Study of Coagulation parameters in HIV patients and its relation to CD4 counts and ART status

Seemitr Verma*¹,Ruchee Khanna², Vishwapriya Godkhindi³, Anjali Vijay S⁴,

Shashidhar V⁵, S M Zeeshan⁶

¹Assistant Professor (MD Pathology), Dept. of Pathology, Kasturba Medical College,

Manipal Academy of Higher Education, Manipal, Karnataka.

²Associate Professor (MD Pathology), Dept. of Pathology, Kasturba Medical College,

Manipal. Manipal Academy of Higher Education, Manipal, Karnataka.

³Assistant Professor (MD Pathology), Dept. of Pathology, Kasturba Medical College,

Manipal Academy of Higher Education, Manipal, Karnataka.

⁴Assistant Professor (MD Pathology), Dept. of Pathology, Melaka Manipal Medical College,

Manipal Academy of Higher Education, Manipal, Karnataka.

⁵Professor (MD Microbiology), Dept. of Microbiology, Kasturba Medical College,

Manipal. Manipal Academy of Higher Education, Manipal, Karnataka.

⁶Assistant Professor (M.Sc. PhD), Dept. of Statistics, VIT University, Bhopal, Madhya-Pradesh.

*Corresponding Author E-mail: seemitr.verma@manipal.edu, ruchee.khanna@manipal.edu, vishwapriya.mg@manipal.edu, anjali.vijay@manipal.edu, shashidhar.v@manipal.edu, sayed.zeeshan@vitbhopal.ac.in

ABSTRACT:

Introduction: We started this study with a research question that whether prolonged APTT, prolonged PT and decreased platelet counts have any correlation with the patients having HIV, as compared to normal healthy controls and also do these changes go hand in hand with the level of CD4 count thus reflecting disease progression. We look for an answer to the question that, can these coagulation parameters be included in the routine testing and care of the HIV patients? Does the treatment have an effect on these parameters? Aims and Objectives: 1) To evaluate PT, APTT, and platelet count of HIV patients and compare them with normal healthy controls. 2) To analyse these parameters with respect to their CD4 count. Conclusion: In the present study the mean APTT value was prolonged which was statistically significant when compared to normal healthy controls. The mean PT value was not prolonged and the difference between HIV patients and controls was not statistically significant. Mean platelet count was not decreased, but the difference was statistically significant when compared to normal controls. The difference in mean APTT, PT and platelet count was not statistically significant when patients with CD4 count <200cell/mm³ were compared with those having CD4 count >200cells/mm³. Hence these parameters cannot be used for disease monitoring.

KEYWORDS: Activated partial thromboplastin time, Prothrombin time, Platelet count, HIV, CD4 count.

INTRODUCTION:

HIV infection is a rapidly spreading disease contributing to the global burden. According to UNAIDS, by the end of 2018, globally, there were 37.9 million (32.7 million–44.0million) people living with HIV, 1.7 million (1.4 million – 2.3 million) newly infected cases, and 770 000 million (5,70,000 – 1.1 million) deaths from AIDS-related illnesses¹. According to National Aids Control Organization (NACO), by the end of 2017, the prevalence of HIV in India was 0.22% (0.16% – 0.30%) and incidence was 0.1%². There were 21, 00,000 people living with HIV, 88000 were newly infected and 69000 died of AIDS-related illness and 56% adults were on anti-retroviral treatment. Among the various states, Karnataka had a prevalence of 0.47% (0.37%-0.63%)³ which was higher than the national prevalence rate. The highest prevalence of HIV in Karnataka is its south region, in and around Bangalore and in its north region³. HIV in children is not uncommon. Ninety percent of these faultless kids have it as it is vertically transmitted from the infected mother⁴. What adds to the burden is the lack of Knowledge, Attitude and Perception on HIV/AIDS⁵^,⁶^,⁷^,⁸ even among Nursing and other Healthcare Professionals⁹.

HIV results in considerable morbidity and mortality by various mechanisms. One of the serious complications is coagulation abnormalities, seen especially in the late stage of HIV. The cause of these abnormalities is multitude including the host, drug and viral factors.

Host factors include age, CD4 count, IV drug abuse, acquired hypercoagulable state, endothelial dysfunction, presence of opportunistic infections and associated malignancies¹⁰. Anti-retroviral drugs especially protease inhibitor are also proposed to cause endothelial dysfunction by their effects on the metabolism of lipid and glucose¹¹. The viral load is also another important determinant¹².

HIV along with antiretroviral (ART) drugs cause hepatic damage, contributing to coagulation abnormalities seen in HIV patients¹⁰.

HIV infection causes various abnormalities predisposing to a hypercoagulable state including endothelial cell dysfunction, thrombocytopenia, activation of a coagulation factor, presence of antiphospholipid antibodies and lupus anticoagulant, deficiencies of protein C, protein S, heparin cofactor II and antithrombin and increased levels of vWF and D-dimers. ¹⁰¹³¹⁴

Thrombocytopenia is seen in HIV patients due to various mechanisms, which include autoimmune destruction of platelets, direct infection of megakaryocytes by the virus and due to consumption coagulopathies seen in AIDS patients.

The basic tests to assess the coagulation pathway is Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT). Hence we have used the above parameters along with platelet count to assess the coagulation abnormalities in HIV infected individuals.

OBJECTIVES:

1) Evaluate PT, APTT, platelet count of HIV patients

2) Analyse these parameters against their CD4 count and ART status.

MATERIALS AND METHODS:

1. Study design: A hospital-based retrospective study was conducted at Kasturba Medical College, Manipal, Karnataka, India for 1 year from January 2018 to December 2018 after taking the ethical clearance

2. Study population: The following were the selection criteria

a. Inclusion criteria: Serologically confirmed HIV-infected patients who were HAART-naive and those on HAART for at least 1 year during the study period were included as the case groups. Serologically confirmed HIV negative in apparently healthy adults who visited our hospital for a routine check-up during the study period were taken as healthy controls

b. Exclusion criteria: Pregnant women and patients on anticoagulants therapy were excluded

Thus the total no. of study subjects were 173 which included 102 HIV positive cases and 71 healthy controls.

An approval from the Institutional Ethics Committee, Kasturba Hospital, Manipal was obtained before the study.

Sample collection and processing:

1. PT and aPTT

A 3ml blood was collected in a vacutainer containing 3.8% trisodium citrate under all aseptic precautions, with blood to anticoagulant ratio being 9:1 and was processed in automated blood coagulation analyser Sysmex® CS-2000i System™ (Sysmex Corporation, Wakinohama-Kaigandori, Chuo-ku, Kobe, Japan) for PT and aPTT values.

Platelet count

2. A 3ml blood was collected in a vacutainer container Dipotassium salt of ethylene diamine tetraacetic acid (EDTA) under all aseptic precautions, with blood to anticoagulant ratio being 4:1, and was processed in Coulter LH 800 haematology analyzersTM (Beckman Coulter, Miami, FL, USA) for platelet count.

3. CD4 count

A 3ml blood was collected in a vacutainer container Dipotassium salt of ethylene diamine tetraacetic acid (EDTA) under all aseptic precautions, with blood to anticoagulant ratio being 1:4. Fifty microliters of this EDTA blood was mixed with 10ul of BD Multitest (antibodies CD3/CD4/CD8/CD45), vortexed for 5 secs, and incubated for 15mins in dark at room temperature. To this 450 microlitres of 1:10 diluted FACS Lysing solution was added and incubated for 11 minutes at room temperature. This mixture was then analysed in BD FACSCantoTM II flow cytometer (4-2-2 and 5-3 configurations) (Becton Dickinson, San Jose, CA, USA) with BD FACSCanto™ clinical software.

4. Human immunodeficiency virus testing was done using chemiluminescence and rapid tri-dot test.

Statistical analysis:

The data was analysed using SPSS version 22.0. The unpaired t-test was used for calculating statistical significance. The p-value of less than 0.05 was taken as statistically significant.

RESULTS:

The present study enrolled 173 study subjects which included 102 HIV positive cases and 71 healthy controls. Among the HIV positive cases, 70 (68.6%) had received ART and 32 (31%) were not on ART.

Demography:

Gender profile:

There was a male predominance seen in the HIV positive cases (71 cases, 69.4%). The male predominance was also seen in HIV on ART group (49 cases, 70%) and HIV patients, not on ART (22 cases, 68.8%).

Age profile:

The mean age of HIV positive patients was 44.8 years (range 17-70 years). Most of the cases were in the 41-50 years age group (37 cases, 36.3%). The HIV positive patients on ART group had a mean age of 44.7 years whereas HIV patients not on ART had a mean of 44.8 years.

When HIV positive cases were compared with the control group, aPTT and platelet count were found to be significantly different, whereas the mean difference in the PT values was not significant (Table 1).

Among the HIV positive cases, those who received ART and those who did not were compared. There was no significant difference in the mean values between the two groups in aPTT, PT and platelet count.

Haematological parameters in the study participants (Table 2):

Among the study participants with HIV on ART, prolonged PT was seen in 10(14.5%) cases. In one case PT was not evaluated. Prolonged APTT was seen in 17 (24.3%) cases and thrombocytopenia was seen in 21 (30%) cases.

Among the study participants with HIV not on ART, prolonged PT was seen in 5 cases (15.6%), prolonged APTT was seen in 11 cases (34.4%) and thrombocytopenia was seen in 11 (34.4%).

CD4 count in the HIV positive study participants¹⁵

Of all the HIV positive patients the mean CD4 count was 230.45 cells/mm³ (range 7.87 to 1920.01 cell/mm³). Out of 102 HIV positive cases studied the number of cases with CD4 count <=200cells/mm³ were 58 (56.9%) and cases with CD4 count >200 cells/mm3 were 44 (43.1%).

Among the 70 HIV cases on treatment, 36(51.4%) cases had a CD4 count of less than 200 and 14(20%) cases had a CD4 count of more than 500. Among 32 HIV cases not on ART, 22(68.8%) cases had a CD4 count of less than 200 and 2(6.3%) cases had a CD4 count of more than 500.

Table 1: Comparison of PT, aPTT and platelet count in seropositive HIV patients versus controls as well as HIV on ART versus HIV not on ART

Parameters	Controls (n=71)		HIV infected cases (n=102)		p - value	HIV -Not ART cases (n=32)		HIV on ART cases (n=70)		p - value
	Mean	S.D.	Mean	S.D.		Mean	S.D.	Mean	S.D.
PT (in sec)	11.11	0.68	11.8	2.99	0.059	11.75	2.08	11.81	3.34	0.924
aPTT (in sec)	29.17	1.47	31.14	5.9	0.007	31.75	6.92	30.87	5.46	0.489
Platelet-Count (x 10⁹/L)	300.39	70.04	203.15	114.09	<0.05	192.41	108.75	208.06	116.89	0.523

Table 4: Comparison of APTT in HIV vs control as noted by various authors

Authors name/year of publication	No of cases with prolonged APTT out of total HIV cases (%)	p-value* on comparing HIV cases with controls (significant/non-significant)	Concordance with the present study
Masresha Seyoum et al. (2018)¹⁶^**	72/200 (36%) ^##	<0.001*	Concordant
Nasir et al. (2016)¹⁷^***	8/128 (6.3%)	0.14	Non-concordant
Jong et al. (2010)¹⁸^**	3/81 (2%) ^##	>0.05	Non-concordant
Present study^***	28/102 (27.4%)	<0.05*

*p-value <0.05 is considered as significant

^**Median was compared

^***Mean was compared

^##Median compared was not prolonged

Table 5: Comparison of PT in HIV vs control as noted by various authors

	No of cases with prolonged PT out of total HIV cases (%)	p-value* on comparing HIV cases with controls (significant/non-significant)	Concordance with the present study
Masresha Seyoum et al. (2018)¹⁶ ^**	149/200 (74.5%)	<0.001*	Non-concordant
Nasir et al. (2016)¹⁷^***	PT was prolonged^#	0.358	Concordant
Jong et al. (2010)¹⁸^**	6/81 (5%) ^##	>0.05*	Concordant
Present study^***	15/102 (14.7%)^##	0.059

*p-value <0.05 is considered as significant

^**Median was compared

^***Mean was compared

^#Exact value not mentioned

^##Median/mean compared was not prolonged

Table 6: Comparison of Platelet count in HIV vs control as noted by various authors

	No of cases with thrombocytopenia, out of total HIV cases (%)	p-value* on comparing HIV cases with controls (significant/non-significant)	Concordance with the present study
Masresha Seyoum et al. (2018)¹⁶^**	34/200 (17%) ^##	<0.001*	Concordant
Nasir et al. (2016)¹⁷^***	8/128 (6.3%) ^##	0.0010*	Concordant
Tene et al. (2014)¹⁹	19/139 (13.67%)	>0.005	Non-concordant
Omoregie et al. (2009)²¹	Thrombocytopenia was seen^#	<0.05*	Concordant
Present study	32/102 (31.37%) ^##	<0.05

*p-value <0.05 is considered as significant

^**Median was compared

^***Mean was compared

^#Exact value not mentioned

^##Median/mean compared was not below the reference range

The explanation for thrombocytopenia was HIV induced bone marrow toxicity and platelet destruction, immune complex-mediated platelet destruction and as a side effect of ART¹⁹.

The next research question we dealt with was whether ART affected APTT, PT and platelet count. We tried to answer this by comparing seropositive HIV on ART with those not on ART. In our study, the mean APTT, PT and platelet count of seropositive HIV on ART when compared with those, not on ART, were not statistically significant and these findings resonated with R Thulasi Raman et al. (2016)¹⁰ and Ifeanyichukwu (2016) ²². Masresha Seyoum et al. (2018)¹⁶ also documented non-significant difference in APTT as in the present study but in contrast to our findings, got a significant difference in PT and platelet count. (Table 7)

Table 7: Comparison of APTT, PT and platelet count of seropositive HIV on ART with those not on ART as noted by various authors

	PT (Significant or not)*	APTT (Significant or not)*	Platelet counts (Significant or not)*
Masresha Seyoum et al. (2018)¹⁶	Significant	Not-significant^#	Significant
R Thulasi Raman et al. (2016) ¹⁰	Not-significant^#	Not-significant^#	Not-significant^#
Ifeanyichukwu (2016) ²²	Not-significant^#	Not-significant^#	Not-significant^#
Present study	Not-significant	Not-significant	Not-significant

The reason for how ART causes less prolongation of APTT and PT is by reducing the level of lupus anticoagulants. Also as the viral load goes down, the platelet count improves¹⁶.

The third research question we tried answering was whether immunosuppression had any effect on APTT, PT and platelet count. To find an answer we compared APTT, PT and platelet count in HIV cases with a CD4 count of less 200 cell/mm³with those having more than 200 cells/mm³, as CD4 count of lower than 200 cells/mm³ is known to have more immunosuppression and opportunistic infection¹⁵. In the present study, APTT had a statistical difference when HIV cases with a CD4 count of less 200 cell/mm³were compared with those having CD4 count more than 200 cells/mm³, which was in concordance with R Thulasi Raman et al. (2016)¹⁰. Also, PT and platelet count were statistically different in these 2 groups, which was in concordance with Okoroiwu et al. (2014)²³ and Omoregie et al. (2009)²¹ (Table 8).

Table 8: Comparison of APTT, PT and platelet count in HIV patients with CD4 count <200 cells/mm³ versus CD4 count >200 cells/mm³as noted by various authors

	PT (Significant or not)*	APTT (Significant or not)*	Platelet count (Significant or not)*
R Thulasi Raman et al. (2016)¹⁰	Not-significant	Significant^#	Not-significant
Okoroiwu et al. (2014)²³	Significant^#	Not-significant	Significant^#
Omoregie et al. (2009)²¹	Significant^#	Not-significant	Significant^#
Present study	Significant	Significant	Significant

*p-value <0.05 is considered as significant

^#Concordant with the present study

The cause for more prolonged APTT, PT and lesser platelet count in HIV patients with CD4 count less than 200 cells/mm³ is higher levels of lupus anticoagulants and anticardiolipin antibodies (table 8). The other reason proposed is endothelial activation and liver damage, when CD4 count is low, exaggerating the procoagulant state¹⁶.

CONCLUSION:

In our study, prolonged APTT and low platelet count were significantly different in HIV patients as compared to the control group. PT was not statistically significant between these 2 groups. Thus, APTT and platelet count can be utilized as a screening tool along with other routine tests in evaluating HIV suspected cases.

The ART status did not have a significant effect on PT, APTT and platelet count among HIV patients. Thus these 3 parameters cannot form a dependent tool in treatment follow-ups.

APTT, PT and platelet count were found to be significantly different when the HIV group with a CD4 count of lower than 200 cells/mm³ were compared with those having CD4 count of more than 200 cells/mm³. Thus these 3 parameters can have their value in screening for disease progression, especially where the facility for CD4 count in not available. With further large sample sized studies, a cut-off for these parameters can be established, as a marker for opportunistic infection and can form an area of research.

Based on the above findings, the coagulation profile can be altered in HIV patients. Hence we recommend inclusion of coagulation profile along with platelet count in routine testing for HIV management and care Map for HIV patients²⁴ .

CONFLICTS OF INTEREST:

The authors declare no conflicts of interest.

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Received on 07.05.2021 Modified on 24.01.2022

Research J. Pharm. and Tech 2023; 16(2):489-494.

DOI: 10.52711/0974-360X.2023.00083

Parameters		HIV on ART n=70 (%)	HIV not on ART n=32(%)	Reference range
PT (secs)	Normal	59	27	9.4-12 secs
PT (secs)	Prolonged	10	5	9.4-12 secs
APTT (secs)	Normal	53	21	23.3-30.5 secs
APTT (secs)	Prolonged	17	11	23.3-30.5 secs
PLATELET COUNT ( x 10⁹/L)	Normal	46	19	150-400 x 10⁹/L
	Low	21	11
	High	3	2

Parameters	CD4 < 200cells/ mm³ (n= 58)		CD4 > 200 cells/ mm³ (n=44)		p - value
	Mean	S.D.	Mean	S.D.
PT (in sec)	12.21	3.74	11.25	1.38	<0.05
aPTT (in sec)	33.01	6.92	28.69	2.9	<0.05
Platelet Count (x 10⁹/L)	161.14	112.90	258.52	90.32	<0.05