      seropositive rate -
    –   69.6% of patients with severe hemophilia A
        receiving factor concentrates prior to 1985
    –   48.6% of patients with severe hemophilia B
        receiving factor concentrates prior to 1985
Nursing Considerations

   Factor replacement to be given on time
    Laboratory monitoring
   Increase metabolic states will increase factor
    requirements
   Factor coverage for invasive procedures
   Document - infusions, response to treatment
   Avoid NSAIDS
   Utilize Hemophilia Center staff for questions /
    problems
Psychosocial Issues

 Guilt
 Challenge of hospitalizations
 Control issues
 Financial / insurance challenges
 Feeling different / unable to do certain
  activities
 Counseling needs
Hemophilia Treatment Center
Team Members

   Patient / Family        Primary Care
   Hematologist            Infectious Disease
   Nurse                   Genetics
   Social Worker           Pharmacy
   Physical Therapist      Dental
   Orthopedist             Hepatology
Role of Hemophilia
Treatment Centers
   State-of-the-art medical treatment for
    persons with hemophilia through the life span
   Education
   Research
   Outreach
   Model of comprehensive care for chronic
    disease
von Willebrand’s Disease
Outline

   vWF
     – Structure
     – Location
     – Function
   vWD
     – History
     – Clinical manifestations
     – Categories
     – Diagnosis
     – Treatment
vWD

   Family of bleeding disorders
   Caused by a deficiency or an abnormality of von
    Willebrand Factor
    vWF

   VWF gene : short arm of chromosome 12
     – VWF gene is expressed in endothelial cells and
        megakaryocytes
   vWF is produced as a propeptide which is extensively modified
    to produce mature vWF
     – Two vWF monomers bind through disulfide bonds to form
        dimers
     – Multiple dimers combine to form vWF multimers
vWF Production

   Vascular endothelial cells      Release stimuli (EC)
   Megakaryocytes                    – Thrombin
   Most vWF is secreted              – Histamine
   Some vWF is stored                – Fibrin
     – Weibel-Palade bodies           – C5b-9 (complement
       in endothelial cells             membrane attack
     – Alpha granules of                complex)
       platelets                    Release stimuli (platelets)
   Constitutive and stimulus-        – Thrombin
    induced pathways                  – ADP
                                      – Collagen
vWF Function

                  Adhesion
                    – Mediates the adhesion
                      of platelets to sites of
                      vascular injury
                      (subendothelium)
                         Links exposed
                          collagen to platelets
                    – Mediates platelet to
                      platelet interaction
                         Binds GPIb and
                          GPIIb-IIIa on
                          activated platelets
                         Stabilizes the
                          hemostatic plug
                          against shear forces
vW Factor Functions in Hemostasis

   Carrier protein for Factor VIII (FVIII)
     – Protects FVIII from proteolytic degradation
     – Localizes FVIII to the site of vascular injury
     – Hemophilia A: absence of FVIII
vWD History

   1931: Erik von Willebrand
    described novel bleeding
    disorder
     – Hereditary
       pseudohemophilia
     – Prolonged BT and
       normal platelet count       1950s: Prolonged BT
     – Mucosal bleeding             associated with reduced
                                    FVIII
     – Both sexes affected
                                   1970s: Discovery of vWF
                                   1980s: vWF gene cloned
Frequency

   Most frequent inherited bleeding disorder
     – Estimated that 1% of the population has vWD
     – Very wide range of clinical manifestations
     – Clinically significant vWD : 125 persons per million
       population
     – Severe disease is found in approximately 0.5-5
       persons per million population
   Autosomal inheritance pattern
     – Males and females are affected equally
vWD Classification

   Disease is due to either a quantitative deficiency of vWF
    or to functional deficiencies of vWF
     – Due to vWF role as carrier protein for FVIII,
        inadequate amount of vWF or improperly functioning
        vWF can lead to a resultant decrease in the available
        amount of FVIII
vWD Classification

   3 major subclasses
     – Type I: Partial quantitative deficiency of vWF
          Mild-moderate disease
          70%
     – Type II: Qualitative deficiency of vWF
          Mild to moderate disease
          25%
     – Type III: Total or near total deficiency of vWF
          Severe disease
          5%
   Additional subclass
     – Acquired vWD
Clinical Manifestations

   Most with the disease        Types II and III: Bleeding
    have few or no symptoms       episodes may be severe
                                  and potentially life
   For most with symptoms,       threatening
    it is a mild manageable      Disease may be more
    bleeding disorder with        pronounced in females
    clinically severe
    hemorrhage only with          because of menorrhagia
    trauma or surgery            Bleeding often
                                  exacerbated by the
                                  ingestion of aspirin
                                 Severity of symptoms
                                  tends to decrease with
                                  age due to increasing
                                  amounts of vWF
Clinical Manifestations

   Epistaxis 60%
   Easy bruising / hematomas 40%
   Menorrhagia 35%
   Gingival bleeding 35%
   GI bleeding 10%
   Dental extractions 50%
   Trauma/wounds 35%
   Post-partum 25%
   Post-operative 20%
vWD Type I

   Mild to moderate disease
   Mild quantitative deficiency of vWF
    – vWF is functionally normal
   Usually autosomal dominant
    – Penetrance may vary dramatically in a single
      family
vWD Type 2

   Usually autosomal dominant        Type 2C
                                        – Recessive
   Type 2A
                                        – High molecular weight vWF
     – Lack high and                      multimers is reduced
       intermediate molecular           – Individual multimers are
       weight multimers                   qualitatively abnormal
   Type 2B                           Type 2M
                                        – Decreased vWF activity
     – Multimers bind platelets
                                        – vWF antigen, FVIII, and
       excessively                        multimer analysis are found
          Increased clearance            to be within reference range
           of platelets from the      Type 2N
           circulation                  – Markedly decreased affinity
                                          of vWF for FVIII
     – Lack high molecular
                                             Results in FVIII levels
       weight multimers                       reduced to usually
                                              around 5% of the
                                              reference range.
vWD Type III

   Recessive disorder
   vWF protein is virtually undetectable
     – Absence of vWF causes a secondary
       deficiency of FVIII and a subsequent severe
       combined defect in blood clotting and platelet
       adhesion
Acquired vWD

   First described in 1970's
   fewer than 300 cases reported
   Usually encountered in adults with no personal or family
    bleeding history
   Laboratory work-up most consistent with Type II vWD
   Mechanisms
     – Autoantibodies to vWF
     – Absorption of HMW vWF multimers to tumors and activated
        cells
     – Increased proteolysis of vWF
     – Defective synthesis and release of vWF from cellular
        compartments
   Myeloproliferative disorders, lymphoproliferative disorders,
    monoclonal gammopathies, CVD, and following certain infections
vWD Screening

   PT
   aPTT
   (Bleeding time)
vWD: aPTT and PT

   aPTT
     – Mildly prolonged in approximately 50% of patients with
       vWD
          Normal PTT does not rule out vWD
     – Prolongation is secondary to low levels of FVIII
   PT
     – Usually within reference ranges
   Prolongations of both the PT and the aPTT signal a
    problem with acquisition of a proper specimen or a
    disorder other than or in addition to vWD
vWD and Bleeding Time

   Historically, bleeding time is a test used to help
    diagnose vWD
     – Lacks sensitivity and specificity
     – Subject to wide variation
     – Not currently recommended for making the
       diagnosis of vWD
vWD Diagnostic Difficulties

   vWF levels vary greatly
     – Physiologic stress
     – Estrogens
     – Vasopressin
     – Growth hormone
     – Adrenergic stimuli
   vWF levels may be normal intermittently in patients with vWD
     – Measurements should be repeated to confirm abnormal
       results
     – Repeating tests at intervals of more than 2 weeks is
       advisable to confirm or definitively exclude the diagnosis,
       optimally at a time remote from hemorrhagic events,
       pregnancy, infections, and strenuous exercise
   vWF levels vary with blood type
vWD Diagnosis

   Ristocetin
     – Good for evaluating vWF function,
     – Results are difficult to standardize
     – Method
          Induces vWF binding to GP1b on platelets
          Ristocetin co-factor activity: measures agglutination of
           metabolically inactive platelets
          RIPA: metabolically active platelets
          Aggregometer is used to measure the rate of aggregation
   vWF Antigen
     – Quantitative immunoassay or an ELISA using an antibody to
        vWF
   Discrepancy between the vWF:Ag value and RCoF activity
    suggests a qualitative defect
     – Should be further investigated by characterization of the
Additional Assays

                       Multimer analysis
                       PFA-100 closure
                        time
                         – Screens platelet
                           function in whole
                           blood
                         – Prolonged in vWD,
                           except Type 2N
                       FVIII activity assay
vWD Treatment

   DDAVP
   Cryoprecipitate
   FVIII concentrate
vWD and DDAVP

   Treatment of choice for vWD type I
     – Synthetic analogue of the antidiuretic hormone
       vasopressin
     – Maximal rise of vWF and FVIII is observed in 30-60
       minutes
     – Typical maximal rise is 2- to 4-fold for vWF and 3- to
       6-fold for FVIII
     – Hemostatic levels of both factors are usually
       maintained for at least 6 hours
     – Effective for some forms of Type 2 vWD
          May cause thrombocytopenia in Type 2b
     – Ineffective for vWD Type 3
Factor VIII Concentrates

   Alphanate and Humate P
   Concentrates are purified to reduce the risk of
    blood-borne disease
   Contain a near-normal complement of high
    molecular weight vWF multimers
vWD Treatment

   Platelet transfusions
     – May be helpful with vWD refractory to other therapies
   Cryoprecipitate
     – Fraction of human plasma
     – Contains both FVIII and vWF
     – Medical and Scientific Advisory council of the National
        Hemophilia Foundation no longer recommends this treatment
        method due to its associated risks of infection
   FFP
     – An additional drawback of fresh frozen plasma is the large
        infusion volume required
Disseminated Intravascular
      Coagulation
DIC

   An acquired syndrome                                                      6

    characterized by                            Thrombosis
    systemic intravascular
                                    Platelet
    coagulation                                              Red Blood Cell

   Coagulation is always the
    initial event.
                                                             Fibrin
   Most morbidity and
    mortality depends on
    extent of intravascular
    thrombosis
                                WWW. Coumadin.com
   Multiple causes
                                    SYSTEMIC
DIC                               ACTIVATION OF
                                  COAGULATION

   An acquired syndrome
    characterized by         Intravascular    Depletion of
    systemic                 deposition of    platelets and
                                 fibrin       coagulation
    intravascular
                                                 factors
    coagulation
   Coagulation is always
    the initial event       Thrombosis of
                              small and         Bleeding
                            midsize vessels



                            Organ failure        DEATH
Pathophysiology of DIC

   Activation of Blood Coagulation
   Suppression of Physiologic Anticoagulant
    Pathways
   Impaired Fibrinolysis
   Cytokines
Pathophysiology of DIC

   Activation of Blood Coagulation
    –   Tissue factor/factor VIIa mediated thrombin
        generation via the extrinsic pathway
            complex activates factor IX and X
    –   TF
            endothelial cells
            monocytes
            Extravascular:
               – lung
               – kidney
               – epithelial cells
Pathophysiology of DIC

   Suppression of Physiologic Anticoagulant
    Pathways
    –   reduced antithrombin III levels
    –   reduced activity of the protein C-protein S system
    –   Insufficient regulation of tissue factor activity by
        tissue factor pathway inhibitor (TFPI)
           inhibits TF/FVIIa/Fxa complex activity
Pathophysiology of DIC

    Impaired Fibrinolysis
      – relatively suppressed at time of maximal activation
        of coagulation due to increased plasminogen
        activator inhibitor type 1
Pathophysiology of DIC -
Cytokines

    Cytokines
     –   IL-6, and IL-1 mediates coagulation activation in DIC
     –   TNF-
            mediates dysregulation of physiologic anticoagulant
             pathways and fibrinolysis
            modulates IL-6 activity
     –   IL-10 may modulate the activation of coagulation



                    Inflamation    Coagulation
Diagnosis of DIC

 Presence of disease associated with DIC
 Appropriate clinical setting
    –   Clinical evidence of thrombosis, hemorrhage or
        both.
   Laboratory studies
    –   no single test is accurate
    –   serial test are more helpful than single test
Conditions Associated With DIC

   Malignancy                    Pulmonary
    –   Leukemia                   –   ARDS/RDS
    –   Metastatic disease         –   Pulmonary embolism

   Cardiovascular                Severe acidosis
    –   Post cardiac arrest       Severe anoxia
    –   Acute MI                  Collagen vascular
    –   Prosthetic devices         disease
   Hypothermia/Hyperthermia      Anaphylaxis
Conditions Associated With DIC

   Infectious/Septicemia        Tissue Injury
    –   Bacterial                 –   trauma
            Gm - / Gm +          –   extensive surgery
    –   Viral                     –   tissue necrosis
            CMV                  –   head trauma
            Varicella
                                 Obstetric
            Hepatitis
                                  –   Amniotic fluid emboli
    –   Fungal
                                  –   Placental abruption
   Intravascular hemolysis
                                  –   Eclampsia
   Acute Liver Disease           –   Missed abortion
   Clinical Manifestations of DIC

Ischemic FindingsORGAN         ISCHEMIC            HEMOR.
   are earliest!               Pur. Fulminans      Petechiae
                 Skin
                               Gangrene            Echymosis
                               Acral cyanosis      Oozing
              CNS              Delirium/Coma       Intracranial
                               Infarcts            bleeding
              Renal            Oliguria/Azotemia   Hematuria
                               Cortical Necrosis
              Cardiovascular   Myocardial
                               Dysfxn
                                                                  Bleeding is the most
              Pulmonary        Dyspnea/Hypoxia     Hemorrhagic
                               Infarct             lung                  obvious
              GI               Ulcers, Infarcts    Massive           clinical finding
              Endocrine        Adrenal infarcts    hemorrhage.
Clinical Manifestations of DIC
Microscopic findings in DIC




   Fragments
   Schistocytes
   Paucity of platelets
Laboratory Tests Used in DIC

   D-dimer*                Thrombin time
   Antithrombin III*       Fibrinogen
   F. 1+2*                 Prothrombin time
   Fibrinopeptide A*       Activated PTT
   Platelet factor 4*      Protamine test
   Fibrin Degradation      Reptilase time
    Prod                    Coagulation factor
   Platelet count           levels
   Protamine test
                         *Most reliable test
Laboratory diagnosis

   Thrombocytopenia
    –   plat count <100,000 or rapidly declining
   Prolonged clotting times (PT, APTT)
   Presence of Fibrin degradation products or positive
    D-dimer
   Low levels of coagulation inhibitors
    –   AT III, protein C
   Low levels of coagulation factors
    –   Factors V,VIII,X,XIII
   Fibrinogen levels not useful diagnostically
Differential Diagnosis

   Severe liver failure
   Vitamin K deficiency
   Liver disease
   Thrombotic thrombocytopenic purpura
   Congenital abnormalities of fibrinogen
   HELLP syndrome
Treatment of DIC

   Stop the triggering process .
    –   The only proven treatment!
   Supportive therapy
   No specific treatments
    –   Plasma and platelet substitution therapy
    –   Anticoagulants
    –   Physiologic coagulation inhibitors
Plasma therapy

    Indications
     –   Active bleeding
     –   Patient requiring invasive procedures
     –   Patient at high risk for bleeding complications
    Prophylactic therapy has no proven benefit.
    Cons:
    Fresh frozen plasma(FFP):
     –   provides clotting factors, fibrinogen, inhibitors, and platelets
         in balanced amounts.
     –   Usual dose is 10-15 ml/kg
Platelet therapy

   Indications
    –   Active bleeding
    –   Patient requiring invasive procedures
    –   Patient at high risk for bleeding complications
   Platelets
    –   approximate dose 1 unit/10kg
Blood

   Replaced as needed to maintain adequate
    oxygen delivery.
    –   Blood loss due to bleeding
    –   RBC destruction (hemolysis)
Coagulation Inhibitor Therapy

   Antithrombin III
   Protein C concentrate
   Tissue Factor Pathway Inhibitor (TFPI)
   Heparin
Antithrombin III

    The major inhibitor of the coagulation cascade
     –   Levels are decreased in DIC.
     –   Anticoagulant and antiinflammatory properties
    Therapeutic goal is to achieve supranormal levels of
     ATIII (>125-150%).
     –   Experimental data indicated a beneficial effect in preventing
         or attenuating DIC in septic shock
             reduced DIC scores, DIC duration, and some improvement in
              organ function
     –   Clinical trials have shown laboratory evidence of attenuation
         of DIC and trends toward improved outcomes.
     –   A clear benefit has not been established in clinical trials.
Protein C Concentrates

   Inhibits Factor Va, VIIa and PAI-1 in conjunction with
    thrombomodulin.
   Protein S is a cofactor
   Therapeutic use in DIC is experimental and is based
    on studies that show:
    –   Patients with congenital deficiency are prone to
        thromboembolic disease.
    –   Protein C levels are low in DIC due to sepsis.
    –    Levels correlate with outcome.
    –   Clinical trials show significantly decreased morbidity
        and mortality in DIC due to sepsis.
Tissue Factor Pathway Inhibitor

   Tissue factor is expressed on endothelial cells and
    macrophages
   TFPI complexes with TF, Factor VIIa,and Factor Xa
    to inhibit generation of thrombin from prothrombin
    TF inhibition may also have antiinflammatory effects
   Clinical studies using recombinant TFPI are
    promising.
Heparin

   Use is very controversial. Data is mixed.
   May be indicated in patients with clinical
    evidence of fibrin deposition or significant
    thrombosis.
   Generally contraindicated in patients with
    significant bleeding and CNS insults.
   Dosing and route of administration varies.
   Requires normal levels of ATIII.
Antifibrinolytic Therapy

   Rarely indicated in DIC
    –   Fibrinolysis is needed to clear thrombi from the micro
        circulation.
    –   Use can lead to fatal disseminated thrombosis.
   May be indicated for life threatening bleeding under
    the following conditions:
    –   bleeding has not responded to other therapies and:
    –   laboratory evidence of overwhelming fibrinolysis.
    –   evidence that the intravascular coagulation has ceased.
   Agents: tranexamic acid, EACA
Summary

   DIC is a syndrome characterized systemic
    intravascular coagulation.
   Coagulation is the initial event and the extent of
    intravascular thrombosis has the greatest impact on
    morbidity and mortality.
   Important link between inflammation and
    coagulation.
   Morbidity and mortality remain high.
   The only proven treatment is reversal or control
    of the underlying cause.

				
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