Transcript Bleeding Disorders

Bleeding Disorders
Meera Shreedhara
8/25/08
What is it?
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A bleeding disorder is an acquired or inherited
tendency to bleed excessively
Mechanisms of bleeding
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Vascular Integrity
Platelets
Clotting factors
Fibrinolysis
Derangement of any of these factors can cause
abnormal bleeding
Key to diagnosis
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History
History
History
Bleeding history
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Epistaxis
Gingival hemorrhage
Mucosal Bleeding
Heavy Menses
Child birth
Easy bruisability
Bleeding following tooth extractions
Hematomas
Bleeding following surgery
Hemarthrosis
Medication History
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Aspirin
Warfarin
NSAIDS
B- Lactam antibiotics
Clopidogrel and other antiplatelet agents
Herbal medications.
Nutritional history
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Vit K deficiency
Vit C deficiency
Broad spectrum antibiotics
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
History
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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?
Hereditary
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Deficiency of coagulation factors
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Platelet disorders
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Glanzmann thrombasthenia
Bernard-Soulier syndrome
Platelet granule disorders
Fibrinolytic disorders
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Hemophilia
Fibrinogen deficiency
Von Willebrand disease
Alpha 2 antiplasmin deficiency
PAI 1 deficiency
Structural disorders
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Hemorrhagic Telangiectasias
Ehler Danlos syndrome
Acquired
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Thrombocytopenis
Liver disease
Renal failure
Vit K deficiency
Acquired antibodies to coagulation factors
DIC
Drugs
Vascular
Lab testing
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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
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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 (>70 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
Platelet function assay
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Collagen/epinephrine closure time (CEPI-CT)Abnormal in Aspirin intake
Collagen/adenosine diphosphate (CADT-CT)Normal in aspirin intake
Prothrombin time
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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
Prolonged PT
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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
aPTT
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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
Thrombin time
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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
Factor deficiencies/ inhibitors
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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
Fibrinolysis
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Fibrin and fibrinogen
degradation products
(FDP) are protein
fragments resulting
from the action of
plasmin on fibrin or
fibrinogen
Fibrinolysis
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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
Fibrinolysis
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Assays for plasminogen,
Tissue plasminogen activator (t-PA),
Alpha-2 antiplasmin,
Plasminogen activator inhibitor-1 (PAI-1),
Thrombin-activatable fibrinolysis inhibitor
(TAFI).
Normal PT and PTT
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Thrombocytopenia
vWD
Factor 13 deficiency
Platelet dysfunction
Vascular purpuras
Psychogenic purpura
Normal PT and Prolonged aPTT
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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
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Factor VII deficiency
Warfarin therapy
Early liver disease
Early DIC
Prolonged PT and PTT
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Vit K deficiency
Liver disease
Warfarin treatment
Acquired inhibitor to factor V
Factor X deficiency- seen in Amyloidosis
DIC
Acute Promyelocytic Leukemia
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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
Hemophilia
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Hemophilia A and B are X-linked recessive
diseases
Severe disease <1 % factor activity,
Moderate disease- 1 to 5 %
Mild disease >5 %
The most common sites are into joints and
muscles and from the gastrointestinal tract
Treatment
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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.
Dosing
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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
von Willebrand’s disease
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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
Acquired von Willebrand’s disease
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Malignant diseases
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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
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Immunologic disorders
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Other disorders
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Systemic lupus erythematosus
Other autoimmune diseases
Hypothyroidism
Ventricular septal defect
Aortic stenosis
Mitral valve prolapse
Gastrointestinal angiodyplasia
Uremia
Hemoglobinopathies
Drugs and other agents
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Valproic acid
Antibiotics
Treatment
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DDAVP
Replacement of vWF
EACA
Tranexamic acid
Recombinant factor 7
Its better to bleed than
clot!
Therapies other than factor
replacement
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DDAVP
EACA
Tranexamic Acid
Factor 7 inhibitor- Novoseven
Liver disease Vs DIC
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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