1. HAEMATOLOGY IN THE ICU
Bryony Ross
3/8/2010

2. Topics Anaemia Thrombocytopaenia Blood products and their use
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

3. 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

4. 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

5. Thrombocytopaenia Plt count <100 Plt count <50 EXTENSIVE causes
~40% of ICU patients
Plt count <50
~ 10-20% of ICU patients
EXTENSIVE causes
Again, usually multifactorial

6. 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

7. 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)

8. Schistocytes
underlying thrombotic microangiopathy
TTP/HUS/DIC
MAHA

9. Poikilocytes or nucleated RBC
Myelophthisic process (severe sepsis, MF, metastatic ca)

10. Abnormal leukocytes
Malignancy, myelodysplasia, or syndrome of congenital thrombocytopaenia

11. 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

12. Thrombocytopaenia – massive transfusion
Transfusion of more that 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.

13. 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 (timentin), vancomycin, cephalothin, carbamazepine, hydrochlorothiazide, nonsteroidal antiinflammatory drugs, phenytoin, procainamide, quinidine and quinine, rifampin, sulfasalazine, sulfonylureas, and valproic acid.

14. 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

15. 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)
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.

16. 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

17. 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

18. HITT HITT screen Alternate anticoagulation
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 (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 ;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 ;101:502–7.
Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med ;344:1286–92.

19. 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

20. 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

21. TTP
Pathogenesis unclear, likely involves 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

22. 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.

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

24. DIC

25. 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 VIIa to initiate coagulation
TNF, IL-1, and neutrophil elastase all damage the endothelium, causing the expression of TF.

26. DIC

27. DIC
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.

28. 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)

29. 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

30. 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)

31. 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

33. Coagulation – the basics
The tissue-factor VIIa complex is the most important in vivo initiator of coagulation

34. 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

35. Coagulation – the basics
In Vitro

36. 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

38. 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

39. A few notes on coags pH Temp has similar effect
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

40. 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

41. Malignant Haematology in the ICU
Usually post chemotherapy or diagnosis febrile neutropaenia

42. 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

43. 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

44. 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 )
FFP
10-20 ml/kg
Cryoprecipitate
5-10ml/kg
See Clinical Practice Guideline on Kaleidoscope

45. Warfarin Reversal Guidelines

46. 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

47. 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)

48. Last words Clexane can’t be reversed
Always monitor clexane – Xa levels in renal impariment (and pregnancy)
If someone is adequately anticoagulated, they don’t need a second anticoagulant
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

49. 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
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!!!

50. Thanks!
Feel free to drop in to the lab for advice and to meet the lab staff.
Any Questions???????