I think we are all in violent agreement here actually. It’s not at all clear that TRT or Hct was the cause although previous study has shown correlation between Hct and VT (not causation between Hct and VT). See this review and paper cited therein. So I am agreeing that the Provider above may have little evidence to throw the event at TRT/Hct but worth being cautious since we don’t completely understand it.
As stated previously many many times, primary concern with elevated Hct would be potential wear and tear on the heart but clotting issues do get discussed and correlate with elevated Hct. The rub is that both clotting and elevated Hct may be correlated to another (not fully understood) cause(s).
An increased risk of venous and arterial thrombosis in relation to primary erythrocytosis has been well described. However, the mechanisms are complex and being debated14 and a direct relation between the hematocrit level and the risk of venous thrombosis is not clearly present in these conditions. An old study from 1978 found a striking correlation between hematocrit level and thrombosis in patients with polycythemia vera,15 but this correlation was not confirmed in a recent study in which no such relation could be demonstrated.16
With respect to the association of venous thrombosis with hematocrit in the general population, data are scarce and inconclusive. Vaya et al. performed a case-control study in 109 patients with a first deep vein thrombosis, without thrombophilia, and 121 healthy controls. They reported that the percentage of cases with a hematocrit above 45% was higher in cases than in controls, i.e. 43% versus 27%. The association was attenuated when several other factors were included in a multivariate model.17 In one other population-based study (the LITE study, a cohort study in subjects above 45 years of age), no relation between high hematocrit levels and risk of venous thrombosis was demonstrated, but the authors used a relatively low cut-off level for the hematocrit (43.5%).18
The strengths of the new study by Braekkan and colleagues are that it is large, prospective, and carried out in a general population with a high response rate, a long follow-up, and well-validated venous thrombotic events.2 We may, therefore, assume that the link found between high hematocrit and risk of venous thrombosis is real, but again, the important issue is to decide whether or not the relation is causal or explained by other diseases.
Hematocrit is one of the major determinants of blood viscosity,5 and increases in the hematocrit might favor clot formation by increasing the residence time of circulating platelets and coagulation factors adjacent to dysfunctional endothelium. Furthermore, elevated hematocrit has been shown to promote the transport of platelets towards the vessel wall, thereby increasing the interaction with the vasculature.23 Blood clotting is also dependent on the velocity gradient at which the clotting takes place. The influence of the hematocrit on blood viscosity increases when the shear rate decreases.5,24 Under low-flow conditions, such as in the venous system, increases in hematocrit may have a strong influence on blood flow and, thereby, clinical outcome.
RBC mass may also have a direct effect on thrombotic mechanisms. A recent experimental study investigating the effect of RBC on thrombin generation, showed that the total amount of thrombin activity generated, and the maximum concentration of thrombin achieved, was proportional to the hematocrit.25 RBC may also take part in thrombus formation by other mechanisms, such as stimulation of platelet aggregation through ADP release,26–28 or possibly through the exposure of phosphatidylserine.29
The main strengths of our study are its prospective design, the large number of participants recruited from a general population with high attendance rate, the long-term follow-up, and the validation of the venous thromboembolic events. All hospital care and radiological imaging in the region is provided exclusively by a single hospital, which enhances the possibility of a complete VTE registry. However, the study has some limitations. Modifiable risk factors, such as hematocrit and related hematologic variables, are a potential weakness of cohort studies, especially when the time between exposure and disease manifestation is long. However, this type of non-differential misclassification generally leads to underestimation of the true associations. In our study, smoking was assessed as a dichotomous variable (current smoker: yes/no). Thus, we were unable to take into consideration the potential dose-dependent effect of smoking on hematocrit, and thereby unable to remove all possible confounding by smoking. Underlying medical conditions such as lung, heart and kidney diseases can influence the level of hematocrit. In our study, information on other medical conditions was only available for those who developed VTE. In men, the presence of other medical conditions did not differ across various levels of hematocrit ( data not shown ). In women, the presence of other medical conditions was slightly higher among those whose hematocrit was in the upper 20th percentile. Since there was no available clinical information on underlying disease during follow-up in the reference group, we did not have sufficient clinical information for the total population to consider underlying disease as a possible cause of high hematocrit and risk of thrombosis in detail.
In conclusion, hematocrit and the related variables hemoglobin and RBC count were identified as risk factors for VTE in our prospective, population-based study. The size of red blood cells, expressed as MCV, was not associated with VTE. Our findings may suggest that hematocrit should be taken into consideration for risk assessment in VTE.