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Coagulation disorders
Thrombocytopenias
Differential diagnosis of thrombocytopenia
This should include:
- ITP
- Leukaemias
- TTP
- Rare conditions such as viral haemorrhagic fevers (sick, febrile, abnormal LFTs, often uraemic).
- In anaemic patients with a macrocytosis also consider nutritional anaemias (folate or B12).
Idiopathic thrombocytopenic purpura (ITP)
Patients with ITP present with either petechiae or mouth or nose bleeding, or a combination of these. A FBC shows a very low platelet count with normal white cell count and haemoglobin (unless bleeding has been substantial). The diagnosis is confirmed by bone marrow demonstrating adequate or increased platelet production. Severe anaemia or a raised white cell count should always raise concerns about a marrow problem such as a leukaemia, and ITP itself may be the initial manifestation of lymphoma.1
Diagnosis is classically made by finding severe thrombocytopenia with a well-functioning bone marrow. Several case series have suggested that in the presence of a normal physical examination and no other abnormalities on the smear a marrow biopsy seldom if ever leads to a change in management.2. A study in HIV positive patients found that isolated thrombocytopenia was still likely immune, although as soon as there was a bicytopenia the diagnostic spectrum broadened considerably, with about half being due to “haematological” causes (lymphoma, leukaemia, myelodysplasias, aplastic anaemia, myeloma) and the rest being either sepsis or pure HIV related (“peripheral causes”.)3
Treatment of ITP
Initial therapy is commonly stated to be prednisone 1 mg/kg/day. If there isn’t a rapid response (within a few days) then increase the dose to 2 mg/kg/d. (Some clinicians prefer to start straight away with 2 mg/kg/day.) Once the platelet count has normalised, keep the patient on that dose for a month and then slowly reduce the dose over months, keeping a careful eye on the platelet count. Too abrupt a reduction often seems to lead to a recurrence.
Check the ANF and consider whether there are other features of SLE, as ITP may be a presenting feature of SLE. Sometime the ‘ITP’ precedes the rest of the features of SLE by some months or even a year or more. Another common association is with HIV, and this is an indication to consider starting ART.
In patients who are HIV positive, immune thrombocytopenia is best managed by also starting anti-retroviral therapy promptly (as well as the corticosteroids)
In patients who fail to respond to corticosteroids, discuss with a specialist as splenectomy is probably the next option.
Thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome
These syndromes were relatively rare prior to the HIV epidemic, but are now being seen with increasing frequency. They are probably different manifestations of the same or similar underlying pathologies, and management is similar.
HUS is a combination of renal dysfunction, thrombocytopenia and haemolytic anaemia associated with E coli infection and diarrhoea; TTP is a pentad of:
- Thrombocytopenia (normal INR and D-dimer, so DIC unlikely)
- Haemolytic anaemia (high LDH, negative Coombs, RBC fragments on smear)
- Renal dysfunction
- Neurological signs (focal, or sometimes just confusion)
- Fever
TTP is due to deficiency (usually acquired) of a von Willebrand cleaving protein called ADAMTS13, resulting in vWF multimers causing platelet aggregation in high sheer environments such as the brain and kidneys. About half of patients have a positive troponin T, reflecting cardiac involvement.
Diagnosis of TTP
This is usually based on a combination of several of the features of the pentad (not all are required) in the presence of fragments on smear without evidence of a DIC (i.e. normal INR, D-dimer and fibrinogen)
Therapy
This is not wildly successful, but consists of either plasma exchange, or in the absence of facilities for this, the infusion of FFP (30ml/kg/day, which would amount to about 6 units (1.8 l) per day in a 60 kg person. This is a significant fluid and sodium load (Na 165 mmol/l) and one needs to watch fluid balance carefully.
Corticosteroids and vincristine have also been tried, and in HIV positive patients, starting on ARVs may ameliorate or reverse the condition.
Haemophilia
The diagnosis is usually already known; in a young person presenting with recurrent bleeding a prolonged PTT is an adequate screening test.
When a haemophiliac patient presents to you, assume that he is bleeding.
Do not use non-steroidal anti-inflammatory agents!
You don’t need to send off factor VIII assays unless there appears to be a resistance problem, in which case discuss with a haematologist.
Joint bleeds
The commonest site for bleeding is intra-articular, and all new swollen joints in haemophiliacs should be treated immediately with Factor VIII. The product used (Factor VIII concentrate) is available from the blood bank in 250, 500 and 1000 IU strengths.
Duration of treatment: A fresh joint bleed treated early may only require a single dose of 25 IU/kg. The frequency of repeat doses (if any) is controversial – on the one hand under-treatment is associated with significant joint disability, but on the other hand giving unnecessary therapy is both dangerous in terms of infection and antibody development (this latter ultimately leading to resistance to Factor VIII) and is also extremely costly. Firm guidelines are difficult, and haematologists are extremely difficult to pin down on this subject. CNS or major internal bleeding, or bleeding with the risk of a compartment syndrome (e.g. fore-arm bleed), or neck soft tissue with possibility of airway compromise, should be treated with 50 IU/kg.
In a resource-constrained environment, two factors worth considering are that because of transport logistics patients often don’t present that early, and secondly the marginal return on successive infusions once pain has settled is probably very small. Give a good first dose, and expect to give another dose after 8 – 12 hours, but assess the patient first. If the pain has settled well after the first dose, it is probably reasonable to stop at that, but watch carefully.
Get the help of a physiotherapist to assist with mobilisation once the pain has gone – the principle is to start with gentle passive and then gradually incremented active movements.
Soft tissue bleeding
Soft tissue bleeding (e.g. retroperitoneal, pharyngeal, etc.) can also be managed using 25 units/kg, but this may need to be repeated 12 hourly.
Major bleeds and surgical conditions
Head injuries, major trauma, and major GIT bleeds should get 40 units/kg, and this should be repeated 8 hourly until the problem settles. Patients undergoing surgery need 40 units/kg 8 hourly for several days.
Dental work
Minor tooth and gum bleeds may respond to topical tranexamic acid (250 mg dissolved in 10ml saline and swirled gently around the mouth four times per day). Alternatively, give tranexamic acid 1 g PO 4x/d.
Tooth extractions should be done in hospital under cover of a pre-extraction infusion of 40 units/kg on the day of the procedure. Observe for a full day after the extraction and minimise the trauma to the forming clot by avoiding toothbrushes and hard foods for a day or two. Use tranexamic acid as mentioned under minor bleeds above. The dentist should obviously suture the socket if it is bleeding excessively. In patients with mild haemophilia DDAVP may suffice (give intranasal desmopressin 20 mcg twice daily.)
Disseminated intravascular coagulation.
DIC should be considered in any potentially septicaemic patient, and as the cause for an incidentally discovered thrombocytopenia in any ill patient. (Be aware of another rare but important condition – thrombotic thrombocytopenic purpura, which present with thrombocytopenia and neurological and renal changes and fever.)
The key management strategy in DIC is to treat the underlying cause (i.e. uterine evacuation in eclampsia, antibiotics and surgical drainage for sepsis) but it is usually necessary to give blood products to control bleeding – platelets and fresh frozen plasma (15 ml/kg) usually suffice. Give FFP if active bleeding and fibrinogen > 1 g/l, but if it is less than this consider cryoprecipitate (1 unit/10 kg). Give packed cells as needed to maintain the haematocrit.
Perspective: testing for DIC
The diagnostic performance of individual and combination tests in DIC has been explored4,5,6 Platelets of greater than 130 000 make the diagnosis very unlikely. Useful ‘rule in’ tests are D-dimer (sensitivity 91%, specificity 68%, LR+ 2.84), FDPs >0.01 g/l (sens 100%, spec 67%, LR+ 3.03, LR- 0.00!) and fibrinogen < 1.5 g/l (sens only 22% but spec 100%, LR+ > 100, and LR- 0.78.)
The INR, PTT, fibrinogen and platelet count reflect the later consumptive stage of DIC, and the first two may be influenced by the use of anticoagulants. Fibrinogen and D-dimer are thus reasonable screening tests for earlier disease.
Marino S, Di Cataldo A, Magro G, D’Amico S, La Spina M, Di Benedetto V, Meli M, Moscheo C, Russo G. A difficult diagnosis of Hodgkin lymphoma due to immune thrombocytopenia. Clin Case Rep. 2015 Mar;3(3):179-82. doi: 10.1002/ccr3.176. Epub 2015 Feb 4. PMID: 25838909; PMCID: PMC4377251. ↩
Purohit A, Aggarwal M, Singh PK, Mahapatra M, Seth T, Tyagi S, Saxena R, Pati HP, Mishra P. Re-evaluation of Need for Bone Marrow Examination in Patients with Isolated Thrombocytopenia Contributors. Indian J Hematol Blood Transfus. 2016 Jun;32(2):193-6. doi: 10.1007/s12288-015-0533-2. Epub 2015 Mar 28. Erratum in: Indian J Hematol Blood Transfus. 2016 Jun;32(2):197. PMID: 27065582; PMCID: PMC4788996. ↩
Abdullah I, Subramony N, Musekwa E, Nell EM, Alzanad F, Chetty C, Gantana E, Lohlun RK, Cerfontein W, Cochrane B, Chapanduka ZC. Indications and diagnostic value of bone marrow examination in HIV-positive individuals: A 3-year review at Tygerberg Hospital. S Afr J Infect Dis. 2021 Aug 23;36(1):273. doi: 10.4102/sajid.v36i1.273. PMID: 34522695; PMCID: PMC8424746. ↩
Mujun Y, Nardella A, Pechet L. Screening tests for disseminated intravascular coagulation: guidelines for rapid and specific laboratory diagnosis. Crit Care Med. 2000;28:1777-80 ↩
Levi, M. Pathogenesis and diagnosis of disseminated intravascular coagulation. Int J Lab Hem. 2018; 40(Suppl. 1): 15- 20. https://doi.org/10.1111/ijlh.12830 ↩
Adelborg, K., Larsen, J.B. and Hvas, A.-M. (2021), Disseminated intravascular coagulation: epidemiology, biomarkers, and management. Br J Haematol, 192: 803-818. https://doi.org/10.1111/bjh.17172 ↩