1. HIV associated thrombocytopenia

2. Clinical case presentation

3. Presenting complaint
38 year old admitted to sugical ward with frank hematuria
and generalized weakness
Admitted with a history of:
Passing blood in urine for a week
Tiredness and feeling weak
Physical Exam
Pallor
No thrush
No splenomegaly

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. 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. 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. LABORATORY (ON
ADMISSION)
Hb 11.3 g/dl
MCV 100
WCC 4.89 109/l
Platelets 6.000/μl
Diff. count: normal
LFT: normal
U+E: Normal
LFT: Normal
PT/PTT/INR Not
available

8. Imaging
• U/S KUB:
NORMAL STUDY

9. Other blood workup
• HIV- Reactive
• VDRL- Non reactive

10. Diagnosis
• HIV Thrombocytopenia

11. Treatment
• Patient was started on Oral
steroids(Prednisone), ZIDOLAM-N and vitamin
suppelements

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. 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. Megakaryocyte and Platelets

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. • 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. • 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. 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 any
cumulativeAffects up to 45% has been reportedA 10-year
cumulative incidence of up to 45% has been reported
time during their illness

19. HIV associated
thrombocytopenia
Primary HIV-associated thrombocytopenia (PHAT)
• Most common
• Resembles Idiopathic Thrombocytopenia
• Complex etiology
Secondary 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

21. 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

22. 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

23. 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%)

24. 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

25. 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

26. 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

27. 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 uncertain
The recommended treatment for TTP is plasmapheresis and plasma
exchange.

28. 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

29. EDTA dependant
pseudothrombocytopenia
Pathophysiology:
• 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

30. EDTA dependant
pseudothrombocytopenia
Left: peripheral blood smear from Right: second blood sample from the
routine blood sample, anticoagulated same patient, anticoagulated with
with EDTA heparine
Electronic counting: 44.000/μl Electronic counting: 560.000/μl
Source: Shalev O, Lotman A. NEJM, 1993; 329: 1467

31. EDTA dependant
pseudothrombocytopenia
Consequences:
• 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

32. 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 antibodies
FIRST STEP IN MANAGING DITP = STOP INCITING
DRUG(S)

33. 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

34. Considerations for Treatment of
PHAT
• The patient's 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

35. Asymptomatic and ART
thrombocytes >30,000/μl
Thrombocytes <30,000/μl or ART plus
thrombocytes <50,000/μl and First-line therapy: glucocorticoids
significant mucous membrane Subsequent therapies*: intravenous
bleeding immunoglobulins,
anti-(Rh)D, rituximab, splenectomy
Severe bleeding Platelet transfusions, high-dose
glucocorticoids,
intra-venous immunoglobulins, either
alone
or in combination

36. 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)

37. PRE-AZT ERA
Steroids
Pre-AZT (early 1980s)
Steroids, only!
Mean: 10 months
Median: 5 months
20/24 clinical sequelae:
“moon face”
oral candidiasis,
reactivation of HSV
etc…

38. AZT-MONOTHERAPY
1988: 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: 718
1989: 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: 365
1993: 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

39. HAART IN PHAT
Summary:
• 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

40. ADDITIONAL THERAPY
Therapy 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%

41. 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…

42. 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

43. THANK YOU