Bleeding Disorders Jaya V Juturi, MD Texas Oncology, PA

Bleeding DisordersBleeding Disorders

Jaya V Juturi, MDJaya V Juturi, MD

Texas Oncology, PATexas Oncology, PA

HEMOSTASISHEMOSTASISRegulating factorsRegulating factors

Vessel Wall IntegrityVessel Wall Integrity

Adequate Numbers of PlateletsAdequate Numbers of Platelets

Proper Functioning PlateletsProper Functioning Platelets

Adequate Levels of Clotting FactorsAdequate Levels of Clotting Factors

Proper Function of Fibrinolytic PathwayProper Function of Fibrinolytic Pathway

HEMOSTASIS

1. VASCULAR PHASE

2. PLATELET PHASE

3. COAGULATION PHASE

4. FIBRINOLYTIC PHASE

VASCULAR PHASEVASCULAR PHASE

WHEN A BLOOD VESSEL IS WHEN A BLOOD VESSEL IS DAMAGED, VASOCONSTRICTION DAMAGED, VASOCONSTRICTION

RESULTS.RESULTS.

Vascular wallVascular wall ( Endothelium) ( Endothelium)

AntithromboticAntithrombotic propertiesproperties

– Antiplatelet effectsAntiplatelet effects

– Anticoagulant propertiesAnticoagulant properties

– Fibrinolytic propertiesFibrinolytic properties

ProthromboticProthrombotic properties properties

– Von Willebrand factorVon Willebrand factor

– Tissue factorTissue factor

– Fibrinolysis inhibitorsFibrinolysis inhibitors

HEMOSTASIS

1. VASCULAR PHASE

2. PLATELET PHASE

3. COAGULATION PHASE


PLATELET PHASEPLATELET PHASE

PLATELET PHASEPLATELET PHASE

Glanzmann’s

From Henry’s Clinical Diagnosis and Management by Laboratory Methods, McPherson and Pincus, eds, Saunders Elsevier, 2006.

Platelet Activation MechanismsPlatelet Activation Mechanisms

Platelet PlugPlatelet Plug Initial hemostatic response at the site of injuryInitial hemostatic response at the site of injury

Adhesion – deposition of platelets on the subendothelial Adhesion – deposition of platelets on the subendothelial matrix with vWf. (GP Ib)matrix with vWf. (GP Ib)

Aggregation – platelet-platelet cohesion with GP IIb/IIIa Aggregation – platelet-platelet cohesion with GP IIb/IIIa (ADP mediated, calcium facilitated)(ADP mediated, calcium facilitated)

Secretion – release of granule proteinsSecretion – release of granule proteins

Procoagulant – enhancement of thrombin generationProcoagulant – enhancement of thrombin generation

PLATELETS ADHERE TO THE DAMAGED SURFACE AND FORM PLATELETS ADHERE TO THE DAMAGED SURFACE AND FORM A TEMPORARY PLUG.A TEMPORARY PLUG.

HEMOSTASIS

1.VASCULAR PHASE

2.PLATELET PHASE

3.COAGULATION PHASE


COAGULATION PHASECOAGULATION PHASE

THROUGH TWO SEPARATE PATHWAYS THROUGH TWO SEPARATE PATHWAYS THE CONVERSION OF FIBRINOGEN TO THE CONVERSION OF FIBRINOGEN TO

FIBRIN IS COMPLETE.FIBRIN IS COMPLETE.

THE CLOTTING MECHANISMINTRINSIC EXTRINSIC

PROTHROMBIN THROMBIN

FIBRINOGEN

FIBRIN(II) (III)

(I)V

X

Tissue Thromboplastin

Collagen

VII

XII

XI

IXVIII

Coagulation cascadeCoagulation cascade

Vitamin K dependant factorsVitamin K dependant factors

XIIaXIIa

IIa

Intrinsic system Intrinsic system (surface contact)(surface contact)

XIIXII

XIXI XIa

Tissue factorTissue factor

IXIX IXa VIIa VIIVII

VIIIVIII VIIIaVIIIa

Extrinsic system Extrinsic system (tissue damage)(tissue damage)

XX

VV VaVa

IIII

FibrinogenFibrinogen FibrinFibrin

(Thrombin)(Thrombin)IIa

Xa

Factors produced in the Factors produced in the liverliver

Prothrombin Factor XIProthrombin Factor XI Factor V Factor XIIFactor V Factor XII Factor VII PrekallikreinFactor VII Prekallikrein Factor IX HMWKFactor IX HMWK Factor X Factor XIIIFactor X Factor XIII Fibrinogen Protein CFibrinogen Protein C AT IIIAT III

HEMOSTASIS

1.VASCULAR PHASE

2.PLATELET PHASE

3.COAGULATION PHASE


FIBRINOLYTIC PHASEFIBRINOLYTIC PHASE

ANTICLOTTING MECHANISMS ARE ANTICLOTTING MECHANISMS ARE ACTIVATED TO ALLOW CLOT ACTIVATED TO ALLOW CLOT

DISINTEGRATION AND REPAIR OF DISINTEGRATION AND REPAIR OF THE DAMAGED VESSEL.THE DAMAGED VESSEL.

Approach to a bleeding Approach to a bleeding disorderdisorder

HistoryHistory– Very importantVery important– Duration of Duration of

symptomssymptoms– When do they occurWhen do they occur– Prior trauma/surgeryPrior trauma/surgery– Other medical Other medical

conditionsconditions– Family historyFamily history

Medication usageMedication usage

ExaminationExamination– PetechiaePetechiae– EcchymosisEcchymosis

LabsLabs– CBC with smearCBC with smear– PTPT– PTTPTT– Thrombin timeThrombin time– FibrinogenFibrinogen– Platelet function Platelet function

assayassay

REVIEW PATIENT’S MEDSREVIEW PATIENT’S MEDS

FIVE DRUGSFIVE DRUGS THAT INTERFERE WITH THAT INTERFERE WITH HEMOSTASISHEMOSTASIS

ASPIRINASPIRIN ANTICOAGULANTSANTICOAGULANTS ANTIBIOTICSANTIBIOTICS ALCOHOLALCOHOL ANTICANCERANTICANCER

Diagnosis of Bleeding Diagnosis of Bleeding DisorderDisorder

HistoryHistory Neonatal bleedingNeonatal bleeding Bleeding after circumscisionBleeding after circumscision Delayed bleeding from umbilical stump (factor XIII)Delayed bleeding from umbilical stump (factor XIII) Deep hamatoma after IM injectionsDeep hamatoma after IM injections Epistaxis Epistaxis Dental extraction, tonsils, adenoidsDental extraction, tonsils, adenoids Site of bleeding: skin, mucous membranes, jointsSite of bleeding: skin, mucous membranes, joints Family history of bleeding disordersFamily history of bleeding disorders Drug exposureDrug exposure The presence of conditions causing bleeding: SLE, The presence of conditions causing bleeding: SLE,

nephrosis, hypothyroidism, Ehler Danlosnephrosis, hypothyroidism, Ehler Danlos

Primary Vs Secondary Defect: Primary Vs Secondary Defect: Clinical Manifestations Clinical Manifestations

Normal Peripheral SmearNormal Peripheral Smear


Platelet lumi-Platelet lumi-aggregation: aggregation: Examples of Examples of

Normal and of Normal and of Glanzmann Glanzmann

ThrombasthenThrombastheniaia

Overview of Common Coagulation Overview of Common Coagulation TestsTests


PetechiaePetechiae

Do not blanch with Do not blanch with pressure, Not pressure, Not

palpablepalpable

ORAL MANIFESTATIONSORAL MANIFESTATIONS

Petechiae & Ecchymosis Petechiae & Ecchymosis

Gingival Hyperplasia Gingival Hyperplasia

Spontaneous Gingival BleedingSpontaneous Gingival Bleeding

Ulceration of Oral MucosaUlceration of Oral Mucosa

LymphadenopathyLymphadenopathy

Copyright ©2008 American Society of Hematology. Copyright restrictions may apply.

Maslak, P. ASH Image Bank 2008;2008:8-00089

Figure 1. This picture demonstrates petechiae in dependent areas of a thrombocytopenic patient with AML

LABORATORY EVALUATIONLABORATORY EVALUATION

PLATELET COUNTPLATELET COUNT

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

PARTIAL THROMBOPLASTIN TIME (PTT)PARTIAL THROMBOPLASTIN TIME (PTT)

THROMBIN TIME (TT)THROMBIN TIME (TT)

FIBRINOGENFIBRINOGEN


Maslak, P. ASH Image Bank 2004;2004:101214

Figure 1. Review of the peripheral smear reveals a paucity of platelets

THROMBIN TIME

Time for Thrombin To Convert

Fibrinogen Fibrin A Measure of Fibrinolytic Pathway

NORMAL VALUENORMAL VALUE

9-13 SECS9-13 SECS

Initial Evaluation of a Bleeding Patient - 1Initial Evaluation of a Bleeding Patient - 1

Normal PTNormal PTT

Consider evaluating for: Mild factor deficiency Monoclonal gammopathy Abnormal fibrinolysis Platelet disorder (2 anti-plasmin def) Vascular disorder Elevated FDPs

Ureasolubility

Normal

Abnormal

Factor XIIIdeficiency

Normal PTAbnormal PTT

Test for factor deficiency: Isolated deficiency in intrinsic pathway (factors VIII, IX, XI) Multiple factor deficiencies (rare)

Repeatwith

50:50mix

50:50 mix is normal

50:50 mix is abnormal

Test for inhibitor activity: Specific factors: VIII,IX, XI Non-specific (anti-phospholipid Ab)


Abnormal PTNormal PTT

Test for factor deficiency: Isolated deficiency of factor VII (rare) Multiple factor deficiencies (common) (Liver disease, vitamin K deficiency, warfarin, DIC)

Repeatwith

50:50mix

50:50 mix is normal


Test for inhibitor activity: Specific: Factor VII (rare) Non-specific: Anti-phospholipid (rare)


Abnormal PTAbnormal PTT

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)

Repeatwith

50:50mix

50:50 mix is normal


Test for inhibitor activity: Specific : Factors V, X, Prothrombin,

fibrinogen (rare) Non-specific: anti-phospholipid (common)

Coagulation factor deficienciesCoagulation factor deficienciesSummarySummary

Sex-linked recessiveSex-linked recessive Factors VIII and IX deficiencies cause bleedingFactors VIII and IX deficiencies cause bleeding

Prolonged Prolonged PTT; PTT; PT normalPT normal

Autosomal recessive Autosomal recessive (rare)(rare) Factors II, V, VII, X, XI, fibrinogen deficiencies cause bleedingFactors II, V, VII, X, XI, fibrinogen deficiencies cause bleeding

Prolonged Prolonged PTPT and/or and/or PTTPTT

Factor XIII deficiency is associated with bleeding andFactor XIII deficiency is associated with bleeding andimpaired wound healingimpaired wound healing

PT/ PTT normal; PT/ PTT normal; clot solubilityclot solubility abnormal abnormal

Factor XII, prekallikrein, HMWK deficienciesFactor XII, prekallikrein, HMWK deficienciesdo not cause bleedingdo not cause bleeding

Bleeding disorders

Vascular abnormalities

Platelet disordersClotting factorabnormalities

DIC

PathologyPathology

Vascular abnormalitiesVascular abnormalities CausesCauses

– InfectionsInfections Meningococcemia, Rickettsioses , Infective endocarditisMeningococcemia, Rickettsioses , Infective endocarditis

– Drug reactionsDrug reactions

– Hereditary hemorrhagic telangiectasiaHereditary hemorrhagic telangiectasia Autosomal dominant Autosomal dominant

– Cushing syndromeCushing syndrome

– Henoch - Schönlein PurpuraHenoch - Schönlein Purpura systemic hypersensitivity disease of unknown cause systemic hypersensitivity disease of unknown cause polyarthralgia, and acute Glomerulonephritis polyarthralgia, and acute Glomerulonephritis Palpable purpuric rash, colicky abdominal pain Palpable purpuric rash, colicky abdominal pain

– Scurvy and the Ehlers-Danlos syndromeScurvy and the Ehlers-Danlos syndrome

– Amyloid infiltration of blood vessels Amyloid infiltration of blood vessels

Bleeding disorders


***Platelet disorders

Clotting factorabnormalities

DIC

Bleeding disorders

Platelet disorders

↓production ↑destruction

SequestrationHypersplenism

Primary/IdiopathicITP

Acute/Chronic

SecondaryDrugs, HIV

Immune Thrombocytopenic Immune Thrombocytopenic Purpura (ITP)Purpura (ITP)

CauseCause– Antiplatelet antibodies Antiplatelet antibodies – Antigen - platelet membrane glycoprotein complexes IIb-IIIa Antigen - platelet membrane glycoprotein complexes IIb-IIIa

and Ib-IXand Ib-IX MorphologyMorphology

– Peripheral BloodPeripheral Blood thrombocytopenia, abnormally large platelets (megathrombocytes thrombocytopenia, abnormally large platelets (megathrombocytes

or Giant platelets),or Giant platelets),– MarrowMarrow

Normal or Increased magakaryocyte #Normal or Increased magakaryocyte # Diagnosis - by exclusion, normal PT and PTTDiagnosis - by exclusion, normal PT and PTT

DiagnosisDiagnosis

Exclude other causesExclude other causes Evaluate for other syndromesEvaluate for other syndromes

– SLESLE– APSAPS– LymphomasLymphomas– HIVHIV

Look at peripheral blood smearLook at peripheral blood smear– Pseudothrombocytopenia, hemolysis, Pseudothrombocytopenia, hemolysis,

large plateletslarge platelets

ITPITP

FeatureFeature AcuteAcute ChronicChronicAge / SexAge / Sex ChildrenChildren Adult/FemaleAdult/Female

OnsetOnset AbruptAbrupt GradualGradual

Predisposing Predisposing FactorsFactors

Viral infection/ Viral infection/ vaccinevaccine

--

DurationDuration <2 months<2 months >6mnoths>6mnoths

PathogenesisPathogenesis -- IgG against IgG against Platelet GPPlatelet GP

Peripheral Peripheral smearsmear

ThrombocytopenThrombocytopenia & Giant PLTSia & Giant PLTS

SameSame

Bone marrowBone marrow Normal or Normal or ↑Megakaryocyte↑Megakaryocytess

SameSame

ITPITP

FeatureFeature AcuteAcute ChronicChronicTestsTests Normal PT & Normal PT &

PTTPTTSameSame

Complication Complication (most (most dangerous)dangerous)

Intracranial Intracranial bleedbleed

SameSame

Clinical courseClinical course Spontaneous Spontaneous remissionremission

NoNo

TreatmentTreatment PLT. PLT. Transfusion/treatTransfusion/treat SplenectomySplenectomy

If <20,000If <20,000

NoNoIf <50,000If <50,000

Yes (refractory Yes (refractory cases)cases)

TreatmentTreatment

No need to treat if platelet count No need to treat if platelet count above 20-30k. above 20-30k.

Initial therapyInitial therapy– Prednisone 1 mg/kg divided bidPrednisone 1 mg/kg divided bid– Decadron 40 mg daily x 4 daysDecadron 40 mg daily x 4 days– High dose solumedrol High dose solumedrol

May increase platelet count fasterMay increase platelet count faster More side effectsMore side effects

– IVIG for serious presentationIVIG for serious presentation

TreatmentTreatment 50% relapse after initial therapy or remain steroid 50% relapse after initial therapy or remain steroid

dependentdependent Splenectomy especially for steroid responsive casesSplenectomy especially for steroid responsive cases

– 80% response rate80% response rate– Immunize priorImmunize prior

Anti-D immune globulin in Rh+ patientsAnti-D immune globulin in Rh+ patients RituxanRituxan DanazolDanazol DapsoneDapsone VincristineVincristine Immunosuppression with azathioprine, cytoxanImmunosuppression with azathioprine, cytoxan Thrombopoietan receptor agonists – Nplate and PromactaThrombopoietan receptor agonists – Nplate and Promacta

– ?rebound worsening when drugs stopped?rebound worsening when drugs stopped– Myelofibrosis Myelofibrosis

Drug induced thrombocytopeniaDrug induced thrombocytopeniaHeparin induced thrombocytopenia Heparin induced thrombocytopenia

(HIT)(HIT)

Seen inSeen in 3-5% of patients treated with3-5% of patients treated with unfractionatedunfractionated heparinheparin

thrombocytopenic after 1-2 weeks of Rxthrombocytopenic after 1-2 weeks of Rx Caused byCaused by IgG antibodies against IgG antibodies against platelet factor platelet factor

4/heparin complexes4/heparin complexes on platelet surfaces on platelet surfaces ExacerbatesExacerbates thrombosisthrombosis, both arterial and venous (in , both arterial and venous (in

setting of severe thrombocytopenia) setting of severe thrombocytopenia) – Antibody binding results in platelet activation and Antibody binding results in platelet activation and

aggregation.aggregation. Rx -Rx - cessation of heparincessation of heparin

Other drugs???

Thrombotic MicroangiopathiesThrombotic Microangiopathies

1.1. Thrombotic thrombocytopenic Purpura Thrombotic thrombocytopenic Purpura (TTP)(TTP) 2.2. Hemolytic-Uremic syndrome Hemolytic-Uremic syndrome (HUS)(HUS)

Thrombotic Thrombotic MicroangiopathiesMicroangiopathies

common for both disorderscommon for both disorders

Mechanism =Mechanism =***hyaline (platelets) thrombi in the ***hyaline (platelets) thrombi in the microcirculationmicrocirculation

Pathogenesis = Pathogenesis = Systemic endothelial cell damage Systemic endothelial cell damage Clinically =Clinically = Fever, Thrombocytopenia, Renal failure, Fever, Thrombocytopenia, Renal failure,

Hemolytic anemia, neurological symptomsHemolytic anemia, neurological symptoms

***How to differentiate them from DIC?

HEMOLYSIS/HEMOLYTIC ANEMIAS HEMOLYSIS/HEMOLYTIC ANEMIAS DUE TO RBC TRAUMADUE TO RBC TRAUMA

Mechanical heart valves Mechanical heart valves breaking RBC’sbreaking RBC’s

MICROANGIOPATHIES:MICROANGIOPATHIES:– TTPTTP– Hemolytic Uremic Hemolytic Uremic

SyndromeSyndrome

Schistocytes: Microangiopathic Schistocytes: Microangiopathic Hemolytic AnemiaHemolytic Anemia

Thrombotic Thrombotic MicroangiopathiesMicroangiopathies

HUS TTP

Absent Absent Neurological Neurological symptomssymptoms

Prominent Prominent

Prominent Prominent Acute Renal FailureAcute Renal Failure Less prominentLess prominent

Children Children Age Age Adults Adults

InfectionInfection

( E.coli O157 : H7)( E.coli O157 : H7)

CauseCause GeneticGenetic

(vWF (vWF metalloprotease- metalloprotease-

ADAMTS 13ADAMTS 13) ) deficiencydeficiency

SupportiveSupportive Rx.Rx. Plasma ExchangePlasma Exchange

Good in children Good in children

Bad in adultsBad in adults

Prognosis Prognosis Better with plasma Better with plasma exchangeexchange

Feature

Mannucci PM. Pathophysiol Haemost Thromb. 2006;35(1-2):89-97. Thrombotic thromboytopenic purpura: another example of immunomediated thrombosis.

In the absence of ADAMTS13 (or when the concentrations of ADAMTS13 are not sufficient to cleave the increased quantity of UL VWF multimers released by the activated endothelial cells), UL VWF aggregates the platelets within the vessels causing thrombi that block blood flow. The red cells passing through the thrombi become fragmented and form schistocytes.

Mechanisms of thrombocytopenia and anemia in TTP: Comparison with the normal physiological state

Platelet functional Platelet functional disordersdisorders


Maslak, P. et al. ASH Image Bank 2009;2009:9-00008

Figure 1. Lumiaggregometry tracing demonstrates simultaneous platelet aggregation (red and blue curves) and ATP release (green and black curves) in response to collagen used as

an agonist

Bleeding disorders



DIC

Clotting factor Clotting factor abnormalitiesabnormalities

Congenital disordersCongenital disorders– Von Willebrand disease –MC with minimal bleedingVon Willebrand disease –MC with minimal bleeding

– Factor VIII Deficiency - Hemophilia A or Classic TypeFactor VIII Deficiency - Hemophilia A or Classic Type

– Factor IX Deficiency – Hemophilia BFactor IX Deficiency – Hemophilia B

Acquired disordersAcquired disorders– Vit. K deficiency =Due to deficient carboxylation of factors II, Vit. K deficiency =Due to deficient carboxylation of factors II,

VII, IX &XVII, IX &X

– Oral anti-coagulantsOral anti-coagulants Coumarin derivatives= warfarin – inhibit Vit. K factors Coumarin derivatives= warfarin – inhibit Vit. K factors Liver diseases Liver diseases ↓↓ synthesis of factors synthesis of factors

Von Willebrand DiseaseVon Willebrand Disease

MCMC inherited bleeding disorder with mild bleeding inherited bleeding disorder with mild bleeding Autosomal dominantAutosomal dominant TYPE I =Most commonTYPE I =Most common (70% of all cases) (70% of all cases) Prolonged Prolonged bleeding time but bleeding time but normal platelet countnormal platelet count ↓↓Plasma Plasma vWF vWF levelslevels Secondary Secondary ↓↓ in Factor in Factor VIII VIII levelslevels

von Willebrand Diseasevon Willebrand DiseaseClinical featuresClinical features

von Willebrand factorvon Willebrand factor Carrier of factor VIII Carrier of factor VIII anchors platelets to subendotheliumanchors platelets to subendothelium Bridge Bridge between plateletsbetween platelets

InheritanceInheritance Autosomal dominantAutosomal dominant

Incidence Incidence 1/10,0001/10,000

Clinical featuresClinical features Mucocutaneous bleedingMucocutaneous bleeding

Effect of blood group on Effect of blood group on plasma vWF levelplasma vWF level

Blood groupBlood group Plasma vWF Plasma vWF level level U/dIU/dI

OO 7575

AA 106106

BB 117117

ABAB 123123

Treatment of von Willebrand Treatment of von Willebrand diseasedisease

Varies by ClassificationVaries by Classification CryoprecipitateCryoprecipitate– Source of fibrinogen, factor VIII and VWFSource of fibrinogen, factor VIII and VWF– Only plasma fraction that consistently contains VWF Only plasma fraction that consistently contains VWF

multimersmultimers– Correction of bleeding time is variableCorrection of bleeding time is variable

DDAVP (Deamino-8-arginine vasopressin)DDAVP (Deamino-8-arginine vasopressin)– Increases plasma VWF levels by stimulating secretion from Increases plasma VWF levels by stimulating secretion from

endotheliumendothelium– Duration of response is variableDuration of response is variable– Used for type 1 diseaseUsed for type 1 disease– Dosage 0.3 µg/kg q 12 hr IVDosage 0.3 µg/kg q 12 hr IV

Factor VIII concentrate (Humate-P)Factor VIII concentrate (Humate-P)– Virally inactivated productVirally inactivated product– Used for type 2 and 3Used for type 2 and 3

******Hemophilia AHemophilia A MC MC hereditaryhereditary disease disease with serious bleedingwith serious bleeding

– X-linked recessiveX-linked recessive– In 30%In 30% No family historyNo family history (new mutations) (new mutations)– 15% of severe cases develop 15% of severe cases develop factor VIII inhibitorsfactor VIII inhibitors

↓↓ amount or activity of factor VIIIamount or activity of factor VIII

factor VIII = cofactor for activation of factor X in the coagulation factor VIII = cofactor for activation of factor X in the coagulation cascadecascade

Symptoms usually develop in Symptoms usually develop in severesevere cases (factor VIII cases (factor VIII <1% of <1% of normalnormal) – ) – hemoarthrosis, hemoarthrosis, bruising, hemorrhage after trauma or bruising, hemorrhage after trauma or surgerysurgery

Hemophilia BHemophilia B

Factor IX deficiencyFactor IX deficiency

X-linked recessiveX-linked recessive

Much less commonMuch less common

Clinically= Clinically= indistinguishableindistinguishable from Hemophilia A with from Hemophilia A with Similar Similar lab findingslab findings

Diagnosis by factor IX levelsDiagnosis by factor IX levels

Treat with recombinant IX Treat with recombinant IX

HemophiliaHemophilia

X-linked disorderX-linked disorder Factor VIII or IX Factor VIII or IX Females carriersFemales carriers

– SymptomsSymptoms New mutationNew mutation

– 30%30%– VIII gene hugeVIII gene huge

Infectious risksInfectious risks HemarthropathyHemarthropathy

MildMild ModerateModerate SevereSevere

Factor Factor levellevel

>5%>5% 1-5%1-5% <1%<1%

BleedingBleeding RareRare 3-4x/year3-4x/year MultipleMultiple

TreatmeTreatmentnt

SupportiveSupportive SupportiveSupportive prophylaxiprophylaxiss

Acquired HemophiliaAcquired Hemophilia

Occurs in malignancy, autoimmune Occurs in malignancy, autoimmune disorders, post-partumdisorders, post-partum

PTT prolongedPTT prolonged Mixing studies – immediate and delayedMixing studies – immediate and delayed Bethesda assay – measurement of Bethesda assay – measurement of

strength of the inhibitorstrength of the inhibitor Treatment is with alternative factor Treatment is with alternative factor

concentratesconcentrates Immunosuppression to clear inhibitorImmunosuppression to clear inhibitor

Fresh Frozen PlasmaFresh Frozen Plasma

Advantages:Advantages:• Availability.Availability.

Disadvantages:Disadvantages:• Volume problemsVolume problems• Infectious exosure: hep. C, HIV, hep. BInfectious exosure: hep. C, HIV, hep. B• Clotting activity by freezing and thawing (-15%)Clotting activity by freezing and thawing (-15%)

IndicationsIndications::• Deficiency of factors V, VII, IX, X and XIIIDeficiency of factors V, VII, IX, X and XIII• Multiple deficiencies: servere liver disease and DIC.Multiple deficiencies: servere liver disease and DIC.• Unknown cause.Unknown cause.

CryoprecipitateCryoprecipitate

Prepared form single units of donor plasma.Prepared form single units of donor plasma.

Contains 50% of VIII C, vW activity, fibrinogen, XIII.Contains 50% of VIII C, vW activity, fibrinogen, XIII.

= 100 units of factors vIII C.= 100 units of factors vIII C.

Main uses:Main uses: Treatment of choice of VW disease except type 1.Treatment of choice of VW disease except type 1. Hemophilia A, Hypo & dysfibrinogenemia.Hemophilia A, Hypo & dysfibrinogenemia.

Disadvantages:Disadvantages: Should be kept at deep freeze (-20 to -30 C).Should be kept at deep freeze (-20 to -30 C). Difficult to handle at home.Difficult to handle at home. Cryoprecipitate vary in factor VIII C content from bag to bag.Cryoprecipitate vary in factor VIII C content from bag to bag.

Dosages: similar to factor VIIIDosages: similar to factor VIII

1 bag 100 units1 bag 100 units

Commercially Prepared Factor Commercially Prepared Factor VIII ConcentratesVIII Concentrates

Advantages:Advantages: Easy storage, reconstitution and Easy storage, reconstitution and

infusion.infusion. Each bottle contains a fixed amount Each bottle contains a fixed amount

of factor VIII.of factor VIII. No volume problem.No volume problem.Disadvantages:Disadvantages: Infectious exposure HIV.Infectious exposure HIV. Hep C. Hep B and others.Hep C. Hep B and others.

Prothrombin complex Prothrombin complex concentratesconcentrates

Contains: vit. K dependent factors + protein C.Contains: vit. K dependent factors + protein C.Activated factors: hemophilia A & B.Activated factors: hemophilia A & B.Uses:Uses: Hemophilia B.Hemophilia B. Hemophilia A with inhibitors.Hemophilia A with inhibitors.Advantages:Advantages: Easy to store (-4C) and to administer.Easy to store (-4C) and to administer.Main problems:Main problems: Infection risk.Infection risk. DIC and thromboembolic phenomena.DIC and thromboembolic phenomena. Thromboembolic phenomena, this risk increase in:Thromboembolic phenomena, this risk increase in:

– Injury & high tissue thrompoblastin activity.Injury & high tissue thrompoblastin activity.– Liver disease because of low levels of antithrombin III.Liver disease because of low levels of antithrombin III.– Neonates.Neonates.

Recombinant concentratesRecombinant concentrates

Factors VII, VIII, IXFactors VII, VIII, IX

Effective in clinical trialsEffective in clinical trials

AdvantagesAdvantages No infectious risk.No infectious risk. No volume problems.No volume problems.

Bleeding disorders



DIC

Disseminated Intravascular CoagulationDisseminated Intravascular Coagulation

Characterized byCharacterized by = =activation of the coagulationactivation of the coagulation sequence sequence systemic micro- systemic micro- thrombi thrombi

SequelaeSequelae= = tissue hypoxiatissue hypoxia due to due to microinfarcts (Thrombotic) or bleedingmicroinfarcts (Thrombotic) or bleeding problemsproblems

Triggering PathwaysTriggering Pathways – Release of tissue factor / thromboplastic factors into circulation Release of tissue factor / thromboplastic factors into circulation – Widespread endothelial injuryWidespread endothelial injury

Mechanism=Activated monocytesMechanism=Activated monocytes release IL-1 and TNF release IL-1 and TNF αα ↑↑ expression of expression of tissue Thromboplastic factor on endothelial cells & decrease Thrombomodulintissue Thromboplastic factor on endothelial cells & decrease Thrombomodulin– Mechanism = Consumption Mechanism = Consumption of coagulation factors , platelets, and activation of coagulation factors , platelets, and activation

of fibrinolytic pathwaysof fibrinolytic pathways

Disseminated Intravascular CoagulationDisseminated Intravascular Coagulationcontd…contd…

Sources of thromboplastic substancesSources of thromboplastic substances::– Leukemic Leukemic cell granulescell granules– Placenta in Placenta in obstetric obstetric complicationscomplications– CarcinomasCarcinomas- (Mucin - secreting adenocarcinomas)- (Mucin - secreting adenocarcinomas)– Bacterial Bacterial endo and exotoxinsendo and exotoxins

Endothelial injury can also be Caused byEndothelial injury can also be Caused by– Antigen-antibodyAntigen-antibody complexes =S.L.E. complexes =S.L.E.– TemperatureTemperature extremes= Heat stroke or burns extremes= Heat stroke or burns– Microorganisms=Microorganisms=Rickettsae, meningococciRickettsae, meningococci

Disseminated Intravascular Disseminated Intravascular CoagulationCoagulation

contd…contd…

Plasmin Plasmin Fibrinolysis Fibrinolysis formation of fibrin degradation products formation of fibrin degradation products ((FDP)FDP)– D-Dimer most important of FDPsD-Dimer most important of FDPs

Organ damage due to Micro thrombiOrgan damage due to Micro thrombi – Kidney =Kidney =microinfarcts in the renal cortexmicroinfarcts in the renal cortex

In severe cases = In severe cases = bilateral renal cortical necrosisbilateral renal cortical necrosis– Adrenals Adrenals = bilateral adrenal hemorrhage= bilateral adrenal hemorrhage

resembles resembles waterhouse - Friderichsen syndromewaterhouse - Friderichsen syndrome– Brain= MicroinfarctsBrain= Microinfarcts surrounded by foci of hemorrhage surrounded by foci of hemorrhage– Heart and anterior pituitary= Heart and anterior pituitary= show Similar changesshow Similar changes

Disseminated Intravascular Disseminated Intravascular CoagulationCoagulation

contd…contd…

Clinically= Clinically= Bleeding tendency in presence of widespread Bleeding tendency in presence of widespread coagulationcoagulation– Acute Acute D.I.C.= dominated by a D.I.C.= dominated by a bleedingbleeding

seen in obstetrical complications and trauma seen in obstetrical complications and trauma – Chronic Chronic D.I.C.= presents with D.I.C.= presents with Thrombotic Thrombotic complicationscomplications

seen in cancersseen in cancers Manifestations =Manifestations = variable variable

– Minimal to profound shock, renal failure, dyspnea, cyanosis, Minimal to profound shock, renal failure, dyspnea, cyanosis, convulsions, and comaconvulsions, and coma

– Hypotension isHypotension is characteristic. characteristic.

Disseminated Intravascular CoagulationDisseminated Intravascular Coagulationcontd…contd…

Lab = Lab = PT And PTT Are typically prolonged.PT And PTT Are typically prolonged.– ThrombocytopeniaThrombocytopenia– low Fibrinogenlow Fibrinogen– Elevated plasma Fibrin split products Elevated plasma Fibrin split products

PrognosisPrognosis = = Highly variableHighly variable– Depends upon:Depends upon:

Underlying disorderUnderlying disorder Degree of intravascular clottingDegree of intravascular clotting Activity of mononuclear phagocytic systemActivity of mononuclear phagocytic system Amount of FibrinolysisAmount of Fibrinolysis

Treatment of the underlying disorder is most important!!Treatment of the underlying disorder is most important!!

How to differentiate DIC form HUS/TTP using lab parameters?

ALL CLL

Antithrombin III concentrateAntithrombin III concentrate

Neutralizes mainly thrombin.Neutralizes mainly thrombin. Inhibits activated factor xa.Inhibits activated factor xa.Also factor IXa, XIa, XIIa.Also factor IXa, XIa, XIIa. Uses:Uses:

1.1. Congenital deficiency states acute Congenital deficiency states acute thrombosis.thrombosis.

2.2. Congenital deficiency states before Congenital deficiency states before surgery.surgery.

3.3. Acquired deficiency states thrombosis Acquired deficiency states thrombosis or DIC.or DIC.

Antifibrinolytic therapyAntifibrinolytic therapy

Effective in controlling mucosal bleeding Effective in controlling mucosal bleeding especially the oral mucosa (prevent rebleeds)especially the oral mucosa (prevent rebleeds)

Not well studied for: nasal, urinary and GIT Not well studied for: nasal, urinary and GIT bleedingbleeding

EACA (Amicar) 500 mg tab, 250/mL elixirEACA (Amicar) 500 mg tab, 250/mL elixir Dose 100-200 mg/Kg (maximum 10 g initial)Dose 100-200 mg/Kg (maximum 10 g initial)

50-100 mg/kg/dose (max 5 g) every 6 hours50-100 mg/kg/dose (max 5 g) every 6 hours

Transexamic acid (cyclockapron) 500mg cap.Transexamic acid (cyclockapron) 500mg cap. 25 mg/kg/dose every 6 hours25 mg/kg/dose every 6 hours

tranexamic acid effective locally as mouth washtranexamic acid effective locally as mouth wash

Documents

Bleeding Disorders Jaya V Juturi, MD Texas Oncology, PA