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Disorders of Hemostasis

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Title: Disorders of Hemostasis


1
Disorders of Hemostasis
  • Dr. Batizy
  • 11/2/06

2
Primary Hemostasis
  • The platelet contains lysosomes, granules, and
    trilaminar plasma membrane, microtubules.
  • Granules are key in primary hemostasis and
    contain ADP, Thromboxane, platelet factor 4,
    adhesive and aggregation glycoproteins,
    coagulation factors, and fibrinolytic inhibitors

3
Primary Hemostasis
  • Dependent on Platelets and Von Willebrand Factor
    (vWF)
  • Platelets gather and attach to vWF
  • Platelets degranulate after attachment and
    release ADP and Thromboxane which attracts more
    platelets
  • Forms a platelet plug
  • Requires endothelial damage to adhere

4
Secondary Hemostasis
  • Platelet aggregation initiates secondary
    hemostasis through the coagulation cascade
  • Coagulation cascade is initiated by the intrinsic
    or extrinsic pathway
  • The final cascade results in fibrin deposition
    cross-linking platelets and clot formation

5
The Coagulation Cascade
Common Pathway
6
A word on clotting factors
  • Vitamin K Dependent Factors
  • Intrinsic Pathway IX, X
  • Common Pathway II
  • Extrinsic Pathway VII
  • All clotting Factors are produced in liver except
    vWF/VIII
  • VIII produced by the vascular endothelium
  • Sites of heparin activity
  • IIa, IXa, Xa ( major site), XIa, Platelet factor 3

7
A word on clotting factors
  • Factor VIII A factor by any other name?
  • Same factor 3 different activities
  • VIIIC antihemophilic or coagulation activity
  • vWF supports platelet adhesion and carries VIII
    in the blood
  • VIIIAg reacts with rabbit antibodies, relates
    to measured plasma level rather than activity

8
Fibrinolysis
  • The Ying to the Yang of clot formation
  • Tissue Plasminogen activator (tPA)
  • Released from endothelial cells
  • Converts plasminogen to plasmin which degrades
    fibrinogen and fibrin into fibrin degradation
    products
  • Cross linked fibrin is cleaved into D-Dimers

9
Testing the hemostatic system
  • CBC
  • H/H drops often lag behind actual RBC loss due to
    slow equilibration
  • Blood smear
  • Schistocytes and fragemented RBC- DIC
  • Teardrop-shaped or nucleated RBC Myelophthisic
    disease
  • Characteristic WBC morphologies seen in
    thrombocytopenia in infectious mononucleosus,
    folate, B12 deficiency, or leukemia

10
Testing the hemostatic system
  • Platelet count
  • Thrombocytopenia Less that 100,000/mL
  • Spontaneous bleeding possible Less than
    20,000/mL
  • Count does not have anything to do with
    functionality of platelet

11
Testing the hemostatic system
  • Bleeding time
  • Tests vascular integrity and platelet function
  • Incision on volar aspect of the forearm 1mm deep
    and 1 cm long
  • BP cuff inflated to 40 mmHg
  • Normal lt 8 minutes
  • Borderline 8-10 minutes
  • Abnormal 10 minutes
  • Affected by ASA (permanent) and NSAIDs

12
Testing the hemostatic system
  • Bleeding time
  • Prolonged with platelet counts below 100,000
  • When prolonged with platelet count over 100,000
    suggests platelet dysfunction

13
Testing the hemostatic system
  • Prothrombin Time
  • Test of extrinsic and common pathways
  • International Normalized Ratio used to compensate
    for differences in thromboplastin reagents
  • Used for coumadin
  • Elevated in patients with liver disease and
    abnormalities in vitamin K sensitive factors

14
Testing the hemostatic system
  • Partial Thromboplastin Time (PTT)
  • Tests intrinsic and common pathway
  • Average normal 25-29
  • Factor levels usually less than 40 to be
    affected
  • Affected by heparin
  • Can be effected by coumadin at supra-therapeutic
    levels due to effects on the common pathway

15
History and Physical
  • Platelet Disorders
  • More common in Women
  • Petechiae, Purpura, mucosal bleeding
  • More commonly acquired
  • Coagulation Disorder
  • More common in Men
  • Delayed deep muscle bleeding, hemarthrosis,
    hematuria
  • More commonly congenital

16
Thrombocytopenia
  • Usually mucosal bleeding
  • Epistaxis, menorrhagia, and GI bleeding is common
  • Trauma does not usually cause bleeding

17
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

18
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

19
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

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

21
ITP
  • Acute Form
  • Most common in children 2 to 6 years
  • Viral Prodrome common in the 3 weeks prior
  • Self Limited and gt 90 remission rate
  • Supportive Treatment
  • Steroids are not helpful

22
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

23
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)

24
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

25
TTP??HUS
  • Labs
  • PT, PTT, and fibrinogen are within reference
    range
  • Helmet Cells (Shistocytes) are common

26
TTP??HUS
  • HUS
  • Most common in infants and children 6mo - 4 years
  • Often associated with a prodromal diarrhea
  • Strongest association to E. coli O157H7 but also
    associated with SSYC as well as multiple virus
  • Prognosis
  • Mortality 5-15
  • Younger patients do better

27
TTP??HUS
  • HUS
  • Treatment
  • Mostly supportive
  • Plasma exchange reserved for sever cases
  • Treat hyperkalemia
  • Avoid antibiotics with Ecoli
  • May actually increase verotoxin production with
    TMP-SMX
  • May be helpful with cases of Shigella dysenteriae

28
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

29
TTP??HUS
  • AVOID PLATELET TRANSFUSION
  • May lead to additional microthrombi in
    circulation
  • Transfuse only with life threatening bleeding

30
Dilutional Thrombocytopenia
  • PRBC are platelet poor
  • Monitor platelet count with every 10 u PRBC
  • Transfuse when count below 50,000
  • Get them upstairs before you transfuse 10 units
    PRBC

31
DIC
  • A few harmless snowflakes working together can
    create an avalanche of Destruction.

32
DIC
  • Early recognition important secondary to
    potentially devastating sequelae and effective
    therapy
  • DIC Sequence ? Platelets and coagulation factors
    consumed ? Thrombin directly activates fibrinogen
    ?Fibrin deposition ? Fibrinolysis ? Inhibition of
    platelets and fibrin polymerization ? Decrease in
    inhibition levels
  • Entire process leads to a massive consumption of
    coagulation factors

33
DIC
  • Life threatening combination of bleeding
    diathesis with small vessel ischemia
  • There are varying levels of acuity
  • Recommended testing
  • Peripheral Smear Low platelets, schistocytes
  • Platelet count Low (lt100,000)
  • Pt, PTT, Thrombin Time Prolonged
  • Fibrinogen Low
  • Fibrin degredation products zero to large

34
DIC
  • Treatment
  • Dependent on whether bleeding or ischemia
    predominate
  • If bleeding
  • Platelets, FFP or Cryoprecipitate, and blood
    recommended
  • With Ischemia
  • Heparin has a place in treatment
  • Examples include Retained fetus, purpura
    fulminans, giant hemangioma, and acute
    promyelocytic leukemia

35
DIC
  • Treatment
  • Goal in ER is suspicion, aggressive pursuit of
    diagnosis, understanding complications, and
    rarely initiation of therapy

36
Coagulation Pathway Defects
  • Hemophilia A
  • Von Willebrands Disease
  • Hemophilia B ( Christmas Disease)

37
Hemophilia A
38
Hemophilia A
  • Variant form of Factor VIII
  • 60 to 80 persons per million
  • 70 Sex linked recessive
  • Severity linked to level of VIIIC activity
  • 1 Severe
  • 1-5 Moderate
  • 5-10 mild ( little risk of spontaneous bleeding)

39
Hemophilia A
  • Bleeding can occur anywhere
  • Deep muscles
  • Joints
  • Urinary Tract
  • Intracranial
  • Recurrent Hemarthrosis and progressive join
    destruction are major cause of morbidity
  • Intracranial bleed is major cause of death in all
    hemophiliacs

40
Hemophilia A
  • Mucosal bleeding is rare unless associated with
    von Willebrands or Platelet inhibition
  • Unlike platelet defects Trauma initiates bleeding
  • Bleeding can occur usually by 8 hours but as late
    as 1 to 3 days after trauma

41
Hemophilia A
  • Management
  • Home therapy is increasingly common and most
    report to ER only with complicated problems or
    Trauma
  • Hospitals should have files of known hemophiliacs
    in the area
  • Accepted therapy is with Factor VIII replacement
    or VIIIC
  • Newer preparation carry lower risk for Hep B and
    Hep C transmission

42
Hemophilia A
  • Management
  • Multiple guidelines for therapy institution
  • Most important physician should believe a patient
    saying they are bleeding and institute early
    therapy

43
Hemophilia A
  • Prophylaxis
  • May require admission for anticipation of delayed
    bleeding
  • Candidates
  • Deep lacerations
  • Soft tissue injury where hematoma could be
    destructive ie eye, mouth, neck, back, and
    spinal column

44
Hemophilia A
  • Treatment of haemophilic synovitis
  • COX-2 important in Hemophiliacs because of
    antiinflammatory,and analgesic properties but
    they do not affect the platelet fuction
  • With withdrawl of rofecoxib from the market
    celecoxib had become popular
  • Study has shown that Celecoxib gives good relief
    of synovitis without serious adverse effects

45
Von Willebrands Disease
  • Most common inherited bleeding disorder
  • Without vWF the ability of platelets to adhere is
    diminished
  • VIIIC has diminished activity
  • Bleeding sites are primarily mucosal
  • Hemarthrosis is rare
  • Menorrhagia and GI bleed are common

46
Von Willebrands Disease
  • Factor VIII replacement is treatment of choice
  • FFP may be given in extreme circumstances
  • Desmopressin is only useful for specific types of
    vWD and should only be give with advice from
    hematologist

47
Hemophilia B (Christmas Disease)
48
Hemophilia B (Christmas Disease)
  • Clinically indistinguishable from hemophilia A
  • Deficiency of factor IX
  • Factor IX preparation used in treatment
  • FFP and plasma prothrombin complex are also
    useful
  • Gene manipulation in animals shows promising
    results for the future

49
Take home message
  • All Bleeding stops. Eventually

50
References
  • Rosens
  • Emedicine
  • Celecoxib in the treatment of haemophilic
    synovitis, target joints, and pain in adults and
    children with haemophilia, Haemophilia (2006),
    12, 514-517
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