Thrombocytopenia Flashcards
Heparin-induced Thrombocytopenia
Heparin-induced thrombocytopaenia (HIT)
- immune mediated - antibodies form against complexes of platelet factor 4 (PF4) and heparin
- these antibodies bind to the PF4-heparin complexes on the platelet surface and induce platelet activation by cross-linking FcγIIA receptors
- usually does not develop until after 5-10 days of treatment
- despite being associated with low platelets HIT is actually a prothrombotic condition
features include a greater than 50% reduction in platelets, thrombosis and skin allergy
- treatment options include alternative anticoagulants such as lepirudin and danaparoid
Heparin-Induced Thrombocytopenia - Diagnostic Criteria
Thrombocytopenia:
>50% fall, and nadir >20*109/l = 2 points
30-50% fall, or nadir 10-19*109/l = 1 point
fall < 30%, or nadir < 10*109/l = 0 points
Timing of platelet fall:
Between 5-10 days, or <1 day if exposure to heparin within last 20 days = 2points
Consistent with immunisation, unclear due to missing samples = 1 point
Fall <4 days after exposure (with no recent exposure history = 0 points
Sequelae:
Thrombosis, skin necrosis or systemic reaction post-bolus = 2 points
Progressive or recurrent thrombosis, suspected but unproven thrombosis, erythematous skin reaction = 1 point
Alternative Cause:
None = 2 points
Possible = 1 point
Definite = 0 points
TOTAL SCORE INTERPRETATION FOR HIT:
0-3 - Low
4-5 - Intermediate
6-8 - High
Heparin-induced Thrombocytopenia - Mx
The recommendations for treatment are as follows:
DIRECT THROMBIN INHIBITOR:
DANAPAROID/ BIVALIRUDIN/ ARGATROBAN/ DABIGATRAN
- Therapeutic danaparoid should be used
- The anticoagulant effect of danaparoids can be measured with anti-Xa assay
- Therapeutic dose fondaparinux is an acceptable alternative anticoagulant (although it is unlicensed)
- Therapeutic anticoagulation should be continued for 3 months (in those with thrombosis) and 4 weeks (in those without thrombosis)
- When transitioning from argatroban to warfarin, the INR should be >4 for 2 days prior to discontinuing argatroban
- Warfarin should not be used till platelet count is back in normal range
Example Question:
You are looking after a 76-year-old man on an orthogeriatric ward. He is day 7 post dynamic hip screw for neck of femur fracture. He appears to be doing relatively well, but the nurse has noticed that he has a dark black necrotic looking skin over his left iliac fossa, and has asked you to come and look at it.
His past medical history includes hypertension, mild chronic kidney disease and atrial fibrillation.
He is currently on Ramipril 2.5mg once daily, Bisoprolol 5mg once daily, and treatment dose Clexane (patient was on Warfarin pre-operatively).
Pre-admission operative bloods:
Hb 142 g/l
Platelets 212 * 109/l
WBC 14.1 * 109/l
Na+ 138 mmol/l
K+ 4.6 mmol/l
Urea 8.2 mmol/l
Creatinine 167 µmol/l
Bloods yesterday:
Hb 112 g/l
Platelets 27 * 109/l
WBC 10.1 * 109/l
Na+ 136 mmol/l
K+ 4.0 mmol/l
Urea 9.1 mmol/l
Creatinine 182 µmol/l
What should you do with regards to his Clexane?
Stop Clexane and give Warfarin (target INR 2-3) > Stop Clexane and give treatment dose Argatroban Switch treatment dose Clexane to Unfractionated Heparin infusion Give 1 pool of platelets Switch treatment dose Clexane to prophylactic Clexane
This is a case of heparin induced thrombocytopaenia
Heparin-Induced Thrombocytopenia Mx - Example Question
A 76-year-old man presented with shortness of breath to the emergency department. On the basis of a recent knee replacement operation and unremarkable chest x-ray a CT pulmonary angiogram was performed and demonstrated a segmental pulmonary embolus with evidence of mild right heart strain. The patient was haemodynamically stable and required only minimal supplemental oxygen therapy.
The patient had known chronic kidney disease stage IV secondary to type 2 diabetes and hypertension. Treatment was therefore initiated with an intravenous unfractionated heparin infusion.
The patient’s condition was stable over the following week with warfarin loading cautiously started at day 6 of admission. Routine blood tests at this point indicated a new abnormality in full blood count leading to further investigations as detailed below.
Haemoglobin 14.5 g / dL White blood cells 8.6 x 10>3 / microlitre Neutrophils 4.5 x 10>3 / microlitre Lymphocytes 2.1 x 10>3 / microlitre Platelets 67 x 10>3 / microlitre Mean cell volume 85 fL Mean cell haemoglobin 30.1 pg B12 252 pmol / L Folate 20 nmol / L
Heparin induced thrombocytopenia antibodies: positive (high titre)
Following cessation of IV heparin infusion, what is the appropriate management of the patient’s thrombocytopenia?
> Bivalirudin Enoxaparin Warfarin Tirofiban Platelet transfusion
This patient has a confirmed diagnosis of heparin induced thrombocytopenia (HIT) based on the suggestive clinical picture and positive HIT antibody screen. Decision tools such as the Warkentin probability scale can be useful by providing a pre-test probability score of HIT based on the clinical picture. In this case, the timing of thrombocytopenia with onset between 5-10 days after initial exposure to heparin is highly suggestive.
In suspected or confirmed cases of HIT, heparin anticoagulants must be withheld immediately. Treatment with a non-heparin anticoagulant such as bivalirudin should be started to reduce the risk of HIT-related thrombosis.
Vitamin K antagonists such as warfarin such be withheld or reversed as they do not prevent HIT-associated thrombosis and increase the risk of venous gangrene. Platelet transfusion would not be indicated in this patient.
Heparin-Induced Thrombocytopenia - Mx: Example Question
You are asked to review a 75-year-old lady on the surgical ward. She has malignant carcinoma of the colon and had a large bowel resection seven days ago. Despite being on dalteparin since admission, she had developed a right-sided deep venous thrombosis (DVT). She tells you she had a similar problem ten years ago and had to take ‘blood-thinning injections’ for several months.
On examination she looks well with no signs of respiratory distress. Her oxygen saturations are 99% on room air and on auscultation she has vesicular breath sounds throughout both lung fields.
Her pre-operative blood tests are as following:
Hb 119 g/l Na+ 135 mmol/l Bilirubin 12 mol/l Platelets 457 * 109/l K+ 4.5 mmol/l ALP 111 u/l WBC 6.8 * 109/l Urea 4.9 mmol/l ALT 45 u/l Neuts 4.0 * 109/l Creatinine 81 µmol/l γGT 30 u/l Lymphs 0.9 * 109/l Albumin 34 g/l Eosin 0.0 * 109/l
Her blood results today are as follows:
Hb 105 g/l Na+ 133 mmol/l Prothrombin time 10.7 s Platelets 77* 109/l K+ 4.1 mmol/l APTT 27.5s WBC 7.6 * 109/l Urea 5.7 mmol/l APTT ratio 45 u/l Neuts 4.9 * 109/l Creatinine 98 µmol/l D-Dimer >1000 ng/ml Lymphs 1.1 * 109/l Albumin 31 g/l Eosin 0.1 * 109/l
Which of the following represents the optimal management for this patient whilst she remains an inpatient?
Warfarin > Bivalirudin IV heparin infusion Plasma exchange Rivaroxaban
This lady has heparin-induced thrombocytopaenia (HIT). She needs anticoagulation but should ideally be switched to a non-heparin drug for now. Bivalirudin is a direct thrombin inhibitor and is not associated with HIT.
Plasma exchange would be the treatment of choice for thrombotic thrombocytopenic purpura, which is note the case here.
Warfarin causes a rapid fall in protein C levels, risking complications such as skin necrosis, so is not used acutely.
Causes of Thrombocytopenia
Causes of severe thrombocytopenia ITP DIC TTP haematological malignancy
Causes of moderate thrombocytopenia heparin induced thrombocytopenia (HIT) drug-induced (e.g. quinine, diuretics, sulphonamides, aspirin, thiazides) alcohol liver disease hypersplenism viral infection (EBV, HIV, hepatitis) pregnancy SLE/antiphospholipid syndrome vitamin B12 deficiency
Causes of Thrombocytopenia - Example Question
A 30-year-old man with acute myeloid leukaemia receives a bone marrow transplant from a matched unrelated donor.
7 days post-transplant, he develops a non-blanching purpuric rash over both legs. The rash is not itchy or scaly.
His heart rate 98/min and his blood pressure is 124/72 mmHg. His temperature is 37.3 ºC and he is otherwise asymptomatic.
Blood tests are as follows:
Hb 89 g/l Na+ 138 mmol/l Platelets 9 * 109/l K+ 3.2 mmol/l WBC 0.8 * 109/l Urea 4 mmol/l Neuts 0.2 * 109/l Creatinine 62 µmol/l CRP 10 mg/ll
What is the most likely cause for the rash?
Fungal infection Graft vs host disease Henoch Schonlein purpura Meningitis > Thrombocytopenia
This man is on day 7 of his transplant and his blood counts are starting to drop, including his platelets. Thrombocytopenia typically causes small purpuric spots that are otherwise asymptomatic.
A fungal infection is possible in an immunosuppressed patient but would be more likely to cause an itchey or painful rash with a different appearance.
Graft vs host disease typical causes a dry scaley rash and develops when the patients immune system is starting to recover, around 2 weeks after transplant.
Henoch Schonlein purpura typically affects children and is associated with a glomerulonephritis. It is immune mediated so unlikely in someone who is still profoundly immunosuppressed.
Meningitis can cause a non-blanching purpuric rash but the patient would be symptomatic with headache, fever, meningism and a CRP rise.
Thrombotic Thrombocytopenic Purpura (TTP) - Pathogenesis
Pathogenesis of thrombotic thrombocytopenic purpura (TTP)
- Abnormally large and sticky multimers of von Willebrand’s factor cause platelets to clump within vessels
- In TTP there is a deficiency of protease which breakdowns large multimers of von Willebrand’s factor
- Overlaps with haemolytic uraemic syndrome (HUS)
TTP - Mx
Management
The standard treatment for TTP is IV plasma exchange which should be initiated as soon as possible.
No antibiotics - may worsen outcome
plasma exchange is the treatment of choice
steroids, immunosuppressants
vincristine
TTP - Causes
Congenital TTP is caused by a deficiency in von Willebrand factor. However the majority of cases are secondary and can occur in pregnancy, HIV and associated with some drugs. In particular the chemotherapeutic agents mitomycin C, bleomycin, tamoxifen and gemcitabine are all associated with secondary TTP. Other drugs in association include penicillin, rifampicin and immunosuppressive drugs eg. ciclosporin A.
TTP - Example Question:
A 64 year old female undergoing chemotherapy treatment with mitomycin for bladder cancer presents to the Emergency Department with confusion, epistaxis and a widespread rash. On examination she is febrile and has a diffuse petechial rash.
Hb 10.6g/dl Platelets 54 * 109/l WBC 11.2 * 109/l Urea 11mmol/l Creatinine 117µmol/l Bilirubin 58µmol/l ALP 42u/l
A blood film shows fragmented erythrocytes.
What is the most appropriate treatment for this patient?
Renal dialysis Supportive treatment A pool of platelets and fluid resuscitation > Urgent plasma exchange IV tazocin, a pool of platelets and fluid resuscitation
Thrombotic thrombocytopenic purpura (TTP) is characterised by fluctuating neurological signs, fever, renal dysfunction, microangiopathic haemolysis and thrombocytopenia. The key to diagnosis is differentiating between TTP and haemolytic uraemic syndrome (HUS). The presence of neurological signs in TTP and more severe renal dysfunction in HUS usually helps in distinguishing the two.
TTP - Features
Features rare, typically adult females fever fluctuating neuro signs (microemboli) microangiopathic haemolytic anaemia thrombocytopenia renal failure
TTP - Causes
Causes
post-infection e.g. urinary, gastrointestinal
pregnancy
drugs: ciclosporin, oral contraceptive pill, penicillin, clopidogrel, aciclovir
tumours
SLE
HIV
Post-partum TTP - Example Question:
A 26 year old female who is 14 days post-partum (spontaneous vaginal delivery) presents to your medical admissions unit with her partner who is worried that she is confused. She is unable to provide any history but her partner tells you that she has gradually gotten worse over the past few days. Her observations are as follows: temperature 38ºC, pulse 90/min, blood pressure 154/88 mmHg, respiratory rate 16/min, sats 99% on room air.
On examination, she looks pale. Her chest is clear and abdomen is soft, non-tender. She has multiple bruises on her arms. Her blood results are pending.
What is the most likely diagnosis?
Haemolytic uraemic syndrome > Thrombotic thrombocytopenic purpura Idiopathic thrombocytopenic purpura Retained products of placenta Disseminated intravascular coagulation (DIC)
Thrombotic thrombocytopenic purpura is associated with fever, anaemia, thrombocytopenia, renal failure and confusion. Pregnancy and the post-partum state account for about 20% of cases seen.
Haemolytic uraemic syndrome is not associated with fever and confusion. Retained products of placental is more unlikely as her abdomen is soft, non-tender. DIC would be a differential diagnosis but is not the most likely diagnosis here. Idiopathic thrombocytopenic purpura would not cause confusion.
HIT - Example Question
75-year-old man underwent a right hemicolectomy as radical treatment for a caecal adenocarcinoma. During the immediate post-operative period the patient was noted to be significantly confused and investigations to assess for a septic source were requested. Blood tests indicated new neutrophilia and thrombocytopenia. Noting that the patient had been started on enoxaparin for venous thrombosis prophylaxis on the first day after the operation, heparin induced thrombocytopenia antibodies were requested by the surgical junior team.
A specialist medical review was requested on day 6 post-operatively to assess the patient in the light of the results of these investigations. The patient was found to be back to his cognitive baseline and was starting to mobilise on the ward with the help of physiotherapy. Clinical examination was unremarkable except for the healing abdominal surgical incision.
Aside from his recent cancer diagnosis, the patient’s past-medical history included only hypercholesterolaemia treated with simvastatin. He had no known allergies or drug sensitivities.
Blood result: Pre-op > Day 1 post-op> Day 4 post-op> Day 6 post-op Platelets (x 10>3 / microlitre) 175 95 125 141 Neutrophils (x 10>3 / microlitre) 5.3 14.8 12.8 8.8 C-reactive protein (mg / L) 6 142 94 25 International normalised ratio 1.0 1.2 1.1 1.1
Chest x-ray: clear lung fields aside from minor bibasal atelectasis
Urine culture: no growth
CT abdomen: minimal abdominal free fluid, no evidence of focal collection, large bowel anastomoses intact
Heparin-induced thrombocytopenia antibodies: positive (moderate titre)
What is the likely cause for the patient’s thrombocytopenia?
Heparin induced thrombocytopenia Post-operative sepsis > Post-operative thrombocytopenia Thrombotic thrombocytopenic purpura Disseminated intravascular coagulation
Heparin induced thrombocytopenia (HIT) antibodies have a high false positive rate and their interpretation needs to take into account careful consideration of the entire clinical picture. Decision tools to assess the likelihood of HIT such as the Warkentin probability scale are useful in this setting. This provides a pretest probability score to assist with interpretation of HIT antibody results based on the extent of the thrombocytopenia, the timing of onset relative to heparin administration, thrombotic events and the presence or absence of other causes of thrombocytopenia.
In this case, there are few clinical features consistent with HIT and a low pretest probability score would be calculated. The combination of this and moderate titre positive HIT antibodies is considered to exclude a HIT diagnosis.
In this patients case a post-operative thrombocytopenia is the most likely cause in the absence of evidence for other possible answers. The patients elevated inflammatory markers are secondary to surgery with no septic source identified on investigation. TTP can cause thrombocytopenia associated with delirium, although the patients clinical and haematological recovery make this an unlikely cause. DIC is excluded by the normal prothrombin time and improving clinical picture.
