Episode 49: Thrombocytopenia Part 2-Managing in Critical Settings

Welcome to Med Pods, the audio podcast from the Department of Internal Medicine at AFMC. In our last edition, we spoke to Karn Lude, Professor of Medicine and Hematologist in the department on a very important issue of approaching thrombocytopenia. The topic that was covered in that episode of podcast was on approaching thrombocytopenia in outpatient settings. But today we move on to approaching the same problem in an intensive care setting where often this issue may be more severe and life threatening at times. So welcome back Uday. Sir, the drawing sir. The last episode was well received and it cleared lot of our concepts about thrombocytopenia and its approach and I am sure when we talk about thrombocytopenia in ICU, it is going to be on similar line with of course certain aspects which are very unique to ICU. So what are the issues as far as when you talk about platelets in ICU settings? So platelets play a very important role in a critically ill patient. It can have both beneficial effects as well as harmful effects. As we discussed in the last podcast, platelets has a huge interplay with endothelium, with inflammation and also as a acute phase reactant. So in critically ill patients, a platelet can lead to activation of macrophages and cup for cells which can further lead to release of chemokines like CCL2. It can also lead to activation of phagocytosis by these macrophages. Platelets can lead to activation of ADP and thrombin and can lead to activation of coagulation cascade. So when we keep wondering the patient with sepsis end up with DIC, so the interplay or the link between these two is platelets. Thirdly, platelets can lead to leukocyte recruitment and activation and it can activate the whole bone marrow system of inflammation of histiocytes and dendritic cells leading to HLH. So when we say sepsis leads to HLH, an important link in between again remains to be platelets. And lastly, this leukocyte recruitment and activation if done well can actually lead to curbing of the bacterial spread and a multi-organ dysfunction. To just summarize, the beneficial effects of platelets in ICU patients could be wound healing and vascular remodelling. It could enhance the integrity of endothelial membranes. It could lead to reduction in vascular permeability and it can help in mediation of various inflammatory processes and host defenses. The harmful effects could be because of aggressive activation of the coagulation cascade, it can lead to multiple minor clots which can lead to impairment of microcirculatory flow and lead to tissue hypoxia leading to lactic acidosis. Simultaneously, it can lead to propagation of inflammation to an extent wherein a patient might have severe SIRS or sepsis syndrome or HLH can which can finally lead to succumbing of that individual in the clinical care settings. Right. So that means managing thrombocytopenia in ICU is of extreme importance as far as survival of the patient is concerned in severe diseases and also the fact that it contributes by itself to the patient worsening. Now how common is this problem in the ICU and if you see in various sets of ICU or if I can say different types of specialties which deal with patients in intensive care, what is the prevalence and incidence? Sir, this is a very complicated and a loaded question to answer because there are two problems in this question. One, as you yourself brought out, it all depends upon which ICU setting are we talking about, are we talking about medical ICU, surgical ICU, are we talking about trauma care settings or cardiac surgeries. All of them have different variations because they are all different sets of people and different amount of platelet activation going on in different subsets of patients. But to keep the answer simple, if we take thrombocytopenia as less than 1.5 lakh, then the prevalence can be as high as 70 percent. The incidence is somewhere between 15 to 50 percent. Why the incidence is lower than the prevalence is most of the patients who end up in ICU already have thrombocytopenia before they come in. But for those patients who develop new onset thrombocytopenia after coming to ICU, it is roughly around 35 to 40 percent that we have. Right, so now when you have such high prevalence in the ICU, I am sure to understand the mechanism and causes becomes equally important. So in ICU setting, what are the usual causes of thrombocytopenia? Sir, I would like to classify my this particular answer into three groups. The commonest causes, the less common and the uncommon ones. When we look at common causes, sepsis, DIC, consumptive thrombocytopenia secondary to any major trauma or extracorporeal circuits, dilution secondary to massive transfusions in trauma settings and myelosuppressive therapies because of the various drugs that we give are the common causes. So to broadly put it again, infection, consumption, dilution. When we talk about less common causes, the important understanding is for the condition known as HITD or Heparin induced thrombocytopenia with thrombosis. As most of the patients in the ICU settings get pharmacological thrombofilaraphylaxis using Heparin. So Heparin can lead to this condition of HID and that can be leading to the thrombocytopenia. And second condition is HLH which is again not very common. So those are the less common causes. Lastly, the uncommon causes would be hematological malignancies, thrombotic thrombocytopenia in perpira or TMAs, thrombotic microangiopathies, immune thrombocytopenias or just a plain simple post transfusion perpira after the patient has been transfused for any other condition. So a PRBC transfusion leading to a post transfusion perpira on a later date. So these are the common, less common and the uncommon causes. Right. So when we discussed thrombocytopenia in the outpatient settings, the mechanism that you told us was whether it is less in production or there is increased consumption or destruction or there is dilution. Now coming to ICU patients where most of the problems are very complex, what I understand is that it could be multiple mechanisms that play in the same patient. So are there any different mechanisms or it is the same mechanisms with different proportion of involvement? Sir, so it is the same mechanisms but with different proportion. Here consumption remains to be the most important cause. But as usual, a good physician should always rule out pre-analytical variables that we have discussed in the last podcast and should take ahead the factors particularly the dilution because of centerline sampling and others. Once we have ruled out pre-analytical variables. Now the important causes are the first and foremost is consumption via thrombin mediated platelet activation. So infections leading to DIC either over or subclinical and this is further leading to thrombocytopenia. So as a physician resident or a young physician, please check for PT, APTT, D-Dimer and Fibrinogen. In every patient who has got a new onset thrombocytopenia in the ICU settings because an ICU patient might not give you all the clear history, symptoms and signs as an OPD patient. So a subclinical DIC needs to be ruled out. Now once we have done that, the next important thing which is important is among all these markers that we have spoken and generally for the DIC all of you use IHCTH scoring. Out of all of them, D-Dimer is the most important marker to follow. So clotting screen can still be normal, Fibrinogen may be normal in 70% of the cases. But if a patient of sepsis is having falling platelet count with worsening D-Dimer, it is DIC until unless proven otherwise. Now second important cause is liver dysfunction. So a plain simple liver enzyme abnormality is not liver dysfunction. So DIC and liver dysfunction, they closely mimic each other. So you should be careful about it. After we have spoken about DIC and liver dysfunction, the third important thing that all of you need to understand is those conditions where the patient has got thrombosis with thrombocytopenia and here again DIC and liver dysfunction. After that please think of catastrophic aplar, HITT, malignancy or TTP as a cause or a thrombotic micro angiopathy as a cause. If the patient in ICU is having other cell lines also afflicted along with thrombocytopenia, consider immune mediated or HLH in such situation and go ahead and do a bone marrow. Now how would I look for a patient who has got other cell lines along with platelet? First I will do a liver and spleen evaluation both serologically and radiologically. Then I will send a DCT-ICT to rule out immune mediated and then I would end up doing a bone marrow for these particular individuals and the best way is to treat them with IVIG whenever you suspect an immune mediated or HLH. Lastly is bone marrow suppression and again the cutoffs with bleeding manifestations without bleeding manifestations are as discussed in the previous podcast. So in a patient in the ICU who has thrombocytopenia while he is being managed in the ICU, does that in any way correlate with the prognosis? Yes sir. Patients with thrombocytopenia are found frequently to have a lower mortality, lower survival or a higher mortality when compared to those patients in ICU without thrombocytopenia. Now there are different studies where they have done and the most important of this is what is known as a PROTECT TRILE and they have clearly shown that those patients with thrombocytopenia with or without thrombocytopenia or those patients who have a gradually declining platelet count irrespective of the patient condition are found to have higher mortality when compared to others. Also it forms an important surrogate for the various scoring that we use like the MOTS 2 score or the Apache scoring or those patients with SOFA scoring. So people have correlated it quite well and it can act as a surrogate marker. Right, so on one hand we say that it is a acute phase reactant and goes up in inflammation but when it starts going down it also correlates with poor survival, so that is interesting and has to be understood better but definitely most of the time it is I think surrogate for underlying severity of the disease. Right, now let us talk about how you would approach a patient in the ICU who is being detected to have real thrombocytopenia. For this particular question sir I would like to answer it in a different style. I would say I will look at past, present and future or to put it in simple terms I will look at the trajectory of how the platelets are going. Now when I mean past I will look at the clinical context of the patient, I would try to look at what are the underlying critical illnesses he is suffering from and was there any previous thrombocytopenia present or not. When I am looking at the present I will look at the trajectory, the severity, the another to which it has fallen to and the thrombosis is it simultaneously present or not and if a patient has got he presents with low and it stays low. Now in such patients you should always think of an independent cause of thrombocytopenia irrespective of the ICU condition or you can also think about conditions like marrow failure or hypersplimism being present from before. A second possibility now, it falls immediately but recovers quickly. Now these are those patients who have had this thrombocytopenia probably because of a surgery or because of the extracorporeal circuit or a massive transfusion. You need not worry about these patients. Now the third trajectory could be it falls during the first few days but recovers with improvement of the clinical condition. This means a patient is suffering from sepsis or pancreatitis or burns or a multi organ dysfunction and here the platelet count clearly go along with the clinical condition of the patient and a rise in platelet will also tell you that over next few days the patient would improve. The fourth trajectory, it falls but it never rises, it stays low. Now these are those patients where the patient clinical condition is improving but the platelet count is not improving. In these situations consider iotrogenic causes like heparin induced thrombocytopenia, drug mediated thrombocytopenia or also post transfusion perpura. The last trajectory that we are going to talk about is it falls in the first few days stays low in a patient but the patient is also having a persistent multi organ failure. Now these are the sickest of the lot, they have the worst of the prognosis and in such situations it is not clear to what extent the thrombocytopenia contributes to the poor outcomes but more or less the patient ends up by succumbing to the illness. This is I think a very unique way of approaching this problem and I found it very interesting. So what my understanding is that if the platelet trajectory follows the clinical disease trajectory then it is likely that it is correlating with the survival and it is likely due to the disease. When it is not then you need to look for other reasons why it is happening. So that is very interesting way to put it and I think something to be revised and understood again. So now how do you manage these patients with thrombocytopenia? Now those patients who have less than 1.5 lakh, the first thing we will look for is the patient bleeding or not. If he is bleeding, is the thrombocytopenia the cause for bleeding? So basically I would like to look at PT, APTT or any platelet dysfunction being present or not. I feel that thrombocytopenia is causing the bleeding, go ahead and transuse platelet but if you simultaneously see abnormality with the coagulation cascade, raise de-dimer then in those patients giving platelets will not be of any benefit, you need to first treat the underlying cause for the DIC and when you are giving platelets you also need to give associated with it along with it other factor replacement to ensure that these platelets stay off and the patient does not have bleeding because of the DIC person. The second way of looking at is, is the patient having any organ impairment or not? If the patient has organ impairment, is there a recent significant drop in the platelet count or not? If yes and if there are no contraindications in such situations, I am talking of antithrombotic therapy here and it should be considered in such patients if there are no other contraindications to that particular thing. The most important thing as far as platelet count in ICU setting is concerned is to treat the underlying cause. Just by transusing platelets and to keep the platelets high will not help you at all. So please understand it is a harbinger for something sinister which is going to happen and that is a red flag which you need to take a clue from and take it forward. Now if the patient is having sepsis, people have found improvement is not expected in platelets until two days after discontinuation of the vasopressors. Also you should not get panicky, have been giving platelets, platelets or not, it takes time. If the patient is on cytotoxic chemotherapy and has come to your ICU, it will take 12 to 18 days for the platelets to improve. If a patient has undergone a major surgery and ended up in ICU, the platelets will take 4 to 5 days post-operatively for them to start rising and if a patient is on ECMO or VAD in such situations till the time the device is not removed or the circuit is not removed, the platelet will not rise. So there are timelines, incubations for these platelets to start rising. So have patience and please consider low platelet as a surrogate for something sinister happening. Right. So in the ICU, the platelets become very good indicator of how the patient is doing and it is very interesting to see that you may not require to transuse platelet in more settings if the underlying disease is being managed properly and the patient is responding. And of course, the mechanism remains same, but they are very complex and may coexist. So I think these two episodes have covered this very important aspect of clinical practice very comprehensively for which I must thank you there for making it very lucid and also making it very learner friendly in a way that now it seems pretty easy to handle. And not just that it also opens up the curiosity to read more which is I think is the aim that we do with our podcast where we try and cover a topic in a brief while and ensure that students know enough and also get curiosity to read more. I must also tell our audience that we have reached a very landmark figure of number of episodes that we've done today and that happens to be 49 and the next one will be 50 and with that we would move on to next year and up the ante and probably change the way we would address this aspect of educating our students. We are asking our students themselves for suggestions on this, but we have some things in our mind which we will be coming with for which whatever we've achieved till now I must thank all the faculty who have spent their time and of course, Major Hari Krishnan from the department who has been the man behind this podcast. So thank you very much Uday for your time and thanks Hari. Thank you sir. [Music]