Hem Onc Presentation

7/31/2019 Hem Onc Presentation

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HPI44 years old F with PMH of migraine BIBEMS for

headache, which started the day before during the

eveningShe describes it as located to her R neck and occipital

area. On the next morning when she woke up the pain

was slighly worse so she took excidrin without

improvement .


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HPIDescribed as throbbing, 7/10 intensity, radiated to her R

frontal area

The patient states that the headache this time was

different from her previous headaches related to her

Migraine

No aggravating/alleviating factors


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HPIAssociated with nausea and 1 episode of NBNB

vomiting

No fever, photophobia, blurry vision, arm or leg

weakness, gait disturbances, slurred speech, dizziness or

facial asimmetry

VS: 98.9, 64, 15, 110/65


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Social/Family HistoryLives with a sibling, in US x 12 years with no

recent travel

Works as a nanny caring for young childrenG1P1, denies miscarriages, denies OCP

Drinks occasionally , does not smoke or use drugs

Family Hx: noncontributory, no hx of DVT/bleeding or

clotting disorders in the family


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Physical ExamAlert, oriented x3 fluent without disarthria or obviousdyhsphasiaCN: PERRL EOMI, intact visual field, no facial

paralysis or loss of sensation,uvula and tongue movesymmetrically about the midlineMotor : tone nl, strenght 5/5 all 4 ext decreased DTRs,planters downgoing

Sensory equal bilaterally to pinCoordination intactNeck suppleChest, CV, Abd exam unremarkable


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ED meds Tylenol 650 mg x2

Metoclopramide 10 mg IVPB x1

Zantac 50 mg IVPB x 1 NS 1 L bolus


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Labs11.3

35.3

1887.2137

3.8

102

28

7

0.7

89

Calcium: 8.9LDH 135

PT/PTT/INR : 10.9/1/26.8


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Imaging CT brain: hyperdense R transverse sinus, concerning

for venous sinus thrombosis. No evidence of venousinfaction. No acute intracranial hemorrage, midlineshift, hydrocephalus or fracture


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CT brain +


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MRI / MRV w contrast


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MRV reconstruction lack of contrast in the R

transverse sinus


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Pt then admitted to the ICU for further management:

placed on neurochecks q2h and symptomatic

management, pending neurology consult

MRI C+/MRV: Confirms the R transverse sinusthrombosis . No evidence of parenchimal hemorrage,edema, or acute ischemic changes


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Consults Neurosurgery : no neurosurgical intervention advised

Neurology: LMWH, keep good hydration and consult

hematology for possible hypercoagulable state Hematology: hypercoagulable w/u, peripheral flow

cytometry (CD55/CD59), AC

Neuro follow up: MRI/MRV rules out any other lesion,

especially AVM. AC warranted, 3-6 months vslifelong


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Hypercoagulable workup AT III activity 104 Protrombin gene analysis: G20210A mutation not detected Protein S Ag: 134 Protein S activity: 67

Factor V Leiden (R506Q) Mutation: not detected Protein C Ag: 102 Protein C activity: 135 Haptoglobin 192 Beta 2 Microglobulin: 1.71 (VN


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Hyercoagulable workup Factor XI activity: 99%

Factor VIII activity: 205% *

Factor IX activity: 34%* Lupus anticoagulant : detected


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Discharge diagnosis Right transverse sinus thrombosis, secondary to

APLAS/ ?Elevated Factor VIII levels

Patient was told to f/u with Hem Onc clinic and that

she needed lifelong AC with coumadin (INR goal 2- 3)


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Cerebral Venous Thrombosis (CVT)


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Cerebral Venous Thrombosis (CVT)

Is the thrombosis of the cerebral veins and dural sinuses

Rare, represents less than 1% of all the strokes


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Cerebral Venous Thrombosis (CVT) A prothrombotic risk factor or a direct cause is identified in

about 85% of the patients

Genetic predisposition (thrombophilia)

Acquired factors : Trauma, Infections (Sepsis,

Meningitis,Otitis, mastoidistis, sinusitis), LP, cancer,myeloproliferative diseases,Inflammatory diseases,Pregnancy, Nephrotic Syndrome, APS

Interestingly ,the prothrombin mutation was more than

twice as common in patients with CVT vs LE DVT andactivated protein C resistance, factor V Leiden, and proteinC deficiency were more common in patients with DVT(Wisokinska Wisokinsky at al Neurology 2008)


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Cerebral Venous Thrombosis (CVT) Most common symptoms and signs: HA, focal or

generalized seizures, focal or generalized neurologicaldeficits, altered mental status, papilledema

Diagnosis is confirmed by MRI to visualize the thrombosedvessel and MRV to confirm the absence of flow in the vessel


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Cerebral Venous Thrombosis (CVT) Although documented the tendency of venous infarcts to

become hemorrhagic (40%, Ferro, Canhao et al) evenbefore the AC treatment is started, there is indication to

treat patients with CVT with either UFH or LMWH, evenin patients with cerebral venous infarction and hemorragicconversion (Einhaupl, Bousser, de Bruijn et al)

Prognosis is good if appropriate treatment received early,

Risk factors for a bad outcome (13%) are male gender, age>37, AMS, coma, cerebral hemorrhage, cancer, thrombosisof deep cerebral venous system, CNS infection


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Thrombophilia Is a genetically determined increased risk of venous

thrombosis or thromboembolism (VTE)

Multiple possible acquired predisposing risk factorscouple the effect of the genetic predisposition


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Thrombophilia


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Coagulation cascade


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Coagulation Cascade


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Coagulation Cascade


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ThrombophiliaIn inherited thrombophilias, thrombosis is most often caused by impaired

neutralization of thrombin or failure to control the generation of thrombin

Seligsohn U and Lubetsky A. N Engl J Med 2001;344:1222-1231


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Thrombophilia



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Thrombophilia


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Thrombophilia


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Factor V Leiden (FVL)


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Factor V Leiden (FVL) >90% of hereditary APCR subjects have the same

abnormality, Factor V Leiden with a G1591A alterationcausing an Arg506Gln substitution

Deep and superficial venous thromboses are the mostcommon manifestations ; PE less frequent that insubjects with deficiencies in AT, prot C, prot S

Unusual (cerebral, hepatic, portal, mesenteric and

upper-extremity) venous thromboses reported


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Prothrombin G20210A Substitution


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Prothrombin G20210A Substitution Replacement of G byA at nt 20210 in the 3-

untranslated region of the prothrombin geneaugments translation and stability of prothrombinmRNA increased synthesis and secretion by theliver

Venous thrombosis (usual/unusual sites)


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Hyperhomocysteinemia

Loscalzo J. N Engl J Med 2006;354:1629-1632


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Hyperhomocysteinemia


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Hyperhomocysteinemia The most common genetic cause of mild

hyperhomocysteinemia involves an MTHFR genepolymorphism ntC677T which causes a conservativereplacement of Ala222 by Val that results in a variantenzyme with reduced specific activity and increased

thermolability Suboptimal Folate, B6 or B12 Vitamin levels can contribute

to acquired mild to moderate hyperhomocysteinemia byproviding inadequate cofactor levels to support theenzymes that regulates homocysteine metabolism. Other

causes are renal failure, hypothiroidism, smoking, excessivecoffee consumption, IBD, psoriasis and RA

VTE, unusual sites venous thrombosis

Blood samples should be obtained in a fasting state, keptcold and centrifuged immediately


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Protein C deficiency


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Protein C deficiencyVitamin K dependant protein More than 150 mutations described

Deep and superficial vein thromboses the mostcommon clinical presentation (usual/unusual sites)

Immunoassays are used to distinguish type I defectsfrom type II

Liver disease or OCPs can lower or increaserespectively its level

A waiting period of at least 2 weeks afterdiscontinuation of AC therapy is required for a reliablediagnosis


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Protein S deficiency


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Protein S deficiency Vitamin K dependant protein Circulates as both a free protein (40%) and bound C4b-binding

protein (60%), which is part of the classic complement system

Only free Protein S can act as a cofactor to APC for the inhibition ofFactors Va and VIIIa

C4b is increased in acute phase reactions, causing free Protein Sto be decreased

DVT/PE/thrombosis at unusual sites

Levels are reduced during pregnancy, OCPs, HRT, oral AC

therapy, DIC, liver disease, nephrotic syndrome, inflammatorycondition, acute VTE

Assessment of total and free Protein S plus Protein S activityshould allow classification of patients in type I, II, or III


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Antithrombin deficiency


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Antithrombin deficiency

vitamin K-independent protein Prevalence: 1:2000-1:5000 persons 30% of heterozygotes develop a thrombosis by

30yrs, 65% by age 50yrs Homozygous deficiency is almost always

incompatible with life 60% will have recurrent thrombosis

Risk of thrombosis is particularly high in pregnancy Heparin prophylaxis recommended throughout

pregnancy and coumadin for 6 weeks postpartum


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Antithrombin deficiencyAT Ag measurement and acitvity assays help

distinguish type I from type II defects

Levels affected by acute VTE, liver disease, DIC,

nephrotic syndrome, chemotherapy with asparaginase,and preeclampsia


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Elevated Factor VIII Levels ?Genetic, no specific genetic abnormality described The mechanism by which increases the risk of

thrombosis are unknown (by diminishing the effect ofAPC?)

Levels can be elevated in pregnancy, increasedage/BMI, surgery, chronic inflammation, liver disease,hyperthyroidism , DM, exercise, acute VTE

Represents the most common prothrombotic riskfactor for CVT (Bugnicourt J, Russel B, J NeurolNeurosug Psychiatry 2007)


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Elevated Factor VIII Levels

Studies done on ABO groups showed that there is anassociation between non-O groups and higher levels ofVWF/Factor VIII

Individuals with blood group O have 25-30% lowerVWF levels than non-O groups

In individuals with the FVL who have the AB genotype,the weak deactivation of FVIII thought to be mediated

by a lower catabolism of the VWF influenced by theAB alleles in combination with high levels of thisfactor are thought to result in an exponential increasein the risk of developingVTE (Morelli et al., 2005)


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Anti Phospholipid (aPL) syndrome (APS)

Is a disorder in which vascular thrombosis orpregnancy complications attributable to placentalinsufficiency occur in patients with laboratoryevidence of antibodies directed against proteins thatbind to phospholipids

aPL Ab are defined as antibodies that recognizephospholipids, proteins that binds to phospholipids,

or inhibit phospholipid-dependant coagulationreactions


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Anti Phospholipid (aPL) syndrome (APS)

Antigen targets: domain I ofb2 GPI, prothrombin,factor V, Protein C, Protein S, annexin A2, annexin A5,high and lw molecular weight kininogens, factorsVII/VIIa

Molecular mimicry between b2 GPI-related syntheticpeptides and structures within bacteria, viruses, andtetanus toxoid have been demostrated in expreimental

models


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Anti Phospholipid syndrome (APS)


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Anti Phospholipid syndrome (APS)Sidney Investigation Criteria for the diagnosis of APSo Clinical

one or more episodes of arterial, venous or small vessel thrombosis pregnancy morbidities attributable to placental insufficiency ,

including : three or more otherwise unexplained recurrentspontaneous miscarriages, before 10 weeks gestation. Also, one ormore fetal lossess after the 10 week of gestation, stillbirth, pretermlabor, placentar abruption, intrauterine growth restriction oroligohydramnios that are otherwise unexplained

o Laboratory aCL or anti-b2 GPI IgG or IgM in medium or high titer in2 or more

occasions at least 12 weeks apart Lupus anticoagulant in plasma on two or more occasions at least 12

weeks apart

Definite APS if at least one of the clinical criteria and one of thelaboratory criteria are met


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Workup for suspected hypercoagulability


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Workup for suspected hypercoagulabilityPossible Indications for extension of Anticoagulant

Therapy Beyond 6 months*6-18 months: Elevated factor VIII level

Increased level of D-dimerActive cancerSevere venous insufficiencyIliofemoral venous thrombosis

Residual thrombosis detected by U/SPersistence of inciting cause

Indefinite: Life threatening eventCVT

Visceral vein thrombosisRecurrent event

Deficiencies of AT, Protein C, or Protein SCombined thrommbophiliasPresence of aPL Antibodies

* An extension of the therapy should be carefully evaluated and probably not applied inpatients with a great risk of bleeding, for example age >70 years, renal failure, or poorlycontrolled AC therapy


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Some interestingarticles

Cerebral sinus vein thrombosis N Engl J Med 2005;352:1791-8. The "cord sign" in cerebral venous thrombosisassociated with high plasma levels of factor VIII.Giraldo EA, Petrinjac-Nenadic RNeurocrit Care. 2011 Aug;15(1):186-9.

J Neurol Neurosurg Psychiatry 2007;78:699-701 doi:10.1136/jnnp.2006.103465Cerebral venous thrombosis and plasma concentrations ofFactor VIII and von Willebrand factor: a case control studyJean-Marc Bugnicourt1, Bertrand Roussel2, Blaise Tramier3,Chantal Lamy1Olivier Godefroy1

ASH Education Program Bookasheducationbook.hematologylibrary.org doi:10.1182/asheducation-2005.1.462ASH Education Book January 1, 2005 vol. 2005 no. 1 462-468 Thrombosis and the Antiphospholipid Syndrome , Thomas Ortel
http://www.ncbi.nlm.nih.gov/pubmed?term=%22Giraldo%20EA%22[Author]http://www.ncbi.nlm.nih.gov/pubmed?term=%22Petrinjac-Nenadic%20R%22[Author]http://jnnp.bmj.com/search?author1=Jean-Marc+Bugnicourt&sortspec=date&submit=Submithttp://jnnp.bmj.com/search?author1=Bertrand+Roussel&sortspec=date&submit=Submithttp://jnnp.bmj.com/search?author1=Blaise+Tramier&sortspec=date&submit=Submithttp://jnnp.bmj.com/search?author1=Chantal+Lamy&sortspec=date&submit=Submithttp://jnnp.bmj.com/search?author1=Olivier+Godefroy&sortspec=date&submit=Submithttp://jnnp.bmj.com/search?author1=Olivier+Godefroy&sortspec=date&submit=Submithttp://jnnp.bmj.com/search?author1=Chantal+Lamy&sortspec=date&submit=Submithttp://jnnp.bmj.com/search?author1=Chantal+Lamy&sortspec=date&submit=Submithttp://jnnp.bmj.com/search?author1=Chantal+Lamy&sortspec=date&submit=Submithttp://jnnp.bmj.com/search?author1=Blaise+Tramier&sortspec=date&submit=Submithttp://jnnp.bmj.com/search?author1=Blaise+Tramier&sortspec=date&submit=Submithttp://jnnp.bmj.com/search?author1=Blaise+Tramier&sortspec=date&submit=Submithttp://jnnp.bmj.com/search?author1=Bertrand+Roussel&sortspec=date&submit=Submithttp://jnnp.bmj.com/search?author1=Jean-Marc+Bugnicourt&sortspec=date&submit=Submithttp://jnnp.bmj.com/search?author1=Jean-Marc+Bugnicourt&sortspec=date&submit=Submithttp://jnnp.bmj.com/search?author1=Jean-Marc+Bugnicourt&sortspec=date&submit=Submithttp://jnnp.bmj.com/search?author1=Jean-Marc+Bugnicourt&sortspec=date&submit=Submithttp://jnnp.bmj.com/search?author1=Jean-Marc+Bugnicourt&sortspec=date&submit=Submithttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Petrinjac-Nenadic%20R%22[Author]http://www.ncbi.nlm.nih.gov/pubmed?term=%22Petrinjac-Nenadic%20R%22[Author]http://www.ncbi.nlm.nih.gov/pubmed?term=%22Petrinjac-Nenadic%20R%22[Author]http://www.ncbi.nlm.nih.gov/pubmed?term=%22Petrinjac-Nenadic%20R%22[Author]http://www.ncbi.nlm.nih.gov/pubmed?term=%22Petrinjac-Nenadic%20R%22[Author]http://www.ncbi.nlm.nih.gov/pubmed?term=%22Giraldo%20EA%22[Author]http://www.ncbi.nlm.nih.gov/pubmed?term=%22Giraldo%20EA%22[Author]http://www.ncbi.nlm.nih.gov/pubmed?term=%22Giraldo%20EA%22[Author]

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Hem Onc Presentation