The association between cancer and venous thromboembolism (VTE) is well established. Saddle pulmonary embolism is not uncommon in hospitalized cancer patients and confers a higher mortality. We report a case of saddle pulmonary embolism in a cancer patient with thrombocytopenia, discuss the bleeding risks, complexity of managing such patients and review current guidelines.
Pulmonary embolism (PE) is common in hospitalized patients. Overall mortality for major pulmonary embolism is 22% and as high as 65% in those who require cardiopulmonary resuscitation [
We report a case of saddle pulmonary embolism in a cancer patient with thrombocytopenia and discuss the bleeding risks, complexity of managing such patients and review current guidelines.
A 73-year-old female with history of hepatocellular carcinoma due to long-standing hepatitis C, presented to the emergency center with a sudden syncopal episode at home. Her past medical history was significant for portal hypertension, and variceal bleeding requiring blood transfusions. She was receiving sorafenib, which required dose reduction due to thrombocytopenia. Her platelets fluctuated between 46,000–113 × 109 during the treatment.
On examination she was stable with a blood pressure of 128/72 mmHg; heart rate of 80 beats per minute; respiratory rate of 22/minute; temperature 36.7°C; and O2 saturation of 96% on 2-3 liters oxygen via nasal cannula. Heart sounds were normal with no signs of heart failure.
Relevant investigations included a 12 lead electrocardiogram (ECG), which showed sinus rhythm with left axis deviation, and no evidence of ischemia.
Serum troponin was marginally elevated at 0.12 ng/mL (Normal values: 0.00–0.03 ng/mL). Computerized (CT) scan of the lungs showed saddle PE with extension into the lobular braches (Figure
CT scan showing a saddle pulmonary embolus, extending into the right and left pulmonary arteries.
She was treated with LMWH (Enoxaparin in a dose of 1 mg/kg subcutaneously twice daily) and inferior vena cava (IVC) filter was placed to prevent migration of the lower extremity thrombus. In view of her thrombocytopenia, hemodynamic stability and no evidence of RV dysfunction, she was not given thrombolytics. The patient’s hemoglobin and platelets remained stable throughout the hospitalization and she was discharged home on LMWH.
Venous thromboembolism (VTE) is common in cancer patients; with significant in hospital mortality [
Cancer induces a prothrombotic state [
Saddle pulmonary embolism in cancer patients carries a very poor prognosis, with mortality of >80% at one year [
Treatment of saddle PE includes anticoagulants, thrombolytics and catheter based or surgical embolectomy [
National and international guidelines recommend LMWH as the first-line agent and Vitamin K antagonist (VKA) warfarin as a second line agent for the initial and long-term treatment of VTE in cancer patients [
Summary of guidelines for treatment of VTE in cancer [
Condition | ASCO | NCCN | AIOM/ESMO | ACCP |
---|---|---|---|---|
Initial treatment (acute phase) | - 5–10 days = LMWH preferred | - LMWH, UFH (IV), FXa-I according to clinical situation | - LMWH, UFH (IV) | - LMWH or VKA for minimum of 90 days |
Long-term treatment (chronic phase) | - LMWH for 180 days | - LMWH preferred | - LMWH for 90–180 days | - LMWH or VKA for as long as cancer active |
Thrombolytic for initial treatment | Only in limb-threatening thrombosis | Massive DVT or PE with hemodynamic instability | NA | NA |
IVCF | - Presence of CI | - Presence of CI | - Presence of CI | - In patients with acute PE, if anticoagulant is not possible due to high-risk of bleeding |
VTE: venous thromboembolism; ASCO: American Society of Clinical Oncology; NCCN: National Comprehensive Cancer Network; AIOM: Italian Association of Medical Oncology; ESMO: European Society of Medical Oncology; ACCP: American College of Chest Physician; LMWH: low-molecular-weight-heparin; UFH: unfractionated heparin; FXa-I: factor- Xa inhibitor; VKA: vitamin K antagonist; RF: risk factors; DVT: deep-vein thrombosis; PE: pulmonary embolism; IVCF: inferior vena-caval filter; CI: contraindication; PHTN: pulmonary hypertension; AC: anticoagulation; IV: intravenous; NA: not addressed. CrCl: creatinine clearance.
In a study of 146 cancer patients with VTE, in which enoxaparin 1.5 mg/kg was compared to warfarin (INR goal of 2-3), there were no significant differences at 3 months between the two treatment groups based on combined outcomes of recurrent VTE or major bleeding episodes (warfarin 21.1%; (95% confidence interval (CI), 12.3%–32.4%) versus enoxaparin 10.5%; (95% CI, 4.3%–20.3%); (
In another randomized trial of 676 cancer patients with VTE in which dalteparin in a dose adjusted protocol (200 IU/Kg daily for the first month and then 150 IU/Kg daily for the next 5 months) was compared to warfarin, there was a significant decrease in the cumulative risk of recurrent VTE in patients receiving dalteparin compared to warfarin (8.3% versus 15.8%; hazard ratio, 0.48;
In another trial of 91 cancer patients with VTE, in which 3 different regimens were compared: (1) enoxaparin 1.0 mg/Kg twice daily for 5 days followed by once daily 1.0 mg/Kg for 175 days; (2) enoxaparin 1.0 mg/Kg twice daily for 5 days then enoxaparin 1.5 mg/Kg once daily for 175 days; (3) enoxaparin 1.0 mg/Kg twice daily with warfarin for minimum of 5 days with an INR goal of 2-3; there were no significant differences between enoxaparin and warfarin in safety profile and recurrent VTE. In this study 45% of cancer patient with VTE had PE [
In a recent study of 200 cancer patients with VTE, in which tinzaparin in a dose of 175 International Factor Xa Inhibitory Units/Kg was compared to warfarin for an INR goal of 2-3, there was a significant decrease in cumulative risk of recurrent VTE at 10 months in patients assigned to tinzaparin (
Pharmacokinetics of different anticoagulants [
Anticoagulant | Molecular weight | Elimination route | Antidote | Platelet monitoring | AntiXa monitoring | |
---|---|---|---|---|---|---|
Enoxaparin (lovenox) | 3,500–5,500 | 4.5–7 | Renal | - Thrombocytopenia of any degree should be monitored closely | - 1 mg/kg Q12 = 0.6–1.1 IU/mL | |
Dalteparin (fragmin) | 5,600–6,400 | 3–5 | Renal | Protamine sulfate 1 mg per 100 U of heparin or less than 100 mg over 2 hours to lower risk of reaction. Protamine partially reverses the effect of LMWH | - For platelet counts between 50,000 and 100,000/mm3, reduce dose of dalteparin by 2,500 IU until the platelet count recovers to ≥100,000/mm3 | - 100 IU/kg Q12 = 0.4–1.1 IU/mL |
Tinzaparin (innohep) | 5,600–7,500 | 3-4 | Renal | - Thrombocytopenia of any degree should be monitored | 175 IU/kg = 0.85–1.0 IU/mL | |
Unfractionated heparin | 5,000–30,000 | 1-2 | Renal/endothelial | Protamine sulfate 1 mg per 100 U of heparin or less than 100 mg over 2 hours to lower risk of reaction. | - Thrombocytopenia of any degree should be monitored | aPTT monitoring |
Fondaparinux (arixtra) | <2,500 | 17–21 | Renal | Recombinant factor VIIa 90 mcg/kg | - Thrombocytopenia of any degree should be monitored | - 2.5 mg = peak at steady state 0.39–0.5 mg/L; trough at steady state 0.14–0.19 mg/L |
IV: intravenous; SC: subcutaneous; U: unit; UFH: unfractionated heparin; LMWH: low-molecular-weight heparin;
Warfarin is considered an alternative agent to LMWH. Due to major drug interactions between warfarin and chemotherapy, nutritional deficiency, and use of nonchemotherapy agents in cancer patients, frequent dose monitoring and modifications for warfarin is needed.
The difficulty in maintaining the narrow therapeutic index of warfarin also was shown in a major cancer trial where a therapeutic range INR (2-3) was achieved in only 46% of the patients [
Direct factor-Xa inhibitor, fondaparinux, can also be considered for the initial (acute phase) treatment of PE. Fondaparinux was studied in a randomized clinical trial that showed noninferiority to unfractionated heparin in the acute treatment of PE; however, only 20% of patients enrolled in each arm had cancer. The incidence of VTE recurrence was 3.8% in the fondaparinux group and 5.0% in the unfractionated-heparin group, for an absolute difference in favor of fondaparinux of 1.2% (95% confidence interval, −3.0 to 0.5). The reported incidence of major bleeding was 2% in the fondaparinux group and 2.4% in the unfractionated heparin [
Recently fixed-dose subcutaneous weight-adjusted unfractionated heparin (UFH) has also been recommended for the acute treatment of VTE [
Recommended treatment duration of VTE in cancer patients is 6–12 months and indefinite in cases of metastatic or active cancer [
In the absence of contraindications, systemic thrombolytics should be considered in patients with massive PE and hemodynamic instability [
However, cancer patients have been excluded from thrombolytic trials; hence evidence-based guidelines for the use of thrombolytics in this subset of population is lacking.
Except for a case report where streptokinase was used for the treatment of PE associated with heparin-induced thrombocytopenia [
Catheter and surgical thrombectomy are an option in selected patients. In a pregnant patient with PE and thromobcytopenia (due to myelodyplastic syndrome), successful emergency pulmonary embolectomy has been reported [
Placement of IVC filter is recommended in patients with contraindication to anticoagulation, failure of anticoagulation, massive pulmonary embolism, severe cardiopulmonary disease with deep vein thrombosis, and free floating iliofemoral or inferior vena cava thrombus [
To date, there are no randomized clinical trials available in the cancer literature to assess the long-term safety and efficacy of filters. IVC filters carry short-term and long-term complications such as hematoma; misplacement, migration, thrombosis, recurrent PE, filter fracture, IVC occlusion and vena caval syndrome [
Prior to initiation of anticoagulation risk of bleeding should be assessed. Reported bleedings (major and minor combined) in cancer trials associated with VKA and LMWH are 3%–16% and 6%–11%, respectively [
Multivariate analysis of the risk of developing fatal and major bleeding in cancer patients with venous thromboembolism (VTE) [
Fatal bleeding | Major bleeding | ||||
Variables | Odds ratio (95% CI) | Variables | Odds ratio (95% CI) | ||
Body weight <60 kg | 2.5 (1.1–5.3) | .021 | Recent major bleeding | 2.4 (1.1–5.1) | .003 |
Recent major bleeding | 3.0 (0.96–9.1) | .058 | CrCl < 30 ml/min | 2.2 (1.5–3.4) | <.001 |
Serum creatinine >1.2 mg/dL | 2.8 (1.3–5.8) | .008 | Immobility for ≥4 days | 1.8 (1.2–2.7) | .005 |
Immobility for ≥4 days | 4.1 (1.9–8.7) | .001 | Metastatic cancer | 1.6 (1.1–2.3) | .03 |
Metastatic cancer | 3.1 (1.4–7.1) | .006 |
Confidence interval: CI; creatinine clearance: CrCl.
Multivariate analysis for major bleeding and bleeding risk index classification [
Risk factors | Odds ratio (95%CI) | Points | |
---|---|---|---|
Recent major bleed | 2.7 (1.6–4.6) | <.001 | 2 |
Serum creatinine >1.2 mg/dL | 2.1 (1.7–2.8) | <.001 | 1.5 |
Anemia | 2.1 (1.7–2.7) | <.001 | 1.5 |
Cancer | 1.7 (1.4–2.2) | <.001 | 1 |
Clinically overt pulmonary embolism | 1.7 (1.4–2.2) | <.001 | 1 |
Age >75 y | 1.7 (1.3–2.1) | <.001 | 1 |
0 point: low risk 0.1% (95% CI: 0.0–0.2) | 1–4 points: intermediate risk 2.8% (95% CI: 2.4–3.3) | >4 points: high risk 7.3 % (95% CI: 4.0–9.1) |
Transient thrombocytopenia due to myelosuppressive chemotherapy needs to be taken into consideration prior to initiation of anticoagulation as bleeding risks double from 10% at a platelet count of 20,000/mm3 to 20% when the platelet count drops to below 10,000/mm3 in solid tumor patients [
Risk of intracranial hemorrhage with thrombolytics in PE is about 3% [
The exact risk of bleeding in thrombocytopenic patients with PE is unknown. Platelet count less than 150,000/mm3 has been a predictor of short-term composite event such as mortality [
No recommendations can be made regarding the use of thrombolytics in patients with thrombocytopenia and acute PE, until large-scale data is available. Use of thrombolytic agents in cancer patients requires close attention to bleeding risks and overall prognosis.
There are several published guidelines for the treatment of VTE in cancer patients.
However, data on the management of saddle PE and particularly in patients with thrombocytopenia is lacking. Large-scale prospectively collected data and future studies are needed to address the best possible treatment option in these patients.
The authors do not report any conflict of interests regarding this work.