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Coagulation Corner
Monday, April 5, 2010
KIDDIE COAGULATION
Kiddie Coagulation
A Case Study Approach
Coagulation is complicated enough considering the issues with pre-analytical variables, interfering substances and reagent sensitivity. When you have a pediatric sample the puzzle becomes even more difficult. One of the largest considerations is that most tests in the laboratory are based on adult ranges.
How do you interpret pediatric results? How do you treat pediatric patients? Establishing normal ranges on apparently healthy children is a daunting task.
To obtain that patient population is very difficult. It is also difficult to obtain that population to determine dosing of anticoagulants and administering products.
Being a pediatric hematologist requires the expertise to be able to look at each piece of the puzzle before putting it in place to make a complete picture.
A study using retrospective chart review including variables of age and gender in pediatric patients have demonstrated that the most significant assessment of coagulopathies is the presence of symptoms and a positive family history. (SHAH, CLINICAL PEDIATRICS) One of the first studies that looked at developmental hemostasis was conducted by Maureen Andrews MD from Children's Hospital in McMasters University in which age specific ranges were determined for neonates, infants and ranges up to 18 years of age for coagulation parameters demonstrating the differences between adults and children. Reasons for this include difference in the:
1. Concentrations of components in the hemostatic system.
2. Turnover rate of components in the coagulation cascade
3. Rate of synthesis
4. Ability of the coagulation and fibrinolytic systems to generate and
Regulate plasmin and thrombin. (ANDREWS 1989)
Since then a few other studies have been conducted using new coagulation reagents and analyzers. One study looked at 902 healthy children from the age range of 7-17 and found differences in the PT, F VIII and von Willebrand factor versus adult ranges, as well as age dependent differences in FIX and FXI. (RODGERS, CLINICAL CHEM 2005.)
It was also noted that the coagulation system of children has a reduced incidence of thrombosis without an increased risk of bleeding. This supports the concept that patients with thrombophilia usually do not present until early adulthood. Also children rarely present with thrombosis when undergoing prolonged stasis or following surgery. (Mongale et al) However, coagulation parameters of Antithrombin, Protein C and S are reduced in neonates as well as throughout childhood.
Understanding all of these nuances relating to pediatric coagulation samples as well as working with very small volumes all are needed when looking at results and reflexive testing.
Case 1:
A 7 year old boy with chronic sore throats and ear infections is scheduled for a tonsillectomy and removal of adenoids. His coagulation results are as follows:
PT = 19.2 (10.5-12.5 seconds)
APTT= 40.1 (24.5-34.5 seconds)
Coagulation factors are made in the liver, at the age of 7 years, in the absence of disease, the level of factor production should be comparable to an adult.
These levels are clearly prolonged. The next step would be a mixing study.
PT APTT
Result 19.2 40.1
PNP 12.1 30.0
1:1 mix 18,1 38.8
Whatever range you are looking at, this clearly doesn't correct, so it appears this patient has an inhibitor. It is important to understand the type of reagent you are using, is it lupus sensitive or insensitive and what does that mean? In the laboratory, a lupus anticoagulant manifest as an antibody to phospholipids, which constitutes a large portion of coagulation reagents? A reagent that is lupus insensitive is made with a high concentration of phospholipids; this will overtake or mask the antibody. .A sensitive LA reagent, has a lower concentration of phospholipids that allows the antibody to manifest, resulting in a prolongation of the clotting time. This mostly occurs in the APTT reagents, since PT reagents generally have high concentration of phospholipids. Occasionally an inhibitor can prolong the PT. Clinically, if the patient was bleeding, you would look at specific factor inhibitors. This test was done as a pre-operative screen, so now what is next? A dilute Russell Viper Venom test (DRVVT) which alters the concentration of phospholipids and activated the coagulation cascade at Factor X is performed. In this case the results are normal.
Non specific inhibitor, most likely caused by chronic infections, just a phenomenon, and this child should not bleed due to the presence of a non specific circulating inhibitor. Surgery will proceed.
CASE 2:
A 2 year old little girl is an inpatient in the ICU has had 3 prolonged APTTs results, but has no history of bleeding. The results are as follows:
APTT = 54.8 seconds (25.5-35.5 seconds)
``````` 66.1
60.9
The surgeon needs to determine the cause prior to performing a procedure, and requested a full prolonged APTT workup. The first question anyone should ask in a prolonged APTT on any in-patient is if that patient is receiving heparin. If that can not be confirmed, it may be easier to just run a thrombin time before investing time and money on in-patient factor assays. A thrombin time is the most sensitive test to residual heparin. . Most will be prolonged at 0.1U/ml of unfractionated heparin.
The results are as follows:
Thrombin time = 25.1 second (12-19 seconds)
Pooled Normal Plasma = 16.1 (11-18 seconds)
A thrombin time detects abnormalities to fibrinogen. We can use Reptilase to distinguish between heparin and a fibrinogen deficiency. Reptilase is expensive, and fibrinogen deficiencies are rare. Additionally, you would see a prolongation in the PT as well as a decreased fibrinogen. How can we get the clinician a good answer? You can use HEPZYME© (Siemens)This will neutralize the presence of heparin in the sample..
Place 0.5=1.- ml of plasma into HEPZYME for 16 minutes-
The sample can them be re-run for an APTT:
APTT = 33.0
Result is normal; no additional testing is required for factor assays- the samples were most likely drawn through a line.
CASE 3
A 1 month old needed to have an operation for a strangulated hernia. The baby was given unfractionated heparin for ease of use, and the ability to neutralize an overdose of heparin by administration of protamine sulfate. Patient was given heparin and an anti-Xa activity level was performed.
Results:
Anti-Xa 0.15U/ml anti-Xa, (0.3-0.7U/ml) another dose was given and the anti-Xa was 0.2U/ml heparin. Should more heparin be given or am I putting this patient at a risk for bleeding?
First the range is based on adult therapy levels, a target anti-Xa level of 0,3-0.7 may not be appropriate for a child. Additionally the binding site for heparin is antithrombin, and children have decreased levels of AT. It may be helpful to measure their Level-
1 month old AT = 48%-108%--ANDREWS
72-134% (Mongale)
May not be able to get an accurate result - AT is the binding site for heparin.
CASE 4
A 7 year old girl has a history of easy bruising and her mother has always had heavy menses, but so did her grandmother. The child seems to bleed longer when scraped. A PT and APTT were performed and were within normal limits. Since she had a positive bleeding history, factor assays were also performed and were all normal. A CBC result show normal platelet count, however primary hemostasis should be evaluated. A platelet aggregation would require 30 mls of blood and the child is very agitated and will not tolerate that large volume of blood nor could a bleeding time be performed as the mother refused due to scarring and trauma to the child.
A PFA 100 test was performed.
- ADP/Collagen= 59-120 seconds
- EPI/Collagen= 80-160 seconds
Children's Hospital in Toronto:
Healthy children with normal platelets and HGB =
- EPI/Collagen= 83-163
- ADP/Collagen=72-111
- Healthy neonates:
- EPI/Collagen=61-108
- ADP/Collagen=48-65
Screened with EPI/Collagen = 198
Ran ADP/Collagen = 180
Further investigation: vWF antigen and activity
Decreased, TYPE 1 vWF.
Conclusions:
Dealing with pediatric patients and their parents creates anxiety for everyone. Being able to serve that population and understand the limitations and the variability's that influence their results can improve patient care and outcomes.
REFERENCES:
1. Mongale, P., Barnes, C., Ignjatovic, v., Furmedge, J., et al, Developmental hemostasis; Impact for Clinical Laboratories, Thrombosis and Haemostasis, 2006, 95: 362-372.
2. Rodgers, G., Roberts, W., Flanders, M., Crist, R., Pediatric References Intervals for Seven Common Coagulation Tests, Clinical Chemistry, 2005, 9, 1738-1742,
3. Andrew, M., Paes, B., Johnston, M., Development of the Hemostatic System in the Neonate and Young Infant, The American Journal of Pediatric Hematology and Oncology, 1990, 1:95-104.
Donna Castellone
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About the Author
Donna Castellone,
MS, MT(ASCP)SH
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