Correlation between thrombocytopenia and the development of PHH
Póvoa et al. [
23] reported that fetal/neonatal alloimmune thrombocytopenia is one of the most common causes of severe thrombocytopenia in the newborn. It results from fetomaternal mismatch for human platelet alloantigens leading to antibody-mediated destruction of fetal platelets. In severe cases, intracranial hemorrhage may occur and lead to death or neurologic sequelae. On the contrary, Bu et al. [
24] explained in adults the development of PHH as a sequel of IVH; they focused on the mechanisms of hydrocephalus after adult IVH, including blood clot blockage, barrier impairment, inflammation, and blood components. Hence, a normal coagulation function is needed to develop the full-blown picture of PHH. Clinically, hematoma volume after GMH-IVH is a prognostic indicator of future neurologic outcomes [
25‐
27]. Various preclinical models of stroke have shown that rapid hematoma clearance after hemorrhagic stroke ameliorated inflammation and improved neurological deficits in the short and long terms [
28]. Rappard et al. [
29] found that the blood clot firmness is highly depending on the platelet count and that thrombocytopenia results in a soft unstable clot. Similarly, thrombocytopenia may help in the decrease of clot formation with its sequelae of blockage, barrier impairment, and inflammatory reaction, and even if the intraventricular hematoma is formed it is not firm and usually resorbs faster.
In our cohort, we found that initial thrombocytopenia was detected in more patients who developed IVH (group B) in comparison with the control group (group K) 21.1% vs 11.9% (p value 0.052) but statistically not significant. This could be explained either that thrombocytopenia is the cause for IVH through a bleeding tendency or as a sequel through consumption of platelets in forming the blood clot in the ventricular system. Regarding the two groups who developed IVH, we found a marked increase in the incidence of thrombocytopenia in the group who did not develop PHH (group B2) in comparison with those who developed PHH (group B1) 25.9% vs 2.7% (p value 0.002). This raises the assumption that the platelet count may be crucial in deciding whether, after development of the IVH, the cascade will continue to develop PHH or the process will be less severe with less damage and less sequelae evading the development of PHH.
TGF-β stimulates mesenchymal stem cells and fibroblasts, which produce ECM matrix proteins and deposit connective tissue (Bowen et al. 2013). TGF-β can be secreted from activated microglia, and TGF-β secretion can be induced by thrombin (Schuliga 2015). ECM production induced by TGF-β stimulation may deposit in the cerebroventricular system, disrupting CSF dynamics (Tada, Kanaji, & Kobayashi, 1994). A rabbit pup GMH model indicated TGF-β, fibronectin, and laminin expression levels were significantly increased in the ependymal and subependyma tissues after GMH (Cherian, Thoresen, Silver, Whitelaw, & Love, 2004a). Mice with transgenic TGF-β overexpression developed hydrocephalus with higher expression of ECM proteins in the brain than wild types (Wyss-Coray et al., 1995). In a clinical study, increased TGF-β1 and ECM protein expression in the CSF were associated with PHH development in preterm infants (Aquilina, Chakkarapani, & Thoresen, 2012; Douglas-Escobar & Weiss, 2012). The TGF-β1 isoform is mostly associated with PHH after IVH in neonates and adults (Gomes, Sousa Vde, & Romao, 2005). Intrathecal TGF-β1 injection in mice resulted in hydrocephalus development, and TGF-β1 expression was significantly increased in brains of neonatal rats with PHVD after intraventricular blood injection (Cherian, Thoresen et al., 2004a; Tada et al., 1994). Indeed, TGF-β1 was elevated in both animal models and premature infants with PHH, although some studies dispute this (Heep et al., 2004). In a rat GMH model, TGF-β1 was elevated within hours after GMH, but normalized by 24-h post-ictus (Tang, Chen et al., 2015). Additionally, inhibiting TGF-β1 ameliorated long-term PHH and neurocognitive deficits as well as reduced vitronectin and GFAP expression in rats (Manaenko et al. 2014). Although the mechanism of TGF-β signaling after GMH and its association with PHH development has been established, studies are lacking that discern the changes to CSF dynamics as a consequence of TGF-β signaling and fibrosis.
Transforming growth factor β1 (TGF-β1) is a platelet-derived cytokine involved in both normal wound healing and scarring [
30]. TGF-β activates mesenchymal stem cells and fibroblasts, to produce extracellular matrix (ECM) proteins and deposit connective tissue [
31]. TGF-β can be secreted from activated microglia, and its secretion can be induced by thrombin [
32]. Monroe et al. [
33] showed that platelets play a major role in localizing and controlling the burst of thrombin generation leading to fibrin clot formation. Additionally, the increased level of ECM proteins, induced by TGF-β stimulation, may lead to its deposition in the cerebroventricular system and disruption of the CSF dynamics causing hydrocephalus [
19,
34]. Mice with transgenic TGF-β overexpression developed hydrocephalus with higher expression of ECM proteins in their brains than wild types [
35]. Intrathecal TGF-β1 injection in mice resulted in development of hydrocephalus, and TGF-β1 expression was significantly higher in brains of neonatal rats with post-hemorrhagic ventricular dilatation after injection of blood intraventricular [
34,
36]. In a clinical study, increased TGF-β1 and ECM protein expression in the CSF was associated with PHH development in preterm infants [
37,
38]. Additionally, inhibiting TGF-β1 minimized the long-term PHH and neurocognitive deficits in germinal matrix hemorrhage (GMH) model in rats [
39]. Although the mechanism of TGF-β signaling after GMH and its association with PHH development has been established, we are still in short of studies that detect the changes to CSF dynamics as a consequence of TGF-β signaling and fibrosis.
To summarize, platelets play a decisive role in fibrin clot formation and to a major extent decide its firmness and stability. Additionally, platelets through mediating TGF-β complex play an important role in the development of the astrogliosis disrupting the CSF dynamics intraparenchymally and contributing to the development of PHH. Hence, we hope that through further studies focusing on these information, we could help to minimize the incidence of development of PHH following IVH in neonates.