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