Bleeding Disorders

What is it?

 A bleeding disorder is an acquired or inherited

tendency to bleed excessively
 Mechanisms of bleeding

 Vascular Integrity
 Platelets
 Clotting factors
 Fibrinolysis

 Derangement of any of these factors can cause

abnormal bleeding
 Key to diagnosis

 History
 History
 History
 Bleeding history
 Epistaxis
 Gingival hemorrhage
 Mucosal Bleeding
 Heavy Menses
 Child birth
 Easy bruisability
 Bleeding following tooth extractions
 Hematomas
 Bleeding following surgery
 Hemarthrosis
 Medication History

 Aspirin
 Warfarin
 NSAIDS
 B- Lactam antibiotics
 Clopidogrel and other antiplatelet agents
 Herbal medications.
 Nutritional history

 Vit K deficiency
 Vit C deficiency
 Broad spectrum antibiotics
Clinical Clotting factor
Platelet defect
Characterisitc deficiency

Deep in soft
Skin, mucous membranes (gingivae,
Site of bleeding tissues (joints,
nares, GI and genitourinary tracts)
muscles)
Bleeding after
Yes Not usually
minor cuts

Petechiae Present Absent

Ecchymoses Small, superficial Large, palpable

Hemarthroses,
muscle Rare Common
hematomas
Bleeding after
Immediate, mild Delayed, severe
surgery
 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?
 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
 Acquired

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

 Collagen/epinephrine closure time (CEPI-CT)-

Abnormal in Aspirin intake
 Collagen/adenosine diphosphate (CADT-CT)-
Normal in aspirin intake
 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
 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
 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
 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
 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

 Fibrinolysis

 Fibrin and fibrinogen

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

 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

 Thrombocytopenia
 vWD
 Factor 13 deficiency
 Platelet dysfunction
 Vascular purpuras
 Psychogenic purpura
Normal PT and Prolonged aPTT

 Hemophilia A
 Hemophilia B
 Factor XI deficiency
 Factor VIII inhibitor
 Malignancy,
 Clonal lymphoproliferative disorders,

 Pregnancy,

 Rheumatologic disorders
Prolonged PT and normal aPTT

 Factor VII deficiency

 Warfarin therapy
 Early liver disease
 Early DIC
 Prolonged PT and PTT

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

 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

 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

 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

 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
 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
 Treatment

 DDAVP
 Replacement of vWF
 EACA
 Tranexamic acid
 Recombinant factor 7
Its better to bleed than
clot!
 Therapies other than factor
replacement
 DDAVP
 EACA
 Tranexamic Acid
 Factor 7 inhibitor- Novoseven
 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