Intraventricular haemorrhages continue to be a source of concern to families of very preterm babies, and to all of us; severe hemorrhages are associated with poorer outcomes, especially bilateral extensive periventricular haemorrhagic infarction.
This is one of my occasional series of reviews of a particular neonatal issue, that are not particularly triggered by a new publication but by a question about current clinical practice. The question being: “When we find a serious intracranial haemorrhage in an at-risk very preterm baby, should we perform coagulation studies?” and of course the related questions “how should we interpret the results?” and “how should we respond to the results?”
Reviewing the literature for this is frustrating, there are not a large number of publications but they are contradictory.
Some studies have found an association between serious IVH and prolonged clotting times, whereas others have not. Some have shown associations between genetic abnormalities relating to clotting factors, whereas others have not.
Earlier studies from the ’70s and ’80s tended to use the same normal values for babies of all gestational ages. But babies with haemorrhages are generally less mature, and less mature babies have more prolonged clotting times, even in the absence of an IVH. For example, Christensen et al showed that babies under 28 weeks had longer PT and aPTT than babies of 29 to 34 weeks. Neary et al enrolled more extremely immature babies and showed that at 23 to 24 weeks the mean PT was 22.6 s with a Standard Deviation of 7 seconds (at 24 to 25 weeks the mean was 21s), the aPTT was a mean of 83s, with an SD of 37 s in the most immature babies, and 72 s (SD 21s) at 25 to 26 weeks, this study only included babies without serious IVH. Another study by the same group also showed very low concentrations of factors II and IX, and a low concentration of factor VII in the preterm
As more immature babies have more IVH and also have more prolonged clotting times in the lab, then, by chance, there will seem to be an association between coagulopathies and IVH, unless you use gestational age-adjusted normal values, or adjust statistically for GA. It is of course possible that the reason more immature babies have more IVH is because they have disrupted coagulation. The only way to be sure would be to have large numbers of babies with and without IVH of each gestational age and determine within GA strata whether babies with longer clotting times are more likely to have IVH.
We also should remember that as well as lower concentrations of procoagulant factors, newborns, adn preterm newborns in particular also have lower concentrations of anticoagulant factors (Protein C, Protein S, and Antithrombin). Full term newborn at least are at higher risk of thrombotic complications as a result.
In general, among very preterm babies, I find that those studies which prospectively obtained cord blood, or early blood samples prior to the occurrence of IVH show no difference between babies with and without haemorrhages (such as Neary et al 2015). Those which studied coagulation tests taken later on, such as at 48 hours, show more prolonged clotting times in babies with IVH, which suggests that perhaps prolonged coagulation tests are a result, rather than a cause, of IVH. This is illustrated by a study by Beverly et al. Babies who had “grade 4 IVH” had a mean of 28.7 weeks compared to those without IVH (32.3 weeks), cord blood aPTT was somewhat longer in those who eventually developed an IVH, but only by 10 seconds, at 48 hours, those without an IVH had an aPTT which had shortened by 10 seconds, whereas the IVH babies had not changed much, and the difference was then “statistically significant”.
The answer to the first question I asked therefore is “not clear”, it doesn’t appear that there is much difference between the baseline coagulation studies of very preterm babies who go on to develop IVH compared to GA matched controls without IVH, so routinely measuring coagulation studies is of no proven value. Results should probably be evaluated compared to GA appropriate standards if you do obtain them, recognizing that among the most extremely immature infants’ values are not well documented (Neary’s study for example only had 9 babies of 23-weeks).
If you find clotting times which are even longer than GA appropriate standards, what should you do about it? There are four RCTs of Fresh Frozen Plasma use analyzed in the Cochrane Review, which appears to have been last updated in 2004. That review includes all of the interventions which could be classified as “volume expansion” but has one of their comparisons as FFP versus no treatment. The analysis shows no overall difference in IVH between groups, but none of the studies had coagulopathy as an entry criterion. It is interesting that one small controlled trial (Beverley 1985) seemed to show a reduction in IVH with FFP administration, but did not show that FFP improved coagulation study results! The 2 groups had practically identical PT and aPTT after either FFP or no treatment, and only slightly higher fibrinogen concentration after FFP.
To answer my initial questions, then: “When we find a serious intracranial haemorrhage in an at-risk very preterm baby, should we perform coagulation studies?” I would say this is of no proven value, disturbed coagulation studies may be a result rather than a cause of IVH; of course, the occasional patient with congenital coagulation disorders that may warrant intervention may be missed if we never do such tests. Haemophilia A in Canada has an incidence of about 20/100,000 male births, and Haemophilia B is about 4/100,000, Von Willebrand’s is about 12/100,000 births, and other factor deficiencies together are somewhere between Haemophilia A and VWD; so overall about 0.05% of boys and 0.025% of girls.
Given the low risk of missing a congenital disorder, I think it is reasonable to limit coagulation screens to babies with something unusual in their presentation, such as an unexpected IVH, or bleeding in other sites in addition to the IVH; unless, of course, new data in the future demonstrates a clear link between disturbed coagulation studies and the development of IVH.
“How should we interpret the results?” I think we should use GA appropriate standards, with the proviso that different laboratories give different results; but differences between good quality labs are nowhere near the same order of magnitude as the differences between mildly, moderately, and extremely preterm infants. So if your lab does not have good normals for a 25-week infant (for example) you won’t go far wrong using published normal values.
“How should we respond to the results?” I think that unless a baby is actively bleeding we have no evidence that responding to abnormal coagulation studies will improve any outcomes. If we do find a result which is outside of GA appropriate normals, then replacement of the missing factors could possibly be the right thing to do, but volume expansion may be hazardous, so I think giving the replacement as slowly as feasible, or giving factor concentrates if a specific factor deficiency is discovered, should be the approach.
It is also possible that haemorrhages cause disturbances of coagulation which then lead to progression of the grade of IVH, but that also is unproven, and seems to me to be unlikely, as the pathophysiology of the worst haemorrhages appears to be venous infarction rather than continued bleeding.
A large prospective study of very early coagulation studies among babies under 27 weeks gestation, with enough numbers to determine with more certainty the link between coagulopathies and IVH would be great. It is getting harder to obtain cord blood now that delayed clamping is the norm, so such a study would be difficult to complete, but it would really help in the clinical care of our tiniest, at-risk, babies.
Keith, it may be more about the platelets & von Willebrand Factor and less about clotting factors. See “Ontogeny of platelet function” by Andreas Margraf, et al (Germany) in Blood Adv 2019 Feb 26;3(4):692-703.
That’s a really nice platelets article Brian, thanks.
We did a little study in our centre a few years back looking at platelet counts temporally in babies with major IVH. We found the majority became significantly thrombocytopenic *in the wake of* the major IVH; only a small minority of babies were significantly thrombocytopenic *before* the IVH occurred. Sorry never formally written up (yet!), but here’s the abstract:
Thanks Brian, that is a really nice review and it is certainly a possibility that platelet dysfunction plays a role
And thank you Keith for another lovely review.
I think it’s likely that coagulation factors most often get ‘consumed’ in the wake of occurrence of major IVH just as platelets often seem to. You mention that the historical Beverley trial (done 1983-4) found no improvement in coagulation results with FFP transfusion. We (Norwich and Cambridge, UK) also analysed paired coagulation studies done pre- and post FFP transfusion. For 193 plasma transfusion episodes where FFP was administered primarily to correct isolated “abnormal” coagulation values, we found that FFP successfully corrected the APTT and PT back into the normal range in only 15% and 10% of cases respectively. So not particularly effective! And as you allude, may (like platelet transfusions) have associated harms… overload, sepsis, adverse immune effects…etc.
Ref. Catford K, et al. Routine neonatal coagulation testing increases use of fresh-frozen plasma. Transfusion. 2014 May;54(5):1444-5. doi: 10.1111/trf.12610.
Thanks Paul, when I was reviewing this topic, I saw the letter detailing your review, which showed that basically the only impact of routine coagulation studies was to increase FFP use, and that FFP use varied dramatically between the 2 centres involved without any apparent benefit.
Your data on platelets is also fascinating, as I mentioned in the post, I guess it is possible that the consumption of clotting factors and platelets might be a factor in the progression of haemorrhages, but even if that was true, I don’t know what we would do about it. FFP often does not correct abnormal clotting times, and the PLANET-2 trial showed that platelet transfusions seem to lead to more bleeding!
1) We need to be careful when we use the phrase « normal for gestational age » in that it may fit a population descriptor, but physiologically add risk.
2) I can imagine that prolonged coagulation times may add to the severity of the bleed, but should not add to the incidence of IVH. As long as the blood vessel is intact, there will not be bleeding. With disruption of the blood vessel, I can understand a larger bleed in those with longer clotting times.
I agree David, you put it better than I did, but that’s what I meant by the idea that it’s possible that the longer clotting times and higher risk of IVH in the most preterm could be causally related.