Case presentationCase presentationMr K Ntombela, 44 year old gentlemanReferred from CJM hosp, and presented to Grey’s Hospital on 6th

February 2003 with a bicytopenia Hb 2,2 and platelet count of 34. On arrival to CJM the patient was actively bleeding, and it was decided to transfuse him with 2 units of packed red cells and platelets, with no response

Main complaint: 4 day history of sudden onset epistaxis followed more recently by haematemesis (dark red blood)In addition reports bleeding from the gums with easy bruising tendencies.No other bleeding diasthesis reportedNo history of trauma, toxin ingestion, or any other haematologicaldisorders, including family hxDescribes one other similar episode last year March 2002. Managed by a private GP who transfused 2 units of packed cells, with no history of further investigations or follow-up thereafter.

Systemic enquiry

CVS- Fatigue, dyspnoea grade II,No orthopnea or PND

Neurological- painful paraesthesia’s soles of feet dizziness (non-vertiginous)

No other significant past medical or surgical historyMedications- no previous ingestion of anti-inflammatory’s,

anticoagulants etc.Family history-nilEthic origin-Zulu(KZN)

On examinationGenerally

Well lookingNo active bleeding

Pallor ++

Not jaundicedOral thrush notedLymphadenopathy (<1cm)

-posterior cervical triangle

-axillary

Petechial Haemorrhages noticed on the gums, hard palate, tongue and forearms bilaterally

Bruises noticed over the anterior aspect of both foreams

Vitals:

BP122/51 Pulse 68, regular, good volume

RR 28bpm Temp 36.8 C

CardiovascularNormotensiveNot in Failure, no features of infective endocarditisS1 and S2 present and normal

Short ESM at LPSB grade 2/6- probably in keeping with a a flow murmurRespiratory:NAD (including no hilar lymphadenopathy)

Abdominal

No liver or spleen palpatedNo features of liver failureNo abdominal lymphadenopathyPR: malaena

Peripheries

Nails-no koilonychiaBruises of varying sizes over arms and lower limbsNo bony tenderness? Kaposi’s sarcoma lesion over anterior tibial surface LHS

Special investigationsSpecial investigationsBloods

FBC 31/1 06/2 14/2 16/2 22/2

HB 2,2 5,4 3,4 6,0 8,3WCC 23,5 12.3 7,3 7,0 11,3Platelets 34 9 13 3,0 5,0Corr retics 4,95RPI 1,9

Smear showed target red cells with assoc anisocytosis. Unfortunately no comment was made on platelets.

•U & E: Na 129 K2,3 Cl 101 HCo3 U 4,7 Cr 132

•INR 0,85

•PTT 20,1(p) 29,7(c)

•Bleeding time : prolonged

•Blood cultures: negative

•Malaria smear: negative

•Urine dipstix: trace blood, 1+leuco’s and 1+blood

•BMA: inadequate spp

•BMT: showed hypercellularity,all the haemopoeitic elements are seen. Good maturation noticed in the myeloid and erythroid series. Megakaryocytes are increased in number. Some have dysmorhic morphology with micro-megakaryocytes and hyperchromatic nuclei. There is no increase in reticulin fibrosis and no abnormal infiltrate. Granulomas not noticed.

Findings suggestive of ITP

•RVD status – positivetotal lymphocytes 800CD4 count not available yet

ManagementManagement

Patient was initially commenced on haematinics (pregamal, Vit B12), with 2 units of packed red cells and 5 units of pooled platelets being transfused. Subsequent repeat bloods and the patients clinical condition remained unchanged (platelets dropped to 5), suggesting an immune process in place. On confirmation of the diagnosis of ITP via BMT, oral prednisone 60mg dly was initiated with once again no clinical and biochemical improvement.

Dr Asmal (haematologist) at ALH was contacted on 24/2 and it was decided in view of the marked thrombocytopenia which was not responding to oral steroids and the patients RVD positive status, a splenectomy be considered as a next step.

Patient is currently being managed further at KEH.

ConclusionConclusion

Here we have a 44 year old gentleman who suddenly developed a bleeding diasthesis, following which relevant work-up confirmed an idiopathic thrombocytopenic purpura. As to the underlying predisposing factor, we felt that the most likely precipitant was his retroviral positive status, which brings us to the core of our discussion today: HIV and its effects it has on the haematological system.

ImmuneDrugs

Idiopathic

Non-immuneProstehesisSepsis/DICVasculitis

Excess destruction

Normal marrow

Production defect

Abnormal MarrowAplasia

Haem d/o

Normal spleen

Normal marrowLiver disease

TumourCongestive splenomegaly

Abnormal marrowLeukaemiaLymphomaHaem d/o

Splenomegaly

THROMBOCYTOPENIA

HAEMATOLOGY AND HIVHAEMATOLOGY AND HIV

Haematological effects are common in HIV infection.

The severity of its effects increases in advanced diseaseHaematological influences may be due to: HAART, opportunistic infections, malignancy or HIV infection itself.These may range from deviation in one cell line to a pancytopenia.

Bone Marrow

Usually displays a decreased cellularity and myelodysplasiaDecreased CD34 and Progenitor cellsIncrease cytokines TGF, TNF-alpha, IFN-gamma, IL-1Drug inducedInfections

Red blood cells

Anaemia is the most common abnormality in HIV infection. There is a disproportionate decrease in reticulocytes. Usually a normocytic normochromic anaemia manifests. A positive coombs tests may be present in 18-100% of patients. Of interest,a persistently low haemoglobin is predictive of a poor outcome.

Causes:

- Nutritional-Decrease in Vitamin B12 commonly, rarely folate- Opportunistic infections- TB, CMV- AZT- Hereditary syndromes- Pure red cell aplasia’s- Cytokine induced suppresion- Clinically significant haemolysis (rare)

Treatment:

1) Fe deficiency-ferrous sulphate2) Periodic packed cell transfusion3) Erythropoeitin4) IV immunoglobulins for Parvovirus B-19 related anaemia

White blood cells

- Neutropenia tends to occur with a decreased haemoglobin, howeverneutrophils may be increased in bacterial infections.

- Lymphopenia occurs due to the progressive decrease in CD4 countsAetiology:

1) Myelosuppression-HIV-Infections-Drugs (AZT/Bactrim/Acyclovir)

2) Peripheral destruction

Management

• Antibiotics if pyrexialGM-CSF which enhances HIV replication in monocytes and enhances

AZT antiretroviral effect

• G-CSF which partially corrects bacteriacidal defect

Thrombocytes

Thrombocytopenia is a common initial finding in HIV infection. The incidence increases with advancing disease. It is mainly of an immune basis, as opposed to anaemia and leucopenia which are mainly due to decreased haematopoesis.

Aetiology

1) Immune mediated destructionSimilar to ITP with a severe decrease in platelets and abundance ofmegakaryocytes in the bone marrow.

2) Decrease production3)TTP –usually seen in advanced HIV4)Sepsis/DIC5)Drugs

Treatment

- Spontaneous resolution in 10-20%.- AZT often improves the platelet count.- Steroids, however relapse is common with tapering- Splenectomy - IV Ig-rapid response of transient duration- Anti-D preparation-useful I refractory ITP

IMMUNE THROMBOCYTOPENIC PURPURAIMMUNE THROMBOCYTOPENIC PURPURA

ITP is an auto-immune disorder characterised by a low platelet count and muco-cutaneous bleeding. The incidence is 100/1million per year and half of these are children. This disorder occurs three times more commonly in females than males.

Classification1)Primary vs Secondary2)Acute vs Chronic (>6 months)

Adult onset and child onset ITP are strikingly different, with the acute form occuring in children and the chronic in adults.

NormalCoagulation time

Normal

Prolonged Bleeding time

Prolonged

ShortPlatelet survival (t)

Very short

Hyperplasia not present unless active bleeding

Bone marrowNormoblastic & myeloid hyperplasia

Same if purpura excessive

LeucocytesLeucocytosis

Normochromic with reticulocytosis

AnaemiaNormocytic normochromic

Larger bizzare platelets

MorphologyNormal

40000-200000Platelet count5000-20000

CHRONICACUTE

PathophysiologyITP is mediated by an auto-immune response. The following diagram illustrates this in detail.

Diagnosis

The diagnosis is mainly one of exclusion. Secondary causes which need to be excluded include SLE, Anti-phospholipid syndrome, immunodeficiency states, lymphoproliferative disorders, infection with HIV and hepatitis C virus and therapy with drugs such as quinidine and heparin.A few patients have concurrent auto-immune haemolytic anaemia, neutropenia or both which carry a less favourable prognosis.History and examination are important in excluding secondary causes and in distinguishing acute from chronic forms. Marked splenomegaly should trigger consideration of an alternative diagnosis. Apart from the thrombocytopenia the blood count should be normal. If abnormal it should be readily explained, for eg. anaemia due to epistaxis. A peripheral blood smear is required to rule out other haematolgic disorders like pseudothrombocytopenia, or inherited giant platelet syndromes. Large immature platelets are often seen. Much controversy surrounds the need for bone marrow studies in diagnosing ITP. According to the American Society of Haematology a bone marrow examination is not required if the presentation is typical but is appropriate before splenectomy is performed.

Some indications for a bone marrow investigation are:- Patients with atypical features for eg. those with additional cytopenias- Patients without a brisk response to therapy- Children, to rule out acute leukaemias- Atypical cases such as those with lassitude, protracted fever, bone orjoint pain, unexplained macrocytosis or neutropenia.

ManagementManagement

HaemorrhagePlatelet tx

IV IgPrednisone

30,000-50,000Prednisone orno treatment

Active BleedingIV Ig

PrednisoneSplenectomy

Splnectomy

<30,000

Spenectomy Gradual discontinuationof therapy or contmedical therapy

>30,000

Medical thereapyPrednisone/Danazol/

Dapsone

<30,000platelets

< 30,000 plateletsPrednisone

Anti-d Ig

30,000-50,000Prednisone orno treatment

>50,000 plateletsNo Rx

Advances in the management of HIV patients with ITP Advances in the management of HIV patients with ITP

Given that ITP occurs in as many as 40% of patients infected with HIV, much research and publications have been made regarding the bestmanagement of these patients

1) HAART- According to a study done in Virginia in 2000, showed that these drugs are effective in improving platelet counts, enhancing CD4 counts and reducing HIV loads

2) Interferon-Alpha-study conducted at University of California portrayed that a low dose continuous therapy of IFN resulted in a meaningful increases in platelet counts

3) Immune globulin IV according to study in Scotland showed a definite increase in platelet count and was beneficial. It seems to have a particular role in HIV patients suffering from Parvovirus B19,or measles infection, or patients with auto-immune disease.

4) Splenectomy has proved effective in the course of HIV infection prior to the onset of symptomatic AIDS.

SummarySummary

In summary, our case discussion serves as a mere example in which the HIV virus may affect the haematological system. It therefore should always be borne in mind when faced with any haematological disorder, in the South African context in particular.

Of interest, in our experience here at Grey’s Hospital, we have witnessed numerous cases of HIV patients presenting with a range of haematological disturbances, most of which have been mentioned here today.

ReferencesReferences

1) The New England Journal of Medicine, Vol 346, March 28,2002, no.13, Medical Progress: Immune Thrombocytopenic Purpura

2) Harrison’s Principles of Internal Medicine Volume I, 14th Edition

3) The Southern African Journal of HIV Medicine, July 2002 pg 37-38, The Haematology of HIV infection

4) Colour Atlas and Textbook of Haematology, 2nd Edition, William R.Platt

5) Internet: Abstract articles - Pubmed