Bleeding Disorders

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Bleeding Disorders

• Meera Shreedhara
• 8/25/08

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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

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Key to diagnosis

• History
• History
• History

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Bleeding history

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

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Medication History

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

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Nutritional history

• Vit K deficiency
• Vit C deficiency
• Broad spectrum antibiotics

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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?

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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

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Acquired

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

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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

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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

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Platelet function assay

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

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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

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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

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Fibrinolysis

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

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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

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Fibrinolysis

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

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Normal PT and PTT

• Thrombocytopenia
• vWD
• Factor 13 deficiency
• Platelet dysfunction
• Vascular purpuras
• Psychogenic purpura

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Normal PT and Prolonged aPTT

• Hemophilia A
• Hemophilia B
• Factor XI deficiency
• Factor VIII inhibitor
• Malignancy,
• Clonal lymphoproliferative disorders,
• Pregnancy,
• Rheumatologic disorders

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Prolonged PT and normal aPTT

• Factor VII deficiency
• Warfarin therapy
• Early liver disease
• Early DIC

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Prolonged PT and PTT

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

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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

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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

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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.

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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

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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

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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

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Treatment

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

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Its better to bleed than clot!
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Therapies other than factor replacement

• DDAVP
• EACA
• Tranexamic Acid
• Factor 7 inhibitor- Novoseven

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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