Episode 48: Thrombocytopenia Part 1- Approach in OPD and Non-Critical Settings

Welcome to Med Pods, the audio podcast from the Department of Internal Medicine at AFMC. Today we move back to the topics on Hematology and we have already had some conversations with Karn Lodhe who is Professor of Medicine and Hematologist in the department and we had spoken to him about approach to anemia and efficiency anemia and macrocytic anemias. We move to another of those important cell lines in the body and we today discuss about thrombocytopenia. So, welcome back Lodhe. Thank you, sir. So, we understand that platelets are very important and most often patients come to us with reports which are abnormal while the disease may not be so sinister or at times it can be so low that it becomes a life-threatening problem. And especially in the recent viral epidemic that we are facing we have seen so much of thrombocytopenia. So, I am sure this topic will be of great clinical relevance to our audience which is mainly undergraduate students, postgraduate residents and young MOs in field. So, going into this topic why are platelets important in the first place? So, platelets like RBCs and WBCs hold a very important role in the body. Many people have a notion that platelets are only relevant as far as the primary hemostasis, bleeding and coagulation is concerned. But platelets play a role beyond a primary hemostasis and that primarily includes maintaining a good endothelial function. So, we require adequate numbers of platelets to ensure that the endothelial injuries, the minor injuries are taken care of and by an interplay by the various ICAMs and WECAMs it ensures that the inflammatory cycle does not propagate. So, platelets other than the endothelial function also have a role in inflammation and that is why it is one of the acute phase reactant. Now, thirdly platelet also has an important role in host defense because when any of the gram-negative baseline or the viruses they have to be acted upon by the body. So, the CD40, PAMP and CD162 these are the various markers which are present on the platelets which allow the various host defense mechanism to be home down to the various inciting agents like bacteria and viruses in the body. And lastly, there is a evolving role of platelets in tumor biology wherein people feel or have evaluated and researched that the metastasis of various solid oncological malignancies or solid oncology conditions is actually because of platelet. The platelet covers these cancer cells and they help them to evade the host defense mechanisms and allow them to be metastasized to a totally different location. So, anti-platelet therapy has been formed to be of benefit in preventing metastasis in certain types of cancers. So, platelets have got role beyond much beyond hemostasis. So, that is very interesting and in fact it is news to me. We always very simplistically put platelets as something just to prevent bleeding or form clots. But the fact that you say it also deals with inflammation, immunity and also cancer is something that is worth reading further. Now, moving on how do you define thrombocytopenia? So, when individuals have any platelet count less than 1.5 lakh irrespective of the gender or age it is defined as thrombocytopenia. But to further evaluate or to understand the severity of it we classify the thrombocytopenia into three particular grapes mild thrombocytopenia between 1 to 1.5 lakh moderate between 50,000 to 1 lakh and severe thrombocytopenia is less than 50,000. But when it comes to bedside practice we need to understand that spontaneous bleeding with platelet count less than 10,000 and surgical bleeding with count less than 50,000 is what is relevant and requires further management. Right, so it is very important to know that clinically relevant thrombocytopenia is quite different from what the lab values might tell and that is something that we need to know so that we can also convince our patients who are often quite anxious about it. Now, how do you approach a case of thrombocytopenia? Sir, so when a patient comes to us with thrombocytopenia there are two different ways of approaching these individuals, one is I organize the thought processes in my mind based on the mechanism of thrombocytopenia which helps me in evaluating or creating an algorithm. Second is I would like to organize my thoughts based on the equity or the speed with which I should evaluate a case. So by mechanism we primarily look at decreased production either increased destruction or consumption of platelets, dilutional mechanism or because of redistribution of hypersprimism and when it comes to equity, most important is to look at is the patient having any thrombocytopenic emergencies or not which requires immediate ICU care, second is the patient suffering already from any acute illnesses or ICU requiring immediate care or the patient has got any infections of fever wherein he requires an acute care and is the patient having any bleeding symptoms or any symptoms secondary to the other mechanisms of platelet that we spoke about slightly previous. So is the patient having that wherein we need to manage the patient in next few days or is it just an incidental finding of thrombocytopenia where we can take either a weeks to months to evaluate the patient further. So we would like to approach it in these two different ways. Right, so when you talk about various mechanisms like you have mentioned, can you elaborate further on what are these various mechanisms. So out of all the mechanisms, there are three important mechanisms that we always consider. First is decreased production. So the way we approached anemia in the same way bone marrow happens to be the warehouse or the factory wherein the platelets are being produced. So we can have problems with bone marrow and this could be secondary to micronutrient deficiencies like B12, folate or copper or it could be qualitative problems inside the bone marrow like myelodysplastic syndrome or the bone marrow or the factory is being replaced by some abnormal sense like a hematological malignancies or tumor infiltration of metastasis from some solid organ malignancies or lastly there could be a eplasia. So a plastic anemia and its closed sister that is PNH, so either of them leading to a decreased production of mega karyocytes. So these are the ones which are the bone marrow disorders and more importantly various viral infections starting from dengue to chicken gunia to various other viral infections like respiratory sensation virus can lead to a transient bone marrow suppression. Other than this inherited platelet disorders wherein there is a genetic problem in production of platelets and this is more important in children who come with thrombocytopenias where they are commonly confused with ITV. Now mega karyocyte loss can also occur because of drugs that the individual is taking or a liver disease can lead to decreased thrombopoietin production and can lead to decreased production. So this is in total about the decreased production of the platelets, second coming to increased destruction or consumption. The commonest prototype is immune thrombocytopenia or what we call it as ITV wherein antibodies lead to increased destruction or sometimes these antibodies can also lead to decreased production at the bone marrow level. Other than the ITV various drugs or transfusion practices can lead to production of antibodies which could be haptan mediated or allogenic antibodies and they can lead to at increased destruction leading to thrombocytopenia. Other than this coagulation disorders when we have disseminated coagulation in the form of DIC or in thrombotic micro angiopathy platelets can be decreased because of increased consumption as seen in any other coagulation disorders. Extracorporeal circuits like cardiac bypass or ECMO can lead to a consumption of platelets wherein platelets go and adhere on to these extracorporeal circuits and can lead to decreased platelets quantitatively. Last but not the least any surgery in a postoperative series state by day 3 can have another and there can be a fall of around 30 to 40,000 platelets from the baseline. So if the baseline itself is low so the patient might end up with platelets less than 1.5 lakhs after the surgeries. The last mechanism is about dilution. So whenever we are aggressively resuscitating a patient with fluids or with massive transfusions then in such situations there could be dilutional thrombocytopenia. We can also have thrombocytopenia as I just said in increased consumption post surgery at the same time because of the fluid shifts postoperatively patients can again have a postoperative dilutional thrombocytopenia and lastly impregnancy by third trimester because of the increased plasma volume there can be gestational thrombocytopenia. Right so it is very important to understand the mechanisms because I am sure the approach to a patient who comes with thrombocytopenia will depend on what mechanism is under play. Now moving on to a patient from having discussed theory when a patient comes to us with thrombocytopenia how do you approach? So the first step would be sir to assess the severity of thrombocytopenia. So as we looked at the various thoughts as per the equity is concerned so my first aim would be to rule out is the patient having any thrombocytopenic emergencies or not either because of bleeding thrombosis or hemolysis. So after ruling out that then we start going by any classical way of medical approach to a medical case in the form of history examination and others but this five there are five important things which any patient with thrombocytopenia should be looked into is the patient having any clinically significant bleeding number one, is the patient having any new onset thrombosis, third is there any evidence of hemolysis in the body, fourth is there any prolongation of PT or APTT and last is the platelet count less than 20,000. So after looking at these five important points then we go on to the history and my history would depend upon is the thrombocytopenia real or not, is the thrombocytopenia new onset or not, are there any other associated hematological abnormalities in the patient and lastly is the patient requires any potentially serious interventions to avoid the consequences of the top five things that we spoke about. Okay so that sounds interesting when you say is thrombocytopenia real do you mean to say that there could be a normal platelet count in a patient but he would be having thrombocytopenia or the other way around where more likely in fact that the platelet counts are low but actually the patient has adequate platelets. Absolutely bang on sir so what you just mentioned is what is known as pseudo thrombocytopenia and wherein actually in vivo the patient has normal platelets but in vitro we have got low platelets this could occur because of one pre analytical variables. So most of the times the sample for CBC is collected in EDTA vacutainer and EDTA classically can lead to a chelation of platelets or platelet clumping. So the coolters are the machines that we currently have they won't measure them as platelets because of clump platelets the size is so huge so they will not count them as platelets and they will give you fallaciously low platelet count. Second, dilution very common in hospital samples wherein most of the time the samples are withdrawn from lines, central lines which are in situ and patient might be getting some IV fluids and when we draw from that and don't discard the first 5 ml from a central line it can lead to fallaciously low platelet. The other thing is the lack between collection and testing. So if I have collected a sample in the morning and I am testing the sample in the evening despite of collecting it in anti-coagulant tube the biggest problem would be the small amount of coagulation or microclots can lead to platelet consumption and can lead to low platelets. Lastly there is a condition known as gene platelets syndrome or gene platelets wherein because of the bone marrow stress or in any condition wherein the patient might have some mega karyocytes coming into the periphery large mega karyocytes which would further break down into platelets. So such patients though have a low platelet count but by looking at huge platelets, gene platelets or mega karyocytes in the periphery we can comfortably presume that the patient would have a normal platelet count. So I think this is very important and I think if a patient is normal as in he does not have any setting or meeting any manifestations already one must re-assertain whether this thrombocytopenia is actually real or not and all those precautions that you mentioned should be done before testing and in case the counter shows low then we can go ahead with the manual confirmation right. So now we confirmed it what next? So after we have confirmed that there is a true thrombocytopenia on a finger pricks mirror then other few things which I would immediately would like to do is to first find out what were the preer platelet count if there is the availability of the past medical records. So did the patient have low platelets in the past or it is a new onset thrombocytopenia. Family history again very important to rule out inherited causes. Any bleeding history to make the platelet count relevant presence of bleeding history and thrombocytopenia makes it one of the important causes to be evaluated. Any drugs or medication history any history of infections in the form of any fever or the patient having any sort of viral symptoms in the past or viral programs makes it important to understand it could be bone marrow suppression secondary to viral. Dietary practices vegans low B12 or patients not on appropriate amount of micronutrient supplementation in their routine dietary habit can lead to thrombocytopenia and lastly any other coexisting medical conditions like hypothyroidism any liver diseases are important to understand. After I take this detailed history under these headings a quick medical examination to look at skin and other sites for bleeding of PTK, perpura and echinosis so mucocutinous junctions and skin fundus examination to rule out any bleeds in the fundus examination to look for hepatitis plenumigale and any lymphedinopathy and any overt sites of thrombosis could be my focused examination to look for overt causes of thrombocytopenia. Once I have done the history and examination taken the history and done the examination I would ask for a repeat CBC immediately if the platelet count is less than 50,000. I will ask the patient to come back in one to two weeks if he has moderate platelet count that is 50,000 to 1 lakh and he is asymptomatic and a retest after one month if the patient has got only isolated thrombocytopenia with platelets of above 1 lakh. I will also ask for a PBS to rule out any features of hemolysis like cystocytes being present or any broken RBCs and to look for any adipical cells and lastly look at MCB to rule out coexisting B12 deficiency. Right, so these are the standard tests that we would approach them with but if the patient has moderate to severe thrombocytopenia are there any further testings that need to be done in addition to these. So there is a classical panel which we do in all patients who come with severe thrombocytopenia which constitutes viral markers for HIV, HBS AG and HCV. We will ask for a thyroid profile, we ask for ANA and if ANA is positive we go ahead and ask for PT and APTT particularly to look for prolongation of APTT and any inhibitors being present. If the patient has got coexisting anemia we ask for DCT/ICT to rule out Ivan syndrome because of the antibody mediated or destruction and lastly we ask for mean platelet volume to look if the patient has got some gene platelet syndromes. Now all these are based on scientific reasoning wherein in Indian scenario people have found 12% of the individuals having coexisting HCV, 8% having coexisting HIV among all asymptomatic thrombocytopenia and severe thrombocytopenia, 6% having hepatitis B. So all three of them put together they constitute 25% of the cases of thrombocytopenia. Thyroid is an association more than causation, huge amount of association of hypothyroidism with ITP or with thrombocytopenias, ANA very common in females up to 20 to 30% of the patients can have ANA positivity. So considering these things these five or six tests are important in every case of severe thrombocytopenia. Right and in our setting infections become very important cause of thrombocytopenia, so which are the infections you would like to screen this patient for. So sir infection screen is only important in those patients where there is a forthcoming history of fever or some viral prodromes being present. It is not relevant other than the HIV, hepatitis B and hep C that we spoke about, it is not relevant to rule out tropical infections in patients who do not have any forthcoming history or symptoms or examination to suggest a tropical infection. But for those who have got a history of fever the important investigations in the serial order would be first would be dengue to rule out in the first few days NS1 and later IgG IgM after 7 to 10 days, malaria ruling out, enteric fever and lastly to rule out tick typhus or scrub typhus that we have. Right and in the current scenario even chicken goonia, we see in thrombocytopenia even in then. Now coming to a very important and invasive test that we do in immunological problems is bone marrow examination. So what is the role of bone marrow in thrombocytopenia and I also want you to clarify because some students do have this doubt whether it is contraindicated in severe thrombocytopenia. So sir I will answer the second part first, no platelet count is a contraindication for bone marrow even if a patient has got 1000 as a platelet count as well as that even then we can go ahead and do a bone marrow. So low platelet count is not a contraindication for bone marrow but the other way round is the indication for bone marrow in patients with thrombocytopenia is extremely limited. So first because we have heard about so many causes we need to rule out all those. ITP remains to be a diagnosis of exclusion. We resort to bone marrow only in patients who are elderly or extremely young when we have ruled out other causes and we could not find any other cause for thrombocytopenia. Now another very important practice problem is transfusion of platelets especially in patients who do not have any symptoms or bleeding. So what are the indications where you would suggest that transfusion should be given. So the national as well as international guidelines on that talk about the cutoff of 10,000 in asymptomatic patients with no signs and symptoms of bleeding less than 10,000 they need to be transfused with platelets for those who have fever for those patients even without any signs and symptoms of bleeding 20,000 is the cutoff other than that those with bleeding manifestations symptoms or signs any platelet even below 50,000 needs to be transfused. So this number of 20,000 would apply to dengue also like you mentioned yes right. So now patients who are planned for surgery and they are detected to have thrombocytopenia in the pre-op assessment what is the indication for transfusion in them. So sir many a times surgeons have upon a certain amount of threshold of platelets before they take them up for surgery for neurosurgery it is 1 lakh a minimum count because high chances or any ophthalmological surgeries where in vitreoretinal surgeries there 1 lakh is required other than that any major surgery requires a platelet count of 60 to 70,000. For gynecological procedures it is 50,000 is a cutoff. So these platelets numbers can be maintained using transfusions or if we have adequate time by giving TPO receptor agonist but beyond this there is no advantage of increasing the numbers to prevent postoperative lead or to decrease the incidence of postoperative lead. So that has been refuted. Second those patients who are aspirin or clopidogrel on today's date the related guidelines say that we do not need to stop them and in such situations giving platelet transfusions would not actually take away the effect of the anti-platelet drugs. So that is a myth of giving platelet transfusions for those patients who are on anti-platelet that would really not help. Right so 50,000 is a figure that one can look at for surgeries right. Okay now what about in situations where you have to give platelets what are the products which are available for transfusions? Sir we have two types of products which are available one is known as random donor platelets and second is known as single donor platelets. Single donor platelets from any blood bank which is donated to a blood bank. So they if it is the packet post-collection and would take it out that is known as RDP. For those patients where we require more number of collection to be done it can be if it is directly from the donor and that is known as single donor platelets RDP rises the platelet count by 6 to 10,000 per packet whereas SDP raises by 30 to 60,000 and a rough calculation is 1 SDP accounts to approximately 4 to 6 units of RDP with less number of a lilic load or an antigen load given to the individual who is being transfused. Right now once the platelet bag has been demanded from the blood bank and it has come to the ward what are the precautions and steps to be taken? So once the platelet is issued by the blood bank it needs to be constantly agitated by gentle movements of the fingers it should not be briskly shaken or stirred. The best way is to come bring it to the ward and put it in the platelet agitator which every hospital has it in their hemat wards or in their transplant wards and put it in the agitator till the time the patient is being actually transfused bedside. The platelet transfusion for RDP it takes around 15 to 20 minutes per bag and for SDP it is 150 ml it takes approximately 1 hour. We pre-medicate these individuals because platelets are stored at room temperature they are not supposed to be kept in refrigerator pre-transfusion and we give a dose of eval and rancidine anti-histamine before giving platelets. Right, now are there any patients who despite giving platelets and you find that the counts are not rising does that happen and what is the reason? So that is one of platelet refractoriness it can occur in two situations one those patients who have been regularly transfused because of bone marrow condition or because of hematological malignancies or inherited disorders. This is some people already have got antibodies present against the donor if the bag which is collected is from close relatives. So the way to calculate it is we have something known as a CCI corrected count for increment wherein we take pre-transfusion platelet count of the individual post-transfusion platelet count of the individual take the difference of that multiplied by body surface area and divide it by the platelet amount in that given bag that we have transfused. If this is less than 5000 then patient is known to have refractoriness and we look at it two occasions not just one time if we have given the individual twice and both the times the CCI is less than 5000 then we call it as refractoriness and in such individuals we resort to what is known as HLA matched platelets or identifying those platelet donors with whom the CCI was more than 10,000 we identify those people and specifically give those platelets. Lately the guidelines suggest that CCI is very difficult to calculate so they have just said collect a post-platelet count of a individual between 10 minutes to 1 hour on two different occasions and if that number is less than 20,000 even then you can label a patient as having platelet refractoriness. And every season of Benghi or most of these epidemic times and otherwise I think constantly there is this prevalent myth about papaya leaves papaya itself and goat milk which can increase platelet levels so what is your answer to these myths or whatever misconceptions. So sir other than goat milk and papaya extract even the kiwi fruits so the prices of these things rise up in the Benghi season and they can make millionaires out of us so sometimes we definitely feel that we should stop practicing hematology and have a kiwi fruit shop or a goat milk shop being played outside the hospitals but coming to the research part of it or the scientific part of it there are few studies which have been done both for the goat milk as well as for the kiwi fruit they are not been formed to be of any benefit. But coming to papaya extract the compound which is there people have found out that it can actually lead to rise in platelets but the rise is extremely moderate it goes only from 1000 to 1500 or 3 months break and it does not act immediately so the benefit of it as far as a significant rise in platelet count is questionable and the design the study designs were not absolutely appropriate but coming to the side effects or the interactions the papaya extract can have interaction with most of the drugs that we routinely use or the antibiotics we routinely use in the hospital. So despite of the moderate benefit with it or the interactions are so huge that we should be very careful and it should be done only by experienced people and who have been trained to give papaya extracts. So I think we have addressed this issue quite comprehensively and in fact this lecture is really important for students and practitioners alike because of the fact that these problems are so common in the hospital and we often get called as physicians to handle such issues. So thank you Uday for making it very lucid and crisp and concise as always we shall actually be discussing more clinically important issue in our subsequent podcast where I would request your time again and that would be thrombocytopenia in ICU because that is where it is a situation of life and death. So thank you very much for your time. Thank you sir. Good day sir. (upbeat music)