Bleeding Bleeding DisordersDisordersMeera ShreedharaMeera Shreedhara
8/25/088/25/08
What is it?What is it?
A bleeding disorder is an acquired or A bleeding disorder is an acquired or inherited tendency to bleed inherited tendency to bleed excessivelyexcessively
Mechanisms of bleedingMechanisms of bleeding
Vascular IntegrityVascular Integrity PlateletsPlatelets Clotting factorsClotting factors FibrinolysisFibrinolysis
Derangement of any of these factors Derangement of any of these factors can cause abnormal bleedingcan cause abnormal bleeding
Key to diagnosisKey to diagnosis
HistoryHistory HistoryHistory HistoryHistory
Bleeding historyBleeding history EpistaxisEpistaxis Gingival hemorrhageGingival hemorrhage Mucosal BleedingMucosal Bleeding Heavy MensesHeavy Menses Child birthChild birth Easy bruisabilityEasy bruisability Bleeding following tooth extractionsBleeding following tooth extractions HematomasHematomas Bleeding following surgeryBleeding following surgery HemarthrosisHemarthrosis
Medication HistoryMedication History
AspirinAspirin WarfarinWarfarin NSAIDSNSAIDS B- Lactam antibioticsB- Lactam antibiotics Clopidogrel and other antiplatelet Clopidogrel and other antiplatelet
agentsagents Herbal medications.Herbal medications.
Nutritional historyNutritional history
Vit K deficiencyVit K deficiency Vit C deficiencyVit C deficiency Broad spectrum antibioticsBroad spectrum antibiotics
Clinical Characterisitc
Platelet defectClotting factor deficiency
Site of bleedingSkin, 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
HistoryHistory
Should the pt undergo a limited or Should the pt undergo a limited or extensive workup?extensive workup?
Is this acquired or hereditary?Is this acquired or hereditary? Is this likely a disorder of clotting Is this likely a disorder of clotting
factors,platelets, fibrinolysis or vWF?factors,platelets, fibrinolysis or vWF? Do medications or intercurrent Do medications or intercurrent
illnesses play a role?illnesses play a role? What is the immediate cause for What is the immediate cause for
which a workup is being done?which a workup is being done?
HereditaryHereditary Deficiency of coagulation factorsDeficiency of coagulation factors
HemophiliaHemophilia Fibrinogen deficiencyFibrinogen deficiency Von Willebrand diseaseVon Willebrand disease
Platelet disordersPlatelet disorders Glanzmann thrombastheniaGlanzmann thrombasthenia Bernard-Soulier syndromeBernard-Soulier syndrome Platelet granule disordersPlatelet granule disorders
Fibrinolytic disordersFibrinolytic disorders Alpha 2 antiplasmin deficiencyAlpha 2 antiplasmin deficiency PAI 1 deficiencyPAI 1 deficiency
Structural disordersStructural disorders Hemorrhagic TelangiectasiasHemorrhagic Telangiectasias Ehler Danlos syndromeEhler Danlos syndrome
AcquiredAcquired
ThrombocytopenisThrombocytopenis Liver diseaseLiver disease Renal failureRenal failure Vit K deficiencyVit K deficiency Acquired antibodies to coagulation Acquired antibodies to coagulation
factorsfactors DICDIC DrugsDrugs VascularVascular
Lab testingLab testing Platelet countPlatelet count Bleeding time-Measure of the Bleeding time-Measure of the
interaction of platelets with the blood interaction of platelets with the blood vessel wall. vessel wall. Thrombocytopenia (platelet count usually Thrombocytopenia (platelet count usually
below 50,000/microL), below 50,000/microL), Qualitative platelet abnormalities (eg, Qualitative platelet abnormalities (eg,
uremia), uremia), von Willebrand disease (VWD), von Willebrand disease (VWD), Vascular purpura, Vascular purpura, Severe fibrinogen deficiency Severe fibrinogen deficiency
Platelet function assayPlatelet function assay Expose platelets within citrated whole blood to high Expose platelets within citrated whole blood to high
shear (5,000 to 6,000/sec) within a capillary tube shear (5,000 to 6,000/sec) within a capillary tube and monitor the drop in flow rate as the platelets and monitor the drop in flow rate as the platelets form a hemostatic plug within the center of a form a hemostatic plug within the center of a membrane coated with collagen and either ADP or membrane coated with collagen and either ADP or epinephrine epinephrine
Abnormal closure times are an indication of platelet Abnormal closure times are an indication of platelet dysfunction, they are not specific for any disorder dysfunction, they are not specific for any disorder
The test is coagulation factor independent The test is coagulation factor independent PFA-100™ is more sensitive (>70 percent) than the PFA-100™ is more sensitive (>70 percent) than the
bleeding time (20 to 30 percent) in detecting all bleeding time (20 to 30 percent) in detecting all subtypes of von Willebrand's disease (vWD) subtypes of von Willebrand's disease (vWD)
Exception is type 2N vWD, in which the hemostatic Exception is type 2N vWD, in which the hemostatic defect resides in the Factor VIII binding site on vWF defect resides in the Factor VIII binding site on vWF
Platelet function assayPlatelet function assay
Collagen/epinephrine closure time Collagen/epinephrine closure time (CEPI-CT)- Abnormal in Aspirin (CEPI-CT)- Abnormal in Aspirin intakeintake
Collagen/adenosine diphosphate Collagen/adenosine diphosphate (CADT-CT)-Normal in aspirin intake (CADT-CT)-Normal in aspirin intake
Prothrombin timeProthrombin time
Measure of the extrinsic pathway Measure of the extrinsic pathway and common pathwayand common pathway
Bypasses the intrinsic pathway and Bypasses the intrinsic pathway and uses thromboplastins to substitute uses thromboplastins to substitute for platelets for platelets
Within the combined pathway, Within the combined pathway, factors VII, X, and prothrombin are factors VII, X, and prothrombin are vitamin-K dependent and are altered vitamin-K dependent and are altered by warfarinby warfarin
Prolonged PTProlonged PT
Vitamin K deficiency Vitamin K deficiency Liver disease, which decreases the Liver disease, which decreases the
synthesis of both vitamin K-dependent and -synthesis of both vitamin K-dependent and -independent clotting factors. independent clotting factors.
Deficiency or inhibition of factors VII, X, II Deficiency or inhibition of factors VII, X, II (prothrombin), V, or fibrinogen(prothrombin), V, or fibrinogen
The infrequent antiphospholipid antibodies The infrequent antiphospholipid antibodies (lupus anticoagulant phenomenon) with (lupus anticoagulant phenomenon) with antiprothrombin activityantiprothrombin activity
Heparin does NOT prolong the PT Heparin does NOT prolong the PT
aPTTaPTT Measures the intrinsic and common Measures the intrinsic and common
pathways of coagulationpathways of coagulation Uses partial thromboplastins; they are Uses partial thromboplastins; they are
incapable of activating the extrinsic incapable of activating the extrinsic pathway pathway
Prolonged in deficiency of, or an inhibitor Prolonged in deficiency of, or an inhibitor to, any of the clotting factors except for to, any of the clotting factors except for factor VII factor VII
Prolonged in the presence of Lupus Prolonged in the presence of Lupus Anticoagulant.Anticoagulant.
Used to monitor heparin activityUsed to monitor heparin activity
Thrombin timeThrombin time
Measure conversion of fibrinogen to Measure conversion of fibrinogen to fibrin monomers and the formation fibrin monomers and the formation of initial clot by thrombinof initial clot by thrombin
Hypofibrinogenemia, Hypofibrinogenemia, DysfibrinogensDysfibrinogens Increased fibrin split products Increased fibrin split products Heparin increases TT but not RTHeparin increases TT but not RT
Factor deficiencies/ Factor deficiencies/ inhibitorsinhibitors
A prolonged aPTT can be due to a deficiency A prolonged aPTT can be due to a deficiency (or absence) of a coagulation factor or the (or absence) of a coagulation factor or the presence of a coagulation factor inhibitor presence of a coagulation factor inhibitor
Mixing studies help differentiate thisMixing studies help differentiate this Lupus anticoagulants can result in a Lupus anticoagulants can result in a
prolonged aPTT that is not correctable by the prolonged aPTT that is not correctable by the addition of normal plasmaaddition of normal plasma
Overcome by adding excess platelet Overcome by adding excess platelet phospholipid (particularly a hexagonal phase phospholipid (particularly a hexagonal phase phospholipid) or by assessing the diluted phospholipid) or by assessing the diluted Russell's viper venom time Russell's viper venom time
FibrinolysisFibrinolysis
Fibrin and Fibrin and fibrinogen fibrinogen degradation degradation products (FDP) products (FDP) are protein are protein fragments fragments resulting from the resulting from the action of plasmin action of plasmin on fibrin or on fibrin or fibrinogenfibrinogen
FibrinolysisFibrinolysis
FDP assays do not differentiate FDP assays do not differentiate between fibrin degradation products between fibrin degradation products and fibrinogen degradation products and fibrinogen degradation products
Fibrin D-dimers are degradation Fibrin D-dimers are degradation products of cross-linked fibrin products of cross-linked fibrin
D-dimers specifically reflect D-dimers specifically reflect fibrinolysis of cross-linked fibrin (ie, fibrinolysis of cross-linked fibrin (ie, the fibrin clot) – so are more reliable the fibrin clot) – so are more reliable indicators of thrombosisindicators of thrombosis
FibrinolysisFibrinolysis
Assays for plasminogen, Assays for plasminogen, Tissue plasminogen activator (t-PA), Tissue plasminogen activator (t-PA), Alpha-2 antiplasmin, Alpha-2 antiplasmin, Plasminogen activator inhibitor-1 Plasminogen activator inhibitor-1
(PAI-1),(PAI-1), Thrombin-activatable fibrinolysis Thrombin-activatable fibrinolysis
inhibitor (TAFI). inhibitor (TAFI).
Normal PT and PTTNormal PT and PTT
ThrombocytopeniaThrombocytopenia vWDvWD Factor 13 deficiencyFactor 13 deficiency Platelet dysfunctionPlatelet dysfunction Vascular purpurasVascular purpuras Psychogenic purpuraPsychogenic purpura
Normal PT and Normal PT and Prolonged aPTTProlonged aPTT
Hemophilia AHemophilia A Hemophilia BHemophilia B Factor XI deficiencyFactor XI deficiency Factor VIII inhibitorFactor VIII inhibitor
Malignancy,Malignancy, Clonal lymphoproliferative disorders, Clonal lymphoproliferative disorders, Pregnancy, Pregnancy, Rheumatologic disorders Rheumatologic disorders
Prolonged PT and normal Prolonged PT and normal aPTTaPTT
Factor VII deficiencyFactor VII deficiency Warfarin therapyWarfarin therapy Early liver diseaseEarly liver disease Early DICEarly DIC
Prolonged PT and PTTProlonged PT and PTT
Vit K deficiencyVit K deficiency Liver diseaseLiver disease Warfarin treatmentWarfarin treatment Acquired inhibitor to factor VAcquired inhibitor to factor V Factor X deficiency- seen in Factor X deficiency- seen in
AmyloidosisAmyloidosis DICDIC
Acute Promyelocytic Acute Promyelocytic LeukemiaLeukemia
DIC is often seen at presentation or during DIC is often seen at presentation or during treatmenttreatment
Medical Emergency as Cerebral hemorrhage Medical Emergency as Cerebral hemorrhage can occur in upto 4% of untreated ptscan occur in upto 4% of untreated pts
Promyelocytes seen on smearPromyelocytes seen on smear Reciprocal translocation between the long Reciprocal translocation between the long
arms of chromosomes 15 and 17, with the arms of chromosomes 15 and 17, with the creation of a fusion gene, PML/RAR-alphacreation of a fusion gene, PML/RAR-alpha
Immediate initiation of ATRA induces de Immediate initiation of ATRA induces de deifferentiation deifferentiation
HemophiliaHemophilia
Hemophilia A and B are X-linked Hemophilia A and B are X-linked recessive diseases recessive diseases
Severe disease <1 % factor activity, Severe disease <1 % factor activity, Moderate disease- 1 to 5 % Moderate disease- 1 to 5 % Mild disease >5 %Mild disease >5 % The most common sites are into The most common sites are into
joints and muscles and from the joints and muscles and from the gastrointestinal tract gastrointestinal tract
TreatmentTreatment
The two components to therapy are The two components to therapy are treatment of active bleeding and inhibitor treatment of active bleeding and inhibitor ablation via immune tolerance induction ablation via immune tolerance induction
Cryoprecipitate has high levels of factor Cryoprecipitate has high levels of factor VIIIVIII
Porcine Factor VIIIPorcine Factor VIII Recombinant human Factor VIIIRecombinant human Factor VIII The choice of factor VIII product usually is The choice of factor VIII product usually is
based upon safety, purity, and cost. based upon safety, purity, and cost.
DosingDosing
One international unit (IU) of One international unit (IU) of clotting factor is that amount clotting factor is that amount present in 1 mL of pooled normal present in 1 mL of pooled normal plasma plasma
Dose of F VIII (IU) = Weight (kg) x Dose of F VIII (IU) = Weight (kg) x (Desired % increase) x 0.5 (Desired % increase) x 0.5
Depends on the clinical indication Depends on the clinical indication and the presence of inhibitorsand the presence of inhibitors
von Willebrand’s diseasevon Willebrand’s disease Most common of the inherited bleeding Most common of the inherited bleeding
disorders disorders In 1926, Erik von Willebrand described In 1926, Erik von Willebrand described
the first patient with the disease the first patient with the disease Von Willebrand factor (VWF) binds to Von Willebrand factor (VWF) binds to
both platelets and endothelial both platelets and endothelial components, forming an adhesive bridge components, forming an adhesive bridge between platelets and vascular between platelets and vascular subendothelial structures and between subendothelial structures and between adjacent platelets at sites of endothelial adjacent platelets at sites of endothelial injury injury
Acquired von Willebrand’s Acquired von Willebrand’s diseasedisease
Malignant diseasesMalignant diseases Monoclonal gammopathy Monoclonal gammopathy
of unknown significanceof unknown significance Multiple MyelomaMultiple Myeloma Non-Hodgkin's Non-Hodgkin's
lymphomalymphoma Chronic lymphocytic Chronic lymphocytic
leukemialeukemia Waldenstrom's Waldenstrom's
macroglobulinemiamacroglobulinemia Essential Essential
thrombocythemiaPolycytthrombocythemiaPolycythemia verahemia vera
Chronic myelogenous Chronic myelogenous leukemialeukemia
Wilms tumorWilms tumor Other carcinomasOther carcinomas
Immunologic disordersImmunologic disorders Systemic lupus Systemic lupus
erythematosuserythematosus Other autoimmune Other autoimmune
diseases diseases Other disordersOther disorders
HypothyroidismHypothyroidism Ventricular septal defectVentricular septal defect Aortic stenosisAortic stenosis Mitral valve prolapseMitral valve prolapse Gastrointestinal Gastrointestinal
angiodyplasiaangiodyplasia UremiaUremia HemoglobinopathiesHemoglobinopathies
Drugs and other agentsDrugs and other agents Valproic acidValproic acid AntibioticsAntibiotics
TreatmentTreatment
DDAVPDDAVP Replacement of vWFReplacement of vWF EACAEACA Tranexamic acidTranexamic acid Recombinant factor 7 Recombinant factor 7
Its better to Its better to bleed than clot!bleed than clot!
Therapies other than factor Therapies other than factor replacementreplacement
DDAVPDDAVP EACAEACA Tranexamic AcidTranexamic Acid Factor 7 inhibitor- NovosevenFactor 7 inhibitor- Novoseven
Liver disease Vs DICLiver disease Vs DIC
Low factor V levels can be used as Low factor V levels can be used as evidence for either reduced hepatic evidence for either reduced hepatic synthetic function or increased synthetic function or increased consumption, as in DIC consumption, as in DIC
Factor VIII is not manufactured by Factor VIII is not manufactured by hepatocytes; factor VIII levels are hepatocytes; factor VIII levels are usually normal or increased in liver usually normal or increased in liver disease disease