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Bleeding Disorders

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Title: Bleeding Disorders


1
Bleeding Disorders
  • Meera Shreedhara
  • 8/25/08

2
What is it?
  • A bleeding disorder is an acquired or inherited
    tendency to bleed excessively

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Mechanisms of bleeding
  • Vascular Integrity
  • Platelets
  • Clotting factors
  • Fibrinolysis
  • Derangement of any of these factors can cause
    abnormal bleeding

6
Key to diagnosis
  • History
  • History
  • History

7
Bleeding history
  • Epistaxis
  • Gingival hemorrhage
  • Mucosal Bleeding
  • Heavy Menses
  • Child birth
  • Easy bruisability
  • Bleeding following tooth extractions
  • Hematomas
  • Bleeding following surgery
  • Hemarthrosis

8
Medication History
  • Aspirin
  • Warfarin
  • NSAIDS
  • B- Lactam antibiotics
  • Clopidogrel and other antiplatelet agents
  • Herbal medications.

9
Nutritional history
  • Vit K deficiency
  • Vit C deficiency
  • Broad spectrum antibiotics

10
Clinical Characterisitc
Clinical Characterisitc Platelet defect Clotting factor deficiency
Site of bleeding Skin, mucous membranes (gingivae, nares, GI and genitourinary tracts) Deep in soft tissues (joints, muscles)
Bleeding after minor cuts Yes Not usually
Petechiae Present Absent
Ecchymoses Small, superficial Large, palpable
Hemarthroses, muscle hematomas Rare Common
Bleeding after surgery Immediate, mild Delayed, severe
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History
  • Should the pt undergo a limited or extensive
    workup?
  • Is this acquired or hereditary?
  • Is this likely a disorder of clotting
    factors,platelets, fibrinolysis or vWF?
  • Do medications or intercurrent illnesses play a
    role?
  • What is the immediate cause for which a workup is
    being done?

16
Hereditary
  • Deficiency of coagulation factors
  • Hemophilia
  • Fibrinogen deficiency
  • Von Willebrand disease
  • Platelet disorders
  • Glanzmann thrombasthenia
  • Bernard-Soulier syndrome
  • Platelet granule disorders
  • Fibrinolytic disorders
  • Alpha 2 antiplasmin deficiency
  • PAI 1 deficiency
  • Structural disorders
  • Hemorrhagic Telangiectasias
  • Ehler Danlos syndrome

17
Acquired
  • Thrombocytopenis
  • Liver disease
  • Renal failure
  • Vit K deficiency
  • Acquired antibodies to coagulation factors
  • DIC
  • Drugs
  • Vascular

18
Lab testing
  • Platelet count
  • Bleeding time-Measure of the interaction of
    platelets with the blood vessel wall.
  • Thrombocytopenia (platelet count usually below
    50,000/microL),
  • Qualitative platelet abnormalities (eg, uremia),
  • von Willebrand disease (VWD),
  • Vascular purpura,
  • Severe fibrinogen deficiency

19
Platelet function assay
  • Expose platelets within citrated whole blood to
    high shear (5,000 to 6,000/sec) within a
    capillary tube and monitor the drop in flow rate
    as the platelets form a hemostatic plug within
    the center of a membrane coated with collagen and
    either ADP or epinephrine
  • Abnormal closure times are an indication of
    platelet dysfunction, they are not specific for
    any disorder
  • The test is coagulation factor independent
  • PFA-100 is more sensitive (gt70 percent) than the
    bleeding time (20 to 30 percent) in detecting all
    subtypes of von Willebrand's disease (vWD)
  • Exception is type 2N vWD, in which the hemostatic
    defect resides in the Factor VIII binding site on
    vWF

20
Platelet function assay
  • Collagen/epinephrine closure time (CEPI-CT)-
    Abnormal in Aspirin intake
  • Collagen/adenosine diphosphate (CADT-CT)-Normal
    in aspirin intake

21
Prothrombin time
  • Measure of the extrinsic pathway and common
    pathway
  • Bypasses the intrinsic pathway and uses
    thromboplastins to substitute for platelets
  • Within the combined pathway, factors VII, X, and
    prothrombin are vitamin-K dependent and are
    altered by warfarin

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Prolonged PT
  • Vitamin K deficiency
  • Liver disease, which decreases the synthesis of
    both vitamin K-dependent and -independent
    clotting factors.
  • Deficiency or inhibition of factors VII, X, II
    (prothrombin), V, or fibrinogen
  • The infrequent antiphospholipid antibodies (lupus
    anticoagulant phenomenon) with antiprothrombin
    activity
  • Heparin does NOT prolong the PT

24
aPTT
  • Measures the intrinsic and common pathways of
    coagulation
  • Uses partial thromboplastins they are incapable
    of activating the extrinsic pathway
  • Prolonged in deficiency of, or an inhibitor to,
    any of the clotting factors except for factor VII
  • Prolonged in the presence of Lupus Anticoagulant.
  • Used to monitor heparin activity

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Thrombin time
  • Measure conversion of fibrinogen to fibrin
    monomers and the formation of initial clot by
    thrombin
  • Hypofibrinogenemia,
  • Dysfibrinogens
  • Increased fibrin split products
  • Heparin increases TT but not RT

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Factor deficiencies/ inhibitors
  • A prolonged aPTT can be due to a deficiency (or
    absence) of a coagulation factor or the presence
    of a coagulation factor inhibitor
  • Mixing studies help differentiate this
  • Lupus anticoagulants can result in a prolonged
    aPTT that is not correctable by the addition of
    normal plasma
  • Overcome by adding excess platelet phospholipid
    (particularly a hexagonal phase phospholipid) or
    by assessing the diluted Russell's viper venom
    time

30
Fibrinolysis
  • Fibrin and fibrinogen degradation products (FDP)
    are protein fragments resulting from the action
    of plasmin on fibrin or fibrinogen

31
Fibrinolysis
  • FDP assays do not differentiate between fibrin
    degradation products and fibrinogen degradation
    products
  • Fibrin D-dimers are degradation products of
    cross-linked fibrin
  • D-dimers specifically reflect fibrinolysis of
    cross-linked fibrin (ie, the fibrin clot) so
    are more reliable indicators of thrombosis

32
Fibrinolysis
  • Assays for plasminogen,
  • Tissue plasminogen activator (t-PA),
  • Alpha-2 antiplasmin,
  • Plasminogen activator inhibitor-1 (PAI-1),
  • Thrombin-activatable fibrinolysis inhibitor
    (TAFI).

33
Normal PT and PTT
  • Thrombocytopenia
  • vWD
  • Factor 13 deficiency
  • Platelet dysfunction
  • Vascular purpuras
  • Psychogenic purpura

34
Normal PT and Prolonged aPTT
  • Hemophilia A
  • Hemophilia B
  • Factor XI deficiency
  • Factor VIII inhibitor
  • Malignancy,
  • Clonal lymphoproliferative disorders,
  • Pregnancy,
  • Rheumatologic disorders

35
Prolonged PT and normal aPTT
  • Factor VII deficiency
  • Warfarin therapy
  • Early liver disease
  • Early DIC

36
Prolonged PT and PTT
  • Vit K deficiency
  • Liver disease
  • Warfarin treatment
  • Acquired inhibitor to factor V
  • Factor X deficiency- seen in Amyloidosis
  • DIC

37
Acute Promyelocytic Leukemia
  • DIC is often seen at presentation or during
    treatment
  • Medical Emergency as Cerebral hemorrhage can
    occur in upto 4 of untreated pts
  • Promyelocytes seen on smear
  • Reciprocal translocation between the long arms of
    chromosomes 15 and 17, with the creation of a
    fusion gene, PML/RAR-alpha
  • Immediate initiation of ATRA induces de
    deifferentiation

38
Hemophilia
  • Hemophilia A and B are X-linked recessive
    diseases
  • Severe disease lt1 factor activity,
  • Moderate disease- 1 to 5
  • Mild disease gt5
  • The most common sites are into joints and muscles
    and from the gastrointestinal tract

39
Treatment
  • The two components to therapy are treatment of
    active bleeding and inhibitor ablation via immune
    tolerance induction
  • Cryoprecipitate has high levels of factor VIII
  • Porcine Factor VIII
  • Recombinant human Factor VIII
  • The choice of factor VIII product usually is
    based upon safety, purity, and cost.

40
Dosing
  • One international unit (IU) of clotting factor is
    that amount present in 1 mL of pooled normal
    plasma
  • Dose of F VIII (IU) Weight (kg) x (Desired
    increase) x 0.5
  • Depends on the clinical indication and the
    presence of inhibitors

41
von Willebrands disease
  • Most common of the inherited bleeding disorders
  • In 1926, Erik von Willebrand described the first
    patient with the disease
  • Von Willebrand factor (VWF) binds to both
    platelets and endothelial components, forming an
    adhesive bridge between platelets and vascular
    subendothelial structures and between adjacent
    platelets at sites of endothelial injury

42
Acquired von Willebrands disease
  • Malignant diseases
  • Monoclonal gammopathy of unknown significance
  • Multiple Myeloma
  • Non-Hodgkin's lymphoma
  • Chronic lymphocytic leukemia
  • Waldenstrom's macroglobulinemia
  • Essential thrombocythemiaPolycythemia vera
  • Chronic myelogenous leukemia
  • Wilms tumor
  • Other carcinomas
  • Immunologic disorders
  • Systemic lupus erythematosus
  • Other autoimmune diseases
  • Other disorders
  • Hypothyroidism
  • Ventricular septal defect
  • Aortic stenosis
  • Mitral valve prolapse
  • Gastrointestinal angiodyplasia
  • Uremia
  • Hemoglobinopathies
  • Drugs and other agents
  • Valproic acid
  • Antibiotics

43
Treatment
  • DDAVP
  • Replacement of vWF
  • EACA
  • Tranexamic acid
  • Recombinant factor 7

44
Its better to bleed than clot!
45
Therapies other than factor replacement
  • DDAVP
  • EACA
  • Tranexamic Acid
  • Factor 7 inhibitor- Novoseven

46
Liver disease Vs DIC
  • Low factor V levels can be used as evidence for
    either reduced hepatic synthetic function or
    increased consumption, as in DIC
  • Factor VIII is not manufactured by hepatocytes
    factor VIII levels are usually normal or
    increased in liver disease
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