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Dr Timur Krivitsky
Executive Producer

Hickams Dictum

Krivitskys Conundrum
It doesnt really matter, because at 3am on a
night shift, as the medical registrar, despite your
best efforts to obtain a thorough history and
examination from the cognitively impaired, NESB,
hypoxic patient and after altering the provisional
ED diagnosis of ceftriaxone, prednisolone and
frusemide deficiency, your diagnosis of infective
exacerbation of COPD, NSTEMI and UTI will be rediagnosed in the morning consultant ward round
as non-infective exacerbation of CCF, type 2 ACS
and asymptomatic bacteriuria.

Mrs I D, 83F

Past
medical history

L) Tibial plateau fracture complicated by compartment syndrome requiring

fasciotomy. 28/2/2015
- further complicated by fasciotomy wound necrosis, requiring repeated
debridement

ORIF L) tibial plateau fracture

TAVR (Aug 2015) complicated by complete heart block requiring PPM

2nd AVR operation complicated by MRSA

Hypercholesterolaemia

DM2
- Insulin dependant

HTN
GORD

GOUT

Medications

Social History
Lives with son (primary carer)
Walks with 4ww
Home help q2/52

HOPC
Worsening epigastric pain over 4 months
10kg weight loss over 4 months

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21/12/2016:
Gastroscopy
Likely malignant gastric biopsy in the incisura and anterior wall of gastrum
Biopsy
Ulcerated poorly differentiated adenocarcinoma
of intestinal type.

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02/01/16:

Radical distal gastrectomy and Roux-en-Y

Histopathology:
Adenocarcinoma
Local invasion to serosal surface (pT4)
No perforation
1/8 lesser curve LN
5/8 greater curve LN

http://www.gastrotraining.com/category/gi-surgery/gastric-operations

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12/02/2016 29/03/2016: Admission UGIG
# epigastric pain (presenting complaint)
# fistula and gastrectomy wound dehiscence, managed with dressings,
slowly resolved.
# Iron deficiency anaemia infused with iron.

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Since discharge from UGIG admission.
Recurrent exertional angina, relieved with rest
Serial troponin negative
Serial ECG negative

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Since discharge from UGIG admission.
Recurrent exertional angina, relieved with rest
Serial troponin negative
Serial ECG negative

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UGIG admission 12/02/2016

29/03/2016:

Distal gastrectomy
02/01/16

10.3
85

9.4
84
2PRBC

1
1
6.9 8
87 9

Fe

7.
6
92

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Med admission 28/4

29/4/16

2PRBC

9.5
96

7.0
105

9.5
97

2PRBC
7.2
99

Fe

B12

Current admission
5/5/16 - .

1PRBC
7.0
96

8.0
95

B12
Fe

Folat
e

WHF ED 20/4/16
Aberrant Hb 9.5 in setting of
?reaction to PRBC?
Lymphocytosis, APO and
transaminitis resolving.

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Causes of anaemia?
1. GI bleed? Recurrence of malignancy?
- Pt denied malena/haematochezia, multiple PR negative
2. Anaemia secondary to Iron or B12 deficiency post RYG
- Timing?
3. Intra-abdominal bleed
- Complicated surgery
4. Haemolysis?
5. Allo antibodies?

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Haemolysis screen:
Haptoglobin: 0.73 (0.36-1.95)
LDH: 251 (240-480)
Br: 3
Direct coombs text: negative
Reticulocyte count: 6% (0.3-2.0)
Absolute reticulocyte count: elevated
Urinary haemosiderin: not done

Blood film:
Known malignancy.
1. Red cell dimorphism and marked polychromasia,
suggestive of blood loss
+/- recent red cell transfusion.
2. Transient lymphocytosis, in keeping with
reactive process

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CT abdo/pelvis 5/5/2016:
Resolution of the previously demonstrated anterior intra-abdominal collection with
communication with abdominal wall. No other appearance is essentially stable when
compared with imaging from 04/03/2016.
Gastroscopy 9/5/16:
Mild gastritis
Normal anastomosis
Mild perianastamotic inflammation
Suggest colonoscopy if continued Hb drop

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TTE 08/07/2015:
Well seated TAVI/AVR. Normal iEOA of 14mm^2/m^2, DPI = 0.82.
PG 12mmHG, MG 5mmHg. No regurgitation.
TTE 07/01/0216:
Well seated bioprosthetic valve. Trivial regurgitation, likely
para-valvular at the native non coronary annulus.

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Medication Safety

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Von Willebrand factor

Smaller vWF multimers are constituitively synthesized by in endothelium and
megakaryocyte.
Ultra large vWF multimers released from endothelial cells and platelets by exposure to
collagen, thrombin and DDAVP.
Travels in the plasma bound to factor VIII
Globular state when inactive,
Activated through conformational change :
Exposure to subendothelial collagen
HIGH SHEAR STRESS
When uncoiled, A1 domain exposed
i) bridge platelets (GP 1b) to sub-endothelium
ii) platelets to each other

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High Shear Stress

Unravelling of HMWvWF in turbulent flow environment (such as intestinal arterioles) is a
protective mechanism
Platelets alone aggregate poorly impaired hemostasis

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Von Willebrand disease

1% of population (lab data)*
AD
Easy brusing, mucosal (GI, epistaxis)

* Sadler JE, Mannucci PM, and Berntorp E et al, Impact, diagnosis and treatment of von Willebrand disease. Thromb Haemost.
2000;84(2):160.

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TYPE
1. Partial deficiency
2. Functional impairment
2A
2B
2M
2N
3. Severe deficiency

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Laboratory
Normal platelets
Normal PT
Normal or increased APTT (depending on degree of factor VIII
involvement)

Screening tests
1. Plasma vWF antigen (quantitative)
2. Plasma vWF activity (qualitative)
i. ristocetin cofactor activity
ii. vWF collagen binding
3. Factor VIII activity
TYPE 2 A,B,M,N (functional) = low vWF activity to antigen
ratio
vWFCB:vWFAg ratio < 0.7= suggests Type2 disease

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Confirmatory tests (if screening

test abnormal)
1. VWF multimer distribution using gel
electrophoresis
- helps diagnose type 2A!
- Size of molecules abnormal
2. cleaving
Ristocetin-induced platelet aggregation
- helps diagnose type 2B
- uses platelets (not just vWF as in ristocetin cofactor
activity)

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Experimental
1. Platelet function analyser assay (PFA 100)
- assesses the VWF-platelet interaction
- measures platelet plug formation in citrated whole blood,
- sample is aspirated through a capillary tube to a collagen + epinephrine
or a collagen + adenosine diphosphate-coated membrane that contains a
central aperture. The time to closure of the aperture by the forming
platelet plug is measured.
- closure time is dependent upon both VWF and intrinsic platelet function.

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HADES

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Heyde syndrome
Described in 1958 by Edward C Heyde, a Canadian internist.
Severe aortic stenosis (AS) + gastrointestinal bleeding due to
angiodysplasia
Acquired type 2A vWD

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https://en.wikipedia.org/wiki/Heyde%27s_syndrome

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Correlation between AS and Angiodysplasia?

AS was present in 31.7% in patients with AVMs and 14.0% in the general population.
(p<0.001)
Significant AS was 2.6 times more common, and severe AS was 4.1 times more
common, in patients with AVMs than in the general population.
Age and sex were not associated with Heyde syndrome.
BUT.
Both diseases are associated with ageing and found more in elderly
populations.

n Batur, MD; William J. Stewart, MD; J. Harry Isaacson, MD. Increased Prevalence of Aortic Stenosis in
ents With Arteriovenous Malformations of the Gastrointestinal Tract in Heyde Syndrome. Arch Intern Med. 2003;163(15):1821-1824

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Gordon E. Pate, Mann Chandavimol, Sheldon C. Naiman et al. Heyde's Syndrome: A review. The Journal of
heart valve disease (Impact Factor: 0.75). 10/2004; 13(5):701-12.

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Does AS cause angiodysplasia?

Altered pulse waveform in aortic stenosis
Cholesterol crystal embolisation from the aortic valve
Chronic low grade hypoxia causing sympathetic vasodilation and smooth
muscle relaxation progressing to true ectasia of vessel walls

1. Review Heyde's syndrome: a review.Pate GE, Chandavimol M, Naiman SC, Webb JG. J Heart Valve Dis.
2004 Sep; 13(5):701-12.
2. Bleeding from the right colon associated with aortic stenosis.Boss EG Jr, Rosenbaum JM. Am J Dig Dis.

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Does replacing valve eliminate Heyde

syndrome?

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(r = 0.56, P<0.001).

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Caspar, Jessel and Desprez et al. 2014

49 patients pre and post TAVI
Mean aortic transvalvular gradient was inversely proportional to levels of vWF
antigen, vWF:RCo and vWFCB

1/52 after procedure significant increase in all cohort of:

vWF:Ag (3.32 vs 2.29 IU/ml, p<0.001)
vWF:RCo (2.98 vs 1.86 IU/mL, p < 0.001)
vWF:CB (3.16 v 2.16 IU/mL, p < 0.001)
No data on longer follow up levels

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Retrospective study assessing Major Late Bleeding complications (>30days post TAVI)
from PARTNER-1 trial (multicenter, randomized clinical trial TAVR vs surgical AVR in
high risk patients)
2,401 pts
Gastrointestinal complications (n = 58 [40.8%]), neurological complications (n = 22
[15.5%]), and traumatic falls (n = 11 [7.8%])

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Conclusion
Post-TAVR paravalvular aortic regurgitation may represent the
perfect storm for acquired thrombophilia, ultimately leading to
major bleeding events.This biological phenomenon may
beamplified byusing aggressive antiplatelet therapy and/or
anticoagulation therapy

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Summary
The correlation between angiodysplasia and severe AS is compelling, but potentially
corrupted by age as a confounder.
The aeitiology of the relationship between angiodysplasia and AS is unclear.
The current evidence, despite a lack of prospective studies seems to point toward a
preponderance towards inherited thrombophillia in high grade AS, which is temporarily
but not sustainably reversed by aortic valve replacement (both surgical and TAVR)

Thank you