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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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