HAEMATOLOGY IN THE ICU – TAKE 2Bryony Ross22/2/2010

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

Anaemia

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% of ICU patients

Plt count <50 ~ 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

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

Poikilocytes or nucleated RBC Myelophthisic process

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 Transfusion of more that 15-20 units of RBC

can lead to dilutional thrombocytopaenia 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 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, vancomycin, cephalothin, carbamazepine, hydrochlorothiazide, nonsteroidal antiinflammatory drugs, phenytoin, procainamide, quinidine and quinine, rifampin, sulfasalazine, sulfonylureas, and valproic acid.

Heparin induced thrombocytopaenia Most common cause of drug-induced,

antibody-mediated 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 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 3-6 months, HITT can occur within a much shorter timeframe (median 10.5 hours)

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

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 HITT screen

Immunologic measurement of antibodies against heparin-PF4 complexes or the ability of such antibodies to activate platelets

Alternate anticoagulation Lepirudin

Intravenous infusion, Monitored using APTT Cease warfarin 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

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

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 Pathogenesis unclear, may involve deficiency of

vWF-cleaving protease (ADAMTS13) leading to in ultra-large 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 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 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 Treat with plasma exchange, aggressive

anticoagulation and antibiotics

DIC

DIC DIC results from the disordered regulation of normal

coagulation 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 VII to initiate coagulation TNF, IL-1, and neutrophil elastase all damage the endothelium, causing

the expression of TF. Other sources of TF 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. 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 transexamic 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 as

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)

It is possible to have a normal PT and APTT and a fibrinogen of <1.5

Fibrinogen levels are not affected 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

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 (will raise plt count by 50-100) FFP

10-20 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

Always monitor clexane – Xa levels in renal impariment All fragments 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

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 25 units/kg + one bag of FFP (for extra VIIa) = about 4 bags of FFP

There is a finite amount of plt in cupboard – that is why you need to ask for it – we often run out and have to triage usage

In desperation you can use a (well labelled) swab for a blood group.

Thanks!

Feel free to drop in to the lab for advice and to meet the lab staff.