Evaluation of the bleeding patient

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Evaluation of the bleeding patient

• V. Kinsella M.D.
• January,27 2006

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MILD bleeding

• Platelets secretion disorders
• vW deficiency
• Platelets dense granules
• deficiency
• 4. Unknown

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Hemostasis and thrombosis

• Dependent on 3 factors
• Vascular endothelium
• Platelets
• Coagulation system

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1.Clinical aspects of bleeding
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1.Clinical aspects of bleeding

• Evaluation of patients with bleeding is a
  multi-step process
• Complete history
• Detailed physical exam
• Laboratory evaluation

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history

• Is there a personal or family history of bleeding
  after surgical procedures, dental procedures,
  childbirth, or trauma?
• When the bleeding episode started?
• Has the patient received medications that can
  cause or make worse a bleeding problem?

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history

• Many drugs can contribute to bleeding
• semisynthetic penicillins
  cephalosporins
• calcium channel blocker dipyridamole
• thiazides
  alcohol
• quinine, quinidine
  chlorpromazine, sulfonamides
  INH, rifampin
  methyldopa
  phenytoin, barbiturates,
  warfarin, heparin,
  thrombolytic agents NSAIDs, ASA
  allopurinol
  
• TMP/SMX
  

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physical exam

• 1. Assess volume status (correct shock if
  present)
• 2. Look for hepatosplenomegaly
• 3. Do a rectal exam for evidence of GI bleeding
• 4. Examine oropharynx for evidence of petechiae

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Clinical aspects of bleeding
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physical exam

• Look for physical signs and symptoms of diseases
  related to capillary fragility
• Cushings syndrome, Marfan syndrome or exogenous
  steroids
• "senile purpura
• Petechiae secondary to coughing, sneezing,
  Valsalva maneuver, blood pressure measurement
• vasculitis ("palpable purpura")
• Telangiectasias (Osler-Weber-Rendu syndrome)
  (HHT)

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petechiae
(typical of platelet disorders)
Do not blanch with pressure (angiomas)Not
palpable (vasculitis)
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vasculitis (palpable rash)
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2. Hematologic disorders causing bleeding

• Platelet disorders
• Coagulation factor disorders

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Clinical differentiation Platelets x
Coagulation Defects
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Platelets Defects

• Generally have immediate onset of bleeding after
  trauma
• Bleeding is predominantly in skin, mucous
  membranes, nose, GI tract, and urinary tract
• Bleeding may be observed as petechiae (lt3 mm) or
  ecchymoses (gt3 mm

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Clinical aspects of bleeding
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Coagulation Defects

• "Deep" bleeding (in the joint spaces, muscles,
  and retroperitoneal spaces) is common. Observed
  on exam as hematomas and hemarthroses.

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Hematoma
(typical of coagulation factor disorders)
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Hemarthrosis (acute)
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Laboratory Evaluation of Bleeding

• CBC and smear Platelet count Thrombocytopenia
• RBC and platelet morphology TTP, DIC, etc.
• Coagulation PT
  extrinsic/common pathways
• PTT
  Intrinsic/common pathways
• Coag. factor assays Specific factor
  deficiencies

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Laboratory Evaluation of Bleeding

• Platelet function von Willebrand factor vWD
• Bleeding time In vivo test (non-specific)
• Platelet function analyzer (PFA) Qualitative
  platelet disorders

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Laboratory Evaluation of the Coagulation Pathways
Partial thromboplastin time (PTT)
Prothrombin time (PT)
Surface activating agent (Ellagic acid,
kaolin) Phospholipid Calcium
Thromboplastin Tissue factor Phospholipid Calcium
Intrinsic pathway
Extrinsic pathway
Common pathway
Thrombin time
Thrombin
Fibrin clot
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Coagulation cascade
Intrinsic system (surface contact)
Extrinsic system (tissue damage)
XII
XIIa
Tissue factor
XIa
XI
IX
IXa
VIIa
VII
VIII
VIIIa
X
Vitamin K dependant factors
Xa
V
Va
(Thrombin)
IIa
IIa
II
Fibrinogen
Fibrin
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Initial Evaluation of a Bleeding Patient
Normal PT Normal PTT
Consider evaluating for Platelet disorder Mild
factor deficiency Factor XIII Monoclonal
gammopathy Abnormal fibrinolysis a2 anti-plasmin
deficiency Vascular disorders Dysfibrinogenemia
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Initial Evaluation of a Bleeding Patient
Elevated PT Normal PTT
5050 mix is abnormal
Repeat with 5050 mix
Test for inhibitor activity 1.Specific
Factor VII (rare) 2.Non-specific
Anti-phospholipid
5050 mix is normal
Test for factor deficiency 1.Multiple
factor deficiencies (common) (Liver disease,
vitamin K deficiency, warfarin, DIC) 2.
Deficiency of factor VII (rare)
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Initial Evaluation of a Bleeding Patient
Normal PT Abnormal PTT
5050 mix is abnormal
Repeat with 5050 mix
Test for inhibitor activity Specific factors
VIII, IX, XI Non-specific (anti-phospholipid)
5050 mix is normal
Test for factor deficiency Isolated deficiency
in intrinsic pathway (factors VIII, IX, XI)
Multiple factor deficiencies (rare)
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Initial Evaluation of a Bleeding Patient
Abnormal PT Abnormal PTT
5050 mix is abnormal
Repeat with 5050 mix
Test for inhibitor activity Specific
Factors V, X, prothrombin,
fibrinogen (rare) Non-specific
anti-phospholipid (common)
5050 mix is normal
Test for factor deficiency Isolated deficiency
in common pathway Factors V, X, Prothrombin,
Fibrinogen Multiple factor deficiencies (common)
(Liver disease, vitamin K deficiency,
warfarin, DIC)
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Bleeding time

• 5-10 of patients hospitalized patients have
  a
  prolonged bleeding time
• Most of the prolonged bleeding times are due to
  aspirin or drug ingestion
• Prolonged bleeding time does not predict excess
  surgical blood loss
• Not recommended for routine testing in
  preoperative patients

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Thrombin Time

• Measures rate of fibrinogen conversion to fibrin
• Procedure
• Add thrombin with patient plasma
• Measure time to clot
• Variables
• Source and quantity of thrombin

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Causes of prolonged Thrombin Time

• Heparin
• Hypofibrinogenemia
• Dysfibrinogenemia
• Paraprotein
• Thrombin inhibitors (Hirudin)
• Thrombin antibodies

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• PLATELETS

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Approach to the thrombocytopenic patient

• History
• Is the patient bleeding?
• 2. Are there symptoms of a secondary illness?
  (neoplasm, infection, autoimmune disease)
• 3. Is there a history of medications, alcohol
  use, or recent transfusion?

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Approach to the thrombocytopenic patient

• History
• 4. Are there risk factors for viral infection?
• 5.Is there a family history of thrombocytopenia?
• 6. Do the sites of bleeding suggest a platelet
  defect?

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Approach to the thrombocytopenic patient

• Assess the number and function of platelets
• CBC with peripheral smear
• Bleeding time
• Platelet aggregation study
• PFA

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Classification of platelet disorders

• Quantitative disorders
• Abnormal distribution
• Dilution effect
• Decreased production
• Increased destruction

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Classification of platelet disorders

• Qualitative disorders
• Inherited disorders (rare)
• Acquired disorders
• Immune
• Medications
• Chronic renal failure
• Cardiopulmonary bypass
• Liver disease

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Inherited platelet disorders

• Rare congenital abnormalities on synthesis or
  release of secretory granules

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Inherited platelet disorders

• Gray platelets syndrome
• No alpha granules

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Inherited platelet disorders

• May-Hegglin
• Thrombocytopenia
• Large platelets
• Neutrophils Dohle bodies

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Inherited platelet disorders

• Glazmanns thrombasthenia
• Congenital deficiency or abnormality of GP
  IIb-IIIa
• Bernard-Solier syndrome
• Congenital deficiency or abnormality of GP Ib

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Acquired platelet disorders

• Decreased production
• Ineffective thrombopoiesis - MDS
• Increased destruction
• Immune
• Non-immune
• Poor aggregation

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Increased platelets destruction
1. Immune-mediated Idiopathic -
ITP Drug-induced Collagen vascular
disease Lymphoproliferative disease Sarcoidosis
2.Non-immune mediated DIC Microangiopathic
hemolytic anemia
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ITP is a diagnosis of exclusion !
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Initial Treatment of ITP
Platelet count Symptoms Treatment
gt50,000 None 20-50,000 Not bleeding None
Bleeding Glucocorticoids IVIG lt2
0,000 Not bleeding Glucocorticoids

Bleeding Glucocorticoids
IVIG Hospitalization Rituximab
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• COAGULATION FACTOR DEFECTS

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Inherited Coagulation factor bleeding disorders

• vonWillebrands disease
• Hemophilia (A and B)

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vonWillebrand disease

• Most common hereditary
• coagulation disorder
• Autossomal dominant
• Incidence 11000

Erik A. vonWillenbrand M.D. (1870-1949)
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vonWillebrand factor

• Synthesis in endothelium and megakaryocytes
• Forms large multimers
• Carrier of factor VIII
• Anchors platelets to subendothelium
• Bridge between platelets

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vonWillebrand disease

• Abnormal synthesis of von Willebrand factor (vWF)
  causes decreased platelet adhesion and decreased
  serum levels of factor VIII

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vonWillebrand disease

• Classification
• Type 1 Partial quantitative deficiency
  (decreased)
• Type 2 Qualitative deficiency
• (abnormal)
• Type 3 Total quantitative deficiency
• (absent)

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vonWillebrand disease
Laboratory evaluation

vonWillebrand type Assay 1 2
3 vWF antigen ß Normal
ßß vWF activity ß ß
ßß Multimer analysis Normal Normal Absent
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Treatment of von Willebrand Disease

• DDAVP (deamino-8-arginine vasopressin)
• ? plasma VWF levels by stimulating secretion from
  endothelium
• Duration of response is variable
• Not generally used in type 2 disease
• Dosage 0.3 µg/kg q 12 hr IV

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Treatment of von Willebrand Disease

• Cryoprecipitate
• Source of fibrinogen, factor VIII and VWF
• Only plasma fraction that consistently contains
  VWF multimers
• Factor VIII concentrate (Intermediate purity)
• Virally inactivated product
• Humate-P or Koate-HS

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Hemophilia

• Clinical manifestations (hemophilia A B are
  indistinguishable)
• Prolonged bleeding after surgery or dental
  extractions
• Hemarthrosis (most common)
• Soft tissue hematomas
• Other sites of bleeding
• Urinary tract
• CNS, neck (may be life-threatening)

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Dosing guidelines for hemophilia A

• Mild bleeding
• Hemarthrosis, oropharyngeal or dental,
  epistaxis, hematuria
• Target 30 dosing q8-12h 1-2 days (15U/kg)
• Major bleeding
• CNS trauma, hemorrhage, lumbar puncture
• Surgery
• Retroperitoneal hemorrhage
• GI bleeding
• Target 80-100 q8-12h 7-14 days (50U/kg)
• Adjunctive therapy
• ?-aminocaproic acid (Amicar) or DDAVP (for mild
  disease only)

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Treatment of hemophilia B

• Agent
• High purity factor IX
• Recombinant human factor IX
• Dose
• Initial dose 100U/kg
• Subsequent 50U/kg every 24 hours

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Acquired bleeding disorders

• Vitamin K deficiency
• Liver disease
• Warfarin overdose
• DIC
• Inhibitors to CF

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Vitamin K deficiency
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Vitamin K deficiency

• Source of vitamin K
• Green vegetables
• Synthesized by intestinal flora
• Required for synthesis
• Factors II, VII, IX ,X
• Protein C and S
• Causes of deficiency
• Malnutrition
• Billiary obstruction
• Malabsorption
• Antibiotic therapy

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Vitamin K deficiency

• Treatment
• Vitamin K replacement
• Fresh frozen plasma

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DIC
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Disseminated Intravascular Coagulation

• Activation of both coagulation and fibrinolysis
• Triggered by

• Sepsis
• Trauma
• Head injury
• Fat embolism
• Malignancy

• Obstetrical complications
• Amniotic fluid embolism
• Abruptio placentae
• Vascular disorders
• Reaction to toxin (e.g. snake venom, drugs)
• Immunologic disorders
• Severe allergic reaction
• Transplant rejection

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Disseminated Intravascular Coagulation
(DIC)Mechanism
Systemic activation of coagulation
Depletion of platelets and coagulation factors
Intravascular deposition of fibrin Activation of
fibrinolysis
Thrombosis of small and midsize vessels tissue
hypoxia and organ failure
Bleeding
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Pathogenesis of DIC
Release of thromboplastic material
into circulation
Consumption of coagulation factors presence of
FDPs ? aPTT ? PT ? TT ? Fibrinogen Presence of
plasmin ? D-dimer Intravascular clot ?
Platelets Schistocytes
Coagulation
Fibrinolysis
Fibrinogen
Plasmin
Thrombin
Fibrin Monomers
Fibrin(ogen) Degradation Products
Fibrin Clot (intravascular)
Plasmin
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Disseminated Intravascular CoagulationTreatment
approaches

• Treatment of underlying disorder
• Anticoagulation with heparin
• Platelet transfusion
• Fresh frozen plasma
• Coagulation inhibitor concentrate (ATIII)

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Hemostasis in liver disease
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Liver Disease and Hemostasis

• Decreased synthesis of II, VII, IX, X, XI, and
  fibrinogen
• Dietary Vitamin K deficiency (Inadequate intake
  or malabsortion)
• Dysfibrinogenemia
• Enhanced fibrinolysis (Decreased
  alpha-2-antiplasmin)
• DIC
• Thrombocytopenia due to hypersplenism

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Management of Hemostatic Defects in Liver Disease

• Treatment for prolonged PT/PTT
• Vitamin K 10 mg SQ x 3 days - usually ineffective
• Fresh-frozen plasma infusion
• 25-30 of plasma volume (1200-1500 ml)
• (immediate but temporary effect)
• Treatment for low fibrinogen
• Cryoprecipitate (1 unit/10kg body

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Warfarin Toxicity
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Warfarin overdoseManaging high INR values
Clinical situation Guidelines INR
therapeutic-5 Lower or omit next dose Resume
therapy when INR is therapeutic INR 5-9 no
bleeding Lower or omit next one or two
dose Resume therapy when INR is
therapeutic Omit dose and give vitamin K (
1-2 mg po) Rapid reversal vitamin K 2-4 mg
po (repeat) INR gt9 no bleeding Omit dose
vitamin K 10 mg po repeat as necessary Resume
therapy at lower dose when INR therapeutic
Chest 2004126 213 S (supplement)
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Warfarin overdoseManaging high INR values in
bleeding patients
Clinical situation Guidelines Serious bleeding
at Any elevation INR Omit warfarin Vitami
n K 10 mg slow IV infusion Omit
warfarin Repeat vitamin K injections every 12
hrs FFP, PCC or Factor VIIa (depending on
urgency) Any life-threatening Vitamin K 10 mg
slow IV infusion PCC ( or recombinant human
factor VIIa) Repeat vitamin K injections
every 12 hrs
Chest 2004126 213 S (supplement)
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Approach to Post-operative bleeding

• Is the bleeding local or due to a hemostatic
  failure?
• Local Single site of bleeding usually rapid with
  minimal coagulation test abnormalities
• Hemostatic failure Multiple site or unusual
  pattern with abnormal coagulation tests

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Approach to Post-operative bleeding

• Evaluate for causes of peri-operative hemostatic
  failure
• Preexisting abnormality
• Special cases (e.g. Cardiopulmonmary bypass)
• Diagnosis of hemostatic failure
• Review pre-operative testing
• Obtain updated testing

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Approach to bleeding disordersSummary

• Identify and correct any specific defect of
  hemostasis
• Laboratory testing is always needed to establish
  the cause of bleeding
• Screening tests (PT,PTT, platelet count) will
  often allow placement into one of the broad
  categories
• Specialized testing is usually necessary to
  establish a specific diagnosis
• Use non-transfusional drugs whenever possible
• RBC transfusions for surgical procedures or large
  blood loss

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• THANK YOU!

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Recombinant human factor VIIa (rhVIIa Novoseven)

• Mechanism
• Direct activation of common pathway
• Use
• Factor VIII inhibitors
• Bleeding with other clotting disorders
• Warfarin overdose with bleeding
• CNS bleeding with or without warfarin
• Dose
• 90 µg/kg IV q 2 hr
• Adjust as clinically indicated
• Cost (70 kg person) - 1 per µg
• 5,000/dose or 60,000/day

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• Drugs and blood products used for
  bleeding

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Treatment Approaches tothe Bleeding Patient

• Red blood cells
• Platelet transfusions
• Fresh frozen plasma
• Cryoprecipitate
• Amicar
• DDAVP
• Recombinant Human factor VIIa

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RBC transfusion therapyIndications

• Improve oxygen carrying capacity of blood
• Bleeding
• Chronic anemia that is symptomatic
• Peri-operative management

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Red blood cell transfusionsSpecial preparation
CMV-negative CMV-negative patients Prevent CMV
transmission Irradiated RBCs Immune
deficient recipient Prevent GVHD or direct
donor Leukopoor Previous non-hemolytic Prevent
s reaction transfusion reaction CMV
negative patients Prevents transmission Wash
ed RBC PNH patients Prevents hemolysis IgA
deficient recipient Prevents anaphylaxis
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Transfusion-transmitted disease
Infectious agent Risk HIV 1/500,000 Hepatitis
C 1/600,000 Hepatitis B 1/500,000 Hepatitis
A lt1/1,000,000 HTLV I/II 1/640,000 CMV 50
donors are sero-positive Bacteria 1/250 in
platelet transfusions Creutzfeld-Jakob
disease Unknown Others Unknown
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Platelet transfusions

• Source
• Platelet concentrate (Random donor)
• Pheresis platelets (Single donor)
• Target level
• Bone marrow suppressed patient (gt10-20,000/µl)
• Bleeding/surgical patient (gt50,000/µl)

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Fresh frozen plasma

• Content - plasma (decreased factor V and VIII)
• Indications
• Multiple coagulation deficiencies (liver disease,
  trauma)
• DIC
• Warfarin reversal
• Coagulation deficiency (factor XI or VII)
• Dose (225 ml/unit)
• 10-15 ml/kg
• Note
• Viral screened product
• ABO compatible

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Cryoprecipitate

• Prepared from FFP
• Content
• Factor VIII, von Willebrand factor, fibrinogen
• Indications
• Fibrinogen deficiency
• Uremia
• von Willebrand disease
• Dose (1 unit 1 bag)
• 1-2 units/10 kg body weight

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Hemostatic drugsAminocaproic acid (Amicar)

• Mechanism
• Prevent activation plaminogen -gt plasmin
• Dose
• 50mg/kg po or IV q 4 hr
• Uses
• Primary menorrhagia
• Oral bleeding
• Bleeding in patients with thrombocytopenia
• Blood loss during cardiac surgery
• Side effects
• GI toxicity
• Thrombi formation

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Hemostatic drugsAminocaproic acid (Amicar)

• Mechanism
• Prevent activation plaminogen -gt plasmin
• Dose
• 50mg/kg po or IV q 4 hr
• Uses
• Primary menorrhagia
• Oral bleeding
• Bleeding in patients with thrombocytopenia
• Blood loss during cardiac surgery
• Side effects
• GI toxicity
• Thrombi formation

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Hemostatic drugsDesmopressin (DDAVP)

• Mechanism
• Increased release of VWF from endothelium
• Dose
• 0.3µg/kg IV q12 hrs
• 150mg intranasal q12hrs
• Uses
• Most patients with von Willebrand disease
• Mild hemophilia A
• Side effects
• Facial flushing and headache
• Water retention and hyponatremia

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Overview

• Clinical aspects of bleeding
• Hematologic disorders causing bleeding
• Coagulation factor disorders
• Platelet disorders
• Approach to laboratory abnormalities
• Diagnosis and management of
  thrombocytopenia
• Approach to acquired bleeding disorders
• Hemostasis in liver disease
• Surgical patients
• Warfarin toxicity
• Drugs and blood products used for bleeding

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Clinical Features of Bleeding Disorders

• Platelet Coagulation disorders factor
  disorders
• Site of bleeding Skin Deep in soft tissues
• Mucous membranes (joints, muscles)
• (epistaxis, gum,
• vaginal, GI tract)
• Petechiae Yes No
• Ecchymoses (bruises) Small, superficial Large,
  deep
• Hemarthrosis / muscle bleeding Extremely
  rare Common
• Bleeding after cuts scratches Yes No
• Bleeding after surgery or trauma Immediate, Delaye
  d (1-2 days),
• usually mild often severe

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Pre-analytic errors

• Problems with blue-top tube
• Partial fill tubes
• Vacuum leak and citrate evaporation
• Problems with phlebotomy
• Heparin contamination
• Wrong label
• Slow fill
• Underfill
• Vigorous shaking

• Biological effects
• Hct 55 or 15
• Lipemia, hyperbilirubinemia, hemolysis
• Laboratory errors
• Delay in testing
• Prolonged incubation at 37C
• Freeze/thaw deterioration

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Coagulation factor deficiencies

• Sex-linked recessive
• ? Factors VIII and IX deficiencies cause
  bleeding
• Prolonged PTT PT normal
• Autosomal recessive (rare)
• Factors II, V, VII, X, XI
• Fibrinogen deficiencies cause bleeding
• Prolonged PT and/or PTT
• ? Factor XIII deficiency is associated with
  bleeding and
• impaired wound healing
• PT/ PTT normal clot solubility abnormal
• ? Factor XII, prekallikrein, HMWK deficiencies
  do not cause bleeding

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Classification of platelet disorders

• Associated with bleeding
• Immune-mediated (Idiopathic) thrombocytopenic
  purpura
• Most others

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Classification of platelet disorders

• Associated with thrombosis
• Thrombotic thrombocytopenic purpura
• Heparin-induced thrombocytopenia
• Trousseaus syndrome
• DIC

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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 1/60,000 males
Severity Related to factor level lt1
- Severe - spontaneous bleeding 1-5 -
Moderate - bleeding with mild injury 5-25 -
Mild - bleeding with surgery or trauma
Complications Soft tissue
bleeding
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Treatment of hemophilia A

• Intermediate purity plasma products
• Virucidally treated
• May contain von Willebrand factor
• High purity (monoclonal) plasma products
• Virucidally treated
• No functional von Willebrand factor
• Recombinant factor VIII
• Virus free/No apparent risk
• No functional von Willebrand factor

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Complications of therapy

• Formation of inhibitors (antibodies)
• 10-15 of severe hemophilia A patients
• 1-2 of severe hemophilia B patients
• Viral infections
• Hepatitis B Human parvovirus
• Hepatitis C Hepatitis A
• HIV Other

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Features of Acute and Chronic ITP
Features Acute Chronic Peak
age Children (2-6 yrs) Adults (20-40
yrs) Femalemale 11 31 Antecedent
infection Common Rare Onset of
symptoms Abrupt indolent Platelet
count at presentation lt20,000 lt50,000 Duration
2-6 weeks Long-term Spontaneous
remission Common Uncommon
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