Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid

©2016 MFMER | slide-1 ©2016 MFMER | slide-1

Malignancy-Associated Coagulopathy: Recognition and Laboratory Diagnosis

Aneel A. Ashrani, M.D., M.S.

©2016 MFMER | slide-2

Disclosures

Relevant Financial Relationship -NONE

Off-Label and/or Investigational Uses -NONE


Malignancy Associated Coagulopathy •  Activation of coagulation

•  Venous and arterial thrombosis

•  Disseminated intravascular coagulation and fibrinolysis (DIC/ICF)

•  Hyperfibrinolysis

•  Immune mediated •  FVIII inhibitor •  Acquired von Willebrand

syndrome •  FV inhibitor

•  Therapy related coagulopathy •  Coagulation factor depletion

•  L-aspariginase •  Drug induced thrombotic

microangiopathy •  Gemcitabine

•  Endothelial dysfunction •  Thalidomide •  Bevacizumab

•  Platelet activation/ dysfunction •  Heparin induced

thrombocytopenia •  Ibrutinib


Case 1: •  59-year-old female with stage III serous

adenocarcinoma of the ovary •  s/p total abdominal hysterectomy and bilateral

salpingo-oophorectomy and receiving paclitaxel and carboplatin

•  Influenza vaccine administered in the right deltoid region

•  Severe pain and swelling in the right shoulder; swelling and ecchymosis in the arm extending down to the wrist

•  No prior history of excessive bleeding or bruising


Case 1 (contd.)

•  Hemoglobin 8.7 g/dL → 5.7 g/dL

•  Platelets: 403,000/mm3

•  PT: 11.7 sec (Ref: 8.4 – 12.0)

•  APTT: 75 sec (Ref: 25 – 37)

•  Ultrasound of right upper extremity: soft tissue fluid collection; no DVT


Prolonged PT or APTT

Mixing study with normal plasma

Correction (factor deficiency)

No correction (inhibitor)

Clotting factor assays to identify deficiency

Determine type of inhibitor

Nonspecific inhibitor (e.g., lupus anticoagulant

Specific factor inhibitor (e.g., FVIII, FV)

Drug: Heparin, IIa inhibitor, Xa inhibitor

Adapted from Mayo Clinic Proc.; Kamal, A.H., 2007;82(7):864-873 with permission from Elsevier http://www.elsevier.com


Case 1 (contd.) •  Hemoglobin 8.7 g/dL → 5.7 g/dL


•  PT: 11.7 sec (Ref: 8.4 – 12.0)

•  APTT: 75 sec (Ref: 25 – 37) •  APTT Mix: 39 sec •  Platelet neutralization procedure: 82 sec

•  DRVVT: 1.2 •  DRVVT Mix: 1.0

•  Factor VIII: <1% •  Factor VIII inhibitor titer: 7 Bethesda Units


Acquired Factor VIII Inhibitor •  Neutralizing autoantibodies against factor VIII

•  Prevalence: ~1.5 cases/million/year

•  Most common in the elderly •  Median age (IQR): 73.9 yrs. (61.4–80.4)

Underlying disorder No. of patients Idiopathic 51.9%

Malignancy 11.8%

Autoimmune diseases 11.6%

Pregnancy 8.5%

Infections 3.8%

Drug induced 3.4%

MGUS 2.6%

Collins, P.W., et al. Blood. 2007;109: 1870-1877 Knoebl, P. , et al. J Thromb Haemost 2012; 10: 622–31


Clinical Presentation • Majority of patients bleed (95%)

•  Spontaneous bleed: 77% •  Subcutaneous: 53% •  Deep muscle or retroperitoneal bleed: 50% •  Mucosal bleeding:32% •  Joint bleeds: 5%

•  Severe bleed: 70%

• Mortality at final follow-up: 28% •  Median (IRQ) time after diagnosis: 75 days (25–240) •  Mortality secondary to the bleed: 3% •  Mortality secondary to the immunosuppression: 3%

Knoebl, P. , et al. J Thromb Haemost 2012; 10: 622–31


Hauser and Lechner. Thromb Haemost 1999;82:1005.

Cancer and FVIII Inhibitors • Not associated with specific type of tumor

• Two-thirds of associated malignancies are solid tumors

• Most frequent primary: lung, prostate, head/neck

• Male:female ratio ≈ 3:1

• Median age of onset = 69 yrs

• May be autoimmune reaction to tumor → tumor antigen similar to FVIII?


Solid Tumors and FVIII Inhibitors

• Standard treatment → chemotherapy, radiation, & surgery do not usually eradicate inhibitors

•  Inhibitor is not a marker of tumor recurrence

Hauser and Lechner. Thromb Haemost 1999;82:1005.


Treatment Strategies Dual Objectives

Management Strategies

Acute Management

Long-term Strategy

Stop the Bleeding

Eradicate Inhibitor


Acute Management of Bleeding

Hemostatic agent No. of patients treated % Response Bypassing agent 219 92%

rFVIIa 159 91% aPCC 60 93%

Replacement therapy 69 70% FVIII 55 70% DDAVP 14 64%

Baudo, F., et al. Blood. 2012;120(1): 39-46)

Thrombotic events similar between rFVIIa (2.9%) and aPCC (4.8%).

Bleeding controlled in 80% of patients treated with a first-line hemostatic agent


Inhibitor Eradication: Efficacy and Safety Regimen N CR (%) Relapse (%) Stable CR (%) Steroids alone 142 58% 11% 48% Steroids + cyclophosphamide 83 80% 10% 70% Rituxan based regimens 51 61% 3% 59%

Regimen N Any AE (%) Infection Mortality (%) Steroids alone 142 25% 16% 28% Steroids + cyclophosphamide 83 41% 27% 33% Rituxan based regimens 51 37% 12% 20%

Cyclophosphamide+steroids versus steroids alone OR 95% CI

CR at final follow-up 3.16 1.20-8.31 Alive at final follow-up: 0.91 0.45-1.82 Alive and in CR 1.26 0.64-2.48

Collins, P, et al. Blood. 2012;120(1):47-55


Case 1 (contd.)

•  Acute bleed management: •  Transfused 4 units PRBCs •  FEIBA 75 units/kg q12

hours

•  Inhibitor management: •  Prednisone 1mg/kg/day

0

10

20

30

40

50

60

Oct Nov Dec Jan Feb Mar

Factor VIII (%) Inhibitor titer (BU)

Tiede, A, et al. Blood. 2015;125(7):1091-1097

Low FVIII at presentation is associated with a lower response rate to immunosuppression Partial response achieved on steroids alone within <21 days is more common in patients with FVIII >1 IU/dL and inhibitor concentration <20 BU/mL



Case 2 •  51-year-old female with iron deficiency anemia underwent

colonoscopy with polypectomy •  About two weeks later, she had hematochezia with

hemoglobin drop to 5.5 g/dL •  Required 4 units of PRBCs

•  As serology for celiac disease were positive, she underwent upper GI endoscopy with biopsies

•  Biopsies were consistent with celiac disease •  She then started having melanotic stools, requiring

PRBC transfusions

•  Despite gluten-free diet, she continued to be anemic requiring PRBC transfusion


Case 2 (contd.) •  A capsule study suggested that the proximal jejunum may

be the site of bleeding •  She then underwent small bowel resection •  She continued to have melanotic stools and was

persistently anemic

•  Over the last three years, she has had frequent epistaxis, unexplained bruises and prolonged bleeding with minor nicks/ cuts

•  Prior to that, no issues with excessive bleeding/ bruising

•  Hemoglobin: 10.3 g/dL

•  Platelets: 443,000/ mm3

•  Leukocyte count: 9200/ mm3


Patient 2 (contd.) •  PT: 8.4 sec (Ref: 8.3 – 10.8)

•  APTT: 35 sec (Ref: 21 – 33) •  APTT mix: 30 sec •  Platelet neutralization procedure: 37 sec

•  FVIII: 28%

•  vWF antigen: 18%

•  Ristocetin cofactor: <12%

•  vWF multimer analysis: Normal vWF multimer distribution

•  Ristocetin inhibitor screen: Negative


Patient 2 (contd.) •  Platelet function analyzer (PFA100):

•  Collagen/Epinephrine closure time: >267 sec •  Collagen/ADP: >166 sec

•  Platelet aggregation studies: •  Arachidonate: Normal •  ADP: Normal •  Epinephrine: Normal •  Collagen: Normal •  Ristocetin: Decreased

•  SPEP: 0.5 g/dL IgG lambda monoclonal paraprotein •  Lambda free light chain: 9.9 mg/dL (UNL: 2.6 mg/dL)


Acquired von Willebrand Syndrome: Pathogenesis •  Autoantibodies

•  Interfering with platelet or collagen binding •  Increasing VWF clearance

•  Sequestration/adsorption of high-molecular-weight vWF •  Multiple myeloma •  Essential thrombocythemia

•  Proteolytic cleavage of VWF •  Shear stress-induced vWF unfolding

•  Aortic valve stenosis •  LVAD

•  Pancreatitis, liver cirrhosis, leukemia

•  Decreased synthesis •  Hypothyroidism

Tiede, A., et al. Blood. 2011;117(25):6777-6785


Differentiating AvWS from Congenital vWD In favor of AvWS In favor of vWD

Personal history •  Late onset of bleeding •  Uneventful prior surgeries

•  Early onset of bleeding •  No uneventful surgery or no

previous high-risk situations Family history •  Negative •  Positive AVWS-associated disorder

•  Present •  Absent

Laboratory evaluation •  Presence of inhibitor or VWF-binding antibodies

•  VWF gene mutation

Treatment response •  Remission after treatment of underlying disorder

•  Response to IVIG (in IgG-MGUS-associated AVWS)

•  Short-lived response to VWF containing concentrates or desmopressin

•  Normal recovery and half-life of VWF-containing concentrate

•  Sustained response to desmopressin

Tiede, A., et al. Blood. 2011;117(25):6777-6785


Diagnostic Tests •  Initial assays for AvWS are same as for vWD

•  FVIII:C •  VWF:Antigen •  VWF:Activity or VWF:RCo •  VWF:Collagen Binding

•  vWF multimer analysis

•  vWF propeptide? •  Increased propeptide/ vWF:Ag ratio reflects accelerated clearance

of vWF •  Increased ratio also seen in subset of patients with type 1 vWD

•  Autoantibodies: No standard assays •  Neutralizing antibodies seen in minority of AvWS

•  Mixing studies of VWF:Activity •  Non-neutralizing antibodies accelerate vWF clearance

•  ELISA assay


•  DDAVP: •  Overall response rate: 32%

•  Response transient and vary by underlying disorder •  Low response: Cardiovascular, MPN •  Higher response: Autoimmune, Lymphoproliferative disorders,

neoplastic, MGUS

•  vWF containing concentrate: •  Half-life short, especially in patients with MGUS or inhibitors

•  IVIG: •  Effective in patients with IgG-MGUS associated AVWS •  Peak effect in 4 days with slow return to baseline within 21 days

•  Plasmapheresis: •  Deplete autoantibodies or paraproteins

•  Antifibrinolytics:

Treatment

Federici AB, et al. Blood. 1998; 92 (8): 2707-2711 Tiede, A., et al. Blood. 2011;117(25):6777-6785.


What About Long-Term Management of AvWS? •  Treatment of the underlying disorder should be

considered whenever possible •  Response to therapy for underlying lymphoproliferative

disorders and multiple myeloma: 35-70% •  Response to cytoreductive therapy for underlying MPN:

~85% •  MGUS usually unresponsive to steroids and chemotherapy

•  Cannot eradicate slowly proliferating plasma cell clones •  ? Bortezomib

Ojeda-Uribe M, et al. Am J Hematol. 2010;85(5):396


Case 2 (contd.)

DDAVP (0.3 mcg/kg x 1)

0 10 20 30 40 50 60 70 80 90

100

0 1 2 3 4

%

Time (hours)

FVIII:C vWF:Ag vWF:RCo

IV IgG (1 g/kg x 1)

0

50

100

150

200

0 2 4 6 8 10 12 14 16 18 20 Time (Days)

vWF:RCo FVIII:C vWF:Ag


Case 3 •  54-year-old male with peripheral

stage IV peripheral T-cell lymphoma

•  Bilirubin: 16 mg/dL •  alkaline phosphatase: 916 U/L •  ALT 503 U/L; AST 405 U/L

•  He was treated with two cycles of gemcitabine, Solu-Medrol, and cisplatin

•  Liver function tests improved significantly

•  Overall significant improvement, but with new skeletal lesions


Case 3 (contd.) •  He then received first cycle of CHOP-etoposide

•  When due for the second cycle: •  Fever up to 103oF and sweats •  Right arm pain and swelling (PICC line in right arm) •  ROS negative

7.3

19.5 80 4.5

125 3.6

84 1.2 30 85

24

Lactate: 2.9 Uric Acid: 8.1 LDH: 324 UA: negative

Bilirubin: 1.6 AST 64 Alk phosphatase: 527

CXR: No infiltrate Cultures: negative



Case 3 (contd.) •  Right UE ultrasound: Acute DVT in

the right subclavian, axillary, and brachial veins

•  Enoxaparin 1mg/kg q12h

•  Persistent fevers, despite negative infection work up

•  Lymphoma?

•  PET-CT scan: Mixed response •  Increased activity in the right

cardiophrenic recess but with improvement in other lesions


Case 3 (contd.) •  Hemoglobin: 7.6 g/dL

•  WBC: 2800/mm3


•  PT: 18.1 sec (Ref: 9.5 – 13.8)

•  APTT: 56 sec

•  Fibrinogen: 107 mg/dL (Ref: 200 – 375)

•  D-Dimer: 1545 ng/ml (Ref: <250)

•  Soluble fibrin monomer complex (SFMC): 52 mcg/ml (Ref: <8)


Case 3 (contd.) Coagulation factor Value Reference range Fibrinogen 58 200 – 375 mg/dL Factor II 36 75 – 145% Factor V 69 70 – 165% Factor VII 77 65 – 180% Factor VIII 168 55 – 200% Factor IX 44 65 – 140% Factor X 44 70 – 150% Factor XI 32 55 – 150% Factor XII 37 55 – 180%


•  Persistent intravascular activation of coagulation leading to fibrin formation and deposition inducing consumption of coagulation factors and platelets

•  Can present as thrombosis or bleeding

•  DIC is a clinical and laboratory diagnosis, based on findings of coagulopathy and/or fibrinolysis

•  No single laboratory test can accurately confirm or eliminate the diagnosis

Disseminated Intravascular Coagulation and Fibrinolysis (DIC/ ICF)


UNDERLYING CONDITION

Activation of intravascular coagulation

Platelet consumption

Coagulation factor consumption

Fibrin deposition fibrinolysis

Endothelial damage

↓ Platelets ↑ PT ↑ APTT

↑ D-Dimer ↑ SFMC

MAHA

Impaired coagulation

Thrombosis

BLEEDING ORGAN ISCHEMIA

DIC Pathophysiology


Acute versus Chronic DIC Parameter Acute (Decompensated) DIC Chronic (Decompensated) DIC

Underlying condition

Trauma, sepsis, malignancy (esp. APL), ABO-incompatible blood transfusion

Malignancy (esp. pancreatic, gastric, ovarian, brain tumors

Presentation Bleeding Venous or arterial thromboembolism

Platelet count Decreased Variable PT Prolonged Normal aPTT Prolonged Normal Thrombin time Prolonged Normal or slightly prolonged Fibrinogen Decreased Normal or elevated Factor V Decreased Normal Factor VIII Decreased Normal D-Dimer Elevated Elevated SFMC Elevated Elevated


Differential Diagnosis •  Severe liver disease

•  Thrombotic microangiopathy (TMA) •  TTP •  HUS •  Drug-induced TMA

Management •  Treat underlying cause

•  Supportive measures •  Transfusion support, if necessary

•  PRBCs, platelets •  Cryoprecipitate, FFP

•  Anticoagulation for thrombotic complications


Case 3 (contd.)

0

50

100

150

200

250

300 Fibrinogen (mg/dL) Platelet count (x1000/mm3)

CHOP-E

Cryoprecipitate



Case 4 •  63-year-old female with history of Stage IA, ER & PR

positive, HER-2 negative infiltrating ductal breast cancer presented with extensive spontaneous ecchymoses

•  Status post mastectomy, followed by six cycles of CMF, and was on letrozole for the prior three years

•  Subsequently, she developed hematuria and soft tissue bleeding

•  CT of the abdomen: non-obstructing renal calculi •  Incidentally, multiple lytic and sclerotic lesions

noted in the LS spine and pelvis

•  No prior history suggestive of a bleeding disorder


Case 4 (contd.) Hemoglobin 9.4 g/dL WBC 7900/ mm3

Platelets 192,000/mm3

Smear No schistocytes

Prothrombin time 10.5 sec (Ref: 8.3-10.8) aPTT 30 sec (Ref: 21-33) Thrombin time 24 sec (Ref: 16-25)


Case 4 (contd.): Coagulation Factors Factor Activity Reference range (%)

Factor II 171% 70-130 Factor V 124% 60-145 Factor VII 108% 50-160 Factor VIII 171% 55-200 Factor IX 107% 60-140 Factor X 67% 60-140 Factor XI 81% 60-140 Factor XII 125% 60-160 vWF Ag 206% 55-200 vWF activity 208% 55-200


Case 4 (contd.): Platelet Function Assays

Agonist Value Reference Arachidonate Normal ADP Normal Epinephrine Normal Collagen Normal Ristocetin Normal

PFA Col/Epi 147 sec 70-165 sec PFA Col/ADP 92 sec 50-115 sec


Case 4 (contd.): Now What? Fibrinogen (Clauss) 159 mg/dL 200-430 D-dimer >20000 ng/ml <250 Soluble Fibrin Monomer Negative

Factor XIII screen Clot dissolved before testing could be completed

•  Clot solubility test for XIII screen – •  Normally, a clot is stable for 2 hours in 5M urea or 2%

acetic acid, while in factor XIII deficiency the clot is unstable and dissolves in minutes

Plasminogen activity 34% 75-140 Alpha-2 antiplasmin 35% 80-140


Fibrinolysis PLASMINOGEN

PLASMIN

FIBRIN FIBRIN DEGRADATION PRODUCTS

FIBRINOGEN

Thrombin Thrombin activable fibrinolysis inhibitor

α2-antiplasmin

α2-macroglobulin

Factor XIa, XIIa, Kallikrein

Tissue plasminogen activator (t-PA)

Urokinase

Plasminogen activator inhibitor 1 and 2


Hyperfibrinolysis

•  Primary

•  Increased fibrinolytic activity independent of other factors

•  Excess of plasminogen activators •  Deficiency of fibrinolysis inhibitors

•  Secondary (e.g., DIC) •  Consequence of activation of coagulation and thrombin

generation •  Stimulates the endothelium to produce increased

amounts of t-PA


Case 4 (contd.) •  Bone marrow biopsy: Involvement by metastatic

adenocarcinoma •  Morphologically and immunophenotypically consistent with

breast primary •  Immunohistochemistry for t-PA on bone marrow: t-PA

expression in ER/PR–positive cells

•  Plasma t-PA antigen: >150 ng/ml (Ref:<14.1 ng/ml)

•  Profuse bleeding from the bone marrow biopsy site •  Hemoglobin 9.4 g/dL → 6.4 g/dL •  4 units of pRBCs •  ε-aminocaproic acid infusion •  Weekly paclitaxel

•  Bleeding and bruising improved



Case 5 •  17 year old male diagnosed with T-cell

acute lymphoblastic leukemia (ALL)

•  Remission induction regimen included: •  Intrathecal cytarabine: Day 1 •  Vincristine: Days 1, 8, 15, 22 •  Prednisone: Days 1-28 •  Daunorubicin: Days 1, 8, 15, 22 •  PEG Asparaginase: Day 4 •  Intrathecal methotrexate: Days 8, 29

•  Day 8: Received intrathecal methotrexate •  Soon following LP, he complained of

back pain that progressively worsened •  By evening, developed lower

extremity weakness


Case 5 (contd.)

Lab Pre-chemo

Pre-LP Post-LP Post-cryo + FFP

Ref. range

WBC (x1000/mm3) 89.5 5.5 4.1 4.4 3.5 – 10.5

Hemoglobin (g/dL) 13.7 14.9 11.9 10.3 13.5 – 17.5

Platelets (x1000/mm3) 62 155 260 177 150 – 450

PT (sec) 15.7 23.8 13.3 9.5 – 13.8

APTT (sec) 30 59 32 28 – 38

Fibrinogen (mg/dl) 326 <60 127 200 – 375

Antithrombin (%) 45 80 – 130

Patient underwent laminoforaminotomies with decompression of T11 through S1 and evacuation of hematoma


Case 5 (contd.)

0

50

100

150

200

250

300

350

Fibrinogen (mg/dL)

PEG-Asparaginase

Cryoprecipitate


L Asparaginase •  L-Asparaginase: enzyme that catalyzes the hydrolysis of L-asparagine

(ASN) to L-aspartic acid and ammonia, resulting in depletion of the circulating pool of ASN

•  Three product types:

Native E. coli asparaginase

Pegylated form of the E. coli asparaginase (long half life)

Erwinia asparaginase (Erwinase)

•  Lymphoblasts typically have low levels of ASN synthetase activity and are dependent on extracellular sources of ASN for protein synthesis

•  Depletion of ASN is associated with cell-cycle arrest in the G1 phase

•  L-Asp is also known to catalyze the hydrolysis of glutamine (GLU) to glutamic acid, resulting in depletion of circulating levels of GLU


L-Asparaginase: Adverse Effect Profile

0 10 20 30 40

Bleeding

Thrombosis

CNS ischemia

Hypofibrinogenemia

Neuropathy

Fatigue

Nausea/vomiting

Pancreatitis

Hyperglycemia

Elevated liver enzymes

Hyperbilirubinemia

Allergy/Hypersensitivity

Pediatric (n=1274) Adult (n=76)

Stock, W et al. Leukemia & Lymphoma.2011; 52(12): 2237–2253


Thrombosis and Bleeding •  L-Asparaginase leads to asparagine depletion

•  Decreased synthesis of: •  Fibrinogen •  Plasminogen •  Antithrombin (AT), protein C, and protein S.

•  AT and fibrinogen are particularly affected

•  Reduction in AT and protein C leads to thrombosis •  Patients with AT <70% are at high risk for thrombosis

•  Depletion of fibrinogen is associated with increased bleeding

•  Patients with fibrinogen <100 mg/dL are at high risk of hemorrhage

Stock, W et al. Leukemia & Lymphoma.2011; 52(12): 2237–2253


Risk Factors for Thrombosis

•  Increasing age •  Pediatric patients: 5% •  Adult patients: 34%

•  Adults > 30 years: 42%

•  Presence of indwelling venous catheters

•  Oral contraceptives

•  Prednisone versus dexamethasone therapy •  Lower thrombosis rates reported for dexamethasone

•  Inherited thrombotic diathesis •  e.g., factor V Leiden, protein S deficiency, protein C

deficiency


Suggested Monitoring During L- Asparaginase Rx Baseline (before first dose)

•  APTT, PT, AT and fibrinogen

•  Prolonged APTT: r/o LAC or heparin or factor deficiency

•  Prolonged PT: r/o Vitamin K deficiency, liver disease, DIC

Serially (after administration)

•  APTT, PT, AT and fibrinogen

•  Twice weekly after last dose of L-asparaginase until there is no evidence of ongoing coagulation factor depletion.

•  This is typically one week after L-asparaginase but may be up to 3 or more weeks after the pegylated form


Suggested Replacement Triggers During and After L-Asparaginase Therapy

• Fibrinogen < 100 mg/dl • AT < 60% (normal: 80-120%)

•  Dosage should be determined by pre-therapy AT level in order to increase AT level to 80%

•  Units required = [desired - baseline AT level] × weight (kg) 1.4

• Confirm restoration of desired level after replacement administered


Summary •  Multiple presentations of cancer coagulopathy

•  Asymptomatic laboratory abnormality •  Bleeding disorder •  Thrombotic disorder

•  Variable mechanisms of cancer coagulopathy •  Activation of coagulation and fibrinolysis •  Immune mediated •  Endothelial damage

•  Therapy related •  Platelet dysfunction

•  Recognition of underlying process important for appropriate management of the patient


Questions & Discussion

Documents

Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid