How I treat thrombocytopenia in pregnancy.

ABSTRACT: Thrombocytopenia is a common hematologic abnormality in pregnancy, encountered in ∼10% of pregnancies. There are many possible causes, ranging from benign conditions that do not require intervention to life-threatening disorders necessitating urgent recognition and treatment. Although thrombocytopenia may be an inherited condition or predate pregnancy, most commonly it is a new diagnosis. Identifying the responsible mechanism and predicting its course is made challenging by the tremendous overlap of clinical features and laboratory data between normal pregnancy and the many potential causes of thrombocytopenia. Multidisciplinary collaboration between hematology, obstetrics, and anesthesia and shared decision-making with the involved patient is encouraged to enhance diagnostic clarity and develop an optimized treatment regimen, with careful consideration of management of labor and delivery and the potential fetal impact of maternal thrombocytopenia and any proposed therapeutic intervention. In this review, we outline a diagnostic approach to pregnant patients with thrombocytopenia, highlighting the subtle differences in presentation, physical examination, clinical course, and laboratory abnormalities that can be applied to focus the differential. Four clinical scenarios are presented to highlight the pathophysiology and treatment of the most common causes of thrombocytopenia in pregnancy: gestational thrombocytopenia, preeclampsia, and immune thrombocytopenia.

COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection.

Patients with coronavirus disease 2019 (COVID-19) have elevated D-dimer levels. Early reports describe high venous thromboembolism (VTE) and disseminated intravascular coagulation (DIC) rates, but data are limited. This multicenter retrospective study describes the rate and severity of hemostatic and thrombotic complications of 400 hospital-admitted COVID-19 patients (144 critically ill) primarily receiving standard-dose prophylactic anticoagulation. Coagulation and inflammatory parameters were compared between patients with and without coagulation-associated complications. Multivariable logistic models examined the utility of these markers in predicting coagulation-associated complications, critical illness, and death. The radiographically confirmed VTE rate was 4.8% (95% confidence interval [CI], 2.9-7.3), and the overall thrombotic complication rate was 9.5% (95% CI, 6.8-12.8). The overall and major bleeding rates were 4.8% (95% CI, 2.9-7.3) and 2.3% (95% CI, 1.0-4.2), respectively. In the critically ill, radiographically confirmed VTE and major bleeding rates were 7.6% (95% CI, 3.9-13.3) and 5.6% (95% CI, 2.4-10.7), respectively. Elevated D-dimer at initial presentation was predictive of coagulation-associated complications during hospitalization (D-dimer >2500 ng/mL, adjusted odds ratio [OR] for thrombosis, 6.79 [95% CI, 2.39-19.30]; adjusted OR for bleeding, 3.56 [95% CI, 1.01-12.66]), critical illness, and death. Additional markers at initial presentation predictive of thrombosis during hospitalization included platelet count >450 × 109/L (adjusted OR, 3.56 [95% CI, 1.27-9.97]), C-reactive protein (CRP) >100 mg/L (adjusted OR, 2.71 [95% CI, 1.26-5.86]), and erythrocyte sedimentation rate (ESR) >40 mm/h (adjusted OR, 2.64 [95% CI, 1.07-6.51]). ESR, CRP, fibrinogen, ferritin, and procalcitonin were higher in patients with thrombotic complications than in those without. DIC, clinically relevant thrombocytopenia, and reduced fibrinogen were rare and were associated with significant bleeding manifestations. Given the observed bleeding rates, randomized trials are needed to determine any potential benefit of intensified anticoagulant prophylaxis in COVID-19 patients.

Gestational thrombocytopenia: a case-control study of over 3,500 pregnancies.

Gestational thrombocytopenia (GT) affects an estimated nine million women annually. Women with GT have recurrent episodes on subsequent pregnancies suggesting that GT is related to a maternal factor rather than a factor unique to the individual pregnancy. We performed a case-control study of over 3 500 pregnancies at a single hospital during 2017. We defined GT as any pregnancy with a platelet count <150 000/µl during the 100 days prior to delivery. We excluded women with platelet counts <50 000/µl or with conditions known to cause thrombocytopenia. GT was present in 12% of pregnancies. The median platelet count at delivery was 134 500/µl in cases versus 208 000/µl in controls, P < 0·0001. During the pregnancy, the platelet count declined 31·8% in cases compared with 18·3% in controls (P < 0·0001) in association with a significant increase in mean platelet volume during each trimester. Among women with GT, platelet counts rapidly increased during the first week postpartum, consistent with a mechanism directly related to high blood flow rates in the gravid uterus. GT, a recurrent condition of at-risk women, is a common haematological disorder of pregnancy. Future research may focus on genetic gain-of-function polymorphisms resulting in increased turnover of platelets uncovered only during periods of high-shear blood flow.

Cancer-Associated Venous Thromboembolic Disease, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cancer-Associated Venous Thromboembolic Disease focus on the prevention, diagnosis, and treatment of patients with cancer who have developed or who are at risk for developing venous thromboembolism (VTE). VTE is a significant concern among cancer patients, who are at heightened risks for developing as well as dying from the disease. The management of patients with cancer with VTE often requires multidisciplinary efforts at treating institutions. The NCCN panel comprises specialists from various fields: cardiology, hematology/hematologic oncology, internal medicine, interventional radiology, medical oncology, pharmacology/pharmacy, and surgery/surgical oncology. This article focuses on VTE prophylaxis for medical and surgical oncology inpatients and outpatients, and discusses risk factors for VTE development, risk assessment tools, as well as management methods, including pharmacological and mechanical prophylactics. Contraindications to therapeutic interventions and special dosing, when required, are also discussed.

Thrombocytopenia in Pregnancy: Approach to Diagnosis and Management.

The impact of thrombocytopenia varies widely depending on the underlying pathophysiology driving it. The biggest challenge in managing thrombocytopenia in pregnancy is accurately identifying the responsible pathophysiology-a task made difficult given the tremendous overlap in clinical and laboratory abnormalities associated with different thrombocytopenia processes. The most common etiologies of thrombocytopenia in pregnancy range from physiology deemed benign to those that are life-threatening to the mother and fetus. Even in cases in which the responsible etiology is deemed benign, such as gestational thrombocytopenia, there are still implications for the management of labor and delivery, a time where hemostatic challenges may prove life-threatening. In most institutions, a minimum platelet count will be mandated for epidural anesthesia to be deemed a safe option. The causes of thrombocytopenia can also include diagnoses that are pregnancy-specific (such as preeclampsia or gestational thrombocytopenia), potentially triggered by pregnancy (such as thrombotic thrombocytopenic purpura), or unrelated to or predating the pregnancy (such as liver disease, infections, or immune thrombocytopenia purpura). It is imperative that the source of thrombocytopenia is identified accurately and expeditiously, as intervention can range from observation alone to urgent fetal delivery. In this review, the approach to diagnosis and the pathophysiological mechanisms of the most common etiologies of thrombocytopenia in pregnancy and associated management issues are presented.

NCCN Guidelines Insights: Cancer-Associated Venous Thromboembolic Disease, Version 2.2018.

Venous thromboembolism (VTE) is common in patients with cancer and increases morbidity and mortality. VTE prevention and treatment are more complex in patients with cancer. The NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease outline strategies for treatment and prevention of VTE in adult patients diagnosed with cancer or in whom cancer is clinically suspected. These NCCN Guidelines Insights explain recent changes in anticoagulants recommended for the treatment of cancer-associated VTE.

Cancer-Associated Venous Thromboembolic Disease, Version 1.2015.

The NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease outline strategies for treatment and prevention of venous thromboembolism (VTE) in adult patients with a diagnosis of cancer or for whom cancer is clinically suspected. VTE is a common complication in patients with cancer, which places them at greater risk for morbidity and mortality. Therefore, risk-appropriate prophylaxis is an essential component for the optimal care of inpatients and outpatients with cancer. Critical to meeting this goal is ensuring that patients get the most effective medication in the correct dose. Body weight has a significant impact on blood volume and drug clearance. Because obesity is a common health problem in industrialized societies, cancer care providers are increasingly likely to treat obese patients in their practice. Obesity is a risk factor common to VTE and many cancers, and may also impact the anticoagulant dose needed for safe and effective prophylaxis. These NCCN Guidelines Insights summarize the data supporting new dosing recommendations for VTE prophylaxis in obese patients with cancer.

Venous thromboembolic disease.

Venous thromboembolism (VTE) remains a common and life-threatening complication among patients with cancer. Thromboprophylaxis can be used to prevent the occurrence of VTE in patients with cancer who are considered at high risk for developing this complication. Therefore, it is critical to recognize the various risk factors for VTE in patients with cancer. Risk assessment tools are available to help identify patients for whom discussions regarding the potential benefits and risks of thromboprophylaxis would be appropriate. The NCCN Clinical Practice Guidelines in Oncology for VTE provide recommendations on risk evaluation, diagnosis, prevention, and treatment of VTE in patients with cancer.

The Conundrum of Anticoagulation for Hospitalized Patients with Covid-19.

Thrombosis in patients with coronavirus disease 2019 (Covid-19) is driven by complex interactions between immune, complement, fibrinolytic, endothelial, and coagulation systems.1 In addition to venous thromboembolism (VTE), microthrombi have also been implicated in contributing to end-organ damage, such as acute respiratory distress syndrome and kidney dysfunction, as well as to overall mortality.1 As available therapies, variants, and vaccines have evolved, so have reported rates of VTE attributable to Covid-19.

Abdominal contouring procedures increase activity of the coagulation cascade.

One of the most serious complications in plastic surgery is a thromboembolic event. However, little physiologic evidence exists to support the observed hypercoagulable state seen in contouring procedures. Twenty-one consecutive patients were enrolled prospectively to assess thrombin generation, which measures activity of the coagulation cascade, at baseline, intraoperative, and 24 hours after surgery. Compared with preoperative values, total thrombin generation increased by a mean of 997 nM intraoperatively (1.3-fold, P<0.004) and 1406 nM postoperatively (1.4-fold, P<0.001) in 9 patients undergoing abdominoplasty without deep venous thrombosis (DVT) chemoprophylaxis. The mean thrombin generation did not significantly change during or after surgery in 12 patients who received heparin for DVT prophylaxis (P=0.3). Thrombin generation was significantly less in patients receiving chemoprophylaxis compared with those who received no prophylaxis (P<0.01). This suggests abdominal contouring procedures induce a significant increase in the activity of the coagulation cascade that can be prevented by DVT chemoprophylaxis.

Venous thromboembolism during pregnancy and postpartum period.

Venous thromboembolism (VTE) is one of the leading causes of maternal mortality. Rates of VTE during pregnancy and the postpartum period have not decreased over the past two decades and pregnancyassociated VTE continues to pose a significant health challenge. Pregnant and postpartum women are at a higher risk for VTE owing to many factors. There are hormonally mediated and pregnancy-specific alterations of coagulation that favor thrombosis, including increased production of clotting factors. There are physiologic and anatomic mechanisms that also contribute, including a decreased rate of venous blood flow from the lower extemities as pregnancy progresses. Cesarean delivery also introduces VTE risk. In addition, studies have demonstrated that pregnancy-associated complications such as pre-eclampsia or peri-partum infections are associated with increased VTE rates. In this review, we discuss the recent epidemiological studies, pathogenesis, risk factors and clinical presentation as well as therapeutic options for VTE during pregnancy and the postpartum period. We also provide proposed diagnostic algorithms for diagnosis and management of VTE during pregnancy and the postpartum period based on updated evidence. Finally, we highlight knowledge gaps to guide future research.

Dana-Farber Cancer Institute/Mass General Brigham Fellowship Response to the COVID-19 Pandemic.

The coronavirus disease (COVID)-19 pandemic has affected graduate medical education training programs, including hematology-oncology fellowship programs, both across the United States and abroad. Within the Dana-Farber Cancer Institute/Mass General Brigham hematology-oncology fellowship program, fellowship leadership had to quickly reorganize the program's clinical, educational, and research structure to minimize the risk of COVID-19 spread to our patients and staff, allow fellows to assist in the care of patients with COVID-19, maintain formal didactics despite physical distancing, and ensure the mental and physical well-being of fellows. Following the first wave of patients with COVID-19, we anonymously surveyed the Dana-Farber Cancer Institute/Mass General Brigham first-year fellows to explore their perceptions regarding what the program did well and what could have been improved in the COVID-19 response. In this article, we present the feedback from our fellows and the lessons we learned as a program from this feedback. To our knowledge, this represents the first effort in the hematology-oncology literature to directly assess a hematology-oncology program's overall response to COVID-19 through direct feedback from fellows.

A modern reassessment of glycoprotein-specific direct platelet autoantibody testing in immune thrombocytopenia.

Platelet autoantibody (PA) testing has previously shown poor sensitivity for immune thrombocytopenia (ITP) diagnosis, but no previous study used both 2011 American Society of Hematology (ASH) guidelines for ITP diagnosis and 2012 International Society on Thrombosis and Haemostasis (ISTH) PA testing recommendations. We therefore performed a comprehensive retrospective study of PA testing in adult patients with ITP strictly applying these criteria. Of 986 PA assays performed, 485 assays in 368 patients met criteria and were included. Sensitivity and specificity of a positive test result for diagnosis of active ITP (n = 228 patients) were 90% and 78%, respectively. Sensitivity and specificity of a negative test result for clinical remission (n = 61 assays) were 87% and 91%. Antibodies against both glycoprotein IIb (GPIIb)/IIIa and GPIb/IX were required for the presence of antibodies against GPIa/IIa in patients with ITP. Logistic regression analysis revealed that more positive autoantibodies predicted more severe disease (relative to nonsevere ITP, relative risk ratio for severe ITP and refractory ITP was 2.27 [P < .001] and 3.09 [P < .001], respectively, per additional autoantibody); however, serologic testing did not meaningfully predict treatment response to glucocorticoids, intravenous immunoglobulin, or thrombopoietin receptor agonists. Sixty-four patients with ITP had multiple PA assays performed longitudinally: all 10 patients achieving remission converted from positive to negative serologic results, and evidence for epitope spreading was observed in 35% of patients with ongoing active disease. In conclusion, glycoprotein-specific direct PA testing performed using ISTH recommendations in patients meeting ASH diagnostic criteria is sensitive and specific for ITP diagnosis and reliably confirms clinical remission. More glycoproteins targeted by autoantibodies predicts for more severe disease.

Pregnancy outcomes, risk factors, and cell count trends in pregnant women with essential thrombocythemia.

Pregnancy in essential thrombocythemia (ET) is associated with increased risk of obstetric complications. We retrospectively evaluated risk factors in 121 pregnancies in 52 ET women seen at 3 affiliate hospitals. Univariable and multivariable analyses were performed at the α = 0.10 level. Cell counts were characterized throughout pregnancy and correlated with outcomes using logistic modeling. The overall live birth rate was 69 %. 48.7 % of all women experienced a pregnancy complication, the most common being spontaneous abortion, which occurred in 26 % of all pregnancies. Maternal thrombosis and hemorrhage rates were 2.5 % and 5.8 %. On multivariable analysis, aspirin use (OR 0.29, p = 0.014, 90 % CI 0.118-0.658) and history of prior pregnancy loss (OR 3.86, p = 0.011, CI 1.49-9.15) were associated with decreased and increased pregnancy complications, respectively. A Markov model was used to analyze the probability of a future pregnancy complication based on initial pregnancy outcome. An ET woman who suffers a pregnancy complication has a 0.594 probability of a subsequent pregnancy complication, compared to a 0.367 probability if she didn't suffer a complication. However, despite this elevated risk, overall prognosis is good, with a >50 % probability of a successful pregnancy by the third attempt. Platelet counts decreased by 43 % in ET during pregnancy, with nadir at delivery and prompt recovery in the postpartum period. Women with larger declines in gestational platelet counts were less likely to suffer complications (p = 0.083). Our study provides important guidance to physicians treating ET women during pregnancy, including counseling information regarding risk assessment and expected trajectory of platelet levels.

Thrombocytopenia in Pregnancy: Mechanisms and Management.

Thrombocytopenia is a common hematologic issue encountered by obstetricians and hematologists, detected in about 10% of all pregnancies. In the vast majority of cases, the thrombocytopenia will be attributed to gestational thrombocytopenia (GT), where the thrombocytopenia is mild, does not necessitate active management, and does not introduce maternal or fetal bleeding risk. Although GT is common, the specific mechanism responsible for it is not known with certainty, and therefore, differentiating it from other causes of thrombocytopenia can be challenging. Previously proposed explanations for GT suggest that a decrease in platelet count is universal in pregnancy, and women diagnosed with GT are simply those with a baseline platelet count on the lower end of normal range. This concept is challenged in this review, and a possible mechanism for GT is proposed. Additionally, a framework for approaching the diagnosis and management of thrombocytopenia in pregnancy is presented.

Management of Venous Thromboembolism in Pregnancy.

PURPOSE OF REVIEW: This manuscript addresses the risks for venous thromboembolism (VTE) during pregnancy and the associated challenges of both diagnosis and treatment. RECENT FINDINGS: The obstacles to diagnosis given lack of specificity of typical biomarkers to predict VTE in pregnancy, as well as the unique fetal and bleeding risks introduced by managing massive pulmonary embolism (PE) with thrombolytics or thrombectomy are highlighted. VTE during pregnancy and the postpartum window occurs at a 6-10-fold higher rate compared with age-matched peers and is a major cause of morbidity and mortality. Hypercoagulability persists for 6-8 weeks after delivery with the highest risk of PE being postpartum. The lack of randomized trials in pregnant women leads to variability in practice, which are largely based on expert consensus or extrapolation from non-pregnant cohorts. The standard treatment of VTE in pregnancy is anticoagulation with low molecular weight heparin (LMWH), which like unfractionated heparin does not cross the placenta and is not teratogenic. LMWH is preferred given the negligible risk for heparin-induced thrombocytopenia and osteoporosis, better bioavailability, and a predictive dose response. Depending on the severity of the VTE, additional treatments including thrombolysis, thrombectomy, inferior vena cava filter placement, or venous stenting may be used. Management requires balancing the competing bleeding and thrombotic risks during labor and delivery and factoring the impact of treatment on the fetus. A multidisciplinary team involving hematology, obstetrics, anesthesia, vascular medicine, and cardiology is critical for safe and timely management. The design and execution of prospective, randomized trials to specifically address optimal diagnosis and management are a top priority in obstetric hematology.

Challenges of Anticoagulation Therapy in Pregnancy.

OPINION STATEMENT: Thrombotic complications in pregnancy represent a major cause of morbidity and mortality. Pregnancy is a primary hypercoagulable state due to enhanced production of clotting factors, a decrease in protein S activity, and inhibition of fibrinolysis. These physiologic changes will yield a collective rate of venous thromboembolism (VTE) of about 1-2 in 1000 pregnancies for the general obstetric population, which represents a five- to tenfold increased risk in pregnancy compared to age-matched non-pregnant peers. A select group of women, however, will carry a significantly higher rate of thrombosis due to primary thrombophilia, either inherited or acquired. This introduces a population of women who may benefit from prophylactic anticoagulation, either antepartum or postpartum. The coagulation changes that occur in preparation for the hemostatic challenges of delivery endure for several weeks postpartum. In fact, daily risk for pulmonary embolism (PE) is the highest postpartum. Use of anticoagulation in pregnancy introduces particular risk at the time of delivery, where bleeding and clotting risk collide. Altered metabolism rates of anticoagulants in pregnant women often necessitate closer monitoring than is required outside of pregnancy in order to ensure efficacy and safety. Heparin products are the mainstay of treating VTE in pregnancy, chiefly because they do not cross the placenta. In women with mechanical heart valves, the ideal anticoagulation regimen remains controversial as heparin use has shown inferior outcomes for preventing thromboembolic complications compared to warfarin, but warfarin carries risk for fetal embryopathy. Other populations where a heparin alternative is necessary include women with a history of heparin-associated thrombocytopenia (HIT) or other heparin intolerance. Further challenging the management of anticoagulation in pregnancy is the dearth of randomized clinical trials. The evidence governing treatment recommendations is largely based on expert guidelines, observational studies, or extrapolation from non-pregnant cohorts. A careful critique of a woman's history, as well as the available data, is essential for optimal management of anticoagulation in pregnancy. Such decisions should involve a multidisciplinary team involving obstetrics, hematology, cardiology, and anesthesia.

Use of direct oral anticoagulants for stroke prevention in elderly patients with nonvalvular atrial fibrillation.

BACKGROUND AND PURPOSE: Four direct oral anticoagulants (DOACs) are available for the prevention of stroke in nonvalvular atrial fibrillation (NVAF): dabigatran (a direct thrombin inhibitor); and rivaroxaban, apixaban, and edoxaban (factor Xa inhibitors). This article summarizes the safety and efficacy of DOACs for the prevention of stroke in elderly NVAF patients. METHODS: PubMed was searched to identify published results of randomized, controlled trials evaluating DOACs for stroke prevention in elderly NVAF patients. Pharmacologic and dose recommendations were obtained from the package inserts. CONCLUSIONS: DOACs are at least as effective as warfarin for stroke prevention in elderly patients with NVAF. Compared with warfarin, DOACs were associated with reduced risk of intracranial hemorrhage, while some DOACs demonstrated an increase in other bleeding events (e.g., gastrointestinal). The faster onset and offset of action and fewer food and drug interactions of DOACs may be an advantage over warfarin for some patients. IMPLICATIONS FOR PRACTICE: DOACs are an alternative to warfarin with overall equivalent safety and efficacy in elderly patients with NVAF, and may be preferable for some. Stroke risk must always be balanced against potential bleeding risk when determining an optimal anticoagulation treatment plan. Patients' needs and preferences will also impact this decision.