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Algorithms for Diagnosis of Disorders in Hemostasis
COAGULATION 7
Algorithms for Diagnosis of Disorders in Hemostasis
Index of the Algorithms
PT and APTT prolongations pag. 4Disseminated Intravascular Coagulation (DIC) pag. 10Warfarin therapy pag. 11Heparin administration pag. 12Algorithm for clinical diagnosis & typing of von Willebrand’s disease pag. 13Evaluation of thrombosis pag. 14Thrombocytopenia pag. 15Acquired qualitative platelet disorders pag. 16Congenital qualitative platelet disorders pag. 17Bernard-Soulier disease pag. 18Glanzmann’s thrombasthenia pag. 19Storage pool disease pag. 20Congenital defects in the Arachidonate-Thromboxane pathway pag. 21
3
Introduction
The diagnostic and therapeutic approach to the patient withabnormal hemostasis varies among physicians.The flow charts on the following pages represent one approach.
Please consult appropriate descriptions of the disorders and laboratoryassays.The following algorithms are reprinted from The Clinical HemostasisHandbook by Michael Laposata, Ann Marie Connor, David G. Hicks,and Deborah K. Philips, published by Mosby-Year Book MedicalPublishers, Chicago, 1989 (first edition).Updated 1993 by Michael Laposata, M.D., Ph.D.Director of Clinical LaboratoriesMassachusetts General HospitalBoston, MA.
Flow Charts
4
PT (Prothrombin Time) and APTT (Activated Partial Thromboplastin Time) prolongations diagnostic algorithm
YES
YES
Is the APTT elevatedwith a normal PT?
Does the 50 : 50 mixcorrect the APTT?
Is the patient on anticoagulant therapy?
The specimen may becontaminated withheparin, especiallyif APTT was previouslynormal in recent days.
Is there a need to ruleout heparin contaminationin specimen in question?
Can perform thrombin time ± protamine sulfate, use heparin-absorbing resin and repeat APTT, or do thrombin time with reptilase time to assess presence of heparin in sample.
Repeat APTT on newsample carefullycollected to avoidheparin contamination.
Is heparin responsible forobserved result?
Go to flow chartsfor anticoagulanttherapy.
Go to Page 7
Go to Page 6
Subsequent specimensshould have muchshorter APTT values.
The patient may havea lupus inhibitor.
Go to Page 5
NO
YES
NO
YES
NO
NO YES
NO
5
NO
Assays for lupus inhibitor withavailable tests; the tissuethromboplastin inhibition (TTI)test, platelet neutralizationprocedure (PNP), and anti-cardiolipin (ACL) antibody assay are commonly used assays forlupus inhibitor.
YESIs there a lupus inhibitor presentby any one of these assays?
Patient has a lupus inhibitor. If PNP fails to correct in the presence of other tests positive for lupus inhibitor, there may bean underlying factor deficiencyas well as a lupus inhibitor.
Does the 50 : 50 mix for the PTTbecome > 5 seconds longer whenthe mixture is incubated 60 minutes at 37° than when the mixtureis incubated for 0 minutes?
Inhibitor to Factor VIII: C unlikely. If still suspincious, check Factor VIII: C levels.
Consider the presence of a Factor VIII: C inhibitor.Highest suspicion of an inhibitor lies in patients knownto have Hemophilia A, butFactor VIII: C inhibitor alsoarise spontaneously.
Is Factor VIII: C low?
For factor VIII: C inhibitors,quantitate inhibitor strengthin Bethesda Units.
Inhibitors to Factor IXmay be present, particulary in patients with hemophilia B. Can check Factor IX level if suspicious. Factor XI or XII inhibitors may be present, but these are very rare.
NO
YES
YESNO
From Page 4
6
Patient may have a deficiency of VIII: C, IX, XI (which can result in bleeding) or XII, HMWK, (High Molecular Weight Kininogen), Prekallikrein (which do not result inbleeding).
Perform Factorassays, emphasizingVIII: C, IX and XI.
If Factor VIII: C or IX isselectively decreased, patientmay have Hemophilia A (VIII: C) or B (IX) or von Willebrand's disease. The clinical presentations of the Hemophilias and von Willebrand's Disease are usually very different. Is the patient likely to haveHemophilia A or B?
Check for sex - linked inheritanceand confirm selective deficiencyof Factor VIII: C or IX.
Are vWF: RCo andvWF: Ag decreased?
YESNO
From Page 4
Is Factor XIselectivelydecreased?
Is Factor XII, HMWK,or Prekallikreinselectively decreased?
Deficiency of any of these factors does not predispose to bleeding.
von Willebrand's disease islikely diagnosis. Check fornon - sex - linked inheritance,autosomal dominant inheritance for most common form of von Willebrand's Disease.
Patient may have a mild inhibitorwhich corrects on 50 : 50 mix withAPTT. Check for presence of inhibitor.
NO
NO
NO
YES
YES
YES
Deficiency of Factor XI may be a risk factorfor bleeding if personal or family history of bleeding exists.
7
YES
Is the PT elevated witha normal APTT?
Does the 50:50 mixcorrect the PT?
Patient may have mild DIC(Disseminated Intravascular Coagulation).
From Page 4
YES
Any suspicion of DIC?
Patient may have mildVitamin K deficiency.
NO
Go to Page 9
Patient may have a veryrare Factor VII inhibitorif indicated, can assay for Factor VII.
NO
NO
Go to Page 9YES
Is it important todocument VitaminK deficiency withfactor assays?
AdministerVitamin K
Are all Vitamin K - dependentfactors selectively decreased?
NO
Patient may have liver disease.
Are liver functiontests abnormal?
YES
Liver disease may bea contributory factorin PT prolongation.
NO
YES
YES
Does PTcorrect?
YES
Presumptivediagnosis ofVitamin Kdeficiency.
Go to Page 8
Vitamin K deficiencylikely. Can confirmby correction of factordeficiencies with Vitamin K administration.
NO
NO
8
Patient may havean isolated FactorVII deficiency.
Is Factor VII low?
Patient may have milddeficiencies of FactorsII, V or X (commonpathway factors), althoughthese deficiencies canaffect both the PT and APTT.
Are Factors II, V or X low?
Other, uncharacterizeddefect responsible forthe prolonged PT whichcorrects on mixing.
NO
NO
From Page 7
YES
Patient has an apparent FactorVII deficiency. If congenitaldeficiency, decreased factorlevel should be reproducibleupon repeat testing.
Patient has an apparentFactor II, V or X deficiency. Confirm with repeat testing.
YES
9
Both the PT andAPTT are elevated.
YES
From Page 7
Do the PT and APTT50 : 50 mixes correct?
Could be heparincontamination witha large amount of heparin. See Page 4.
Patient may haveliver disease. See Page 7.
Patient may havemoderate to severeDIC. See Page 10.
Significant elevation of FDP (Fibrin or Fibrinogen Degradation Products) may result in no correction in mixing studies. Check FDP.
Very rare inhibitorsto common pathwayFactors I, II, V orX may produce thisresult.
Patient may havemoderate to severeVitamin K deficiency.See Page 7.
Patient may have alupus inhibitor withan associated Factor II (Prothrombin) deficiency (PT mix corrects, but APTT mixdoes not).
Is Factor II low andlupus inhibitor testpositive? See Page 5.
YES NO
Patient may have anisolated deficiencyof a common pathwayFactor (I, II, V or X).
Diagnosis of lupus inhibitorwith Factor II deficiency.
NO
Are Factors I, II, V or X low?
Patient has an apparentfactor deficiency. Confirm on repeat testing.
Other, uncharacterizeddefect responsible forobserved laboratoryresults.
YES NO
10
There is a suspicion of DIC because • disorder commonly associated with DIC is present• unexplained bleeding• platelet count or fibrinogen level decreased.
Is PT prolonged; andFibrinogen decreased;and Platelets decreased,and FDP increased?
Obtain PT, platelet count,fibrinogen level and FDP level.
NO
From Page 7
YES
Is PT prolonged; and FDPincreased, and Plateletsand Fibrinogen normal but decreasing withsequential measurements?
Diagnosis of DIC unlikely,especially if FDP is normal.
Is there a change in the clinical picture or treatment given which may affect DIC?Observe patient.
Still suspiciousof DIC?
A diagnosis of DICis likely.
YES
NO
NONO
YES
Disseminated Intravascular Coagulation (DIC) diagnostic algorithm
11
O.A.T. indicated, start treatment.
Obtain PT.
NO
INR = 2.0 - 4.5 depending on clinical indication.
Maintain dose.
INR < 2.0 inadequate anticoagulation, increase dose.
INR exceeds upper limit of therapeutic range for clinical indication.
Treatment overdose,stop drug, reducedosage, or removedrugs potentiatingtreatment effect.
Bleeding present?
Severity of bleeding.
Desire to restoreappropriate levelof anticoagulationas soon as possiblefollowing correctionof PT?
Administer Vitamin Kwait for PT to decrease.
Wait for PTto decrease do not administer Vitamin K
Restart treatmentat lower dose.
Give Fresh frozen plasma (FFP) to reverse anticoagulationimmediately.
Wait for PT to decrease, monitor closely for further bleeding.
NONO YES
YES
YES
YES
NOMAJOR MINOR
O.A.T. (Oral Anticoagulant Therapy) diagnostic and therapeutic algorithm
12
Heparin therapyindicated.
Mini dose-heparin(Subcutaneous).
Full-dose heparin.
Obtain an APTT.
Re-start heparinat decreased dose.
Persistent bleeding?
If severe bleeding,is persistent orlife-threatening,give protaminesulfate.
Stop heparin.
Significant bleeding? APTT > 1.5 times mean of normal range.
Present dose inadequate: increase dose.
Maintain dose,watch for bleeding.
PROPHYLAXIS
NO
YES
YES
YES
NO
NO
THERAPY FORTHROMBOSIS
Heparin administration diagnostic and therapeutic algorithm
13
Algorithm for clinical diagnosis & typing of von Willebrand’s disease
Plasma von Willebrand antigen andRistocetin cofactor measured.
Unlikely to be vonWillebrand's DiseaseRetest if clinicallyindicated.
Plasma Ristocetin cofactor value belownormal?
von Willebrandantigen normal?
Ristocetin cofactorvalue < 100%
Cannot completely exclude vonWillebrand's Disease since vonWillebrand antigen increasedabove baseline in many mildillnesses and other situations.Retest in 1 - 2 months if clinicalsuspincion of bleeding.
Unikely to bevon Willebrand'sDisease
Is plasma Ristocetincofactor valuebelow normal range?
von Willebrandantigen > 15% higherthan plasma Risto-cetin cofactor.
Suspect von Willebrand'sDisease Type other than(most common) Type I.
Determine blood type,increased clinicalsuspicion for vonWillebrand's Disease ifblood type A, B, or ABrather than type O,since von Willebrandantigen normal levels of type O patients 20-50%less than those of otherblood types.
von Willebrand antigen andRistocetin cofactor both low &roughly equivalent.
Suspect vonWillebrand's DiseaseType I.
Crossed immunoelectrophoresis (CIE) or Western Blot for multimer analysis.
High molecular weightmultimers decreased?
Type I von Willebrand'sDisease. Test for response to DDAVP.
Test for Type IIB by plateletRistocetin aggregation test. Isthere hypersensitivity to Ristocetin?
Type IIB von Willebrand's Disease.Avoid DDAVP response testing.
Not type IIBvon Willebrand'sDisease.
Strong history of bleeding without otheridentified cause?
Unlikely to be vonWillebrand's Disease.
May be von Willebrand's Disease. Follow history and laboratoryvalues over time to obtain more definitive diagnosis.
YESNO
NO
YES
NO
YES
YES NO
YES NO
NO
NO
YES
YES
YES
NO
Personal or Family History of Bleeding • Pattern of inheritance not sex-linked • Usually mild bleeding associated with trauma, surgery, or dental procedures.
14
Does the patienthave any of thewell-established,predisposing factors for thrombosis suchas obesity, old age,malignancy, prolongedimmobility, or post-operative status?
Clinical evidenceof thrombosis.
Suspicion exists of primaryhypercoagulable state because:• family history of thrombosis• recurrent thrombosis without apparent precipitating factor• thrombosis at an early age• resistance to conventional anticoagulant therapy.
Obtain a battery of tests for hypercoagulablestate: Antithrombin III(AT-III), Proteins C & S,Plasminogen, ThrombinTime and Reptilase Time,Lupus Inhibitor Assays.
YES
Evaluation of hypercoagulabilityin hemostasis laboratory notlikely to be informative.
Patient has AT-IIIlevel low enough to be at risk forthrombosis
AT III decreased to < 50% ?
Protein C decreased?
Free Protein S decreased?
Plasminogen decreased?
Is there evidence of dysfibrinogenemia, typically manifested as a prolongedthrombin time and markedly prolonged reptilase time?
An association has been madebetween thrombosis and thepresence of a lupus inhibitor,and this may be an explanationfor thrombosis in this patient.
Does the patient havea lupus inhibitor byany of a variety of lupus inhibitor assays?
Defect responsible forthrombosis remains unidentified.
Perform immunologic fibrinogenassay. The results of this assays aretypically higher than the functionalfibrinogen assay in patients withdysfibrinogenemia.
Thrombotic defect due to impaired fibrinolysis.Rare defect.
Proteins C and S are VitaminK - dependent. If patient is being treated with O.A.T. drug diagnosis of deficiency is difficult. If possible, discontinue therapy briefly (heparin can be substituted) and re - test.
YESNO
YES
YES
YES
NO
NO
NO
NO
NO
YES
NO
Evaluation of thrombosis diagnostic algorithm
15
Thrombocytopenia may bedue to sequestration of platelets in the spleen.
Does the patient have hepatosplenomegaly with a stable platelet count above 50,000 per mm ?
Differential diagnosis of decreasedplatelet production includes congenital and acquired disorders of platelet production, most notablymarrow infiltration by tumor in leukemia, lymphoma, other malignancies, or marrow fibrosis; drug-induced marrow suppression; aplastic enemia; and maturation or metabolic defects.
Non-immune-mediated,platelet destruction.
Treat infection andfollow platelet count.
See DIC algorithmon page 10.
Follow platelet countand other parametersaltered in HUS or TTP.
Are there clinical findings suggestive of Hemolytic urenic syndrome (HUS) or Thrombotic thrombocytopenicpurpura (TTP) such as fever, renal dysfunction, or neurological defects?
Other uncommon non-immune-mediatedplatelet destructionprocess.
Consider diagnosis of Idiopathic thrombocytopenic purpura (ITP) by exclusion. If a highlysensitive platelet-associatedantibody test is available,a negative results may be usedto rule out ITP. Typically,this test has a low specificityfor ITP (a positive test does not confirm ITP).
Has the patient recentlybeen transfused?
Is patient takinga drug known tocause immunethrombocytopenia?
Immune-mediated,platelet destruction.
Test for post-transfusion,purpura with anti-PLA1
(Phospho Lipid Antibodies) antibody assay.
Is trombocytopenialikely to be part of multiple coagulationdefects in DIC?
Any evidence thatthrombocytopenia is due to infection?
If assay available, testfor drug-induced, platelet activation in presence of patient's plasma to decide if drug has produced thrombocytopenia. Alternatively, could remove drug and follow plateletcount.
Is there an adequate numberof magakaryocytes in thebone marrow specimen?
Most likely that increasedplatelet destruction responsible for thrombocytopenia.
Is patient persistently or recurrently thrombocytopenic.
Perform bonemarrow exam to assess platelet production.
Follow plateletand clinicalhemostasis
Platelet countis decreased.
YESNO
YES
NO
NOYES
YESYES
YES
NONO
NO
NO
YES
NO
3
YES
Thrombocytopenia diagnostic algorithm
16
Is the patientbleeding or hasthe patient hada history ofbleeding?
No furtherplateletstudies.
Same patients witha paraprotein developa platelet functiondisorder.
Does the patienthave a paraprotein,specifically IgM orIgA paraprotein?
Does the patient haveacquired or previouslyundiagnosed congenitalvon Willebrand's disease as shown by a low von Willebrand antigen and Ristocetin cofactor or other test for vWD?
Increased bleeding timereflects uncharacterizedacquired platelet functionor vascular disorder.
Can follow treatmentwith von Willebrand antigen and Ristocetin cofactor measurements.
Remove drug if possibleand follow clinical bleeding.
Is there a renalfunction defectwith increasedBUN (Blood Urea Nitrogen)?
Has patient ingesteda drug which affectsplatelet function?
Platelet function commonlyimpaired in uremia and improves with dialysis and/or DDAVP.
Treat underlyingdisorder. Blood component therapy as indicated for hemostasis.
If the patient has been on cardiopulmonary bypass within the lastday, the defect should be temporary.
Is there evidence ofa myeloproliferativedisorder?
Is the plateletcount low?
See evaluation ofthrombocytopenia.
Acquired platelet functiondisorder suspected:• history of bleeding not lifelong and no family history of bleeding• normal tests for coagulation factors.
YES
YES
NO
NO
YES
NO
YES
NO
NONOYES
YES
YES
NO
Acquired qualitative platelet disorders diagnostic algorithm
17
Congenital Platelet FunctionDefect Suspected• lifelong bleeding history• positive family history of bleeding• normal tests for coagulation factors.
von Willebrand'sDisease (vWD)?
Determine type of vWD by Crossed immunoelectrophoresis(CIE) or multimer analysis.
Confirm absence ofvWD with repeat study.
Further evaluation ofplatelet function notlikely to be informative.
Suspicious of additional disorder involving platelets?
Suspicious ofcongenitalplatelet disorder as well?
Can acquired causesof platelet dysfunctionbe removed?
Acquired plateletfunction disorderpresent.
Acquired causes of plateletdysfunction (primarilyresulting from drugs, uremia, paraproteins, or underlying myeloproliferative disorder) present?
Perform lab tests for differential diagnosis of congenital platelet disorders.
See StoragePool Disease.
See Glanzmann'sThromboasthenia.
See Bernard-Soulier Disease.
See Defects inArachidonateMetabolism.
YESNO
NO
YES
NO
NO
NO
YESYES
Page 21Page 20Page 19Page 18
YESRemove causes of acquired platelet dysfunction.
Congenital qualitative platelet disorders diagnostic algorithm
18
YES
NO
Normal plateletaggregations withcollagen, ADP, epinephrine, but abnormal response to Ristocetin.
Giant plateletson smear?
Aggregation to Ristocetin normalized when patient'splatelets mixed with normal plasma?
Tentative BS
Low plasmavWF: and RCo?
Very likely BS.
Surface membrane,protein analysisperformed (research lab). Is the amount of glycoprotein Ibdecreased?
vWD previouslyundiagnosed.
Unlikely to be BS.
Not BS.
BS confirmed.YES
YES
YES
NO
NO
NO
YES
NO
From Page 17
Bernard-Soulier (BS) disease
19
Flat or nearly flatplatelet aggregationtracings to all agonists.
Not likely to beGT.
YES
NO
Clot retraction normal.
Highly likely to be GTunless platelets wereinadvertently madenonfunctional whileprocessing sample.
Still suspiciousof GT frombleeding historyor other work - up?
Platelet measurementof glycoprotein IIb: IIIa(research lab).
Not GT.YES NO
YESNO
From Page 17
Glanzmann’s thrombasthenia (GT)
20
Abnormal PlateletAggregations,typically limited to first wave responseonly.
Dense granule deficiency.Therefore, patient haseither α or α δ SPD.
ATP > 3.0ADP
Platelet ATP andADP assays.
ßTG or PF4 decreased?
YES
From Page 17
NO
Assay for BTG or PF4
α δ SPD α SPD
Radio Immuno Assay (RIA) for ß - thromboglobulin(ßTG) or platelet factor 4 (PF4) an α granule marker.
ßTG decreased?
α SPD No SPD
YES
YES
NO
NO
Storage pool disease (SPD)
21
NO
Abnormal platelet aggregations, typically limited to first wave response only.
YES
Most of the following tests areperformed in a research lab
Assay for C - AAconversion to metabolites.
C - TXB formed?
Since aspirin inhibitscyclooxygenase (CO)irreversibly, and generates lab results identical to that found in CO deficiency, repeat drug history - be complete.
Probably no defect inAA/TX pathway. Very rare disorder of TXAreceptor deficiencystill a possibility.Can assays with routine platelet aggregation studies using stable TXA analog as agonist.
Medication with ASA (Acetyl Salicilic Acid) identified?
Assay for C - PGH conversion to metabolites.
Drug - inducedplatelet defect.Aggregation with stable
TXA analog?
No defect in AA/TX pathway. TXA receptor deficiencylikely. Confirm with additional reseach lab tests.
C - TXB formed?
CO deficiency likely.TXA synthetasedeficiency diagnosed.
RIA for CO antigenif possible sincelow immunologicCO value confirmsdeficiency.
Low CO antigen?
Corroborate absence ofaspirin and look for family and personal history of bleeding to substantiatecongenital CO deficiency.
CO deficiency diagnosed.
NOYES
YES NO
YESNO
NO
YES
From Page 17
2 2
2
2
2
2
2
14
14
14
14
2
Congenital defects in the Arachidonate (AA) - Thromboxane (TXA2/TXB2) pathway
22All rights reserved - Printed in Italy - Grafiche Speed 2000 - 1299
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5. The Anticoagulants: Protein C and Protein SMarlies R. Ledford
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Hemostasis Monographs
Part. No 98083-66