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Endgames Case Report

A man with acute venous thromboembolism and thrombocytopenia

BMJ 2014; 348 doi: https://doi.org/10.1136/bmj.g1164 (Published 03 February 2014) Cite this as: BMJ 2014;348:g1164
  1. Muhajir Mohamed, consultant haematologist; senior lecturer in medicine12,
  2. Robert Hayes, senior medical scientist3,
  3. Tefo Mosetlhi, trainee medical registrar4
  1. 1Department of Medicine, Launceston General Hospital, Launceston, TAS 7250, Australia
  2. 2University of Tasmania, Launceston Clinical School, Launceston, Australia
  3. 3Department of Pathology, Launceston General Hospital, Launceston, Australia
  4. 4Department of Medicine, Launceston General Hospital, Launceston, Australia
  1. Correspondence to: M Mohamed muhajirbm{at}yahoo.com

A 64 year old man presented to the emergency department with shortness of breath and pleuritic chest pain of 12 hours’ duration. Eight days earlier he had undergone radical prostatectomy for early stage prostatic cancer. He had been given tramadol for analgesia and unfractionated heparin (5000 units subcutaneously) twice a day for four days for postoperative thromboprophylaxis. His full blood counts and biochemical parameters were within normal limits and he was discharged home on the fourth day after surgery with no complications.

His medical history and family history were unremarkable. On examination his respiratory rate was 25 breaths/min, heart rate was 100 beats/min, blood pressure was 130/88 mm Hg, and oxygen saturation in room air was low (90%). Cardiac, respiratory, abdominal, and neurological examinations were normal. His left leg and thigh were swollen but non-tender. There were no bleeding manifestations or evidence of active infection at that time. Chest radiography and electrocardiography were unremarkable.

However, axial computed tomography pulmonary angiography showed extensive thromboemboli in the right and left main pulmonary arteries extending more distally and associated with bilateral wedge shaped pulmonary infarcts (fig 1). Doppler ultrasound showed thrombosis in the left popliteal vein extending up to the common femoral vein. Full blood counts showed low platelets (34×109/L), normal haemoglobin, and normal numbers of white cells. Blood film examination was unremarkable. His coagulation assays, renal parameters, and liver function tests were within normal limits.

Figure1

Fig 1 Axial computed tomography pulmonary angiogram showing extensive thromboemboli in the right and left main pulmonary arteries (yellow arrows) extending more distally and associated with bilateral wedge shaped pulmonary infarcts (blue arrowheads)

Questions

  • 1 What is the most likely diagnosis in this patient?

  • 2 What are the differential diagnoses?

  • 3. How can this condition be diagnosed?

  • 4 How would you manage this condition?

Answers

1 What is the most likely diagnosis in this patient?

Short answer

Heparin induced thrombocytopenia.

Long answer

Heparin induced thrombocytopenia should be excluded in patients who present with acute onset of thrombocytopenia and venous thromboembolism after exposure to heparin. Heparin induced thrombocytopenia typically occurs five to 10 days after exposure to heparin and is characterised by thrombocytopenia alone or together with arterial or venous thrombosis.1 The condition is an immune mediated response caused by development of IgG antibodies against the heparin-platelet factor 4 (PF4) complex after exposure to heparin. These antibodies bind to heparin-PF4 complex and activate the platelets to generate procoagulant-rich microparticles. This causes platelet aggregation and leads to thrombotic manifestations and thrombocytopenia.2

Heparin induced thrombocytopenia occurs in 0.5-5% of patients treated with heparin.3 Its incidence is higher in surgical patients than in medical patients, and it is more common in patients who received unfractionated heparin than in those who received low molecular weight heparin.4 Without appropriate treatment, 30-50% of patients can develop limb complications or life threatening thrombotic complications.5 Atypical manifestations include heparin induced skin necrosis, venous gangrene, and anaphylactic-type reactions after an intravenous heparin bolus.6

2 What are the differential diagnoses?

Short answer

Acute onset of thrombocytopenia can be caused by disorders that cause a reduction in platelet survival or production or it can be due to dilutional effects. Concurrent thrombosis and thrombocytopenia can occur in heparin induced thrombocytopenia, disseminated intravascular coagulation, thrombotic microangiopathies, and antiphospholipid antibody syndrome.

Long answer

The survival of platelets in the circulation is reduced in immune thrombocytopenia purpura, sepsis, disseminated intravascular coagulation, thrombotic microangiopathies, vasculitis, hypersplenism, and antiphospholipid syndrome. Reduced survival can also be induced by drugs such as heparin, penicillin, quinine, and abciximab. Reduced platelet production can occur in bone marrow disorders (for example, acute leukaemia, myelodysplastic syndrome, aplastic anaemia) or drugs such as valproic acid, linezolid, and chemotherapeutics. Dilutional thrombocytopenia can occur in pregnancy and massive transfusion of platelet poor blood.7

Apart from heparin induced thrombocytopenia, concurrent thrombosis and thrombocytopenia can also occur in disseminated intravascular coagulation, thrombotic microangiopathies (cancer and other causes), and antiphospholipid antibody syndrome.8

3 How can this condition be diagnosed?

Short answer

Heparin induced thrombocytopenia is diagnosed by a combination of clinical criteria and laboratory tests.

Long answer

The clinical criteria commonly used for diagnosing heparin induced thrombocytopenia are known as the “4Ts”—Thrombocytopenia, Timing of thrombocytopenia, Thrombosis, and exclusion of oTher causes of thrombocytopenia (box).9

Diagnostic criteria for heparin induced thrombocytopenia (4Ts)

  • Thrombocytopenia (degree):

    • Platelet counts dropped by more than 50% from baseline

    • Nadir platelet counts typically >20×109/L

  • Timing of thrombocytopenia:

    • Typically 5-10 days after heparin started

    • Early onset (<2 days) with heparin re-exposure

    • Delayed onset after weeks to months

  • Thromboembolic episodes:

    • Deep vein thrombosis

    • Pulmonary embolism

    • Acute limb ischaemia

    • Acute thrombotic stroke or myocardial infarction

    • Skin necrosis at injection site

  • oTher causes of thrombocytopenia to be excluded (see answer 2)

Two types of diagnostic test are available—immunological assays that identify circulating antibodies to the heparin-PF4 complex and functional assays that detect the antibodies that induce heparin dependent platelet activation. Enzyme linked immunosorbent assays (ELISAs) and particle gel immunoassays are highly sensitive and have a rapid turnaround time, but they are less specific than functional assays and have a high false positivity. Functional assays, such as the heparin induced platelet activation test and serotonin release assay, have high specificity for heparin induced thrombocytopenia and are useful for confirming positive immunoassay results. The serotonin release assay uses radiolabelled serotonin (5-hydroxytryptamine labelled with calcium-14; 14C-5HT) and is considered the gold standard owing to its high sensitivity (88-100%) and specificity (89-100%) for heparin induced thrombocytopenia; however, this test is not widely available.10 Limitations of functional platelet studies include higher technical requirements, slower turnaround time, need for reactive donor platelets, and high cost.11

4 How would you manage this condition?

Short answer

When heparin induced thrombocytopenia is suspected on the basis of clinical criteria, all heparin sources should be discontinued immediately and the patient should be started on alternative anticoagulants, such as direct thrombin inhibitors.

Long answer

If heparin induced thrombocytopenia is suspected on the basis of the clinical criteria, all heparin types and sources (such as intravenous, subcutaneous, intravenous flushes, and coated lines) should be discontinued immediately without waiting for laboratory confirmation. Even after stopping heparin, untreated patients have a high cumulative incidence of thromboembolism (about 50%) at 30 days.12 Hence anticoagulation with a non-heparin agent is essential for all these patients, whether or not they have thrombosis. The anticoagulants recommended in heparin induced thrombocytopenia are danaparoid and direct thrombin inhibitors (bivalirudin or argatroban).10 Treatment with warfarin during an acute episode of heparin induced thrombocytopenia can worsen thrombotic manifestations owing to rapid onset of protein C deficiency.13 Hence, in patients with acute heparin induced thrombocytopenia, the transition to warfarin should be done with care and delayed until platelet counts recover. The duration of warfarin therapy for heparin induced thrombocytopenia associated thromboembolism is generally three to six months.8

Newer oral anticoagulants such as dabigatran and rivaroxaban may be considered as alternative treatment options for heparin induced thrombocytopenia. In vitro studies have shown that these drugs do not interact with anti-PF4 or anti-heparin-PF4 antibodies.14 Further clinical studies are needed to confirm their effectiveness in patients with heparin induced thrombocytopenia.

Platelet transfusions were considered to be dangerous in this condition for fear of precipitating or worsening the clots.1 However, a few retrospective studies have shown that platelet transfusions in bleeding patients did not trigger thrombotic episodes.15 Evidence on the safety and benefit of platelet transfusions in patients with heparin induced thrombocytopenia is still limited. Hence platelet transfusions are recommended in these patients only if they have overt bleeding or during invasive procedures in patients with a high risk of bleeding.16

Patient outcome

Our patient fulfilled the “4Ts” clinical criteria and the screening test for heparin induced thrombocytopenia was positive. Soon after he was clinically diagnosed as having heparin induced thrombocytopenia, precautions were taken to avoid heparin administration by any route. He was managed in a high dependency unit and given an infusion of lepirudin for anticoagulation (lepirudin has since been discontinued and is not available now). His shortness of breath and low oxygen saturation recovered completely within 72 hours. His platelet counts started to increase after two days and were normal (>150×109/L) after eight days (fig 2). After his platelet counts recovered, he was gradually moved over to warfarin and was discharged home on warfarin. At the time of clinical diagnosis, a blood sample was also sent to a reference laboratory for testing with the serotonin release assay. This showed high release of 14C-5HT (96%) in the presence of 0.1 U/mL of heparin but no release (0%) with high dose heparin (100 U/mL), which confirmed the diagnosis of heparin induced thrombocytopenia. He was counselled regarding hypersensitivity to heparin and low molecular weight heparin and his medical records were flagged with “heparin allergy-heparin induced thrombocytopenia.” Repeat computed tomography pulmonary angiography and lower limb Doppler scans six months later showed complete clearance of pulmonary emboli and venous thrombosis, respectively, after which warfarin was discontinued.

Figure2

Fig 2 This patient’s platelet counts at baseline and over the course of his illness

Early recognition of heparin induced thrombocytopenia along with prompt administration of alternative anticoagulation helped prevent life and limb threatening complications in our patient.

Notes

Cite this as: BMJ 2014;348:g1164

Footnotes

  • We thank the staff of South Eastern Area Laboratory services (SEALS) in Sydney, Australia for helping us with the serotonin release assay test.

  • Competing interests: We have read and understood the BMJ Group policy on declaration of interests and declare the following interests: None.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

  • Patient consent obtained.

References

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