Approach to the Approach to the Bleeding PatientBleeding Patient

Jack Kuritzky, PGY-2Jack Kuritzky, PGY-2

UNC Internal MedicineUNC Internal Medicine

January 15, 2010January 15, 2010

OutlineOutline

Focusing on patients with a bleeding Focusing on patients with a bleeding diathesisdiathesis Initial clinical evaluationInitial clinical evaluation Initial workupInitial workup Fun with PT and aPTTFun with PT and aPTT

Factor VIII inhibitorsFactor VIII inhibitors EpidemiologyEpidemiology PresentationPresentation DiagnosisDiagnosis TreatmentTreatment

Approach to the Bleeding Approach to the Bleeding PatientPatient

Initial assessment: Vital signsInitial assessment: Vital signs Stabilize the patient, then get the Stabilize the patient, then get the

detailsdetails

Approach to the Bleeding Approach to the Bleeding Patient:Patient:

Differentiating Disorders of Platelets vs.Differentiating Disorders of Platelets vs.Coagulation FactorsCoagulation Factors

History and Physical ExamHistory and Physical Exam Platelets: Think small and earlyPlatelets: Think small and early

Bleed from skin and mucous membranes (nose, Bleed from skin and mucous membranes (nose, GI/GU)GI/GU)

PetechiaePetechiae Tend to bleed after small cutsTend to bleed after small cuts Small and superficial ecchymosesSmall and superficial ecchymoses Bleeding after surgery is immediate and mildBleeding after surgery is immediate and mild

Coagulation Factors: Think big and lateCoagulation Factors: Think big and late Deep in soft tissueDeep in soft tissue No petechiae and don’t bleed after small cutsNo petechiae and don’t bleed after small cuts Ecchymoses are commonEcchymoses are common Bleeding after surgery is delayed and severeBleeding after surgery is delayed and severe

CBCCBC SmearSmear

Ensure no “pseudothrombocytopenia” Ensure no “pseudothrombocytopenia” due to platelet clumping from EDTA due to platelet clumping from EDTA tubetube Can use heparin or citrate insteadCan use heparin or citrate instead

CoagsCoags Type and ScreenType and Screen

Approach to the Bleeding Approach to the Bleeding Patient:Patient:

Initial Laboratory WorkupInitial Laboratory Workup

Coagulation PathwaysCoagulation Pathways

aPTT

PT

Leung, L. Overview of Hemostasis. UpToDate. Sept. 2009.

Approach to the Bleeding Approach to the Bleeding Patient:Patient:

Differentials of PT and aPTTDifferentials of PT and aPTT Prolonged PTProlonged PT, Normal aPTT, Normal aPTT

Inherited: Factor VII deficiencyInherited: Factor VII deficiency Acquired: Acquired:

WarfarinWarfarin Vit K deficiencyVit K deficiency Acquired Factor VII deficiency or inhibitorAcquired Factor VII deficiency or inhibitor Liver diseaseLiver disease

Approach to the Bleeding Approach to the Bleeding Patient:Patient:

Differentials of PT and aPTTDifferentials of PT and aPTT Normal PT, Normal PT, Prolonged aPTTProlonged aPTT

InheritedInherited Hemophilia A (factor VIII deficiency)Hemophilia A (factor VIII deficiency) Hemophilia B (factor IX deficiency)Hemophilia B (factor IX deficiency) von Willebrand Diseasevon Willebrand Disease

Binds platelets to endothelium and themselvesBinds platelets to endothelium and themselves Carrier protein for Factor VIIICarrier protein for Factor VIII

Account for 95-97% of inherited coag Account for 95-97% of inherited coag abnormalitiesabnormalities

Acquired: Acquired: Inhibitor of factors VIII, IX, XI, or XIIInhibitor of factors VIII, IX, XI, or XII Acquired von Willebrand diseaseAcquired von Willebrand disease Lupus anticoagulant (often associated with Lupus anticoagulant (often associated with

thrombosis)thrombosis)

Approach to the Bleeding Approach to the Bleeding Patient:Patient:

Differentials of PT and aPTTDifferentials of PT and aPTT Prolonged PT and aPTTProlonged PT and aPTT

InheritedInherited Deficiency of factors required by both Deficiency of factors required by both

pathwayspathways Prothrombin, fibrinogen or factors V or XProthrombin, fibrinogen or factors V or X

Combined factor deficienciesCombined factor deficiencies Acquired: Acquired:

Liver DiseaseLiver Disease DICDIC Supratherapeutic heparin or coumadinSupratherapeutic heparin or coumadin Inhibitor of prothrombin, fibrinogen or factors Inhibitor of prothrombin, fibrinogen or factors

V or X V or X

Approach to the Bleeding Approach to the Bleeding Patient:Patient:

Differential of aPTTDifferential of aPTT In the case of isolated prolonged aPTT…In the case of isolated prolonged aPTT…

? Heparin ? Heparin Redraw to be certain original Redraw to be certain original sample not contaminated with heparinsample not contaminated with heparin aPTT would normalize with administration of aPTT would normalize with administration of

protamineprotamine Mixing StudyMixing Study

Mix patient plasma with pooled normal plasmaMix patient plasma with pooled normal plasma If aPTT normalizes, there is factor deficiencyIf aPTT normalizes, there is factor deficiency If not, there is an inhibitorIf not, there is an inhibitor

Add phospholipidAdd phospholipid If aPTT normalizes, there is anti-phospholipid If aPTT normalizes, there is anti-phospholipid

antibodyantibody

Measure activity of factors specificallyMeasure activity of factors specifically Bethesda AssayBethesda Assay

Serially dilute patient plasma and mix with Serially dilute patient plasma and mix with normal plasmanormal plasma

Measure Factor VIII activityMeasure Factor VIII activity One Bethesda unit = Dilution of patient One Bethesda unit = Dilution of patient

plasma that results in 50% Factor VIII plasma that results in 50% Factor VIII activityactivity

The stronger the inhibitor, the greater the The stronger the inhibitor, the greater the dilution requireddilution required

Approach to the Bleeding Approach to the Bleeding Patient:Patient:

Differential of aPTTDifferential of aPTT

AKA Acquired HemophiliaAKA Acquired Hemophilia Most common autoantibodies Most common autoantibodies

affecting clotting factor affecting clotting factor Mostly IgGMostly IgG

EpidemiologyEpidemiology 1.3-1.5 patients per million population1.3-1.5 patients per million population >50 years old except post-partum >50 years old except post-partum

In series of 250 patients, average In series of 250 patients, average Bethesda titer was 10 and average Bethesda titer was 10 and average Factor VIII activity was 2%Factor VIII activity was 2%

Approach to the Bleeding Approach to the Bleeding Patient:Patient:

Factor VIII InhibitorsFactor VIII Inhibitors

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Approach to the Bleeding Approach to the Bleeding Patient:Patient:

Factor VIII InhibitorsFactor VIII Inhibitors Causes: postpartum, rheumatoid Causes: postpartum, rheumatoid

arthritis, malignancy, systemic lupus arthritis, malignancy, systemic lupus erythematosus, and drug reaction erythematosus, and drug reaction (penicillin)(penicillin) Each accounts for ~5-10%Each accounts for ~5-10% No identifiable cause in ~50% of patientsNo identifiable cause in ~50% of patients Multiple types of malignancyMultiple types of malignancy

In trial of 41 patients, 25 had solid tumors and In trial of 41 patients, 25 had solid tumors and 16 hematologic16 hematologic

Prostate and Lung most commonProstate and Lung most common

Approach to the Bleeding Approach to the Bleeding Patient:Patient:

Factor VIII InhibitorsFactor VIII Inhibitors PresentationPresentation

Hematomas and ecchymosisHematomas and ecchymosis Mucosal bleedingMucosal bleeding

GI bleedGI bleed EpistaxisEpistaxis HematomaHematoma

Hemarthrosis rareHemarthrosis rare Bleeding often severeBleeding often severe

Series of 215 patients post-partumSeries of 215 patients post-partum 87% major bleeding87% major bleeding 22% died from complications of inhibitor22% died from complications of inhibitor

Approach to the Bleeding Approach to the Bleeding Patient:Patient:

Factor VIII InhibitorsFactor VIII Inhibitors Treatment for acute bleedingTreatment for acute bleeding

ddAVP for minor bleeding, low Bethesda ddAVP for minor bleeding, low Bethesda (<5)(<5) Increases levels of von Willebrand factor and Increases levels of von Willebrand factor and

factor VIIIfactor VIII Treat more serious bleeding with factor Treat more serious bleeding with factor

VIII concentrate for low Bethesda (<5)VIII concentrate for low Bethesda (<5) For serious bleed and high Bethesda, For serious bleed and high Bethesda,

treat with Novoseventreat with Novoseven

Approach to the Bleeding Approach to the Bleeding Patient:Patient:

Factor VIII InhibitorsFactor VIII Inhibitors Treatment – Eliminating inhibitorTreatment – Eliminating inhibitor

~1/3 of inhibitors spontaneously disappear at ~1/3 of inhibitors spontaneously disappear at 14 mos14 mos

Initial prednisone at 1mg/kg/day x3 weeksInitial prednisone at 1mg/kg/day x3 weeks 32% response rate (Green D, et al)32% response rate (Green D, et al)

If no response, then cyclophosphamideIf no response, then cyclophosphamide 50% of initial non-responders (Green D, et al)50% of initial non-responders (Green D, et al)

Response is better in patient with low Bethesda Response is better in patient with low Bethesda titers (<5)titers (<5)

For immediate removal, can consider For immediate removal, can consider plasmapheresisplasmapheresis

Rituximab gaining favor, but not yet standard of Rituximab gaining favor, but not yet standard of carecare

ReferencesReferences Coutre, S. Acquired Inhibitors of Coagulation. Sept 2009. Delgado, J, et al. Acquired haemophilia: review and meta-

analysis focused on therapy and prognostic factors. Br J Haematol 2003; 121:21.

Drews, RE. Approach to the Patient with a Bleeding Diathesis. UpToDate. Sept 2009.

Green, D, et al. A prospective, randomized trial of prednisone and cyclophosphamide in the treatment of patients with factor VIII autoantibodies. Thromb Haemost 1993 Nov 15;70(5):753-7.

Leung, L. Overview of Hemostasis. UpToDate. Sept. 2009. Sallah, S and Wan, JY. Inhibitors against factor VIII in

patients with cancer. Analysis of 41 patients. Cancer 2001 Mar 15;91(6):1067-74.

Stachnik, JM. Rituximab in the treatment of acquired hemophilia. Ann Pharmacother 2006; 40:1151.

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