Low Platelet Count (Thrombocytopenia): Causes and Symptoms

Every true thrombocytopenia can be assigned to one of three mechanisms, and often to a combination of them. First, reduced production: the bone marrow makes too few platelets because of vitamin B12 or folate deficiency, the effect of alcohol, chemotherapy, viral infections, marrow diseases (myelodysplastic syndromes, leukaemias, marrow involvement by cancer) or rare congenital conditions. Second, increased destruction or consumption: the immune system produces antibodies against platelets (immune thrombocytopenia, some drugs, heparin), or platelets are consumed in clots (disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, haemolytic uraemic syndrome).

Third, sequestration, that is, platelets being held in an enlarged spleen. In a healthy person roughly one third of platelets sit in the spleen rather than in the circulating blood. When the spleen is enlarged, for example because of portal hypertension in cirrhosis, it holds back a much larger share of the platelet pool and the count in peripheral blood falls even though the marrow works normally. This mechanism, called hypersplenism, is one of the most common causes of chronic, mild to moderate thrombocytopenia in people with liver disease.

Telling these mechanisms apart has practical value: the first group usually calls for a marrow examination or a search for deficiencies, the second for immunological tests and a review of medicines, the third for imaging of the abdomen. A good doctor therefore does not order every test at once but proceeds according to what the history, the blood smear and the rest of the blood count suggest. It matters, for example, whether only platelets are low (typical of ITP and many drug-related causes) or red and white cells as well (typical of marrow failure, vitamin deficiencies, hypersplenism and haematological diseases).

The first question with low platelets on a blood count, especially when there are no signs of bleeding, is whether the result matches reality. Haematology analysers count platelets by particle size, so clumps of platelets or platelets surrounding white cells can go unrecognised and be counted as fewer than there really are. The best-known phenomenon is the clumping of platelets in a tube containing the anticoagulant EDTA, used in standard blood count tubes.

What does this mean in practice? If the platelets come out low in a person without bruising or bleeding, and the other blood count parameters are normal, it is worth asking for the test to be repeated with a microscopic smear review (a manual smear) and for blood to be drawn into a tube with sodium citrate. In such a tube, platelets that clump in EDTA usually do not clump and the result is reliable. Drawing into another tube is not always sufficient, however, which is why the review of the smear by an experienced technician is decisive. When the cause is pseudothrombocytopenia, there is no disease to treat, and the person should remember this and tell laboratories, to avoid unnecessary worry at later tests.

It is worth knowing that the same artefact mechanism (clumps, giant platelets) can also occur in congenital diseases in which platelets are large and the analyser misses them. This is rare, but it is why a blood smear is regarded as the basic test in any unexpected thrombocytopenia.

When platelets are truly low and the other blood lines (haemoglobin, white cells) are normal, one of the first hypotheses is primary immune thrombocytopenia (ITP). It is an autoimmune disease in which antibodies directed against platelets speed up their removal by the spleen, and platelet production in the marrow may also be impaired. Consensus definitions state that ITP is diagnosed at a platelet count below 100 G/L after other causes have been excluded, because no single test confirms the disease. The diagnosis is therefore one of exclusion.

A typical patient with ITP presents with petechiae (small, red, pinpoint skin lesions, especially on the lower legs, that do not blanch on pressure), easy bruising, nosebleeds or gum bleeding or heavy periods, but a considerable proportion of people have no symptoms at all and low platelets are found by chance. Importantly, treatment does not depend solely on the platelet count but on bleeding symptoms, procedural risk and the patient's preferences. According to the 2019 American guidelines, intended to support decisions about managing ITP, strategies that avoid drug side effects are in many situations preferred, and there is strong emphasis on shared decision-making. A low count without bleeding does not always mean immediate treatment, but it does require follow-up by a haematologist.

ITP is not the only cause of an isolated low platelet count: drug-induced thrombocytopenia, thrombocytopenia accompanying viral infections (HIV, hepatitis C) and thrombocytopenia secondary to other autoimmune diseases such as lupus can look very similar. That is why good ITP work-up also checks for infections and drugs and does not stop at the platelet count alone.

With any new thrombocytopenia the doctor should review the medication list carefully, because some medicines can lower platelets through a toxic effect on the marrow (chemotherapy, some anticonvulsants such as valproate, the antibiotic linezolid) or through immune mechanisms in which antibodies react to a drug bound to the platelet (among others some antibiotics, quinine, some anticoagulants and antiplatelet drugs). Many of these reactions resolve within days to weeks of stopping the drug, but the decision to stop is always made by the treating doctor, because the drug may be essential.

Heparin-induced thrombocytopenia (HIT) holds a special position. It is an immune-mediated drug reaction in which antibodies directed against complexes of heparin and platelet factor 4 activate platelets, which paradoxically leads to an increased risk of clots, not bleeding. It usually develops a few days after heparin treatment is started, and a fall in platelet count of more than half in this period, especially with an accompanying clot, requires immediate consultation. The 2018 American Society of Hematology guideline contains 33 recommendations covering the diagnosis, initial management and treatment of acute HIT. This is a situation met mainly by hospital patients, but it is worth knowing about if low platelets appeared after a hospital stay involving heparin.

Alcohol lowers platelets in two ways: it directly suppresses their production in the marrow and it may also aggravate folate deficiency. In people who drink heavily, low platelets are often one of the earlier abnormalities on the blood count and usually resolve within roughly one to two weeks of stopping drinking. A raised MCV frequently accompanies it. How macrocytosis can point to alcohol misuse or vitamin deficiency we describe separately in the article on high MCV.

Liver disease is one of the most common causes of chronic, mild thrombocytopenia. There are several mechanisms: the sequestration in an enlarged spleen already mentioned (portal hypertension), reduced production of thrombopoietin by the damaged liver and, in hepatitis C infection, immune mechanisms and a direct effect of the virus on the marrow. Low platelets with an enlarged spleen, abnormal liver tests or signs of chronic liver disease on ultrasound should therefore prompt further hepatological assessment, even if the patient has no abdominal complaints.

Vitamin B12 or folate deficiency can disturb the production of all marrow cell lines, including platelets. It is usually accompanied by other changes on the blood count: a raised MCV (large red cells), low haemoglobin and low white cells with characteristic hypersegmented neutrophils on the smear. Isolated thrombocytopenia from B12 deficiency alone is less common but possible, and after the deficiency is replaced the platelet count usually returns to normal within weeks. We describe the interpretation of B12 and folate tests in our entries on vitamin B12 and folic acid.

Less common causes also include infections (especially viral: mononucleosis, HIV, hepatitis, and also bacterial infections and sepsis), autoimmune diseases (lupus, antiphospholipid syndrome), thyroid disease, Helicobacter pylori infection (in some cases of ITP its eradication improves the platelet count) and haematological diseases. Each of these diagnoses requires individual assessment, and a blood count with a smear is only the first step.

Pregnancy is the most common setting in which women first learn of low platelets. According to a review published in Blood, thrombocytopenia develops in 5–10% of women during pregnancy or in the immediate postpartum period, and a low platelet count is often incidental but may also be a biomarker of a coexisting systemic or gestational disorder.

The most common cause is mild gestational thrombocytopenia: platelets usually fall in the second half of pregnancy, most often to values slightly below normal, cause no symptoms in the mother or baby and return to normal within a few weeks after delivery. Telling it apart from more dangerous conditions is important. The latter include pre-eclampsia and HELLP syndrome (with hypertension, protein in the urine, upper abdominal pain and abnormal liver tests), ITP (which can occur in pregnancy or flare up) and rare microangiopathic diseases such as thrombotic thrombocytopenic purpura. The review by Cines and Levine discusses the differential diagnosis by trimester, severity of thrombocytopenia and accompanying features.

In practice: a pregnant woman with platelets slightly below normal, without hypertension and without bleeding, usually needs only follow-up blood counts at intervals set by the obstetrician. A marked fall in platelets, new hypertension, severe headache, visual disturbances or pain in the right upper abdomen are signals that call for immediate contact with a doctor or an emergency department.

This order corresponds to the recommendations of the international ITP consensus, which stresses that the diagnosis requires exclusion of other causes, including infections, drugs and accompanying diseases. The principle is simple: from the commonest and least harmful (an artefact) to the rarest and most serious (marrow diseases), while staying alert to emergencies.

What to do until the cause is clarified? With platelets below about 50 G/L the doctor may advise caution: avoiding contact sports and activities that risk head injury, restraint with alcohol, and a discussion about the use of drugs that affect clotting (aspirin, ibuprofen and other non-steroidal anti-inflammatory drugs can increase the tendency to bleed). Before procedures, including dental ones, tell the doctor about the low platelets. Do not, however, stop medicines prescribed for important reasons, such as anticoagulants after a heart attack or for atrial fibrillation, without consultation.

Mildly lowered platelets (120–150 G/L) with good general health rarely mean anything dangerous, but should not be ignored if they recur or fall. A sensible plan is a recheck in 2–4 weeks with smear review and, if the result persists, a talk with a family doctor about further work-up. Trends over time are more valuable than a single result.

It is also worth knowing that 'stress' and 'weakened immunity' are not diagnoses. Low platelets always have a cause, even if it is only a laboratory artefact or a mild pregnancy-related change. The most unnecessary worry is caused by single results just below the normal range that are never repeated and never checked against a smear.

Low platelets are a result worth taking seriously, but calmly. The first step is making sure the result is real (smear, possibly citrate), the second assessing the context: drugs, alcohol, infections, pregnancy, liver disease, bleeding symptoms. In most cases the answer is found in simple tests and a good conversation with the doctor, and the rare, dangerous causes usually reveal themselves through additional symptoms or changes in the other blood count parameters. If platelets are below 50 G/L, are falling quickly or are accompanied by bleeding, there is no point delaying a haematologist. In our series on unusual blood count results we also cover high platelets, high eosinophils, low white cells and high MCV separately.