Transcript Haematology in the ICU

HAEMATOLOGY IN THE ICU
Bryony Ross
3/8/2010
Topics


Anaemia
Thrombocytopaenia
 DIC/TTP/HUS
 HITTS
–
Blood products and their use
 Selected

Recombinant products
Coagulation
 Interpretation
of investigations
 Common causes of deranged coags


Tips and tricks
A few quick notes on malignant haematology
Anaemia
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
Develops in almost all patients in ICU for prolonged
periods
Patients on mechanical ventilation receive ~75% of
all red cell transfusions
 Usually

multifactorial
erythropoietin production and blunted response
 Bleeding
 Frequent phlebotomy
Anaemia – investigation of cause

Simply,

production
 loss
  destruction of red cells


Exclude ongoing bleeding in surgical and trauma
patients
Consider haemolysis
 Particularly
in the transfused patient (transfusion
associated haemolysis)
 Bilirubin,  reticulocyte count, LDH,
haptoglobins, characteristic blood film
Thrombocytopaenia

Plt count <100
 ~40%

Plt count <50
~

of ICU patients
10-20% of ICU patients
EXTENSIVE causes
 Again,
usually multifactorial
Thrombocytopaenia – pt evaluation


History of prior thrombocytopaenia and setting in
which it occurred
Underlying marrow disease and preexisting
morbidities that can induce chronic
thrombocytopaenia
 Liver
disease (and Etoh intake)
 Neoplasia
 ITP
 Massive transfusion
 Medications
The blood film

EDTA clumping (pseudothrombocytopaenia)

Exclude by repeating test with citrate tube (note: can’t be
added on if coags have already been performed on the
sample)

Schistocytes
 underlying
thrombotic
microangiopathy
 TTP/HUS/DIC
 MAHA
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Poikilocytes or
nucleated RBC
 Myelophthisic
process
(severe sepsis, MF,
metastatic ca)

Abnormal leukocytes
 Malignancy,
myelodysplasia, or
syndrome of congenital
thrombocytopaenia
Thrombocytopaenia - infection

Common in critically unwell patients
DIC
 “Endothelial damage syndrome” – eg meningococcus,
pneumococcus


Platelets clump and block capillaries and  platelet consumption
Enhanced clearance of platelets coated by antiplatelet
antibodies or nonspecifically bound immunoglobulin
 Accelerated platelet phagocytosis induced by 
concentrations of macrophage colony-stimulating factor
 Infection of bone marrow stromal cells and megakaryocytes
with viruses


Treat underlying infection and plt transfusion

Aim for plt count 15-20
Thrombocytopaenia – massive transfusion
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

Transfusion of more that 15-20 units of RBC can
lead to dilutional thrombocytopaenia
Platelets still functionally normal
Hypothermia, platelet dysfunction and dilutional
coagulopathy (if not properly treated) will also
lead to bleeding in the massively transfused
patient.
Levy JH. Massive transfusion coagulopathy. Sem Hematol.2006;43:S59–63.
Drug induced thrombocytopaenia
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

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Diagnosis of exclusion – need temporal relationship,
usually resolves about 7-10 days after cessation of
drug
heparin – discuss separately
Variety of mechanisms
Usual offenders

trimethoprim/sulfamethoxazole, beta-lactam antibiotics
(timentin), vancomycin, cephalothin, carbamazepine,
hydrochlorothiazide, nonsteroidal antiinflammatory drugs,
phenytoin, procainamide, quinidine and quinine, rifampin,
sulfasalazine, sulfonylureas, and valproic acid.
Heparin induced thrombocytopaenia
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Most common cause of drug-induced, antibodymediated thrombocytopaenia
1-2 % of pts on heparin with develop isolated
thrombocytopania (HIT)
In ~30 of those patients, thrombocytopaenia is
accompanied by thrombosis (HITT)
 Both
conditions are 5-10 times more likely in patients
treated with UFH vs LMWH
 Neither condition has been reported with fondaparinux
HITT
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Clinical diagnosis
Consider in patients with an otherwise unexplained
fall in plt count of at least 50% occurring 5-14 days
after starting heparin
NOTE: with recent heparin exposure (within the preceding 36 months, HITT can occur within a much shorter timeframe
(median 10.5 hours)
 HIT should be considered in the differential diagnosis of
patients with new or recurrent venous or arterial
thromboembolism that develops during or shortly after
exposure to heparin.

HITT

Several HITT screening questionnaires available,
which indicate the pre-test probability prior to blood
investigations (ask the Haem reg)
Pre-test probability is extremely important when
interpreting results
 ie. Please don’t order this test without talking to us

HITT

Thrombocytopaenia is the lesser concern
 Bleeding

is very uncommon
Thrombosis is often severe and life-threatening
 Venous
thrombi more common except in pts with
underlying arterial vascular disease
 Mortality ~20%
 Limb amputation ~10%

50% of patients will develop thrombosis on cession
of heparin if alternate anticoagulation is not
initiated
HITT
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HITT screen

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Immunologic measurement of antibodies against heparinPF4 complexes or the ability of such antibodies to activate
platelets
Alternate anticoagulation

Lepirudin
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
Intravenous infusion, Monitored using APTT
Cease warfarin (associated with worsening venous thrombosis, venous
limb gangrene, and/or skin necrosis)
Talk to Haematology
Warkentin TE. An overview of heparin-induced thrombocytopenia syndrome. Sem Thromb Haemost.
2004;30:273–83
Aster RH. Drug-induced immune cytopenias. Toxicology.2005;209:149–53.
Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Med.
1996;101:502–7.
Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med.
2001;344:1286–92.
Thrombocytopaenia – TTP/HUS
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TTP and HUS
 Thrombotic
microangiopathies associated with
microangiopathic haemolytic anaemia and
thrombocytopaenia
Both can be associated with neurologic abnormalities, renal
dysfunction and fever
 TTP usually has  incidence of neurologic manifestations
 HUS usually has  incidence of renal dysfunction
 Generally, microangiopathic haemolytic anaemia and
thrombocytopaenia without another apparent cause is sufficient
criteria to start treatment

HUS

2 main variants
 Most
common is following VTEC with abdominal pain
and bloody diarrhea
 ~ 20% of patients progress to HUS and ARF within 5-6
days
 Most common in paediatrics and in epidemics
 Second is in post-partum period
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

Also familial form associated with deficiency of
complement factor H
HUS not usually associated with ADAMTS13
Does not respond as well to plasma exchange
TTP
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Pathogenesis unclear, likely involves deficiency of vWFcleaving protease (ADAMTS13) leading to  in ultralarge vWF multimers that bind to platelets and induced
agglutination
ADAMTS13 deficiency is most often due to antibodies
against the protease
HAPS is the only lab in NSW that offers ADAMTS13
testing
However,  ADAMTS13 can also occur in liver disease,
pregnancy and DIC

Levels in these conditions are usually about 5% and levels
below this range appear to have high specificity for TTP
TTP
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Fatal in >90% of cases if untreated
Plasma exchange induces remission in ~85% of patients
 Corticosteroids controversial
 ~30% of cases will relapse within 12 months, and some pts
relapse multiple time
 Splenectomy can be useful to  relapse
 Rituximab can be used for refractory cases

George JN. How I treat patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.
Blood.2000;96:1223–9.
McCrae KR, Sadler JE, Cines DB. Thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome.
In: Hoffman R, Benz EJ Jr, Shattil SJ, et al., eds. Hematology: Basic Principles and Practice. Philadelphia:
Elsevier, Churchill, Livingstone; 2005:2287–304.
Sadler JE, Moake JL, Miyata T, et al. Recent advances in thromboticthrombocytopenic purpura.
Hematology: ASH Education Program Book. Washington DC: American Society of Hematology;
2004:407–23.
Thrombocytopaenia – catastrophic
antiphospholipid antibody syndrome
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Rare
Characterized by multiorgan involvement by
microthrombi and thrombocytopaenia
Only 15% have shistocytes on film
Guidelines for diagnosis
Lupus anticoagulant +/- antiphospholipid antibodies
 Involvement of 3 or more organs
 Development of manifestations within 1 week or less
 Confirmation of histopathology of small vessel occlusion in at
least one organ
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Treat with plasma exchange, aggressive
anticoagulation and antibiotics
DIC
DIC
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DIC results from the disordered
regulation of normal
coagulation
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Excess thrombin generation with secondary
activation of the fibrinolytic system.
Uncontrolled thrombin and plasmin
generation results in consumption of clotting
factors and proteolysis of platelet
membrane glycoproteins.
DIC is triggered by diseases that promote
the expression of TF, which then complexes
with factor VIIa to initiate coagulation
TNF, IL-1, and neutrophil elastase all
damage the endothelium, causing the
expression of TF.
DIC
DIC
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
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Sources of TF (apart from trauma and sepsis) include damaged
cerebral tissue; promyelocytic, myelomonocytic, and monocytic
leukemia cells; and placental tissue substances associated with
obstetric catastrophes.
Cysteine proteases and proteases derived from mucin- producing
adenocarcinomas or snake venoms can also directly activate
coagulation factors to induce DIC.
Acute hemolytic transfusion reactions promote DIC indirectly
through the formation of circulating immune complexes that
activate complement or directly by the toxic effects of damaged
erythrocyte membranes; both of these processes result in
endothelial cell damage.
Hypotension from any cause can result in endothelial cell
damage, triggering DIC.
DIC

The clinical and laboratory manifestations of DIC result from
the combined effects of thrombin and plasmin produced in
excess of that required for normal hemostasis.
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Bleeding from venepuncture sites
Spontaneous thrombosis
Lab diagnosis

Evidence of fragmentary haemolysis, fibrinogen and platelet
consumption, combined with enhanced fibrinolytic activity




ie  fibrinogen,  platelets,  XDP’s, and characteristic blood film
PT is usually prolonged, reflecting coagulation factor consumption
APTT is variable, depending on FVIII levels
TT is prolonged (interference by FDP with fibrin polymerization
+/- hypofibrinogenaemia)
DIC - treatment


Treat underlying disease process
Treat the coagulopathy that results in the thrombotic
and haemorrhagic manifestions
 Patients
who are bleeding or who have thrombosis
require treatment of their coagulopathy



Maintain platelets >20
FFP to replace consumed coagulation factors
Cryoprecipitate if fibrinogen <1.5
DIC – further treatment

Failure of the plt count or fibrinogen level to
increase despite vigorous replacement = ongoing
consumption (common)
 Heparin
(low doses, 10 units/kg/hr) may be used to
block activation of the coagulation system, or if there is
thrombosis
 Fibrinolytic inhibitors - ε-aminocaproic acid or
tranexamic acid not useful (exaggerate the thrombotic
component)
DIC – other treatment

Use of endogenous inhibitors of coagulation as a
specific therapy for severe sepsis
 Often

complicated by DIC
Recombinant APC in a 96 hr infusion was shown to
improve survival in a recent trial
 Pts
with significant coagulopathies or
thrombocytopaenia were excluded

Antithrombin has not been shown to be effective in
improving survival with sepsis
Coagulation – the basics

The tissue-factor VIIa complex is the most important
in vivo initiator of coagulation
Coagulation – the basics

TF is a transmembrane protein expressed by fibroblasts
in the subendothelium
During activation of coagulation in response to vascular
injury, TF is expressed on the surface of monocytes and
endothelial cells
 Coagulation is initiated when circulating FVIIa binds to TF,
activating trace amounts of factor X and factor IX.
 After VIIa and TF bind, generation of a definitive clot
requires production of small amounts of thrombin (by factor
Xa) followed by further generation of thrombin (mediated
by XI, VIII, and V)
 Large amounts of thrombin are crucial to cross-link fibrin
(FXIIIa) and reduce fibrinolysis

Coagulation – the basics

In Vitro
Coagulation - tests

PT and APTT measure the integrity of the
coagulation system
 Sensitivity
of different PT and APTT reagents to
deficiencies of coagulation factors or to the presence of
inhibitors may vary.
 Ideally, results are abnormal only when a coagulation
factor deficiency is severe enough to be clinically
important
 Eg.
APTT should not be sensitive to factor VIII or IX levels
that are >50% of normal
A few notes on coags

“coags” on a request form = PT and APTT
 The
lab only adds on a TT if one or both is abnormal
 The lab will do a protamine correction if there is a
suspicion of heparin contamination (ie a prolonged
APTT)
 The lab will do a lupus anticoagulant if this is suspected
(when there is a coag scientist in the lab)

NOTE: Our coag machine corrects for lupus – ie. Lupus
anticoagulants will not give a prolonged APTT in our lab
 It
is possible to have a normal PT and APTT and a
fibrinogen of <1.5
 Fibrinogen levels are not affected by heparin unless the
sample is grossly heparin contaminated

APTT > 100
A few notes on coags

pH
 At
a pH < 7.2, clotting is severely impaired
 If pH <7.0, clotting WILL NOT occur
 Treatment is to reverse the acidosis and give products
as directed by APTT/PT/Fibrinogen as required.

Temp has similar effect
A few notes on coags

Don’t forget about vitamin K

in chronic malnutrition (including those with alcohol
dependency) or conditions that limit absorption of dietary
vitamins such as biliary obstruction, coeliac disease,
ulcerative colitis, regional enteritis, cystic fibrosis, short bowel
syndrome or intestinal resection (particularly of the terminal
ileum, where fat-soluble vitamins are absorbed).
 In addition, some drugs may reduce vitamin K levels by
altering liver function or by killing intestinal flora that make
vitamin K
Malignant Haematology in the ICU

Usually post chemotherapy or diagnosis febrile
neutropaenia
Random other useful stuff

Blood transfusion site on the intranet
 Lists
all blood products available
 Has protocols for administration

ARCBS
 Blood
products
 Useful physiology stuff for exams
 Paul
says it is more up to date than Brandis
Massive Trauma

What’s in the MTP
MTP1 – 4 PRC, 4 FFP, 10 Cryo
 MTP2 – 4 PRC, 4 FFP, 1 plt


Why can’t I use this outside the setting of trauma?
In the absence of hypovolaemic shock and significant liver
dysfunction, exchange of one circulating plasma volume
does not reduce the clotting factor activities below levels
necessary to maintain haemostasis (ie 50%)
 Use PT/APTT/fibrinogen to guide factor replacement
therapy
 Thrombocytopaenia is the most frequent abnormality
associated with massive transfusion
 Talk to haematology

Blood products in Children

Red blood cells


Packed cells (mls) = wt (kg) x Hb rise required (g/L) x 0.4
Platelets
 5-20ml/kg

FFP
 10-20

(will raise plt count by 50-100)
ml/kg
Cryoprecipitate
 5-10ml/kg

See Clinical Practice Guideline on Kaleidoscope
Warfarin Reversal Guidelines
Blood Products

Prothrombinex
 Indicated
in prophylaxis and treatment of bleeding in
patients with single or multiple congenital deficiencies
of factor II or X and in patient with single or multiple
acquired prothrombin complex factor deficiency
requiring partial or complete reversal (eg warfarin)
 Contraindicated
in patients with thrombosis or DIC
Blood Products

Novo7
 Treatment
of deficiency of Factor VIIa or for treatment
of massive uncontrolled bleeding
 Cardiac
surgery, post partum haemorrhage and trauma
 The
use of Factor VIIa in those with advanced
hypovolaemic shock is futile
 MUST





have
Surgical haemostasis
pH above 7.18
Temp above 35
Platelet count above 50
Adequate fibrinogen to clot (give cryo first)
Last words

Clexane can’t be reversed


If someone is adequately anticoagulated, they don’t
need a second anticoagulant


Always monitor clexane – Xa levels in renal impariment (and
pregnancy)
ie. Wait for the INR to fall before starting a patient on
heparin
All fragment comments on a film are not haemolysis
Most commonly seen in renal impairment
 Always do an LDH and retics if you suspect haemolysis


Everyone in ICU probably needs a Fibrinogen when
their coags are checked

To assess coagulation requires APTT/PT/fibrinogen and
platelet count
Last words

Think about using Ptx for a prolonged PT/APTT in liver disease
if there is bleeding or require surgery if fluid volume is an
issue

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

25 units/kg + one bag of FFP (for extra VIIa) = about 4 bags of FFP
There is a finite number of plt bags in the shaker – that is why
you need to ask for them – we often run out and have to
triage usage
Please be nice to the lab staff – they are there to help you – if
you really need a result, call and tell them it is urgent!
Don’t panic if your CXM gets refused – we can (and will)
always give emergency O negative blood
In desperation you can use a (well labelled) swab for a blood
group.
Please give blood – we need (and use) lots of it!!!
Thanks!


Feel free to drop in to the lab for advice and to
meet the lab staff.
Any Questions???????