Interhospital Grand Round€¦ · Grand Round Two opposing processes Dr. CH Ng 24/05/2011 •F/23...

Interhospital Grand Round

Two opposing processes

Dr. CH Ng24/05/2011

• F/23

• NSND

• Good past health, BMI ~ 31

• HPI:

–URTI symptoms x 1/52 with cough and sputum, visited a GP with medications given

–Ascending weakness x 1/7, then 4 limb generalised weakness

–Admitted into Medical on 10/01/2011

–GCS 15/15, BP stable with fever

–P/E: grossly intact CN, and power 3/5 over four limbs; other systems unremarkable

–CBC: WCC 15.6, Hb 12.9, and platelet count ~ 45

–PT 15.1, INR 1.29, aPTT 36.3

–Normal RFT/LFT

–1st CT brain (plain): Lt parietal acute SAH, and Lt maxillary sinusitis

CT brain (plain)CT brain (plain)

CT brain (plain)CT brain (plain)

–Rocephin empirically started

–Generalised convulsion in ward x once, and Dilantin given

–Neurosurgical consultation

–MRI + MRA: bilateral parietal cortical oedema with haemorrhage, and MRA:NAD

– Intubated x DSA

MRI: Lt maxillary, Rt MRI: Lt maxillary, Rt sphenoidal sinusitissphenoidal sinusitis

MRI T1MRI T1

MRI T2MRI T2

MRAMRA

MRAMRA

Rt carotid angiogramRt carotid angiogram

Microcatheter insertionMicrocatheter insertion

PrePre--thrombolysisthrombolysis

ThrombolysisThrombolysis

ThrombolysisThrombolysis

PostPost--thrombolysis Rt carotid thrombolysis Rt carotid angiogramangiogram

PostPost--thrombolysis Rt carotid thrombolysis Rt carotid angiogramangiogram

PostPost--thrombolysis thrombolysis venogram venogram

–DSA: superior sagittal sinus thrombosis, and regional thrombolysis with rt-PA was done on 10/01/2011

–Fibrinogen 1.2, D-dimer 4445 (<500), CRP 66.8 (11/01/201)

–However, developed cardiac arrest upon transfer back to HDU of Neurosurgical Department with ROSC after CPR x one minute

–Blood results showed Hb drop from 12 to 4.5, and platelet count to 38

–Blood and blood products transfusion given

–Also ARF with Cr rising to 220, and metabolic acidosis

–Anuric

–To ICU x further care

–Echo: good biventricular systolic function

–USG: free fluid in Morrison’s pouch and pelvis

–Urgent CT abdomen + pelvis: haemoperitoneum and extensive retroperitoneal haemorrhage involving both perinephric and pelvic areas

CT abdomen + pelvisCT abdomen + pelvis

CT abdomen + pelvisCT abdomen + pelvis

CT abdomen + pelvisCT abdomen + pelvis

CT abdomen + pelvisCT abdomen + pelvis

CT abdomen + pelvisCT abdomen + pelvis

CT thoraxCT thorax

–Formal CT report: bilateral extensive retroperitoneal haemorrhage, bilateral renal infarcts, main portal vein partial thrombosis and Rt portal vein thrombosis, and ? thrombosis in Rt external iliac vein, bilateral common iliac veins and lower part of IVC, and subsegmental PE in Rt LL

–Surgical and Neurosurgical consultation: no bleeders found and anticoagulants stopped

–Haematologists consulted x management of thrombophilia

–Started Heparin infusion and CRRT

–Lupus anticoagulant/anti-cardiolipin Ab/anti-B2GP1 test –ve

–ANF/ANCA/anti-ENA all –ve, JAK2 V617F kinase mutation –ve, and flow cytometry –ve x PNH

–But screening of thrombophilia not done during acute thrombosis

– FU CT brain/abdomen/pelvis: reduced bilateral parietal haemorrhage, and retroperitoneal haemorrhage static

–Extubated, and her GCS later returned to 15/15

–Warfarin started and Dilantin off as no more seizure episodes

–Renal support by intermittent HD

–To Renal ward on 25/01/2011

–On Clexane and Warfarin

–FU MRI: superior sagittal sinus thrombosis with bilateral haemorrhagic infarcts, and new infarcts over Rt motor cortex

–MRV: still some dural sinus narrowing with partial recanalisation of the thrombosed sinuses, and the areas of haemorrhagic infarcts less prominent

–Warfarin stopped on 29/01/2011 for arrangement of thrombophiliac screening test (PS/PC/ATIII/FXa)

–Rehabilitated in ward

–Renal function progressively improved

–Last HD session on 07/02/2011

–RFT static at Ur/Cr 4-6/130-150, MDRD ~45

–Thrombophiliac screening test needed to repeat due to insufficient sample

–Haematologists reconsulted on 25/02/2011: likely a case of DIC secondary to some infection, and less likely to be a case of thrombophilia

–DMSA on 31/03/2011: Rt 3%, Lt 97%, severely impaired Rt kidney function

–Walked unaided in ward

–Educated for self injection of LMWH

–Thrombophiliac screening test cancelled as results affected by LMWH + Warfarin

–WFU by Renal team, on Clexane and Warfarin

–Anti-Xa level 0.19 (therapeutic range: 0.5-1.2 for LMWH)

–Pending Haemotologists’s reassessment

• Summary

–A young, healthy, and obese lady who presented with four limb generalised weakness was found to have multiple sites of bleeding including retroperitoneal bleeding and of thromboses including superior sagittal sinuses, pulmonary arteries, IVC, portal veins, renal veins, and external and common iliac veins

Cerebral venous thrombosis

Cerebral Venous System Cerebral Venous System AnatomyAnatomy

Normal cerebral MR Venogram. 3D TOF images obtained after intravenousinjection of gadolinium in sagittal (a) & coronal (b) planes. There is visualization of dural venoussinuses and superficial & deep cerebral veins. 1=Superior sagittal sinus, 2= Straightsinus,3=Torcular Herophili,4=Vein of Galen,5=Lateral sinus,6=Sigmoid sinus,7=Internal Jugularvein,8=Internal cerebral vein,9=Basal vein of Rosenthal and the arrows points to superficial cerebralveins.

Cerebral Venous ThrombosisCerebral Venous Thrombosis

Digital subtraction angiography showing that thesuperior sagittal sinus was not opacified

Computed tomography of the brain showing theconvexity subarachnoid haemorrhage

SAH from ruptured AVMSAH from ruptured AVM

CT scan of the brain showing subarachnoid hemorrhage as a white area in the center and stretching into the sulci to either side (marked by the arrow)

Cerebral Venous ThrombosisCerebral Venous Thrombosis

• It is RARE for a SAH to be associated with cerebral venous thrombosis because of the capacitance of the cortical veins

• The distribution of a SAH from a superior sagittal sinus thrombosis is usually different from that of one with an arterial origin and has a characteristic pattern

Cerebral Venous Thrombosis Cerebral Venous Thrombosis

• The haemorrhage is usually limited to the sulci of the cerebral convexity, sparing the basal cisterns

• The exact cause of SAH in patients with cerebral venous thrombosis remains UNKNOWN

Cerebral Venous ThrombosisCerebral Venous Thrombosis

• Postulations:

–The SSST causes dilatation of the venous system and venous hypertension � the dilatation, reversed blood flow and subsequent rupture of the adjacent fragile, thin-walled, valveless cortical veins of the involved sinus � haemorrhage entering the subarachnoid space

Cerebral Venous Thrombosis Cerebral Venous Thrombosis

• Postulations:

–The SSST � a venous haemorrhagic infarct in which the blood enters the subarachnoid space

Differential diagnoses ?

Antiphospholipid syndrome?

APS?APS?

• Definition: thrombotic event (venous/arterial thrombosis, recurrent fetal loss) in association with a persistent “lupus anticoagulant” in specialised clotting assays or persistently elevated titres of cardiolipin (IgG or IgM) or b2-glycoprotein 1 antibodies

APS?APS?

• The “lupus anticoagulant” is an acquired biologic abnormality characterised as an anticoagulant in vitro but associated with excessive clotting in vivo

• Increased b2-GP1 antibodies rarely found in absence of a LA or increased cardiolipin IgG or IgM levels

APS?APS?

• Associated with thrombocytopenia, prolonged aPTT, and livedo reticularis

• Associated with SLE, cancer, infections, drugs, and idiopathic

• Patient: thrombocytopenia, normal aPTT, LA/anticardiolipin and anti-b2GP1 Abs –ve, ANA/RF –ve, and no evidence of arterial thrombosis

Disseminated intravascular coagulation?

DIC?DIC?

• Systemic thrombo-haemorrhagic disorder

• Characteristic features:

–activation of coagulation system

–activation of fibrinolytic system

–consumption of clotting factors

– consumption of natural inhibitors

– thrombocytopenia

DIC? DIC?

• Clinical setting

• Laboratory tests

• Criteria– Underlying disease known to be associated

– Initial platelet count < 100 X 109/L, or rapid decline in platelet count

– Prolongation of clotting times (PT & APTT)

– Presence of fibrin degradation products

– Low levels of coagulation inhibitors (e.g. antithrombin)

– Low fibrinogen level in severe cases

DIC?DIC?

• Laboratory results:

–Prolonged PT, APTT and TT

–Reduced fibrinogen level

– Increased D-Dimers

–Thrombocytopenia

–Microangiopathic changes in blood film

DIC?DIC?

DIC?DIC?

DIC?DIC?

Systemic activation of coagulation

Intravascular deposition of fibrin

Thrombosis of small and midsize vessels and organ failure

Depletion of platelets and coagulation factors

Bleeding

DIC? DIC?

• DIC can cause macrovascular thromboses as well, including cerebral venous sinuses, portal veins, pulmonary arteries, etc.

• In acute DIC, fibrinogen is decreased in ~ 50% cases, PT prolonged in ~ 70%, and aPTT prolonged in ~ 50%

DIC?DIC?

• These tests can be normal in a substantial percentage of DIC cases

• Patient: fever, ?sinusitis, leucocytosis, thrombocytopenia, no anaemia, slightly prolonged PT/INR, low fibrinogen level, high D-dimer level and CRP, ARF, no +ve cultures

Thrombotic thrombocytopenic purpura?

TTP?TTP?

• Pentad of fever, neurological involvement, MAHA, ARF, and thrombocytopenia

• Not necessarily all present at the same time

• Caused by ADAMTS13 gene mutations � decreased production or abnormal function of ADAMTS13 � failure to break down vWF in the blood

TTP?TTP?

• Patient: fever, neurological involvement, thrombocytopenia, ARF, no anaemia but recovered without specific treatment

Inherited anti-coagulation factors deficiency?

Inherited coagulation Inherited coagulation factors deficiency?factors deficiency?

• So far not confirmed as thrombophilia screening test not done yet

• Pending Haematologist’s reassessment

Treatment

TreatmentTreatment

• Unfractionated heparin vs LMWH

• UFH is chosen initially in our patient because of renal failure and a high bleeding risk with ACT/aPTT monitoring

• Advantages: UFH can be stopped more quickly due to IV administration; has a shorter half-life time; and can be effectively antagonised

TreatmentTreatment

• Later UFH switched to LMWH + Warfarin with anti-Xa level/INR monitoring when no obvious bleeding is detected and renal function stable

• Advantages of LMWH: easy to administer (SC); and less incidence of HIT

Venous thrombosis

Homeostais between Homeostais between coagulation and fibrinolysis coagulation and fibrinolysis

Coagulation cascadeCoagulation cascade

The coagulation cascade. Legend: HWMK = High molecular weight kininogen, PK = Prekallikrein, TFPI = Tissue factor pathway inhibitor. Black arrow = conversion/activation of factor. Red arrows = action of inhibitors. Blue arrows = reactions catalysed by activated factor. Grey arrow = various functions of thrombin.

Fibrinolytic systemFibrinolytic system

Pathogenesis of venous thrombosis:Pathogenesis of venous thrombosis:VirchowVirchow’’s triads triad

Stasis Injury to the vessel wall

Hypercoagulability

Rudolf Virchow

Pathogenesis of venous thrombosis:Pathogenesis of venous thrombosis:VirchowVirchow’’s triads triad

stasis

hypercoagulability

Injury to the vessel wall

Damage to the vessel wall can be produced by direct trauma such as major hip or knee surgery, stab wound or insertion of venous catheters, by direct invasion from cancer cells, or as a consequence of age. Support structure in vessel walls deteriorates with age, leading to weakness and a predisposition to damage from distension.

Pathogenesis of venous thrombosis:Pathogenesis of venous thrombosis:VirchowVirchow’’s triads triad

Injury to the vessel wall

hypercoagulability

Stasis

Stasis describes the slowing or even cessation of blood flow. This commonly occurs in veins as a result of immobility or paralysis and can lead to concentration and subsequent activation of coagulation factors. Stasis can also cause the vessel walls to become distended resulting in endothelial damage.

Pathogenesis of venous thrombosis:Pathogenesis of venous thrombosis:VirchowVirchow’’s triads triad

Injury to the vessel wallstasis

hypercoagulability

The term hypercoagulability means an increased propensity to clot. Hypercoagulability can occur as a result of a genetic defect, stasis, malignancy, or hormone changes such as during pregnancy, during administration of OCPs or HRT.

Pathogenesis of venous Pathogenesis of venous thrombosisthrombosis

Risk Factors for venous Risk Factors for venous thrombosisthrombosis

• Acquired:

–Advanced age -IBD, Nephrotic sd

–Prior thrombosis -HIT

– Immobilisation -Obesity

–Major surgery -Prolonged airtravel

–Malignancy -Male sex

–Estrogen/Pregnancy (OCP, HRT, SERMs)

–APS

–MPD

Risk Factors for venous Risk Factors for venous thrombosis thrombosis

• Inherited:

–AT deficiency

–PC deficiency

–PS deficiency

–Factor V Leiden (FVL)

–Prothrombin G20210A

Risk Factors for venous Risk Factors for venous thrombosisthrombosis

• Mixed/unknown:

– Increased Homocysteine

– Increased FVIII

–APC Resistance in the absence of FVL

– Increased FIX

– Increased FXI

– Increased TAFI

–Decreased free TFPI

–Decreased fibrinolytic activity

Venous Thrombosis Risk Venous Thrombosis Risk Factor ModelFactor Model

GenesAnticoagulant deficienciesFVL

PT G 20

21 0 A

Acquired risk factorsAgePrevious VTECancerObesity

Intrinsic thrombosis risk

Venous thrombosis

Prophylaxis

Triggering factorsEstrogenPregnancySurgeryImmobilisation

Thrombosed threshold

Sites of thrombosisSites of thrombosis

• Abnormality Arterial Venous

–FVL -ve +ve

–PT G20210A -ve +ve

–AT deficiency -ve +ve

–PS deficiency -ve +ve

–PC deficiency -ve +ve

–LA +ve +ve

Factor V gene mutations

Factor V gene mutations Factor V gene mutations

• Factor V acts as a cofactor in the conversion of prothrombin to thrombin in the coagulation process

• FV FVa

FXa/FIIaAPC

for maintenance of homeostasis

Factor V gene mutationsFactor V gene mutations

• This mechanism of FVa inactivation is an ordered event

• FVa is first cleaved at Arg 506 and then Arg 306 and Arg 679

• The peptide bond cleavage at Arg 506 is essential for the subsequent optimal exposure of cleavage sites at Arg 306 and Arg 679

Factor V gene mutationsFactor V gene mutations

• Peptide bond cleavage at Arg 306 appears to occur in a membrane-bound fashion and only accounts for the initial 70% loss of activity

• The subsequent peptide bond cleavage at Arg 679 is responsible for the loss of remaining activity

Factor V gene mutationsFactor V gene mutations

• Therefore, any defect on one or more of these three cleavage sites can potentially affect the APC inactivation process even though FV procoagulation activity may remain normal

• FV Leiden � Arg 506 � Gln � APC-R +ve

• FV gene mutation (HK) � Arg 306 �Gly � APC-R -ve

Prothrombin G20210A Prothrombin G20210A mutationmutation

• Causes increased level of PT

• Uncertain mechanism for hypercoagulability

Protein S and C deficienciesProtein S and C deficiencies

• PS and PC are Vitamin K-dependent factors that are synthesised in the liver

• PS originates on chromosome 3 and PC on chromosome 2

• Autosomal dominant but may be recessive

• Manifested as deficiency or presence of dysfunctional protein

Antithrombin deficiency Antithrombin deficiency

• AT, activated by heparin, inhibits FIIa, FIXa, FXa, FXIa, and FXIIa

• Autosomal dominant

• Manifested as deficiency or presence of dysfunctional protein

Causes of hypercoagulabilityCauses of hypercoagulability

Prevalence of Hereditary Defects in Prevalence of Hereditary Defects in Patients with venous thrombosisPatients with venous thrombosis

• APC-R (FVL) 12-40%

• PT Gene Mutation 6-18%

• Deficiencies of AT, PS, PC 5-15%

Prevalence of Factor V Leiden (FVL) Prevalence of Factor V Leiden (FVL) and Prothrombin G20210A mutationand Prothrombin G20210A mutation

• Population FVL (%) G20210A (%)

–European

• Northern 5-10 1.7

• Southern 2-3 3.0

–African

–Asian EXTREMELY RARE

11stst episode of Venous Thrombosisepisode of Venous Thrombosis(Leiden Thrombophilia Study) (Leiden Thrombophilia Study)

Risk Normal 1.0PT G20210Aheterozygotes 2.8xOCPs 4.0xFVL heterozygotes 7.0xOCPs + FVL 35.0xFVL homozygotes 80.0x

11stst episode of Venous Thrombosis episode of Venous Thrombosis (Leiden Thrombophilia Study)(Leiden Thrombophilia Study)

Incidence/year (%)

Normal 0.008OCPs 0.03FVL heterozygotes 0.06OCPs + FVL 0.3FVL homozygotes 0.5-1.0

Who should be considered for Who should be considered for evaluation for hereditary evaluation for hereditary

thrombophilia? thrombophilia?

• Yes

–Venous thrombosis at age <50 with +ve FHx (1st degree relatives)

–Cerebral venous thrombosis

–Portal/mesenteric vein thrombosis(r/o MPD, PNH)

–Pregnancy loss (2nd and 3rd trimesters)

Who should be considered for Who should be considered for evaluation for hereditary evaluation for hereditary

thrombophilia? thrombophilia?

• Reasonable

–Venous thrombosis in association with OCPs/HRT or pregnancy

–Patients >50 with 1st spontaneous venous thrombosis

Who should be considered for Who should be considered for evaluation for hereditary evaluation for hereditary

thrombophilia? thrombophilia?

• No

–Arterial thrombosis (save for paradoxical emboli)

–Asymptomatic patients with no personal/FHx of venous thrombosis

–Women going on OCPs/HRT

–Elderly patients with post op venous thrombosis

• Kowloon West Cluster – Haematology Service: Thrombophilia Study Request Form

–Thrombophilia study includes tests for

• Protein C

• Protein S

• Antithrombin

• Activated Protein C Resistance (APC-R)

• Lupus Anticoagulants

• Kowloon West Cluster – Haematology Service: Thrombophilia Study Request Form

–Points to note:

• The test results are misleading when the patient is on heparin or warfarin. Please send specimen after stopping warfarin for more than one month

• Testing for Protein C, Protein S, and Antithrombin should preferably be performed after the completion of anticoagulation treatment rather than during the acute phase of thrombosis

• Kowloon West Cluster – Haematology Service: Thrombophilia Study Request Form

–Points to note:

• There is currently no concrete evidence to suggest an association between arterial thrombosis and Protein C, Protein S, or Antithrombin deficiency

• Activated Protein C Resistance should not be ordered for patients of Chinese ethnicity. The positive predictive value of Activated Protein C Resistance for Factor V Leiden in Chinese is too low to be of any practical value

• Kowloon West Cluster – Haematology Service: Thrombophilia Study Request Form

–The following conditions are known to be associated with acquired Protein C and Protein S deficiency:

• Liver diseases (hepatitis, cirrhosis)

• DIC

• Inflammatory diseases

• Post-viral infection

• Post-operative period

• Kowloon West Cluster – Haematology Service: Thrombophilia Study Request Form

• Type I diabetes

• Chronic renal failure/Nephrotic syndrome

• ANCA-positive vasculitis

• APS

• ACS

• Chemotherapy (cisplatinum, L-asparaginase)

• HIV infection

• Oral contraceptives

• Pregnancy

Considerations for longConsiderations for long--term OAC in term OAC in patients following 1patients following 1stst unprovoked unprovoked

venous thrombosisvenous thrombosis

• Resolution of triggering risk factor

• Sites and severity of thrombosis

• Bleeding risk

• Identification of a prothrombotic defect coupled with FHx of thrombosis

• �an individualised decision

LongLong--term OAC term OAC

• Patients with venous thrombosis have inheritable thrombophilia –Warfarin for a minimum of 3 – 6 months at INR 2 - 3

• Indefinite anticoagulation for high risk groups

LongLong--term OACterm OAC

• High risk groups:

–>= 2 spontaneous thromboses/ 1 spontaneous thrombosis in the case of AT deficiency or the APS

–1 spontaneous life-threatening thrombosis (e.g., near-fatal PE; cerebral, mesenteric, or portal vein thrombosis)

LongLong--term OACterm OAC

• High risk groups:

–1 spontaneous thrombosis at an unusual site (e.g., mesenteric or cerebral veins)

–1 spontaneous thrombosis in the presence of more than a single genetic defect predisposing to a thrombotic event (e.g., combined heterozygosity of PS deficiency, PC deficiency, or AT deficiency)

Thank you