Benign Hematology Consult Cases Annemarie E. Fogerty, M.D.

Clinical Director, Hematology Director, Reproductive Hematology Co-Medical Director, Anticoagulation Management Services

September 2019 • No financial disclosures relevant to this presentation Case 1: 42yoF presenting with shortness of breath and productive cough

Initial presentation • Vitals: T 99.2, HR 133, BP 145/75, RR 33, 92% sat on RA, improves to 95% with 2L 3 hours into presentation…

Admitted to MICU • Vitals: T 100.8 , HR 140, BP 187/45, RR 45, 92% sat on 100% FiO2, 60L high-flow face mask 3 hours into MICU admission (6 hours from presentation) …

• Vitals: Persistently febrile, T up to 105 • Respiratory status: O2 sat 80’s despite paralytics/vent adjustment, FiO2 1.0, inhaled flolan Case 1, continued: 4am in the MICU

• Extracorporeal membrane oxygenation (ECMO) is initiated ECMO has been shown to improve patient survival in acute respiratory distress, but associated with substantial hematologic derangements

Lancet 2009; 374:1351 How does ECMO work?

• An artificial lung (membrane oxygenator) oxygenates blood, which is returned to the circulation via the vein (VV) or artery (VA) – VV: artificial lung is in series with native lung, replacing lung function – VA: artificial lung is in parallel with native lung, replacing both heart and lung function • Blood exposure to the large ECMO circuit area – Initiates the contact factor pathway – Activates platelets – Induces an inflammatory response • Anticoagulation is necessary to prevent clotting the circuit – Intensity of anticoagulation, PTT/ACT have not correlated with clinical outcomes, or risk for bleeding/thrombosis Brodie D, Bacchetta M. N Engl J Med 2011;365:1905-1914. In a patient managed with UFH on ECMO, the optimal laboratory test to assess the degree of anticoagulation is:

A. PTT, traditional therapeutic target B. ACT, target 180-220s C. Anti-Xa D. Thrombin time PANEL QUESTION

• Optimal laboratory test to assess degree of anticoagulation in a patient managed with ECMO and UFH ACT PTT

• Rapid, point of care test • Widely available • Most useful at very high heparin • Provider familiarity concentrations (when PTT is >assay) • Nonspecific to heparin • Nonspecific to heparin • Influenced by factor/fibrinogen deficiency, • Influenced by hypothermia, lupus antiphospholipid antibody thrombocytopenia, impaired platelet function, factor/fibrinogen deficiency Anti-Xa Thrombin time

• Direct measure of heparin effect • Exquisitely sensitive to presence of heparin, thus not an appropriate measure • Can be influenced by hyperlipidemia and for therapeutic heparin levels hyperbilirubinemia • Not widely/routinely available

12 3.7 > 32% < 126K. PTT 89.6, ACT 202s

The ECMO circuit continues to clot, despite increasing UFH doses. The next best intervention is:

A. Initiate antiplatelet therapy B. Initiate FFP therapy C. Transfuse RBCs D. Assess hypercoagulable panel E. Switch to alternative anticoagulant Case 1, continued

• Day 7 into use of ECMO circuit, a persistently falling platelet count is appreciated: – D1 123 -> D2 116 -> D3 108 -> D4 87 -> D5 64 (transfused platelets) -> D6 88 -> D7 57

The next best intervention is: A. Transfuse additional platelets B. Discontinue UFH and reassess platelet count in 12H C. Discontinue UFH in favor of an alternative anticoagulant D. Alternate antibiotic regimen in favor of less BM suppressive agents Case 1b, continued

• Decreasing platelet count concurrent to heparin therapy merits consideration of heparin-induced thrombocytopenia (HIT) – In this case the 4T test predicted high probability; PF4 Ab returned positive (OD >2) – Patient was transitioned to bivalirudin (direct thrombin inhibitor) via standard PTT sliding scale • Should bivalirudin have been used from the start? – Would have avoided the thrombotic complications of HIT complications … BUT • Same challenges of PTT monitoring • Unlike heparin (and warfarin), DTIs do not inhibit the contact pathway (of particular concern with use of ECMO) Case 1, summary

• ECMO was decannulated on hospital day 18 • Patient continued to recover and was ultimately discharged to rehab on day 27 • Surveillance for thrombosis in HIT revealed R femoral vein thrombosis: – Continued on DTI until ECMO was decannulated – Transitioned to warfarin once platelet count was >150K (intended for 6 month course for provoked event) • Total blood component support during hospitalization: – 28 RBCs, 21 platelet doses, 36 FFP, 24 cryo A word on contact pathway inhibitors

• The goal of anticoagulation is to attenuate thrombosis without perturbing hemostasis • FXIa contributes to VTE/CAD, while contributing minimally to hemostasis • Attempt to block FXIIa mediated FXI activation WIHOUT inhibiting FXI’s activation by thrombin may serve as “the perfect model” of anticoagulation Buller HR; Weitz JI. Factor XI Antisense Oligonucleotide for Prevention of Venous Thrombosis. NEJM. Jan 2015.

VTE Bleeding FXI-ASO 27% 3% 200mg sc* FXI-ASO 4% 3% 300mg sc* Enoxaparin 30% 8% 40mg sc qd** * Started 36d before surgery ** Started peri-operatively Lorentz, CU; Gailani D. Contact Activation Inhibitor and Factor XI Antibody, AB023, Produces Safe, Dose-Dependent Anticoagulation in a Phase 1 First-In-Human Trial. Arter , Thromb, Vasc Biol. 39(4). 2019 PANEL QUESTION

• Would you consider drugs that specifically inhibit the contact pathway as the “ideal” anticoagulants for ECMO patients? Case 2

37yoF G3P0020 at 32w referred for platelets of 68K and no bleeding. (WBC 13.9 > HCT 27.6 < Plt 68K, MCV 78) • Reports general malaise and “coming down with a cold” mild headache. No cough or fevers. No GI complaints. • PMH: No bleeding/bruising. Miscarriages: weeks 6 and 11 • FH: no heme disorders or malignancies • Exam: Well appearing, afebrile. 128/90, HR 104, RR 26 – no mucocutaneous bleeding, bruising, enlarged nodes or rash – Soft flow murmur; lungs CTA without wheeze – Gravid, no HSM palpated – Trace pedal edema bilaterally; no palpable cords Case 2, data (13.9>27.6<68, MCV 78)

– ALT/AST 48/38, Alk Phos 194 – TB/DB 1.9/0.4 – LDH 428 – Haptoglobin < 6 – Reticulocyte count: 3.9% – Bun/Cr 12/0.87 – PT/PTT normal – Iron saturation 9% – +proteinuria Case 2 (13.9>27.6<68, MCV 78)

The best next intervention is: A. Initiate plasma exchange B. Initiate eculizumab therapy C. Initiate steroids and rituximab and repeat CBC in 1 week D. Urgent fetal delivery E. Bone marrow biopsy TMA: TTP

• 5-10% of all cases of TTP occur in pregnancy (increased VWF production, decreased ADAMTS13 levels) • ADAMTS13 <10% (congenital or acquired) • Usually 2nd/3rd trimesters (can be in 1st) • High risk for IUFD • Treatment: Plasma exchange (PLEX) – Standard therapy for non-pregnant TTP – Close fetal monitoring TMA: aHUS

• More typically postpartum; predilection for kidneys – Suspect if MAHA, ADAMTS13 is normal/only slightly reduced • Complement deregulation leading to increased activity of the alternative complement pathway. Can see mutations in: – Complement regulatory proteins: Factor H, Factor I, CD46 – Complement-activating genes: Factor B or C3 • Treatment: – Eculizumab (humanized monoclonal Ab inhibitor of C5, preventing formation of the terminal membrane attack complex) • *case reports of safe use in pregnancy – Patients may need RBCs, renal replacement therapy Diseases specific to pregnancy Major treatment = fetus delivery • Pre-eclampsia (3-14% of all pregnancies). Most common in first pregnancy (with same partner)

– HTN (140/90) and proteinuria after 20 weeks (HAs, rapid weight gain, limb edema)

– Defect of trophoblasts to express adhesion molecules, VEGFs and their receptors

– Feto-placental ischemia develops

• HELLP (0.5-0.9% of pregnancies). Fall in plt count often precedes LFTs abnormalities

– Early presenting signs include shoulder/neck, upper body pain, malaise, N/V, HA

– Smear can be similar to TTP (but in TTP, usually don’t see liver derangement).

• Send ADAMTS13 (which will be normal/slightly depressed)

• AFLDP (5/100,000 pregnancies). DIC is the hallmark; microvesicular steatosis of liver biopsy

– Maternal mortality 18%; fetal mortality 23%

– AST/ALT can be 1000: RUQ/epigastric pain, coagulopathy, N/V, headache

– Maternal heterozygote for long chain 3 hydroxyacyl-CoA dehydrogenase deficiency (LCHAD) . Worse if maternal heterozygote is carrying fetal homozygote

– Maternal liver disease may not be reversible Case 2, management

• ADAMTS13: <5% – Inhibitor assay negative • Admitted to obstetrics: – Platelets normalized after 2 PLEX sessions – HCT continued to fall, despite normalization of lytic parameters – Ab CT was negative for RP bleed – Inappropriate response to RBC transfusion – Ultimately delivered via emergent cesarean on hospital day 7 for fetal distress • Placental abruption evident during surgery • Live male born with mild respiratory distress; normal platelet count The best way to decrease the risk for recurrent TTP in future pregnancies in this patient is:

A. A course of rituximab once stabilized postpartum B. Use of aspirin in future pregnancies C. Plan to initiate PLEX in future pregnancies D. Plan for simple FFP transfusion in future pregnancies Pregnancy-Associated TTP

• Increased risk of flare due to increased VWF • This patient had no demonstrated anti-ADAMTS13 antibody – Congenital TTP (cTTP); Upshaw Shulman Syndrome • Recurrent thrombocytopenia with microangiopathic hemolytic anemia • Onset: half first 2 years; half > 20 years • Once symptoms start, rarely stop • Precipitants: etoh, pregnancy, surgery • Chronic sequelae: renal, neurological, accelerated atherosclerosis (mice) Upshaw-Schulman Syndrome

• Autosomal recessive homozygote or compound heterozygotes • 140 mutations (60% missense; 20% deletions/insertions)

Treatment: • Plasma infusion/exchange acutely (until diagnosis is confirmed) • FFP every 2-3 weeks (T1/2=2-3 days) • Partly purified ADAMTS13 (plasma derived VIII compounds like Koate) • Recombinant ADAMTS13 Of no use: Rituximab; corticosteroids Dangerous: Platelet transfusions PANEL QUESTION

• For the more commonly encountered ACQUIRED TTP, are you routinely using rituximab for all cases to decrease risk of recurrent flare? Case 3

• 81yoF readmitted 4 weeks after initial hospitalization with progressive lower extremity edema and anorexia • Previously admitted for management of non-bacterial endocarditis, complicated by multiple subacute cerebral infarcts • PMH: HTN, HL, hypothyroid, anxiety/depression, CKD • FH: 3 sisters with breast cancer • Hematology is consulted for abnormal labs: • Ddimer >10K, • plt 105K • fibrinogen < assay 24H into admission • Antiphospholipid antibodies negative Imaging shows bilateral hydronephrosis and an RP mass Labs reveal an elevated CEA and CA125

Patient requires diagnostic biopsy of the RP mass. How can you best optimize her hematologic abnormalities?

A. Transfuse FFP, cryo and platelets B. Administer novo7 and vitamin K C. Administer cryo and unfractionated heparin D. Infuse an antifibrinolytic (tranexamic acid or aminocaproic acid) E. Defer biopsy until DIC is better controlled with 1-2 cycles chemotherapy for presumed malignancy PT

PLT

DD >10,000

FIB

PTT

admission cryo PT

PLT

DD >10000 FIB

PTT

admission cryo heparin Case 3, continued

• Day 5: patient was given transfusions of cryo • Day 7: IR-guided biopsy of the RP mass • Day 8: unfractionated heparin was started for persistently abnormal coagulation parameters despite maximum transfusion support

The mesenteric soft tissue biopsy on day 7 revealed metastatic adenocarcinoma most likely of (triple-negative) breast origin Why is cancer hypercoagulable?

• Tissue factor (TF) is increased (main activator of factor VII/extrinsic pathway) • often expressed on tumor cells • proinflammatory cytokines (IL-6, IL-1, TNFa) stimulate monocytes and endothelial cells to express TF (up to 125 fold) • Cancer procoagulant activates factor X • A cysteine proteinase found in malignant cells

• Fibrinolysis is suppressed (PAI-1 upregulated) • Natural anticoagulants (AT3, PC and TFPI ) are all decreased • Chronic DIC Transfusions Recommendations for DIC *without strong evidence*

• FFP 7-15 ml/kg (ie, 70 kg patient = 2-5 units FFP) • replaces consumed coagulation factors, natural coagulation inhibitors (PC, PS, ATIII) and plasmin inhibitor (antiplasmin)

• Cryoprecipitate if fibrinogen < 100 mg/dl • 1u FFP raises fibrinogen by ~10 mg/dl • 1u cryo has ~50% fibrinogen as FFP, but in a much smaller volume

• 1 u platelets/10 kg to replace consumed platelets if <50,000 • 6 units platelets raises platelet count by ~30 k/ul Transfusions often fail to increase factors/platelets in severe DIC in bleeding patients Role of UFH in DIC

• Large-vessel thrombosis • Dermal or digital ischemia (e.g. Purpura fulminans) • Chronic DIC of malignancy, when clinically significant • Purpose is to inhibit thrombin and other coagulation factors to interrupt deposition of thrombi • May enhance bleeding Heparin Dosage in DIC

• Controversial and variable • Full therapeutic dose for large-vessel thrombosis (eg. DVT, PE) • 300-700 units/hour often recommended as initial dose for DIC of malignancy without large vessel thrombosis • Low molecular weight heparin is an alternative, but insufficient studies to guide dosing The chief benefit of UFH when used in DIC is: A. Serves as an anticoagulant B. Suppresses thrombin C. Suppresses tissue factor pathway inhibitor (TFPI) D. Increases circulating platelets by releasing platelets from the endothelial wall PANEL QUESTION

• Do you routinely use UFH in management of DIC?