INTRODUCTION — Thrombocytopenia may increase bleeding risk, but it does not protect against venous thromboembolism (VTE) or stroke. Thus, caring for patients with both thrombocytopenia and an indication for anticoagulation (eg, VTE prophylaxis or treatment, stroke prophylaxis or treatment) can be challenging. Evidence to guide appropriate therapy in this setting is very limited.
This topic discusses our approach to the use of anticoagulation in an individual with thrombocytopenia, including decisions about the need for anticoagulation, anticoagulant dosing, therapies to raise the platelet count, and alternatives to anticoagulation if the bleeding risk is thought to be too high.
Related subjects are discussed in separate topic reviews:
●Cancer
•Risk and prevention of VTE – (See "Risk and prevention of venous thromboembolism in adults with cancer".)
•VTE treatment – (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy".)
●Stroke
•Risk in patients with atrial fibrillation (AF) – (See "Atrial fibrillation in adults: Use of oral anticoagulants".)
•Treatment in AF – (See "Stroke in patients with atrial fibrillation".)
●Thrombocytopenia
•Causes – (See "Diagnostic approach to the adult with unexplained thrombocytopenia" and "Drug-induced immune thrombocytopenia".)
•Liver disease – (See "Hemostatic abnormalities in patients with liver disease".)
GENERAL PRINCIPLES OF TREATMENT
Overview of decision-making — Decisions about whether to use anticoagulation in patients with thrombocytopenia must balance the risks of thrombosis and thrombosis progression with the risks of bleeding due to thrombocytopenia as well as other bleeding risk factors.
●There is no simple formula for calculating which risk (thrombosis or bleeding) is greater
●There is no anticoagulant that can reduce thrombotic risk without also increasing bleeding risk
The expected duration of these risks may also factor into decision-making, along with the patient's values and preferences around which risks they feel most strongly about avoiding.
Once the decision to use anticoagulation has been made, the choice of anticoagulant is based on the underlying indication and other patient factors. The choice of anticoagulant risk of bleeding with different anticoagulants is discussed separately in topics on specific indications.
General information is presented in the following sections. Specific clinical scenarios such as cancer-associated venous thromboembolism (VTE) and other common combinations of thrombocytopenia and thrombosis risk are presented below. (See 'Cancer-associated VTE' below and 'Other selected clinical scenarios' below.)
Estimating and managing bleeding risk — The presence of one or more bleeding risk factors increases concerns about bleeding that may be exacerbated by the use of an anticoagulant. Commonly cited risk factors include the following [1,2]:
●Recent major bleeding – Bleeding risk is probably greatest in individuals who have already had a clinically serious bleed, especially if the bleeding occurred at a platelet count >50,000/microL.
●Platelet count <50,000/microL – It is generally accepted that bleeding risk is higher in individuals with platelet counts <50,000/microL, and severe spontaneous bleeding is most likely with platelet counts <10,000/microL, especially if due to an underlying bone marrow disorder rather than due to immune destruction of platelets. However, there is not a good linear correlation between the platelet count and the risk of serious bleeding in thrombocytopenic individuals. (See "Diagnostic approach to the adult with unexplained thrombocytopenia", section on 'When to worry about bleeding'.)
●Hematopoietic stem cell transplant – Individuals who have undergone hematopoietic stem cell transplantation (HCT) are at increased risk of bleeding, likely due to a number of factors including decreased platelet production, toxicities of the transplant conditioning regimen, and graft-versus-host disease (GVHD).
●Coagulation abnormalities – Coagulation abnormalities may be due to conditions such as severe liver disease or disseminated intravascular coagulation (DIC).
●Platelet function defects – Conditions that interfere with platelet function (eg, uremia from renal failure) or certain medications (eg, tyrosine kinase inhibitors such as ibrutinib) may further increase bleeding risk independent of platelet number. (See "Uremic platelet dysfunction" and "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Bleeding'.)
●Older age – Older age, especially >75 years, is associated with increased bleeding risk.
●Fall risk – Some individuals may be at increased risk of bleeding due to conditions that increase their risk of falls or other injuries. This is most relevant for outpatients receiving anticoagulation; during hospitalization, measures are commonly taken to minimize this risk. (See "Falls in older persons: Risk factors and patient evaluation" and "Falls: Prevention in community-dwelling older persons".)
For individuals with VTE or atrial fibrillation who do not have one of these increased bleeding risk factors, anticoagulation can generally be given if the platelet count is ≥50,000/microL. If the platelet count is <50,000/microL, decision-making is individualized and takes into account the likelihood of VTE progression or stroke and the available options for increasing the platelet count, which depend on the reason for the thrombocytopenia, as discussed below and in related topic reviews. (See 'Cancer-associated VTE' below and "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack" and 'Platelet count support' below.)
For individuals with VTE who have an increased risk of bleeding, there are a number of options for preventing VTE progression or recurrence, including the use of lower-dose anticoagulation (either prophylactic dose or reducing the dose by half), temporarily holding the anticoagulant (especially if bleeding risk factors are transient), or placement of an inferior vena cava (IVC) filter. In general, antiplatelet agents are avoided with anticoagulation when platelet counts are <50,000/microL, unless there is a very strong indication such as an intracoronary stent. Decisions of which of these options to use are highly patient-dependent.
●For VTE treatment, the importance of using anticoagulation is most influenced by the acuity of an existing thrombosis, as discussed below. (See 'Estimating risk of VTE and/or VTE progression' below.)
●For stroke prevention, decision-making is individualized according to a number of risk factors, as discussed in separate topic reviews. (See "Overview of secondary prevention of ischemic stroke" and "Atrial fibrillation in adults: Use of oral anticoagulants".)
Estimating risk of VTE and/or VTE progression — The risk of VTE is greatest in the setting of a strongly prothrombotic risk factor, such as orthopedic or major abdominal surgery, certain cancers, active chemotherapy, and certain particularly prothrombotic disorders such as antiphospholipid syndrome (APS), paroxysmal nocturnal hemoglobinuria (PNH) with a large clone (unless receiving anti-complement therapy), or heparin-induced thrombocytopenia (HIT). (See 'APS' below and 'PNH' below and 'HIT' below.)
The risk of VTE progression (or recurrence) is greatest in the initial 30 days after the acute VTE event. Thus, after 30 days, thrombotic risk is expected to decrease, and these individuals are treated as low thrombotic risk. Other risk factors for VTE progression are related to the size and location of the thromboembolism, and whether the risk factor(s) for VTE were transient or permanent (ie, whether the VTE was provoked or unprovoked). For individuals with cancer, the presence of active cancer or chemotherapy and lower performance status are strong risk factors for VTE progression.
We consider the following individuals at high risk for VTE progression/recurrence/embolization:
●VTE within the prior 30 days
●Proximal lower extremity deep vein thrombosis (DVT)
●Segmental or larger pulmonary embolus (PE)
●Poor performance status (eg, bedridden for most or all of the day)
●Active cancer and/or receiving chemotherapy (see 'Cancer-associated VTE' below)
●Strongly prothrombotic syndrome such as APS, PNH, or HIT (see 'APS' below and 'PNH' below and 'HIT' below)
●High-risk thrombophilia such as homozygous factor V Leiden mutation or antithrombin deficiency. However, we do not advocate routine testing for these thrombophilias. Indications for testing are presented separately. (See "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors".)
We consider the following individuals at comparatively low risk for VTE progression/recurrence/embolization:
●VTE that occurred more than 30 days prior
●Isolated distal DVT
●Isolated subsegmental PE (with negative bilateral ultrasound)
●DVT associated with a transient risk factor that has been eliminated
The rate of extension of an isolated distal DVT is approximately 10 percent, and several studies have failed to demonstrate a benefit of anticoagulation in individuals with isolated distal DVT in lower-risk populations [3,4]. Similarly, there is evidence that selected patients with subsegmental PE can be safely observed without anticoagulation [5].
We generally use anticoagulation in those at high risk for VTE progression or recurrence, and often for those who are at high risk for an initial VTE. For those with a low risk for VTE or VTE progression, we use anticoagulation if the platelet count is >50,000/microL and there are no other major bleeding risk factors. However, this decision is highly individualized according to the bleeding and thrombotic risks and the values and preferences of the individual patient.
Estimating risk of arterial thrombosis — The risk of arterial thrombosis is highly dependent on the patient's underlying condition, as discussed in separate topic reviews and in the sections below. (See 'Atrial fibrillation and acute coronary syndromes' below and 'Disorders that simultaneously cause thrombosis and thrombocytopenia' below.)
Similar to VTE risk, thrombocytopenia does not protect against arterial thrombosis. This was illustrated in a series of individuals with a number of underlying risk factors such as atrial fibrillation or antiphospholipid syndrome (APS) who had immune thrombocytopenia (ITP) [6]. There were several instances in which discontinuation of anticoagulation for thrombocytopenia, even temporarily, was associated with thrombosis; in some cases the thromboses were fatal.
Duration of anticoagulation — The duration of anticoagulation depends on whether the risk factors for bleeding and thrombosis were transient or persistent. Details that apply to different patient populations are discussed in separate topic reviews:
●Cancer
•General – (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy", section on 'Follow-up' and "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy", section on 'Duration of anticoagulation'.)
•Brain tumors – (See "Treatment and prevention of venous thromboembolism in patients with brain tumors".)
•Pancreatic cancer – (See "Supportive care of the patient with locally advanced or metastatic exocrine pancreatic cancer", section on 'Venous thromboembolism'.)
•Multiple myeloma – (See "Multiple myeloma: Prevention of venous thromboembolism in patients receiving immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide)".)
●Atrial fibrillation – (See "Atrial fibrillation in adults: Use of oral anticoagulants".)
●Liver disease – (See "Hemostatic abnormalities in patients with liver disease" and "Acute portal vein thrombosis in adults: Clinical manifestations, diagnosis, and management" and "Chronic portal vein thrombosis in adults: Clinical manifestations, diagnosis, and management".)
●Postsplenectomy – (See "Surgical management of splenic injury in the adult trauma patient" and "Elective (diagnostic or therapeutic) splenectomy", section on 'Venous thromboembolism'.)
●Antiphospholipid syndrome – (See "Management of antiphospholipid syndrome".)
●Paroxysmal nocturnal hemoglobinuria –
Platelet count support — If a decision is made to use anticoagulation and thrombocytopenia is severe, there are relatively few options to increase the platelet count.
Platelet transfusions — Platelet transfusions can be administered on an inpatient or outpatient basis to raise the platelet count and allow anticoagulation. When used to facilitate therapeutic anticoagulation, we favor a target platelet count above 50,000/microL. The frequency of platelet administration varies by patient and clinical scenario and is determined by monitoring the platelet count.
Thrombopoietin receptor agonists (TPO-RAs) — Thrombopoietin receptor agonists (TPO-RAs; also called TPO-mimetics) are infrequently used to raise the platelet count to allow anticoagulation for acute venous thromboembolism (VTE), as their effect is not immediate. Eltrombopag has been associated with an increased risk of portal vein thrombosis in patients with cirrhosis, but TPO-RAs do not appear to increase the risk of thrombosis in patients with immune thrombocytopenia (ITP). TPO-RAs have been approved for individuals with liver disease undergoing procedures. However, there is little published information on the usefulness of TPO-RAs to facilitate the administration of anticoagulation, and we do not routinely use these agents as a means of facilitating anticoagulation outside accepted indications such as ITP. (See "Second-line and subsequent therapies for immune thrombocytopenia (ITP) in adults", section on 'TPO receptor agonists' and "Hemostatic abnormalities in patients with liver disease", section on 'General approach to invasive procedures'.)
Correction of underlying disorder — It is also worthwhile to confirm that the cause of the thrombocytopenia has been correctly attributed and there are no other interventions available that might improve the platelet count. There are numerous potential causes of thrombocytopenia including drug-induced immune thrombocytopenia, infection, and vitamin B12 deficiency that may be contributing to a low platelet count. In a series of 101 individuals with multiple myeloma undergoing hematopoietic stem cell collection, the incidence of heparin-induced thrombocytopenia was higher than expected at 4 percent [7]. Causes of thrombocytopenia are reviewed separately. (See "Diagnostic approach to the adult with unexplained thrombocytopenia" and "Approach to the child with unexplained thrombocytopenia".)
CANCER-ASSOCIATED VTE
Risk factors for bleeding and thrombosis in cancer — Bleeding and thrombosis risks are both increased in individuals with cancer, and sometimes the same individual can have both bleeding and thrombosis (algorithm 1).
●Bleeding – The risk of bleeding in individuals with malignancy is higher than in the general population. This is due to many factors, and the contribution of thrombocytopenia to bleeding risk is likely to be greatest when it is due to bone marrow suppression, as opposed to other causes such as hypersplenism or drug-induced immune platelet destruction. (See 'Estimating and managing bleeding risk' above.)
●Thrombosis – The risk of cancer-associated thrombosis (CAT) is especially high with bulky or metastatic tumors, certain tumor types (eg, pancreatic or gastric cancer, brain tumors, acute leukemia, multiple myeloma) and certain cancer chemotherapies (eg, asparaginase, immunomodulatory drugs [IMiDs; thalidomide, lenalidomide]) [8]. The overall/cumulative risk of venous thromboembolism (VTE) in individuals with cancer has been estimated at approximately 10 to 15 percent, as discussed in detail separately. (See "Risk and prevention of venous thromboembolism in adults with cancer", section on 'Incidence and risk factors' and "Overview of the causes of venous thrombosis", section on 'Malignancy'.)
Anticoagulation is generally well tolerated, and mortality from VTE may be greater than mortality from bleeding in most populations. As an example, in data derived from the RIETE registry (a large Spanish registry that included over 40,000 patients), the rate of fatal pulmonary embolism (PE) in patients with VTE and a platelet count <80,000/microL was 3.6 percent, compared with a rate of fatal hemorrhage of 2.0 percent [9]. Both of these rates were significantly higher than seen in participants with normal platelet counts. The benefit of anticoagulation in reducing thrombosis risk is presented below. (See 'Supporting evidence' below.)
Exceptions to the greater risk of mortality from thrombosis than bleeding include hematopoietic stem cell transplant (HCT) recipients, for whom bleeding (including fatal bleeding) was more common than VTE; individuals with brain tumors; and catheter-associated VTE, which may be treated locally (eg, with catheter removal). (See 'Special populations' below.)
Primary VTE prophylaxis — Primary thromboprophylaxis is generally considered safe with platelet counts above 50,000/microL, but there are limited data regarding the safety of primary thromboprophylaxis in more severe thrombocytopenia [10].
The approach to prophylactic anticoagulation for individuals with platelet counts <50,000/microL is more nuanced. We generally do not use anticoagulation for VTE prophylaxis if the platelet count is below the 20,000 to 30,000/microL range.
For individuals with platelet counts above this range but below 50,000/microL, use of prophylactic anticoagulation is individualized; it may be appropriate in those with an especially high thromboembolic risk (eg, high-risk malignancy, history of thrombosis). (See 'Estimating risk of VTE and/or VTE progression' above.)
VTE treatment/secondary prophylaxis
Platelet count 50,000/microL or above — In patients with platelet counts ≥50,000/microL who require anticoagulation for VTE treatment and/or secondary prophylaxis, full-dose anticoagulation is generally appropriate, with the same bleeding considerations as nonthrombocytopenic populations. (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy".).
There are certain exceptions, such as individuals who have increased bleeding risk factors:
●Recent major bleeding episode
●Hematopoietic stem cell transplant (HCT)
●Coagulation abnormalities (including due to liver disease)
●Platelet function defects (including due to kidney disease)
●Age >75 years
●Increased risk for falls
Additional details about these risk factors are presented above. (See 'Estimating and managing bleeding risk' above.)
For individuals with mild-to-moderate thrombocytopenia (platelet count between 50,000 and 149,000/microL), VTE, and one or more of these increased bleeding risk factors, we generally use full-dose anticoagulation, especially for proximal DVT and central PE.
Platelet count <50,000/microL — Our approach to VTE treatment in individuals with cancer who have a platelet count below 50,000/microL depends on three factors: bleeding risk, risk for VTE progression or recurrence, and in some cases, absolute platelet count.
Our approach to incorporating these factors is illustrated in the algorithm (algorithm 1). Key features include the following:
For most individuals with cancer-associated VTE and platelet counts between 25,000 and 50,000/microL, we suggest anticoagulation. The lower threshold is an approximation, not an absolute cutoff. This practice is based on evidence from observational studies, as described below (see 'Supporting evidence' below). The dose of the anticoagulant (full therapeutic dose versus half-dose or prophylactic dose) is initially stratified by the presence or absence of bleeding risk factors other than thrombocytopenia.
Absent randomized trial data, there is true equipoise regarding optimal anticoagulation in patients with an acute VTE in the setting of concurrent thrombocytopenia. In a prospective, observational study of 121 patients with cancer and acute VTE, 62 percent received full-dose anticoagulation and 27 percent received modified-dose anticoagulation [11]. At 60 days, the cumulative incidence of major hemorrhage was 12.8 percent in the group receiving full-dose anticoagulation and 6.6 percent in the group that received modified-dose anticoagulation. The cumulative incidence of recurrent VTE at 60 days was 5.6 percent in the full-dose and 0 percent in the modified-dose anticoagulation groups. A small number of patients with acute PE were included in the modified-dose cohort.
●Without strong bleeding risk factors – For individuals with standard bleeding risk (eg, lacking additional bleeding risk factors such as age >75 years, recent severe bleeding, HCT, renal or hepatic failure, or increased risk for falls in the outpatient setting) who have a high risk of VTE recurrence, we stratify according to the risk of thromboembolism progression or recurrence.
•High risk for VTE progression or recurrence – A high risk for VTE progression or recurrence is suggested by an acute presentation (new VTE within the prior 30 days) of a proximal lower extremity deep vein thrombosis (DVT) or segmental or larger PE. For these individuals, we make an effort to treat with full-dose anticoagulation with platelet support (typically, platelet transfusions to raise the platelet count to ≥50,000/microL), especially for VTE within 30 days plus another thromboembolic risk factor. If the platelet count is low due to immune thrombocytopenia (ITP) or certain other conditions, there may be other means of increasing the platelet count. (See 'Platelet count support' above.)
The rationale is that these individuals are more likely to have an adverse outcome related to thrombosis rather than bleeding, provided the platelet count can be raised above 50,000/microL. However, this decision tree does not take the place of clinical judgment for the individual patient. If the platelet count cannot be consistently raised above 50,000/microL, or if the individual places an especially high value on avoiding full-dose anticoagulation and/or avoiding platelet transfusions (eg, due to a previous adverse reaction), it may be appropriate to use another approach such as reduced-dose anticoagulation or temporarily holding anticoagulation, perhaps with the use of an inferior vena cava (IVC) filter. (See "Placement of vena cava filters and their complications".)
•Low risk for VTE progression or recurrence – A low risk for VTE progression or recurrence is suggested by an isolated distal DVT, isolated subsegmental PE, central-line associated DVT (with the line removed), or a subacute presentation (ie, >30 days since the acute VTE). For these individuals, we further stratify according to the platelet count.
-If the platelet count is <25,000/microL, we temporarily hold anticoagulation, with the plan to re-evaluate once the platelet count increases.
-If the platelet count is between 25,000 and 50,000/microL, we reduce the anticoagulant dose by half (eg, give enoxaparin 0.5 mg/kg twice daily rather than 1 mg/kg twice daily; give dalteparin 100 units/kg once daily rather than 200 units/kg once daily [applies to the initial 30 days of dosing]) [12]. Other adjustment schedules have also been used, such as reduction of the dalteparin dose by 2500 units as done in the Hokusai VTE cancer trial (see 'Supporting evidence' below). Dose reductions for unfractionated heparin have not been described, and we favor use of low molecular weight heparin (LMWH), but if unfractionated heparin is used, it would be reasonable to titrate to the lower end of the target activated partial thromboplastin time (aPTT) range and to avoid a bolus "loading" dose in these individuals.
The rationale is that in these individuals, the lack of the strongest risk factors for VTE progression or recurrence results in a shift of the balance towards a slightly greater concern about bleeding, and thus we do not use full-dose anticoagulation. At the same time, the risk for VTE progression or recurrence is still increased, and thus we still favor anticoagulation at a lower dose if possible. Some individuals who place a higher value on avoiding complications related to VTE progression or recurrence may choose full-dose (therapeutic-dose) anticoagulation with platelet support, and those who place a higher value on avoiding bleeding may choose to hold anticoagulation temporarily.
●With increased bleeding risk factors – For individuals who have one or more additional bleeding risk factors (age >75 years, recent severe bleeding, HCT, renal or hepatic failure, or increased risk for falls in the outpatient setting) along with a platelet count <50,000/microL, we generally do not use full-dose (therapeutic-dose) anticoagulation. Options include reducing the anticoagulant dose by half as noted above, using prophylactic rather than therapeutic dosing or temporarily holding anticoagulation, perhaps with the use of an inferior vena cava (IVC) filter. (See "Placement of vena cava filters and their complications".)
Our approach is generally consistent with a 2018 guideline from the International Society on Thrombosis and Haemostasis (ISTH) [13]. Supporting evidence is presented below. (See 'Supporting evidence' below.)
Exceptions may apply to certain populations such as individuals undergoing hematopoietic stem cell transplantation (HCT), those with central venous catheters, and certain specific malignancies (brain tumors, multiple myeloma, pancreatic cancer). (See 'Special populations' below.)
The choice of anticoagulant in individuals with cancer is evolving, but the greatest experience is with unfractionated heparin and/or low molecular weight heparin (LMWH), as discussed separately (see "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy", section on 'First-line options'). Certain direct oral anticoagulants (DOACs) have been shown to be effective in individuals with cancer, but these agents are associated with an increased risk of gastrointestinal hemorrhage.
Special populations — Certain patient populations deserve special consideration due to especially high risk of bleeding or thrombosis or the possibility of other options for treatment:
●Hematopoietic stem cell transplant (HCT) – In individuals undergoing HCT, the risk of serious bleeding appears to be higher than the risk of serious complications from VTE. Thus, for individuals undergoing HCT who develop a VTE while thrombocytopenic, we favor dose-modified anticoagulation rather than therapeutic anticoagulation with aggressive platelet transfusion support. Studies are evaluating the risk-benefit ratio for temporarily withholding anticoagulation depending on clinical features [14].
The risks of bleeding and VTE complications in individuals undergoing HCT were illustrated in a 2008 series of 1514 individuals undergoing inpatient HCT that identified 75 cases of symptomatic VTE in 70 patients (4.6 percent) within the first 180 days [15]. Most were catheter-associated (55 of 75; 73 percent). Approximately one-third occurred at a platelet count of <50,000/microL; the median platelet count at the time VTE developed was 75,000/microL. In a multivariate analysis, the features most predictive for VTE were prior VTE (odds ratio [OR] 2.9; 95% CI 1.3-6.6) and graft-versus-host disease (GVHD; OR 2.4; 95% CI 1.4-4.0). There were no fatal VTE events. Clinically significant bleeding occurred in 230 individuals (15 percent) and fatal bleeding in 55 (4 percent).
In a smaller retrospective study that included 78 patients with hematologic malignancies, the rate of clinically significant hemorrhage was 27 percent (12 of 45) during periods of therapeutic anticoagulation, compared with 3 percent (1 of 33) when the patients were not receiving anticoagulation. Conversely, while on anticoagulation, the rate of recurrent VTE was 2 percent (1 of 45), compared with 15 percent (5 of 33) while anticoagulation was held. All but one of the recurrent DVTs occurred in the upper extremity. Eight of the 13 hemorrhages (62 percent) occurred following HCT [16].
●Catheter-associated VTE – Management of catheter-associated VTE may involve anticoagulation, thrombolysis within the catheter, or catheter removal. Reduced-dose anticoagulation has been used in individuals at risk for catheter-associated VTE [12]. However, a benefit has not been definitively demonstrated, as discussed separately. (See "Catheter-related upper extremity venous thrombosis in adults".)
●Brain tumors – Management of VTE in an individual with a brain tumor (primary or metastatic) is discussed separately. (See "Treatment and prevention of venous thromboembolism in patients with brain tumors".)
●Multiple myeloma – Management of VTE in an individual with multiple myeloma is discussed separately. (See "Multiple myeloma: Prevention of venous thromboembolism in patients receiving immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide)".)
●Pancreatic cancer – Management of VTE in an individual with pancreatic cancer is discussed separately. (See "Supportive care of the patient with locally advanced or metastatic exocrine pancreatic cancer".)
Supporting evidence — Evidence regarding outcomes of cancer-associated VTE in individuals with concomitant thrombocytopenia comes from observational (often retrospective) studies. There are no randomized trials comparing different approaches to reducing the risks of VTE or VTE progression in people with cancer and thrombocytopenia. The following illustrate some of the larger studies that have reported on outcomes of anticoagulation in patients who have cancer and thrombocytopenia. These generally describe successful anticoagulation for VTE, with dose adjustments for more severe thrombocytopenia; bleeding complications were rare.
●A 2021 prospective study involving 121 patients with cancer, VTE, and thrombocytopenia found better outcomes with modified-dose anticoagulation rather than full therapeutic dosing [11]. With modified dosing (mostly used in individuals with hematologic malignancies), the rate of VTE recurrence was 0 and major bleeding was 6.6 percent (95% CI, 2.4-15.7). With full therapeutic dosing, the rate of VTE recurrence was 5.6 percent (95% CI, 0.2-11) and major bleeding was 12.8 percent (95% CI, 4.9-20.8).
●A 2017 quality initiative project identified 99 individuals with cancer who were receiving therapeutic-dose enoxaparin for VTE and had at least one episode of thrombocytopenia lasting seven or more days (median duration, 12 days) over a three-year period [17]. This represented approximately 0.6 percent of individuals with VTE during the study period. Most had a hematologic malignancy (59 percent) and most had been treated with chemotherapy within the prior month (79 percent). LMWH was used at full therapeutic dosing for those with platelet counts >50,000/microL, reduced to half-dose for those with platelet counts between 25,000 and 50,000/microL, and temporarily held for a platelet count <25,000/microL. Over the course of the project, 95 percent of the patients had some form of LMWH dose adjustment or temporary discontinuation. There were no instances of recurrent VTE or major bleeding in patients treated according to this approach. One individual receiving full-dose enoxaparin with a platelet count of 28,000/microL had a traumatic retroperitoneal hemorrhage.
●A 2015 retrospective review identified 74 individuals with cancer-associated VTE and concomitant thrombocytopenia over a seven-year period [18]. This represented approximately 10 percent of admissions for VTE during this period. Approximately one-fifth of the patients were admitted to the hospital for VTE; the remainder developed VTE while in the hospital, typically while they were not receiving VTE prophylaxis. Full-dose LMWH was administered to 30 individuals (41 percent), reduced-dose LMWH was administered to 27 individuals (37 percent), and no anticoagulation was given to 17 individuals (23 percent). Risk factors for VTE recurrence, which occurred in 23 individuals, included hematologic malignancy, prolonged thrombocytopenia, and upper extremity VTE; those who received full-dose anticoagulation had a lower risk of recurrent VTE. There were 13 bleeding events, all in individuals with hematologic malignancy. In a univariate analysis, only a prior bleeding event was predictive of bleeding. Most of the mortality was related to the underlying malignancy. There were two deaths related to VTE and no bleeding deaths. The authors concluded that VTE prophylaxis would likely have prevented some of the VTE events and would have conferred a lower bleeding risk than the full-dose anticoagulation that was indicated once a VTE occurred.
●The 2018 Hokusai VTE cancer trial randomly assigned 1050 individuals with cancer-associated VTE to receive the LMWH dalteparin or the direct factor Xa inhibitor edoxaban for 6 to 12 months [19]. Anticoagulant dose reduction was not tested as a trial question but was incorporated into the dosing protocol for dalteparin, and the dose was held if the platelet count decreased below 50,000/microL. Findings of the trial suggested similar efficacy and safety of both agents, as discussed separately (see "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy"), as well as the feasibility of LMWH dose reduction based on decreased platelet counts.
●A 2018 retrospective review of individuals enrolled in the Comparison of Acute Treatments in Cancer Hemostasis (CATCH) trial (randomized trial of tinzaparin versus warfarin for six months in 900 individuals with active cancer and VTE) identified 180 clinically relevant bleeding events among 138 individuals (14 percent of participants) [20]. However, there were several exclusions. Tinzaparin was associated with a lower risk of bleeding (13 versus 17 percent; hazard ratio [HR] 0.64; 95% CI 0.45-0.89) and a lower risk of recurrent VTE (7 versus 10 percent). There was a trend towards increased bleeding with thrombocytopenia that did not reach statistical significance (relative risk 0.72; 95% CI 0.24-2.14; p = 0.79).
OTHER SELECTED CLINICAL SCENARIOS — There are a number of other clinical settings in which thrombocytopenia coexists with an increased risk of thrombosis for which anticoagulation should be administered. In some cases, two common conditions, one requiring anticoagulation and one causing thrombocytopenia, may be present (eg, atrial fibrillation plus immune thrombocytopenia [ITP]). Less common causes include antiphospholipid syndrome (APS), especially with ITP; paroxysmal nocturnal hemoglobinuria (PNH); and heparin-induced thrombocytopenia (HIT).
Liver disease — Liver disease has multiple effects on coagulation proteins, resulting in a "rebalanced" hemostasis. It used to be stated that individuals with liver disease were auto-anticoagulated due to reduced levels of certain procoagulant factors made in the liver. However, better documentation of the multiple defects in liver disease has made it clear that this is not the case; thrombosis and bleeding risk are both increased in the same patient (rates of deep vein thrombosis [DVT] and portal vein thrombosis are increased, and cirrhosis is associated with thrombocytopenia and coagulation abnormalities). Management of venous thromboembolism (VTE) in individuals with liver disease is discussed separately. (See "Hemostatic abnormalities in patients with liver disease", section on 'Portal vein thrombosis (PVT)' and "Hemostatic abnormalities in patients with liver disease", section on 'Venous thromboembolism (VTE)'.)
Atrial fibrillation and acute coronary syndromes — Atrial fibrillation is common, and there are likely to be patients who have atrial fibrillation in the setting of another disorder that affects platelet counts such as myelodysplasia or immune thrombocytopenia (ITP). Data from cohort studies suggest that a reduced-dose direct oral anticoagulant (DOAC) is effective and safe with mild thrombocytopenia (platelet count between 50,000 to 100,000/microL) [21].
Approximately 1 in 10 patients with acute coronary syndrome have thrombocytopenia during hospitalization. In a national registry study conducted in the United States that included over 36,000 patients, even mild thrombocytopenia (platelet count of 100,000 to 149,000/microL) was linked to poor outcomes including shortened mortality (odds ratio [OR] 2.01; 95% CI 1.69-2.38) and increased hemorrhage (OR 3.76; 95% CI 3.43-4.12) [22]. Among 99 patients with atrial fibrillation who underwent a percutaneous coronary intervention with a platelet count between 80,000/microL and 150,000/microL, 68 percent received triple therapy (eg, vitamin K antagonist, aspirin, and clopidogrel) and 12 percent received a vitamin K antagonist and aspirin. Comparing mildly thrombocytopenic and nonthrombocytopenic cohorts, there was no difference in ischemic, thromboembolic, or all-cause mortality and no difference in the rates of bleeding (major or minor) [23].
The safety of dual or triple antithrombotic therapy for more severe thrombocytopenia is not established, and the decision to use anticoagulation in an individual with atrial fibrillation and/or an acute coronary syndrome who also has severe thrombocytopenia is based on an estimate of embolic and bleeding risks. Additional information about indications for anticoagulation and choice of anticoagulant is presented separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants".)
Disorders that simultaneously cause thrombosis and thrombocytopenia — For most of these disorders, there are treatments that can be directed at the underlying cause of the thrombocytopenia (eg, immunosuppressive therapy for systemic lupus erythematosus [SLE], anti-complement therapy in PNH).
If these individuals develop thrombosis, therapy for the underlying disorder may lessen bleeding and thrombotic risks. In the interim (while waiting for disease therapy to take effect), it may be necessary to transfuse platelets to facilitate anticoagulation. (See 'Platelet count support' above.)
Some of these disorders are discussed in the following sections; management of disseminated intravascular coagulation (DIC) is presented separately. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)
APS — The antiphospholipid syndrome (APS) is characterized by venous or arterial thrombosis and/or adverse pregnancy outcomes in the presence of persistent autoantibodies (aPL) directed against phospholipid-binding proteins. It can occur as an isolated syndrome or in the setting of systemic lupus erythematosus (SLE) or another autoimmune disorder. The aPL may artificially prolong the activated partial thromboplastin time (aPTT) or, less commonly, the prothrombin time (PT), but in vivo they promote thrombosis. (See "Clinical manifestations of antiphospholipid syndrome", section on 'Thrombotic events'.)
Thrombocytopenia is common in individuals with APS, which may be isolated or associated with SLE (eg, as a form of secondary immune thrombocytopenia [ITP]), with a prevalence of approximately 20 to 40 percent in some series. Typically, the thrombocytopenia is mild (platelet counts 100,000 to 149,000/microL), although more severe thrombocytopenia is seen in some individuals, especially those with SLE and/or ITP. (See "Clinical manifestations of antiphospholipid syndrome", section on 'Hematologic abnormalities' and "Hematologic manifestations of systemic lupus erythematosus", section on 'Thrombocytopenia'.)
For patients with APS who have platelet counts >50,000/microL and are otherwise considered lower risk for hemorrhage, the preferred anticoagulant is warfarin. (See "Management of antiphospholipid syndrome", section on 'Approach to anticoagulation'.)
Thrombocytopenia is not protective against cardiovascular or VTE events related to APS. Our approach in individuals with APS and concurrent ITP is to administer ITP-directed therapies to rapidly raise the platelet count above 50,000/microL to facilitate therapeutic anticoagulation. This may include the use of intravenous immune globulin (IVIG), glucocorticoids (eg, high-dose dexamethasone), and/or a thrombopoietin receptor agonist (TPO-RA) (see "Initial treatment of immune thrombocytopenia (ITP) in adults").
At lower platelet counts, we follow similar approach to that used in cancer-associated thrombosis (algorithm 1), with the one caveat being that platelet transfusion is generally less effective in raising the platelet count and is generally not used unless there is acute bleeding.
PNH — Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired abnormality characterized by expansion of an abnormal clone of hematopoietic cells lacking a glycosylphosphatidylinositol (GPI) anchor, which leads to hemolysis and thrombosis. The mechanism of thrombosis is incompletely understood and probably involves release of free hemoglobin, nitric oxide scavenging, vasoconstriction, and endothelial cell activation. Many individuals with PNH also have aplastic anemia, which can result in severe thrombocytopenia. (See "Pathogenesis of paroxysmal nocturnal hemoglobinuria".)
PNH with severe hemolysis can be treated with eculizumab, a monoclonal antibody directed against complement component C5; severe aplastic anemia may require hematopoietic cell transplantation. As with other disorders, thrombocytopenia is not protective against thrombosis, and individuals with thrombosis are treated with anticoagulation. (See "Treatment and prognosis of paroxysmal nocturnal hemoglobinuria".)
HIT — Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction to heparin in which antibodies to platelet factor 4 (PF4) in a complex with heparin lead to thrombocytopenia and a dramatically increased risk of venous and arterial thrombosis. Management of HIT involves scrupulous avoidance of all heparin-containing products and anticoagulation with a non-heparin anticoagulant. Typically, thrombocytopenia is moderate (eg, mean nadir platelet count approximately 60,000/microL) and resolves rapidly when heparin is discontinued, although some individuals may have more prolonged thrombocytopenia (see "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'Thrombocytopenia').
Despite thrombocytopenia, management of HIT (even in the absence of thrombosis) requires full-dose anticoagulation with a non-heparin anticoagulant and the expectation that discontinuation of heparin exposure will correct the thrombocytopenia, as discussed in detail separately. (See "Management of heparin-induced thrombocytopenia" and "Management of heparin-induced thrombocytopenia (HIT) during cardiac or vascular surgery".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anticoagulation".)
SUMMARY AND RECOMMENDATIONS
●Deciding to use anticoagulation – Decisions about anticoagulation in patients with thrombocytopenia must balance the risks of thrombosis and thrombosis progression with the risks of bleeding due to thrombocytopenia as well as other bleeding risk factors. Risk factors for bleeding (other than thrombocytopenia) and thrombosis are listed above, along with other factors that may contribute to decision-making. (See 'General principles of treatment' above.)
●Malignancy – Cancer-associated venous thromboembolism (VTE) is one of the most common scenarios in which VTE and thrombocytopenia coexist. (See 'Cancer-associated VTE' above.)
•Prophylaxis – For individuals with platelet counts of 50,000/microL or above, anticoagulation for VTE prophylaxis can be done according to established protocols, which are discussed in separate topic reviews. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults" and "Risk and prevention of venous thromboembolism in adults with cancer" and "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)
For those with counts between 25,000 and 50,000/microL, VTE prophylaxis is individualized, and for counts below 25,000/microL, prophylactic anticoagulation generally is not used. (See 'Primary VTE prophylaxis' above.)
•Treatment – For individuals with platelet counts of 50,000/microL or above, anticoagulation for VTE treatment can be administered according to established protocols. (See 'Platelet count 50,000/microL or above' above.)
For most individuals with cancer-associated VTE and platelet counts between 25,000 and 50,000/microL, we suggest anticoagulation (Grade 2C). The rationale is that morbidity from thrombosis is likely to be greater than morbidity from bleeding.
Options for dosing include the following:
-High risk of VTE progression/recurrence – Full (therapeutic)-dose anticoagulation with platelet support (eg, platelet transfusions to raise the platelet count above 50,000/microL). For most individuals with a high risk of VTE progression or recurrence who do not have additional bleeding risk factors other than thrombocytopenia, we suggest this approach (Grade 2C). In those patients whereby transfusion support is not practical or feasible, we use half-dose anticoagulation as outlined below.
-Low risk of VTE progression/recurrence or high risk of bleeding – Half-dose anticoagulation (eg, enoxaparin 0.5 mg/kg twice daily rather than 1 mg/kg twice daily) is the preferred treatment approach for platelet counts between 25,000 to 50,000/microL; holding anticoagulation is appropriate for platelet counts <25,000/microL. Other options include prophylactic-dose anticoagulation or temporarily holding anticoagulation, possibly with insertion of an inferior vena cava (IVC) filter. For most individuals with a low risk for VTE progression and/or those with one or more additional bleeding risk factors besides thrombocytopenia, we suggest one of these approaches (Grade 2C).
Supporting evidence comes from observational studies (see 'Supporting evidence' above). Individuals with VTE may reasonably make different choices depending on their specific circumstances, bleeding risk factors, and VTE recurrence risk, as illustrated in the algorithm (algorithm 1). (See 'Platelet count <50,000/microL' above.)
Platelet transfusions are accepted therapy to raise the platelet count if needed in order to provide full-dose anticoagulation. In contrast, we do not routinely use thrombopoietin receptor agonists (TPO-RAs) as a means of facilitating anticoagulation outside of accepted indications such as immune thrombocytopenia (ITP). (See 'Platelet count support' above.)
Additional considerations may apply to individuals undergoing hematopoietic cell transplant, those with a central venous catheter, and certain malignancies such as multiple myeloma, pancreatic cancer, or brain tumors. (See 'Special populations' above.)
●Other conditions – Other disorders that are commonly associated with thrombocytopenia plus an indication for anticoagulation include liver disease, atrial fibrillation, antiphospholipid syndrome (APS), paroxysmal nocturnal hemoglobinuria (PNH), and heparin-induced thrombocytopenia (HIT). Our approaches to each of these conditions is discussed above and/or in the linked topic reviews. (See 'Other selected clinical scenarios' above.)
