Hiv thrombocytopenia


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Hiv thrombocytopenia

  1. 1. HIV associated thrombocytopenia
  2. 2. Clinical case presentation
  3. 3. Presenting complaint38 year old admitted to sugical ward with frank hematuriaand generalized weaknessAdmitted with a history of: Passing blood in urine for a week Tiredness and feeling weakPhysical Exam Pallor No thrush No splenomegaly
  4. 4. HPI• 38 year old male not known to have any chronic illnesses presented to ER with c/c/o passing blood in urine for past one week which is getting worse for past 2 days.• Patient is also complaining of generalized weakness and feel tired all the day
  5. 5. HPI• Patient denies any bleeding from gums and no red/black spots noted on skin.• Denies any blood in stool• Denies any loose stools/vomitings• No fever/rash/joint pains• Patient is also complaining of weight loss and says it is negligible.
  6. 6. Physical examination• Middle age male in nil CPD M/M : pale/ moist/anicteric acyanotic• Chest: BAE+ clear• Cardiac: Unremarkable• Neuro: Unremarkable• Abdomen: Soft ,nontender, No organomegaly• 300 cc of frank blood noted in Urinary bag
  7. 7. LABORATORY (ON ADMISSION)Hb 11.3 g/dlMCV 100WCC 4.89 109/lPlatelets 6.000/μlDiff. count: normalLFT: normalU+E: NormalLFT: NormalPT/PTT/INR Not available
  8. 8. Imaging• U/S KUB: NORMAL STUDY
  9. 9. Other blood workup• HIV- Reactive• VDRL- Non reactive
  10. 10. Diagnosis• HIV Thrombocytopenia
  11. 11. Treatment• Patient was started on Oral steroids(Prednisone), ZIDOLAM-N and vitamin suppelements
  12. 12. Hospital course• Within 4 days of steroid and ART patient clinical symptoms were totally resolved and Platelets improved to 70000 by the time of discharge
  13. 13. Thrombocytopenia• Normal platelet count= 150 000 – 450 000• Mean values : -Males 237 000 -Females 266 000• Plt count < 150 000 = thrombocytopenia• Recent fall > 50% within normal range heralds severe clinical problems
  14. 14. Megakaryocyte and Platelets
  15. 15. PLATELET KINETICS• Megakaryocytes produce platelets by cytoplasmic shedding directly into bone marrow sinusoids• About 1 000 – 5 000 plts are produced by each MK before undergoing apoptosis• In normal individuals plt production is approx 35000 – 50000 microL of whole blood /day• Above value ↑ more than 8x with increased demand• Plt production rate can be ↑ 20-fold with exogenous thrombopoietin (TPO)• Youngest plts contain RNA (reticulated plts) analogous to reticulocytes
  16. 16. • Thrombocytopenia is one of the most frequently observed haematological complications of HIV infection.• The incidence increases among patients not receiving adequate antiretroviral treatment and does not appear to vary according to the mode of acquisition of HIV.
  17. 17. • HIV-related thrombocytopenia has been generally attributed to two different mechanisms:• First, an immunologically driven destruction of the platelets and second, an insufficient platelet production by the mega - karyocytes.• While in early HIV infection increased platelet destruction appears to be predominant, production failure is often the main cause of thrombocytopenia in late-stage patients.
  18. 18. Prevalence of thrombocytopenia in HIV patients • It can be an initial manifestation in as many as 10% of HIV patients A 10-year • incidence of approx. 40% of HIV patients anycumulativeAffects up to 45% has been reportedA 10-yearcumulative incidence of up to 45% has been reported time during their illness
  19. 19. HIV associated thrombocytopeniaPrimary HIV-associated thrombocytopenia (PHAT) • Most common • Resembles Idiopathic Thrombocytopenia • Complex etiologySecondary thrombocytopenia • Result of underlying pathologies (malignancies, OI, autoimmune diseases, lymphoproliferative disorders, myelodysplastic syndromes, chronic HCV, H. Pylori and drugs) • Heparin-induced thrombocytopenia (HIT) more common in HIV • Thrombotic-thrombocytopenic purpura-hemolytic uremic syndrome (TTP- HUS)EDTA associated Pseudothrombocytopenia
  20. 20. Primary HIV-associated thrombocytopenia (PHAT)Pathophysiology • increased number of BM megakaryocytes driven by: • increased endogenous thrombopoietin, but: • ineffective delivery of viable platelets by MK • doubled splenic sequestration of platelets • shortened lifespan of platelets by two thirds
  21. 21. Primary HIV-associated thrombocytopenia (PHAT)Ineffective platelet production • HIV is able to directly infect megakaryocytes • HIV transcripts are present in MK in PHAT • Disturbance of MK function (platelet development and maturation) • Increased MK apoptosis
  22. 22. Primary HIV-associated thrombocytopenia (PHAT)Shortened platelet life span • Probably the result of anti-platelet antibodies (IgG and IgM) • Platelet-associated IgG antibodies cross-react with PLT GPIIb/IIIa and HIV env GP 160/120 • Such AB are found in >70% in PHAT • Anti-HIV antibodies binding to normal control platelets were more frequent in PHAT compared to non-PHAT patients (50% versus 5%)
  23. 23. Primary HIV-associated thrombocytopenia (PHAT)Clinical manifestation • Marked inter-patient variability • Abrupt to insidious • Incidental mild thrombocytopenia to severe bleeding Expected: Petechiae, purpura, easy bruising Common: Epistaxis, gingival bleeding, menorrhagia Rare: Gastrointestinal bleeding, gross hematuria Uncommon: Intracranial hemorrhage
  24. 24. Primary HIV-associated thrombocytopenia (PHAT)Differential Diagnosis • Opportunistic infections MAC, disseminated TB, leishmania, septicemia, histoplasmosis, CMV, EBV, Rubella… • Malignancies NHL, KS… • Co-morbidity resulting in hypersplenism Portal hypertension (chronic hepatitis/cirrhosis…) • Drug associated thrombocytopenia Heparin induced thrombocytopenia (HIT), TMP-SMX, Ketoconazole, Gancyclovir, Pentamidine, Acyclovir, PZA, RFM, RFB, Valgancyclovir… • TTP-HUS Rare in HIV
  25. 25. Primary HIV-associated thrombocytopenia (PHAT)Diagnosis: • No gold-standard • Clinical diagnosis (usually isolated thrombocytopenia) • Exclude secondary thrombocytopenia Pseudo-thrombocytopenia, drugs, HCV, H.pylori, CMV, MAC, Lymphoma, SLE, Immunothyroiditis, Heparin-induced thrombocytopenia, TTP-HUS, Hypersplenism • Not recommended: anti-platelet antibody testing
  26. 26. Thrombotic thrombocytopenic purpura (TTP) Hemolytic uremic syndrome (HUS)Diagnosis:• Thrombocytopenia• Microangiopathic hemolytic anemia• Presence of fragmented red cells (schistocytes)• Abnormalities of coagulation in DIC• ADAMTS13 measurement is uncertainThe recommended treatment for TTP is plasmapheresis and plasma exchange.
  27. 27. HCV-ASSOCIATED THROMBOCYTOPENIA• HCV infection evolves towards a chronic state in approx 85% of patients• Long-term complications of chronic HCV infection include liver cirrhosis, end-stage liver disease and hepatocellular carcinoma• Mechanism: sequestration of plt by hypersplenism resulting from portal hypertension.• Treatment: Corticosteroids, interferon-alfa, eltrombopag, IVIG or anti-RhD immunoglobulin
  28. 28. EDTA dependant pseudothrombocytopeniaPathophysiology: • In vitro clumping of healthy platelets, in the presence of platelet agglutinating antibodies and EDTA • Incidence ~ 0.1% in the general population • gpIIb/IIIa important factor in physiological haemostasis as receptor for fibrinogene and VWF • EDTA binds the Ca++ which is required for normal gpIIb/IIIa function • Lack of Ca++ results in vitro malfunction and malformation of the gpIIb/IIIa receptor that can be now recognised by platelet agglutinin antibodies
  29. 29. EDTA dependant pseudothrombocytopeniaLeft: peripheral blood smear from Right: second blood sample from theroutine blood sample, anticoagulated same patient, anticoagulated withwith EDTA heparineElectronic counting: 44.000/μl Electronic counting: 560.000/μl Source: Shalev O, Lotman A. NEJM, 1993; 329: 1467
  30. 30. EDTA dependant pseudothrombocytopeniaConsequences: • Wrongly diagnosing an individual with normal platelets as having severe thrombocytopenia Unnecessary evaluation procedures (BM, blood tests…) Unwarranted treatment (steroids, platelets…) Unwarranted splenectomy Needless expenses to the patient and the health system • Know about it! Diagnostic hint: low platelets without any signs of bleeding • How to diagnose it? Do blood smear and watch out for platelet clumping Re-do electronic counting of platelets from citrate or heparin blood
  31. 31. DRUG-INDUCED THROMBOCYTOPENIA• The 1st case of drug-induced thrombocytopenia (DITP) was identified with quinine 140 years ago• Several therapeutic agents have been implicated but few reports are compelling• Diverse mechanisms have been postulated:- BM toxicity- immune-mediated destruction of platelets- Anti-drug-specific antibodiesFIRST STEP IN MANAGING DITP = STOP INCITING DRUG(S)
  32. 32. HEPARIN-INDUCED THROMBOCYTOPENIA• Develops in 1% to 3% of patients receiving unfractionated heparin (UFH) for a minimum of 5 days• Prevalence < in patients exclusively treated with low- molecular-weight heparin• Incidence is highest in patients undergoing cardiopulmonary bypass and orthopedic surgery• Mechanism: UFH binds to platelet factor 4 producing immune complex for which antibody is specific; immune complex activates platelets through Fc receptors
  33. 33. Considerations for Treatment of PHAT• The patients current platelet count• The potential toxicities of therapy• Other co-morbid conditions that increase the risk of bleeding complications (eg, hemophilia, metastatic malignancy)• A spontaneous remission in almost 20% of patients with PHAT
  34. 34. Asymptomatic and ARTthrombocytes >30,000/μlThrombocytes <30,000/μl or ART plusthrombocytes <50,000/μl and First-line therapy: glucocorticoidssignificant mucous membrane Subsequent therapies*: intravenousbleeding immunoglobulins, anti-(Rh)D, rituximab, splenectomySevere bleeding Platelet transfusions, high-dose glucocorticoids, intra-venous immunoglobulins, either alone or in combination
  35. 35. Treatment Options for PHAT• Stop potentially implicated drugs• Non-life threatening (>20,000 & not bleeding) – Observation without specific therapy – AZT-containing antiretroviral therapy• Severe or life threatening (<10,000 or bleeding) – Corticosteroids (1 mg/kg prednisone) – IVIG – Anti-D Immunoglobulin (if RH + & not splenectomized)
  36. 36. PRE-AZT ERASteroidsPre-AZT (early 1980s)Steroids, only!Mean: 10 monthsMedian: 5 months20/24 clinical sequelae: “moon face” oral candidiasis, reactivation of HSV etc…
  37. 37. AZT-MONOTHERAPY1988: 10 patients with PHAT, PLT 20-100, AZT-Monotherapy • 5 patients: 2g AZT 2/52, 1g AZT 6/52, placebo 8/52 • 5 patients: placebo 8/52, 2g AZT 2/52, 1g AZT 6/52 • Platelets increased by 50.000 to 100.000/μl in all in the AZT group, but not in the placebo group, platelets remained increased for 4 weeks in 3/5, 1/5 anemia + neutropenia Ann Intern Med, 1988; 109: 7181989: 34 patients with PHAT, PLT<50, AZT • 10 patients: 250mg qid (1g/day) after 12 weeks: 12 → 57 • 24 patients: 500mg tid (1.5g/day) after 12 weeks: 20 → 77 • Platelets increased in both groups • 1 patient was stopped b/o toxicity, 4 patients discontinued Ann Intern Med, 1989; 110: 3651993: 86 patients with PHAT, PLT<50, AZT • Randomized to two regimen (AZT 500mg/day or AZT 1000mg/day) • In both groups response rate was ~65% • Those on higher regimen responded quicker, better and more lasting at month 6 AIDS, 1993; 7: 209
  38. 38. HAART IN PHATSummary: • ART is clearly beneficial • Proven for AZT (various dosages) • Other ART regimen also work • High dose AZT is more efficient than normal dose AZT • Keep AZT side-effects in mind • The lower the platelets the more delayed the response • Response is to be expected within 1-3 months
  39. 39. ADDITIONAL THERAPYTherapy I – what additional therapy? • Steroids if platelets < 30.000/μl (HIV.NET), after HAART (Zambia) Prednisone 1g/kg/day - taper down once platelets are 60.000/μl 80-90% response, “quick” response, sustained response uncertain (10%) possible risk for Kaposi’s sarcoma if given long term • Packed erythrocytes and platelets for active bleeding plus • Intravenous Immunoglobulins (IVIG) for acute life threatening bleeding • Anti-(Rh)D (WinRho anti-(Rh)DTM)) seems even better and less expensive than IVIG, only for Rh-positive patients, problem: lowers HB up to 2mg/l, intravasal hemolysis ~0.7%
  40. 40. ADDITIONAL THERAPY CONT.....• Other… Dapsone: 9/11 patients with inadequate response responded Danazol: 2/8 patients responded INF-α: 13/13 and 9/13 responded much more… but small numbers/experimental• Splenectomy only in refractory cases, if possible allow 3-6 months conventional treatment good and sustained response in 50% (Scaradavou, 2004) 60% (Zambia) 80- 100% (HIV.NET). risk of post-splenectomy syndrome (OPSI) seems low prior vaccination against Pneumococci, HiB, Meningococci protection in patients with CD4 less than 400 uncertain…
  41. 41. Lessons learned concerning AZT high dose treatment: • High dose AZT was highly effective in this case in increasing initial very low platelet count significantly • Make sure that those following-up the patient are familiar with the AZT high dose treatment: 2 weeks: 1.8g/day (900mg bd) followed by: 6 weeks: 1.2g/day (600mg bd), then 600mg/day (300mg bd) • Although good response with regard to platelets, high risk of AZT associated anemia and neutropenia if not monitored properly • Medium dose AZT seem to keep platelets up with no significant drop in Hb
  42. 42. THANK YOU