Hematologic manifestations of HIV infection: Thrombocytopenia and coagulation abnormalities

Hematologic manifestations of HIV infection: Thrombocytopenia and coagulation abnormalities
Timothy J Friel, MD
David T Scadden, MD
Section Editor
Lawrence LK Leung, MD
Deputy Editor
Stephen A Landaw, MD, PhD
Last literature review version 19.3: Fri Sep 30 00:00:00 GMT 2011 | This topic last updated: Thu Feb 04 00:00:00 GMT 2010 (More)

INTRODUCTION — Shortly after the first description of the acquired immunodeficiency syndrome (AIDS), cytopenias of all major blood cell lines were increasingly recognized among patients infected with the human immunodeficiency virus (HIV). In one early series of patients with AIDS, anemia was noted in approximately 70 percent, lymphopenia in 70 percent, neutropenia in 50 percent, and thrombocytopenia in 40 percent [1].

The incidence of the various cytopenias correlates directly with the degree of immunosuppression. However, isolated abnormalities, particularly thrombocytopenia, may be encountered as the initial presentation of HIV infection. As a result, HIV infection should be considered in the assessment of patients presenting with any type of cytopenia.

The causes and treatment of thrombocytopenia and coagulation abnormalities in patients with HIV infection will be reviewed here [2]. Similar issues regarding anemia, neutropenia, and lymphopenia are discussed separately. (See “Hematologic manifestations of HIV infection: Anemia” and “Hematologic manifestations of HIV infection: Neutropenia” and “Techniques and interpretation of measurement of the CD4 cell count in HIV-infected patients”.)

THROMBOCYTOPENIA — Thrombocytopenia is a common finding in individuals infected with HIV, affecting approximately 40 percent of patients during the course of their illness [1]. HIV-associated thrombocytopenia occurs in patients from all major risk groups, including those exposed via homosexual or heterosexual contact, injection drug use, and blood product transfusion.

Epidemiologic data provide several pertinent observations:


  • Patients may present with thrombocytopenia at any time during the course of HIV infection, from asymptomatic infection to advanced AIDS.
  • The incidence of platelet abnormalities appears to increase with progressive immunosuppression. In one study, for example, the incidence of a platelet count below 150,000/microL was 8 and 30 percent in HIV-infected patients with CD4 counts of 200 to 500/microL and <200/microL, respectively [3].
  • Thrombocytopenia may be the initial manifestation of HIV infection in as many as 10 percent of patients. Therefore, consideration of HIV testing is essential in the assessment of any patient with newly diagnosed thrombocytopenia.
  • The degree of thrombocytopenia at presentation varies. In one prospective evaluation, 27, 11 and 5 percent of patients had platelet counts <150,000, <100,000, and <50,000/microL, respectively [4]. However, spontaneous bleeding is rare in patients with platelet counts above 10,000/microL [5], although prolongation of the bleeding time is detectable with platelet counts up to 100,000/microL.
  • In the current era of combination antiretroviral therapy, thrombocytopenia is more commonly encountered among patients with uncontrolled HIV replication and hepatitis C co-infection. As an example, in a retrospective case-control study of HIV-infected patients, thrombocytopenic patients (ie, platelet counts <100,000/microL for more than three months) were significantly more likely to have HCV co-infection (OR 6.1; 95% CI 1.6-23), cirrhosis (OR 24, 95% CI1.7-338) and detectable HIV viremia (OR 5.3; 95% CI 1.6-17.1) [6].


The causes of thrombocytopenia in HIV-infected patients can be divided into two groups: primary HIV-associated thrombocytopenia and secondary thrombocytopenia.

Primary HIV-associated thrombocytopenia — Primary HIV-associated thrombocytopenia (PHAT) is the most common cause of low platelet counts encountered in HIV-infected patients. Clinically, PHAT is similar to classic idiopathic thrombocytopenic purpura (ITP) except that splenomegaly is more commonly noted in patients with PHAT than in ITP. Platelet counts are often higher in HIV-infected patients, and mild thrombocytopenia occasionally resolves without therapy [7-9]. (See “Clinical manifestations and diagnosis of immune (idiopathic) thrombocytopenic purpura in adults”.)

The etiology of thrombocytopenia in PHAT is complex. Bone marrow examination, as in classic ITP, reveals normal or increased numbers of megakaryocytes in the face of reduced numbers of circulating platelets. This combination suggests the presence of ineffective platelet production and/or increased peripheral destruction. Kinetic studies using radiolabeled autologous platelets from HIV-infected individuals have shown that both factors contribute: there is more than a 50 percent reduction in platelet survival and a 50 percent reduction in platelet production [10].

In a comprehensive study comparing the kinetics of the megakaryocyte-platelet system in HIV-infected thrombocytopenic patients with normal controls, the following differences were found [11]:


  • Reduced platelet survival (87 versus 232 hours)
  • Reduced recovery of infused platelets (33 versus 65 percent)
  • Increased megakaryocyte number [30 x 10(6) versus 11 x 10(6)/kg]
  • Reduced marrow megakaryocyte progenitors [3.3 versus 27 CFU-Meg/1,000 CD34(+) cells]
  • Increased endogenous thrombopoietin (TPO) concentration (596 versus 95 pg/mL) and increased TPO receptor number (461 versus 207 receptors/platelet).


These studies indicate a triad of shortening of platelet life span by two-thirds, a doubling of splenic platelet sequestration, and ineffective delivery of viable platelets, despite a threefold expansion in marrow megakaryocyte mass driven by TPO.

Reduced platelet survival — Peripheral destruction of platelets in patients with PHAT is probably due to the presence of antiplatelet antibodies in the serum and on the surface of platelets [1,12-18]. Platelet-associated IgG crossreacts with the platelet glycoprotein complex (GP)IIb/IIIa and the HIV envelope glycoproteins GP160/120 [15]. In two studies, such antibodies were found in 70 and 73 percent of sera from HIV-infected patients with PHAT [19,20]. IgM antiidiotype antibodies directed against platelet anti-GPIIIa appears to directly regulate the degree of thrombocytopenia [21]. In addition, anti-HIV antibodies that bind to normal control platelets were found in 50 percent of sera from patients with PHAT as compared with only 5 percent of sera from HIV-infected patients with normal platelet counts [19]. These and other observations suggest that molecular mimicry between HIV proteins and platelet GPIIb/IIIa may be important in the pathogenesis of PHAT [22].

Macrophages in the reticuloendothelial system (primarily splenic) are the chief mediators of platelet destruction, binding to the Fc receptors on antibody- or immune complex-bound cells and eliminating them through phagocytosis. Abnormalities in Fc clearance in HIV infection may account for the lack of direct concordance between cell-bound antibody and cytopenia [23,24].

Ineffective platelet production — In situ hybridization techniques have detected HIV transcripts in the megakaryocytes of patients with PHAT, demonstrating the ability of HIV to directly infect platelet progenitor cells [25-27]. Electron microscopy of megakaryocytes from HIV-infected individuals with thrombocytopenia clearly demonstrates ultrastructural abnormalities not encountered in noninfected patients; blebbing of the surface membrane and vacuolization of peripheral cytoplasm are the most common [25]. It is postulated that infection of these platelet precursors impairs subsequent development and maturity, leading to the observed reduction in platelet production. Other alterations in the bone marrow microenvironment may also contribute to poor platelet production [28,29].

Increased programmed cell death (apoptosis) of bone marrow megakaryocytes in HIV-infected patients has also been postulated as a contributor to thrombocytopenia. In one study, the degree of apoptosis in glycoprotein IIb/IIIa-positive megakaryocytes purified from the bone marrow of HIV-positive thrombocytopenic patients was inversely related to the circulating platelet count (p<0.01) [30]. This observation suggests that, in patients with circulating antibodies cross-reacting against glycoprotein IIb/IIIa, there is increased apoptosis of megakaryocytes as well as increased peripheral destruction of platelets bearing these glycoproteins.

Secondary causes of thrombocytopenia — Secondary causes of thrombocytopenia are generally the result of underlying opportunistic infections, malignancy, and co-morbid conditions resulting in hypersplenism (table 1). Patients with HIV infection may also be more susceptible to certain medication-associated thrombocytopenias. As an example, a retrospective evaluation demonstrated a much higher frequency of heparin-induced thrombocytopenia (HIT) among heparin-exposed patients with HIV. Specifically, 13 of 53 (25 percent) hospitalized HIV patients who received either unfractionated heparin or low molecular weight heparin met criteria for HIT compared with zero of 106 concurrently hospitalized and anticoagulated HIV-negative patients (OR 26; 95% CI 7.7-85)[31].

Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) is a rare and potentially fatal cause of thrombocytopenia that must also be considered in the initial evaluation of HIV-infected patients with reduced platelet counts (see ‘Thrombotic thrombocytopenic purpura’ below).

Treatment of PHAT — After the exclusion of secondary causes of thrombocytopenia and discontinuation of potentially marrow-suppressing medications, there are many therapies available for the management of HIV-associated thrombocytopenia. Individual circumstances dictate the necessity and acuity of therapy. As a result, therapeutic decisions should be made on a case-by-case basis, considering:


  • 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 rate of almost 20 percent in patients with PHAT [12]


Zidovudine — Zidovudine (AZT) has been the mainstay of therapy of PHAT. Despite its well-recognized potential for suppression of myeloid and erythroid precursors, AZT increases platelet production in kinetic studies of HIV-infected individuals [10]. In a prospective evaluation of HIV-infected patients with thrombocytopenia (mean platelet count, 53,000/microL; range 25 to 85,000/microL), the platelet count rose by more than 50,000/µL after eight weeks of AZT therapy (2 g/day for two weeks followed by 1 g/day for six weeks) [32]. In another nonrandomized trial using AZT in a dose of 1.5 g/day, a persistent platelet count above 50,000/microL, which represented at least a twofold increase in baseline platelet count, occurred in 15 of 34 patients (44 percent) [33].

While clinical responses have been described with many different doses of AZT, higher daily doses are associated with more prominent and durable elevations in platelet count. This was demonstrated in an open label, randomized, multi-institutional study which compared the efficacy of two doses of AZT (0.5 and 1.0 g/day for six months) in HIV-infected patients with platelet counts below 50,000/microL [34]. The higher dose of AZT resulted in a higher percentage of patients with platelet counts above 100,000/L (39 versus 11 percent); in addition, mean platelet counts remained significantly higher after 6 months of treatment (98,000/microL versus 56,000/microL) at the higher dose. The role of AZT in the therapy of patients with PHAT and AZT-resistant strains of HIV has not been evaluated.

Other antiretroviral medications — There is less information on the impact of other antiretroviral medications or combination regimens on PHAT. A review of early experience with didanosine monotherapy showed a small but statistically significant increase of peripheral platelet counts within four weeks in more than 160 HIV-positive patients. Mean platelet counts at baseline and four weeks were 175,000 and 197,000/microL, respectively (p<0.05) [35].

Despite multiple reports and case series, there are no prospective, controlled trials documenting clinical improvements of PHAT in patients receiving any antiretroviral agent (nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, or combination regimens) other than AZT.

SEE MORE:  Diagnosis of the antiphospholipid syndrome

A number of complications of HIV infection have been reduced by the widespread use of highly active antiretroviral therapy (HAART), including the occurrence of opportunistic infections and Kaposi’s sarcoma. HAART may also be associated with improvement in PHAT. Several retrospective studies support this observation. (See “Selecting antiretroviral regimens for the treatment naive HIV-infected patient”.)


  • In one study, platelet counts rose significantly in all 18 patients with moderate degrees of thrombocytopenia (platelet count <150,000/microL), with a mean increase of 56,000/microL within one month of the start of a protease inhibitor [36]
  • In another study, which included 13 patients with severe thrombocytopenia (platelet count <50,000/microL), median platelet counts increased significantly from 27,000 to 63,000 and 86,000/microL three and six months, respectively, after the initiation of HAART [37]. Several different antiretroviral combinations were utilized in this series.
  • In a third report, 15 patients with thrombocytopenia (platelet count <50,000/microL) were treated with various combinations of antiretroviral regimens [38]. All patients experienced sustained improvement in platelet counts during the first three months of therapy, even those with a prior history of antiretroviral therapy (13 of 15) and a history of failure to respond to AZT monotherapy for thrombocytopenia.


Declines in platelet counts have been reported in patients who discontinue antiretroviral therapy [39,40]. (See “Structured treatment interruptions in the HIV-infected patient”.)


  • In one study of structured treatment interruption among HIV-infected individuals with undetectable viral loads and CD4 counts >350/microL, 3 of 23 enrolled patients developed recurrent thrombocytopenia during the periodic discontinuations of combination antiretroviral therapy [39].
  • In another prospective investigation of 391 HIV patients with undetectable HIV viral loads at baseline, the likelihood of developing thrombocytopenia (ie, platelet count < 150,000/microL) during 96 weeks of follow-up was significantly greater among patients randomly assigned to receive to intermittent antiretroviral therapy compared with those receiving continuous antiretroviral therapy (25.4 versus 9.8 percent, respectively) [40]. Thrombocytopenia was detected at a median of nine weeks following the discontinuation of therapy.


In general, our first line approach to PHAT is to include AZT at a minimum dose of 600 mg/day in the patient’s multiagent antiretroviral regimen. Dose escalation of AZT to 1,000 to 1,500 mg/day should be considered if there is no improvement in platelet counts following four to eight weeks of therapy. The use of additional therapies is based upon the severity of thrombocytopenia, evidence of bleeding (eg, petechiae, epistaxis, hematuria), and other coincident conditions such as coagulation factor deficiencies. Patients with clinical hemostatic defects or in whom surgery is imminent are often treated with either pooled immunoglobulins or specific anti-D antibody (see below).

Intravenous immune globulin — Intravenous immune globulin (IGIV, IVIG) produces dramatic, rapid improvements in platelet counts in the majority of patients with PHAT. A review of published cases described platelet counts exceeding 50,000/microL in almost 90 percent of patients after a single treatment with high-dose IGIV [41]. Dosages typically ranged from 1 to 2 g/kg; many of these patients also received intercurrent steroids. IGIV is thought to saturate Fc receptors in the reticuloendothelial system, thereby preventing the destruction of platelets (and red blood cells) coated with antibodies or immune complexes.

A prospective comparison between various IGIV regimens in non-HIV infected patients with ITP documented that 1 g/kg was as effective as higher doses [42]. Responses in both ITP and PHAT are typically evident within days after the administration of IGIV. (See “Treatment and prognosis of immune (idiopathic) thrombocytopenic purpura in adults”.)

The response seen after therapy is typically transient and multiple repeated administrations may be required [42]. In addition, the high cost, long infusion time (four to five hours), and limited supply of human immunoglobulin reduce the overall utility of this therapy for long-term management. Intravenous immunoglobulins remain a treatment of choice in situations requiring the rapid correction of low platelet counts, such as anticipated surgery or as an adjuvant to platelet transfusion during acute bleeding episodes.

The administration of IGIV has not been associated with increased immunosuppression in HIV-infected patients [43]. Side effects are typically mild and include infusion-related fever, nausea, emesis, myalgia and hypotension. The immunoglobulin infusion does represent a substantial osmotic load and rates of infusion are necessarily slow. Some preparations are associated with the development of acute renal failure due to sucrose-induced osmotic injury. (See “General principles in the use of immune globulin”.)

Anti-D immunoglobulin — A component of IGIV, anti-Rh(D) (anti-D, WinRho™), is effective only in non-splenectomized, Rh-positive patients in whom the immunoglobulin binds to the erythrocyte D antigen. These sensitized erythrocytes undergo immune-mediated clearance by the reticuloendothelial system. By competitively binding Fc receptors in the spleen, these anti-D-bound erythrocytes help reduce the destruction of antibody-coated platelets, thereby increasing circulating platelet counts [44].

Anti-D is an effective alternative to IGIV in patients with PHAT. A prospective evaluation of Rh-positive patients with PHAT demonstrated improved platelet counts in 9 of 14 patients 3 to 12 days after the initiation of therapy (12 to 25 microg/kg intravenously on two consecutive days) [45]. The platelet response to anti-D in PHAT is equivalent to that in HIV-negative patients with ITP [46].

Anti-D is less expensive than high-dose IGIV and requires a shorter infusion time (typically less than five minutes). In addition, maintenance intramuscular administration of 6 to 13 microg/kg per week of anti-D provided sustained responses in 85 percent of patients with ITP who had a prior response to intravenous infusion [47].

Results from a small, prospective, crossover design trial found that anti-D, compared with IVIG, produced a greater increase in platelet counts (77,000 versus 29,000/microL) and a longer duration of response (41 versus 19 days) [48].

The typical starting dose of anti-D is 50 microg/kg IV over three to five minutes. It may be administered as a single dose or in two divided doses on consecutive days. Doses may be escalated to a maximum of 80 microg/kg based upon response. As noted above, hemolysis is an expected feature of anti-D therapy. A reduction in hemoglobin concentration of 0.5 to 2.0 g/dL is typical in the majority of patients; thus, this drug must be used cautiously in patients with concurrent anemia [45,46]. In such patients, the initial dose can be reduced to 25 to 40 microg/kg with subsequent escalation based upon clinical response and the impact upon hemoglobin levels. Repeat infusions are commonly required after three to four weeks; the clinical response dictates the ideal interval between doses for each patient.

According to unpublished data from WinRho clinical trials, intravascular hemolysis with associated anemia and renal insufficiency has been encountered in 0.7 percent of cases following the administration of WinRho Rho(D) immune globulin in the treatment of ITP. (See “Treatment and prognosis of immune (idiopathic) thrombocytopenic purpura in adults”, section on ‘Intravenous immunoglobulin’.)

Other agents — For those patients with an inadequate response to antiretroviral agents alone, danazol and dapsone are two additional agents that may provide some benefit. The synthetic androgen danazol (400 to 800 mg/day) may raise the platelet count, although the documented experience in PHAT is limited. In one series, only 2 of 18 patients responded to danazol [49]. Liver function abnormalities and other androgen-related phenomena may occur and warrant close monitoring.

Oral dapsone (50 to 125 mg/day) may be a better alternative. In one study, 9 of 11 patients (mean platelet count 27,000/microL) who had failed other medical interventions responded to dapsone; six of the nine had sustained platelet counts greater than 50,000/microL [50]. The only major toxicity was a mild reduction (less than 7 percent) in hemoglobin secondary to hemolysis. The exact mechanism of activity remains uncertain although a competitive effect on red cell clearance by the reticuloendothelial system may be hypothesized.

Corticosteroids — Corticosteroids have demonstrated efficacy in HIV-associated thrombocytopenia. In a prospective evaluation of 24 patients (mean platelet count 21,000/microL), 80 percent had a notable improvement in platelet counts and a lower incidence of bleeding after three weeks of prednisone (1 mg/kg per day) [51]. However, fewer than 10 percent had sustained resolution of thrombocytopenia after steroids were tapered. In addition, the risk of steroid-associated side effects was significant: 20 of 24 patients had clinical sequelae, including weight gain, cushingoid faces, oral candidiasis, dysphoria, acne, reactivation herpes simplex virus and proximal myopathy.

Steroids may also accelerate the progression of Kaposi’s sarcoma and increase the risk of many opportunistic processes, including Pneumocystis carinii pneumonia, tuberculosis, and cytomegalovirus infections. For these reasons, steroids can be recommended only for short term use in patients with PHAT.

Interferon alfa — Interferon alfa is another option for the management of chronic PHAT. In a crossover trial of 12 patients with persistent thrombocytopenia despite treatment with AZT (mean baseline platelet count 15,600/microL), three million units of interferon-alfa given three times per week increased mean platelet counts more than fivefold (to 82,000/microL) within four weeks; there was no increase in platelet count during administration of placebo [52]. In another study of 13 patients, partial (platelet counts >30,000/microL for more than one month) or complete (platelet counts >50,000/microL) responses were noted in almost 70 percent of patients [53].

Platelet counts tend to return to baseline levels within a few weeks after discontinuing therapy. Side effects including fever, chills, fatigue, headache, and depression occur in a significant proportion of recipients and complicate the use of this drug.

Vincristine — There is limited experience with vincristine in PHAT. In one series of patients with Kaposi’s sarcoma, vincristine produced an increase in platelet count to above 200,000/microL in three patients with concurrent HIV-associated thrombocytopenia [54]. Two of the three patients had sustained responses after six months, while the platelet count in the third patient fell to less than 50,000/microL after two months.

Splenectomy — Patients with persistent thrombocytopenia or dependence on repeat IGIV or anti-D infusions may benefit from splenectomy. An early series noted a persistent clinical response (platelet count >150,000/microL) in 10 of 10 patients treated with splenectomy (mean follow-up, 10 months; range, 2 to 44 months) [12]. In another prospective evaluation, mean platelet counts increased from 18,000 to 223,000/microL immediately after splenectomy in 68 patients; a sustained response after six months was noted in 82 percent [55].

Despite some early reports of accelerated progression from HIV infection to AIDS after splenectomy [56], later data support the safety of this procedure [57,58]. In one series, for example, there were no reported episodes of overwhelming postsplenectomy infection in a group of 14 patients followed prospectively for a mean observation time of 27 months [59].

SEE MORE:  Anticoagulant and antiplatelet therapy in patients with infective endocarditis

Patients considering splenectomy should receive vaccinations against Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis prior to surgery to reduce the risk of subsequent infection with these encapsulated organisms. (See “Immunizations in HIV-infected patients” and “Pneumococcal vaccination in adults”.)

Splenic irradiation — Although less commonly employed than splenectomy, splenic irradiation is another option for patients refractory to standard interventions or those considered poor surgical candidates [60,61]. In a report of three patients unresponsive to other therapies, there were marked elevations in platelet counts after three to five weeks of biweekly low-dose splenic irradiation (1.0 Gy per dose for a cumulative total of 9 to 10 Gy) [60]. Based upon the absence of Howell-Jolly bodies on the postirradiation smears, the authors concluded that some splenic function was retained after the procedure, potentially reducing the risk for later overwhelming infection with encapsulated organisms.

One problem with splenic irradiation is a short duration of response. In two series, only two of 27 patients had a stable platelet count at six months after therapy [61,62].

Thrombopoietic growth factors — Patients with PHAT, as compared with healthy control subjects, have markedly elevated levels of endogenous thrombopoietin (mean levels of 596 versus 95 pg/mL) and increased thrombopoietin receptor numbers (461 versus 207 receptors/platelet) [11].


  • Dramatic increases in platelet counts in HIV-infected chimpanzees with baseline thrombocytopenia have been noted after the administration of recombinant human megakaryocyte growth and development factor [63]. In addition, all six patients with AIDS-associated thrombocytopenia treated with eight doses of PEG-rHuMGDF normalized their platelet counts [64]. However, this derivative of thrombopoietin is no longer clinically available.
  • Interleukin-11 (Neumega®) has been approved for patients with cancer-related thrombocytopenia and a trial piloting its use in patients with PHAT is planned.
  • The role of eltrombopag and other thrombopoietin receptor agonists in the management of PHAT has not been clearly defined. Clinical trials evaluating the role of eltrombopag in thrombocytopenia patients with HIV and other comorbid conditions are currently underway. (See “Clinical applications of thrombopoietic growth factors”.)


ABNORMALITIES OF THE COAGULATION SYSTEM — There are several abnormalities of the coagulation system that may be encountered in patients with HIV infection, including an increased propensity for the development of thrombosis, presence of antiphospholipid antibodies, abnormalities of several of the factors involved in the regulation of clotting, and thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. These are described in the following sections.

Thrombosis — Using prospective data gathered from more than 42,900 patients in the Adult/Adolescent Spectrum of HIV Disease Surveillance Project, the incidence of venous thrombosis in HIV-infected patients was determined to be 2.6 instances per 1000 patient-years [65]. In this study, risk factors significantly associated with the development of thrombosis included age >45 years, acute hospitalization, and the diagnosis of CMV retinitis or another opportunistic infection. Patients receiving megestrol acetate or indinavir also appeared to have a heightened risk of venous thrombosis, while usage of other protease inhibitors was not significantly correlated with thrombotic events.

A large case-control study of veterans demonstrated an increased occurrence of venous thromboembolism (VTE) among HIV-infected patients compared to age-, race-, and site-matched HIV-negative controls in both the pre- and post-HAART eras (11.3 versus 7.6 events per 1000 person years prior to 1996 and 5.7 versus 3.3 events per 1,000 person years after 1996) [66]. The risk for VTE was significantly higher for HIV-infected patients before and after 1996 even after adjusting for other VTE risk factors. (See “Overview of the causes of venous thrombosis”, section on ‘Acquired thrombophilia’.)

Factors that have been implicated in the development of thrombotic complications in HIV-infected patients, in addition to opportunistic infections, malignancy, and an indwelling central venous catheter, include [66-71]:


  • Lower CD4 counts
  • Elevated HIV viral loads
  • Elevated levels of factor VIII and homocysteine
  • Elevated lipid levels
  • Increased tissue factor expression on circulating monocytes [72]
  • Presence of antiphospholipid antibodies (lupus anticoagulants or anticardiolipin antibodies) or autoimmune hemolytic anemia (see ‘Antiphospholipid antibodies’ below)
  • Acquired deficiencies of proteins S and C and antithrombin (see ‘Deficiency of proteins C and S’ below)


Antiphospholipid antibodies — The antiphospholipid syndrome (APS) may be associated with both anticardiolipin antibodies (aCL) or lupus anticoagulants (LA). (See “Pathogenesis of the antiphospholipid syndrome”.)


  • Anticardiolipin antibodies (aCL) are a broad class of antibodies capable of binding acidic phospholipids. Elevated levels of aCL are often encountered in patients with chronic infections and have been described in as many as 64 percent of HIV-infected patients [73-75].
  • LA are antibodies directed against plasma proteins bound to anionic phospholipids and have been found in some HIV-infected patients [76,77].


The APS is associated with an increased propensity to arterial and venous thrombosis in HIV-negative as well as HIV-infected patients [67,78,79]. (See “Clinical manifestations of the antiphospholipid syndrome”.)

Deficiency of proteins C and S — Acquired deficiencies of proteins S and C have been reported in association with HIV infection [67,79,80], and may be related to the presence of acute opportunistic infections [81]. In one evaluation of 25 patients with HIV infection, reduced levels of free protein S were noted in over 70 percent [82]. Other investigators have failed to confirm this unusually high incidence, and have suggested that it may be an artifact due to high circulating levels of protein S-binding microparticles [83].

Thrombotic thrombocytopenic purpura — Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) has been described among patients with HIV infection, although its incidence in the post-HAART era appears to be declining. Of over 6000 HIV-infected patients followed in a United States cohort study, the incidence of TTP was 0.009 and of HUS 0.069 per 100 person-years [84]. Among the 362 patients recorded in the Oklahoma TTP-HUS registry, HIV infection was detected in six of the 326 adult patients (1.84 percent, 95% CI 0.68-4.0) who received documented HIV screening [85]. None of the pediatric cases (age <20 years) had evidence of HIV infection.

Patients who developed thrombotic microangiopathy, compared with those who did not, were more likely to have a lower CD4+ lymphocyte count (197 versus 439/microL), higher mean log HIV-1 RNA levels (4.6 versus 3.3 log copies/mL), and a history of acquired immunodeficiency syndrome (AIDS) and hepatitis C infection.

The diagnosis of TTP-HUS should be considered in all HIV-infected patients presenting with thrombocytopenia and anemia. However, opportunistic infection with associated thrombocytopenia should be excluded, along with a search for enterohemorrhagic Escherichia coli (E. coli O157:H7) in stool cultures. Of interest, in one study HIV+ patients with TTP demonstrated a more rapid response to fresh frozen plasma infusion and steroids than did HIV- patients, and none required plasma exchange [86]. This subject is discussed separately. (See “Causes of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in adults”, section on ‘HIV infection’ and “Treatment of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in adults”, section on ‘Plasma exchange’.)


Low platelet count — A low platelet count is a common finding in individuals infected with HIV, affecting approximately 40 percent of patients during the course of their illness. There are two general causes.

Primary cause — Primary HIV-associated thrombocytopenia (PHAT) is the most common cause of low platelet counts encountered in HIV-infected patients. Clinically, PHAT is similar to classic immune (idiopathic) thrombocytopenic purpura except that splenomegaly is more commonly noted in patients with PHAT. (See ‘Primary HIV-associated thrombocytopenia’ above.)

Secondary causes — Secondary causes of thrombocytopenia are generally the result of underlying opportunistic infections, malignancy, co-morbid conditions resulting in hypersplenism, and medication side-effects (table 1). (See ‘Secondary causes of thrombocytopenia’ above.)

Coagulation abnormalities — There are several abnormalities of the coagulation system that may be encountered in patients with HIV infection. These include the following. (See ‘Abnormalities of the coagulation system’ above.)


  • An increased propensity for thrombosis
  • Presence of antiphospholipid antibodies
  • Abnormalities of several of the factors involved in the regulation of clotting
  • Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome



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