Rip roaring hematologic dysfunction from solid organ malignancies

Transcription

1 Rip roaring hematologic dysfunction from solid organ malignancies A tale from UWMC hematology consult service in 4/2017 Lindsay Hannan, MD MSPH Discussant: Dr. Sioban Keel.

2 Main objectives 1) DIC scoring systems, fibrinogen transfusion goals 2) DIC in solid tumors 3) Introduction to a rare disease

3 Mr. R.B 50 year old male OSA on CPAP HTN Atrial fibrillation not on a/c Morbid obesity Kennewick, WA Mechanic with occupational exposure to solvents, metals etc as part of job. Lives near Hanford Tank Farms, which processed waste from nuclear reactors

4 HPI 2/2017: non productive cough, fatigue. Presents to his PCP. Given abx. Early 3/2017: Progressive abdominal swelling, new lower extremity swelling 3/6/17: Mr. B bumps abdomen against his truck. That night, wife notes excessive ecchymosis. 3/9/17: ED at Kadlec hospital for his bruising as well as new right flank/hip pain and lower extremity swelling. 3/30/17. Worsening anemia, thrombocytopenia, worsening symptoms > presents to ED 4/1/17: transferred to UWMC for further management and work up.

5 Arrival at UWMC MCV 92 Albumin 2.7 Total bilirubin 3.6 AST 79 ALT 29 Alk phos 86 LDH 1465 Fibrinogen 52 D dimer 38.7 Haptoglobin < (11 to 13.5 s) (25 to 35s) 2.3 Absolute retic 182 Retic 6.4% Last labs available 9/2014: INR 1.0, hemoglobin 16, platelets 247K

6 Initial work up Bone marrow biopsy/aspirate: negative

7 Approaching the liver biopsy Interfaced with transfusion medicine 2 U of cryo prior to procedure Vitamin K 5mg PO qday x 3 days (started prior to procedure) 1 U of platelets given 1 hour prior to procedure No peri or post procedural bleeding noted

8 Results US guided liver biopsy #1: unsuccessful US guided liver biopsy #2: successful

9 Hepatic angiosarcoma * * Not the actual patient s biopsy

10 Hemoglobin low, but stable 1U of prbcs given

11 Platelets low, but stable 3U of platelets given

12 LDH high but stable

13 INR high, but stable

14 Fibrinogen trend. Stuggled to keep it above 100 mg/dl. Half life of fibrinogen = 4 days

15 Fibrinogen in DIC ISTH DIC algorithm

16 An alternative algorithm Japanese Ministry of Health and Welfare

17 Fibrinogen in classification scores Low sensitivity High specificity ISTH criteria ICU pts: After removing DIC from criteria: Sensitivity 98% > 98% Specificity 93% > 92% It s an acute phase reactant and despite ongoing consumption, plasma levels can remain well within the normal range for a long period of time.

18 So, do you need to transfuse fibrinogen to a goal of 100mg/dL?

19 Fibrinogen concentrations below 100mg/dL cause a prolongation of PT and aptt. No effect with higher fibrinogen levels PT PTT

20 Clot strength increases linearly with fibrinogen concentration, even above the normal plasma fibrinogen range (up to 10 g/l), with a minimum threshold of 200 mg/dl required in vitro for the optimal rate of clot formation to be achieved

21 Clot strength increases linearly with fibrinogen Platelet elastic modulus = ratio of downward force (stress) to downward displacment (strain) Platelet contractile force

22 Thresholds general consensus. But these are in trauma and hemorrhage

23 But if it s from cancer and the patient isn t bleeding.. there aren t any recs and there is no data

24 Back to Mr. RB. Post discharge Seen at SCCA by Dr. Pollack after discharge Patient wishes to try treatment > got 1 dose of paclitaxel (d/c ed for allergic rxn), then 2 doses of docetaxel. Hospitalized with progressive liver failure at OSH shortly after 2 nd dose Died at home in hospice 4 weeks after diagnosis

25 Discuss DIC in solid tumors

26 DIC in solid tumors Less fulminant presentation than trauma or sepsis mild or protracted clinical manifestations of consumption or even subclinical disease manifest by only laboratory abnormalities In patients with cancer and chronic DIC, laboratory manifestations are extremely variable. Some patients have all of the classic abnormalities of thrombocytopenia, hypofibrinogenemia, elevated fibrin degradation products (FDP) levels, and prolonged PTT and prothrombin time (PT), whereas other patients have thrombocytopenia only or virtually normal laboratory results, owing to increased synthesis of coagulation proteins.

27 Single institution study: Prospective evaluation of hemostatic abnormalities in overt DIC due to various underlying diseases

28 How common is DIC in solid tumors? Unclear 35%? Maybe 7% in solid tumors Sallah et al. 76 of 1117 cancer patients with DIC (6.8%) Of those with DIC, 76% were metastatic Most common in lung, breast, prostate, colon, rectum (equal proportion in the non DIC group) Those with DIC were were more likely to be diagnosed with liver mets (46 vs 24%) Sallah et al Thomb Haemost 2001;86:828 33

29 Significance of DIC in solid organ malignancy? Of the patients with DIC 59% excessive bleeding 34% thrombosis 7% both bleeding and thrombosis Stage III/IV: Median survival on 9 months with DIC vs 14 months without DIC (p=0.005) Stage I/II: Median survival 16 months vs 44 months. Sallah et al Thomb Haemost 2001;86:828 33

30 How do solid tumors cause DIC? Tumor synthesis of cytokines Solid tumors can express procoagulant molecules Tissue factor > binds VII > activation of IX and X Interactions of P and L selectins > plt microthrombi Fibrinolytic proteins Cancer procoagulant Cysteine protease with factor X activating properties Chemotherapy may enhance the risk of thrombosis due to its damaging effect on the endothelium. Anti angiogenic agents, particularly in combination with conventional chemotherapy, may increase this risk.

31 How do we treat DIC from solid tumors? DIC generally improves by 2 weeks after starting chemotherapy

32 Is angiosarcoma associated with an increased risk of DIC? Maybe? Mount Sinai: cases of angiosarcoma. 11 patients were identified to have evidence of DIC during the course of their illness. Four of these patients were deemed to have had their coagulopathy probably attributable to pharmacotherapy (including chemotherapy) or sepsis, leaving 7 patients (17%) with unexplained DIC. all patients who developed DIC had metastatic disease All patients demonstrated worsening coagulopathy coincident with disease progression. All patients had very short survival, with limited duration of disease control, if any

33 Angiosarcoma patient worsening DIC with relapse

34 Coagulopathy in Angiosarcoma DIC Kasabach Merrit phenomenon: thrombocytopenia and hyperconsumption of coagulation factors within a vascular tumor. Upregulated vwf/factor VIII results in the downstream formation of fibrin nets and subsequent entrapment of platelets within the tumor. platelets are destroyed as they circulate through the aberrant endothelial surfaces associated with these tumors

35 Angiosarcoma Soft tissue sarcoma of endothelial origin Aggressive Malignant Spread hematogenously, with the lungs the most common site for metastases, and may present as pleural disease, hemorrhagic pleural effusion, or pneumothorax. Other common sites include liver, bone, soft tissue structures, and lymph nodes. Rare: they represent <1% of all sarcomas

36 Sarcoma cases, approx , in 3 European regions. Per 100,000 person years

37 Angiosarcoma, incidence by age, sex Age adjusted The incidence of angiosarcoma has risen over the past 30 years, but whether this is a true increase is unclear. The rise could be related to greater use of radiotherapy, improved medical awareness, or a refined histopathological definition.

38 Risk factors Thorotrast was introduced in 1928 as a radiocontrast material and its use was stopped after 30 years following several reports of organ damage and malignancies.

39 Angiosarcoma cases where is the primary? Cases diagnosed between January 1980 to April 2004 in three medical centers in France N % N %

40 Treatment Main curative option: surgery Cytotoxic chemotherapy is the primary treatment option for metastatic angiosarcoma, although the evidence base for this is limited. The main drug groups used are anthracyclines, ifosfamide, and taxanes. Combination chemotherapy is associated with increased toxicity but not necessarily with better outcomes. VEGF inhibitors have been tried not quite ready for prime time.

41 Angiosarcoma, treatment Localized disease: median survival 51 months Metastatic disease: median survival 12 months

42

43 Hepatic angiosarcoma <1% of primary liver malignancies 2001 reported cases of HAS every 10,000,000 persons (approx 20 cases in US per year?) Metastases develop in about 50% of patients. Average survival is 6 months, with death resulting from hepatic failure in 50% of patients and from intra abdominal hemorrhage in 25%. minimal treatment responses and common relapses in most cases, the tumor has diffusely infiltrated the organ at the time of diagnosis. Palliative chemotherapy may be indicated, but a single treatment regimen has not been established

44 Thank you!