Hemorrhagic diathesis – normal hemostasis. Thrombocytopenia – classification. Immune thrombocytopenia.

01Definition and overview

Thrombocytopenia is a platelet count below 150 × 10⁹/L (the normal range is about 150 to 400 × 10⁹/L). It is one of the commonest causes of abnormal bleeding, and it makes sense only against the way bleeding normally stops.

Normal haemostasis

Haemostasis stops bleeding from a damaged vessel within minutes, while keeping blood fluid everywhere else, in four stages that overlap:

1. 1

   The vessel

   The injured vessel constricts, slowing the flow, and exposes collagen and tissue factor.
2. 2

   The platelet plug

   Within seconds, platelets stick to the wall, are activated and clump into a plug: primary haemostasis, enough to seal a capillary.
3. 3

   The fibrin clot

   Over minutes, clotting factors on the platelets generate thrombin, which turns fibrinogen into fibrin that holds the plug: secondary haemostasis.
4. 4

   Fibrinolysis

   Over days, plasmin dissolves the fibrin as the vessel heals, while natural anticoagulants keep the clot to the injury.

The order simplifies: thrombin is the strongest activator of platelets, and activated platelets are the surface on which clotting factors work. The clotting factors, their tests and fibrinolysis are covered with haemophilia.

Haemorrhagic diathesis

A haemorrhagic diathesis is a tendency to bleed abnormally: spontaneously, too much after an injury, or for too long. It is inherited or acquired, and it is classified by what fails:

Immune thrombocytopenia

Immune thrombocytopenia (ITP), once called idiopathic thrombocytopenic purpura, is an acquired autoimmune disorder in which antibodies and T cells destroy platelets and hold back their production. An international working group defined it in 2009:

• a count below 100 × 10⁹/L with no other cause, since counts of 100 to 150 × 10⁹/L are common in healthy people and seldom progress;
• primary, or secondary to another condition: lupus, antiphospholipid syndrome, chronic lymphocytic leukaemia, HIV, hepatitis C, Helicobacter pylori, immunodeficiency or a drug;
• newly diagnosed (up to 3 months from diagnosis), persistent (3 to 12 months) or chronic (more than 12 months).

02Etiology and pathophysiology

Platelets, the vessel wall and von Willebrand factor

Platelets are fragments without a nucleus, shed by marrow megakaryocytes under the drive of thrombopoietin (TPO). The liver makes TPO at a steady rate and platelets remove it, so it is high in marrow failure but only slightly raised in ITP, where many platelets are made and destroyed. A platelet lives 7 to 10 days, and a third are pooled in the spleen. It carries receptors (GPIb–IX–V for von Willebrand factor, GPIIb/IIIa for fibrinogen, GPVI for collagen) and granules of fibrinogen, ADP, serotonin and calcium.

Healthy endothelium keeps blood fluid with prostacyclin, nitric oxide, heparan sulphate and thrombomodulin. Injury exposes collagen and tissue factor and releases von Willebrand factor (VWF), whose largest multimers, up to 20 000 kDa, are the stickiest: at the high shear of arterioles and capillaries VWF uncoils on collagen and catches platelet GPIb. It also carries and protects factor VIII, so a lack of VWF lowers factor VIII too. The enzyme ADAMTS13 trims the largest multimers; without it they clump platelets by themselves, as in TTP. VWF rises with stress, inflammation, pregnancy and oestrogen, and is about a quarter lower in blood group O.

How the platelet plug forms

1. 1

   Adhesion

   Platelets roll on VWF bound to collagen, held by GPIb, then stick firmly to the collagen itself through GPVI and integrin α2β1.
2. 2

   Activation

   The disc becomes a spiny sphere and empties its granules. ADP (through its receptor P2Y12), thromboxane A2 (made by cyclo-oxygenase 1) and, most powerfully, thrombin recruit more platelets.
3. 3

   Aggregation

   GPIIb/IIIa changes shape and binds fibrinogen, which bridges platelets into a plug.
4. 4

   A surface for clotting

   Phosphatidylserine turned outwards carries the clotting factor complexes that make thrombin, and the platelets later contract to retract the clot.

Antiplatelet drugs act at these steps: aspirin blocks cyclo-oxygenase 1 for the platelet's whole life, clopidogrel, prasugrel and ticagrelor block P2Y12, and eptifibatide and tirofiban block GPIIb/IIIa.

How primary haemostasis fails

• The vessel wall, with a normal count and normal clotting tests: hereditary haemorrhagic telangiectasia (telangiectasias of the lips, tongue and gut, nosebleeds, arteriovenous malformations), scurvy, thin skin with age or steroids, and vasculitis.
• Platelet function: rare inherited defects such as Glanzmann thrombasthenia (no working GPIIb/IIIa) and Bernard–Soulier syndrome (no GPIb, giant platelets), and far commoner acquired ones from aspirin, NSAIDs, P2Y12 blockers, uraemia, liver disease and paraproteins.
• Adhesion and factor VIII together: von Willebrand disease, the commonest inherited bleeding disorder.
• Platelet number: thrombocytopenia.

Why the count falls

Mechanisms often combine, as in cirrhosis: a big spleen, less TPO and alcohol. In neonatal alloimmune thrombocytopenia, a mother lacking a platelet antigen, usually HPA-1a, makes antibodies against her baby's platelets, which can cause bleeding into the brain before birth, even in a first pregnancy.

How ITP destroys platelets

1. 1

   Loss of tolerance

   With too few regulatory T cells, B cells make IgG autoantibodies against GPIIb/IIIa or GPIb–IX, found in about 60 per cent. A viral infection often comes first in children; Helicobacter pylori, autoimmune disease or a lymphoid cancer can trigger it in adults.
2. 2

   Destruction

   Macrophages, mainly in the spleen (which also makes much of the antibody), destroy coated platelets through Fc receptors; the liver and cytotoxic T cells clear others.
3. 3

   Too little production

   The antibodies and T cells also damage megakaryocytes, and TPO rises only a little, so the marrow does not make up the loss.

Each treatment targets a step: steroids and rituximab reduce the antibody; IVIG, fostamatinib (a SYK inhibitor) and rilzabrutinib (a BTK inhibitor) blunt destruction by macrophages; TPO receptor agonists raise production; splenectomy removes the main site of destruction. The weight of each step varies, so responses are hard to predict.

03Clinical features

The pattern of bleeding

Petechiae are pinpoint red spots that do not blanch, gathering on the lower legs; purpura are larger, ecchymoses are bruises. The history covers bleeding after tooth extraction, surgery and childbirth, heavy periods, the family and every drug. Blood blisters in the mouth (wet purpura), retinal haemorrhages, blood in the urine or stool, or a new headache mean a high risk of serious bleeding.

Platelet count and bleeding

The bands are rough. The young platelets of ITP work well, so it bleeds less than the count suggests, while patients with marrow failure, sepsis, uraemia or antiplatelet drugs bleed at higher counts.

Immune thrombocytopenia

The patient is otherwise well, with petechiae, purpura and bruising, and sometimes bleeding from the nose, gums or uterus; fatigue is common in chronic ITP, and adults carry a higher risk of thrombosis despite the low count. A big spleen, enlarged lymph nodes, fever, weight loss, bone pain or other abnormal counts point away from ITP.

04Diagnosis and management

Approaching a low count

1. 1

   Is it real?

   Look at the blood film. Clumps, or a well patient who does not bleed, call for a repeat count in a citrate tube.
2. 2

   Is it isolated?

   The full count and film, reticulocytes, PT, APTT, fibrinogen, renal and liver tests and LDH: other low counts point to the marrow, red cell fragments to a microangiopathy.
3. 3

   Is the patient ill?

   Fever, confusion, organ failure, thrombosis or oozing call for urgent tests for TTP, HUS, DIC, HIT and sepsis.
4. 4

   What is the setting?

   Drugs and heparin, alcohol and liver disease, pregnancy, a recent transfusion, travel, the family and earlier counts.

Pseudothrombocytopenia is an artefact: harmless antibodies recognise GPIIb/IIIa once EDTA has removed the calcium in the tube, and the platelets clump. It is found in 0.03 to 0.27 per cent of people, but in about 15 per cent of those referred with an isolated low count. The film shows the clumps, and a count in citrate, analysed at once, is usually normal. It needs only a note in the records, so that it never leads to treatment.

Diagnosing ITP

ITP is a diagnosis of exclusion; no single test proves it.

• The history and examination: bleeding, drugs, alcohol, infections, vaccines, pregnancy, the family and earlier counts, with no big spleen or lymph nodes.
• The blood film: an isolated low count with large platelets, and no fragments or blasts.
• In every adult, tests for HIV and hepatitis C (and hepatitis B before rituximab), the blood group and direct antiglobulin test (with haemolysis, Evans syndrome), immunoglobulins and, where relevant, a pregnancy test; as the picture suggests, a test for Helicobacter pylori (eradication raises the count in some), thyroid tests, and antinuclear and antiphospholipid antibodies.
• A bone marrow examination only when the picture is atypical (other low counts, an abnormal film, systemic symptoms, a big spleen) or first-line treatment fails.

Treating ITP

The aim is a count that prevents serious bleeding, reached with the least harmful treatment, not a normal count.

• Adults with a count of 30 × 10⁹/L or more and at most minor bleeding of the skin or mucosa are observed; American guidance recommends against steroids for them, but offers treatment to newly diagnosed adults below 30 × 10⁹/L and suggests admission below 20 × 10⁹/L.
• Bleeding is treated whatever the count, and so is a count too low for a procedure or with a high bleeding risk (older age, anticoagulant or antiplatelet drugs).
• Children with no bleeding or only skin bleeding are observed, whatever the count.

the count below which ITP is defined

100× 10⁹/Lthe count below which ITP is defined

at or above it, without bleeding, adults are observed

30× 10⁹/Lat or above it, without bleeding, adults are observed

the longest first course of steroids

6weeksthe longest first course of steroids

from diagnosis before a splenectomy

12monthsfrom diagnosis before a splenectomy

Only a minority stay in remission once steroids stop, and longer courses add harm (raised glucose, mood and sleep disturbance, infection, bone loss) without lasting benefit.

ITP that relapses on tapering, depends on steroids or does not respond needs a second-line treatment, never long-term steroids. American guidance of 2026 recommends a TPO receptor agonist first, with rituximab as the alternative, and a BTK inhibitor, mycophenolate or a SYK inhibitor for those who cannot have or do not want these; the patient's wishes and plans for pregnancy weigh in.

Vaccines against pneumococcus, meningococcus (ACWY and B) and Haemophilus influenzae type b are given at least 2 weeks before a splenectomy, with influenza vaccine yearly, and many patients take daily penicillin in the first years. A fever without a spleen is an emergency, for life: antibiotics at once.

Life-threatening bleeding in ITP, into the brain, gut or another critical site, is treated with everything at once: repeated platelet transfusions with IVIG 1 g/kg, intravenous methylprednisolone 1 g a day for 3 days and tranexamic acid, stopping antiplatelet and anticoagulant drugs, and a TPO receptor agonist early.

Pregnancy and childhood

Gestational thrombocytopenia, in about 5 to 10 per cent of pregnancies, is mild (usually above 70 × 10⁹/L), late and harmless. A lower count, an early one or one known before suggests ITP, treated with low-dose prednisolone or IVIG for bleeding, for a count below about 20 to 30 × 10⁹/L, or to reach 50 × 10⁹/L for delivery and about 70 to 80 × 10⁹/L for an epidural or spinal anaesthetic. The antibodies cross the placenta, and about 1 in 10 babies has a count below 50 × 10⁹/L, so fetal scalp electrodes, fetal blood sampling and vacuum delivery are avoided. Late in pregnancy, think also of pre-eclampsia and HELLP syndrome.

Children with ITP (see bleeding disorders in children) are observed if there is no bleeding or only skin bleeding, and given a short course of steroids or IVIG for mucosal bleeding. A child with a low count and also pallor, bone pain, fever, organomegaly or other abnormal counts needs a marrow examination for leukaemia.

Causes that must not be missed

Thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy caused by a severe lack of ADAMTS13 (activity below 10 per cent), usually through an autoantibody and rarely from recessive mutations (congenital TTP). Ultra-large VWF multimers catch platelets into microthrombi in the brain, heart, kidneys and gut, and red cells are torn on them (microangiopathic haemolysis). The classic pentad is thrombocytopenia, haemolysis, neurological signs, renal impairment and fever, but all five are present in only a minority: thrombocytopenia with red cell fragments and no other cause is enough to act.

The PLASMIC score, one point each for a count below 30 × 10⁹/L, haemolysis, no active cancer, no transplant, an MCV below 90 fL, an INR below 1.5 and a creatinine below 177 µmol/L (2.0 mg/dL), makes TTP likely at 6 or 7 points. Blood for ADAMTS13 is taken before any plasma, and plasma exchange with steroids starts the same day without waiting for the result. Caplacizumab, a nanobody that stops VWF binding platelet GPIb, is given daily during the exchanges and for 30 days after, longer while ADAMTS13 stays low (EU licence 2018); in the HERCULES trial it cut TTP-related death, recurrence or major thromboembolism from 49 to 12 per cent, at the cost of more mucocutaneous bleeding. Rituximab prevents relapse, and ADAMTS13 is checked for life. Congenital TTP is treated with plasma or with recombinant ADAMTS13 (EU licence 2024).

Haemolytic uraemic syndrome (HUS) strikes the kidneys hardest. In children it follows bloody diarrhoea from Shiga toxin-producing Escherichia coli such as O157:H7 and is treated supportively; complement-mediated (atypical) HUS is treated with the C5 inhibitors eculizumab or ravulizumab. An ADAMTS13 activity above 10 per cent separates both from TTP (see acute kidney injury).

Heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is caused by IgG antibodies against platelet factor 4 (PF4) bound to heparin, which activate platelets through Fc receptors, consuming them and generating thrombin. HIT causes thrombosis, not bleeding, venous or arterial, in up to half of untreated patients. It is about ten times commoner with unfractionated than with low-molecular-weight heparin, and commonest after cardiac and orthopaedic surgery. The 4Ts score gives the probability before testing:

A total of 0 to 3 is low, and HIT is then very unlikely (American guidance advises against testing or treating for it); 4 or 5 is intermediate and 6 to 8 high. Then stop all heparin, including flushes, and start a non-heparin anticoagulant at a treating dose, even without a thrombosis: argatroban, bivalirudin, danaparoid, fondaparinux, or a DOAC in a stable patient. A PF4–heparin immunoassay is confirmed by a functional assay, and the legs are scanned for silent DVT. Platelets are avoided, and warfarin waits until the count recovers, as it can cause venous limb gangrene. Anticoagulation lasts until the count recovers, or 3 months after a thrombosis.

Disseminated intravascular coagulation

Disseminated intravascular coagulation (DIC), as the ISTH redefined it in 2025, is an acquired, life-threatening disorder in which systemic activation of coagulation, disordered fibrinolysis and endothelial injury form microthrombi, from a silent early phase to an overt one with bleeding and organ failure. Sepsis is the commonest cause, then trauma, obstetric emergencies (see coagulopathies in obstetrics) and cancer, above all acute promyelocytic leukaemia. The updated ISTH score for overt DIC:

A total of 5 or more is overt DIC, and the score is repeated daily; below 5, it is repeated in 1 to 2 days. Treatment is of the cause, with platelets (to keep the count above 50 × 10⁹/L), plasma and fibrinogen (to keep it above 1.5 g/L) for bleeding or a procedure, and heparin where thrombosis dominates.

Platelet transfusion

Platelets are stored at room temperature for up to 7 days, which makes bacterial contamination likelier than with other components. UK thresholds for a platelet transfusion:

American and international guidance of 2025 sets some lower, such as 10 × 10⁹/L for a central line in a site that can be compressed and 20 × 10⁹/L for a lumbar puncture. RhD-negative girls and women who could become pregnant receive RhD-negative platelets, or anti-D (see rhesus blood groups). Platelets can harm in TTP and HIT, where they may feed thrombosis, and help little in ITP, where they are destroyed within hours, in post-transfusion purpura, treated with IVIG, and in the bleeding of uraemia, which responds to desmopressin and dialysis.

05Epidemiology

ITP has an incidence of about 3 per 100 000 adults and 2 to 6 per 100 000 children a year, in studies mostly from Europe; in adults women predominate in middle life, and the incidence rises again after 60, when the sexes are about equal. Gestational thrombocytopenia affects about 5 to 10 per cent of pregnancies. Immune TTP is rare, a few new cases per million people a year, about twice as common in women. HIT affects up to a few per cent of patients given unfractionated heparin after major surgery, far fewer with low-molecular-weight heparin. In intensive care thrombocytopenia is common, mostly from sepsis, DIC, drugs and circuits.

06Prognosis

Most children with ITP recover within a year. In adults ITP is often chronic, with a mortality slightly above that of the general population, from bleeding in older patients with very low counts, from infection, often caused by treatment, and from thrombosis. A response is a count of 30 × 10⁹/L or more that has at least doubled, and a complete response 100 × 10⁹/L or more, each without bleeding.

Without treatment about 90 per cent of patients with TTP die. With plasma exchange and steroids 10 to 20 per cent still died in an acute episode, most in the first days; with caplacizumab and rituximab added from the start, deaths have fallen to a few per cent in recent series. Survivors keep a lifelong risk of relapse and higher rates of cognitive problems, depression and stroke. In HIT, early recognition and a change of anticoagulant prevent most thromboses, amputations and deaths. DIC carries the outlook of its cause, and overt DIC in sepsis markedly raises the risk of death.