Bleeding and Thrombosis in Hematological conditions

 Bleeding in patients with heme malignancies

1. Thrombocytopenia in heme malignancies

2. MPN

3. Tyrosine kinase inhibitors: Ibrutinib, dasatinib

4. APL

Low plt count in heme malignancies

1. PLADO Study: NEJM 2010

Adults had lower bleeding than children. Highest risk of bleeding were as follows:

unrelated donor allo> chemo for heme malignancies> auto/ related donor allo

> 25% bleeding if plt< 5K, 8% bleeding if plt count > 80K

2. Where did the 10K prophylactic threshold come from?

Wandt 2012 Lancet

The therapeutic strategy could become a new standard of care after autologous stem-cell transplantation; however, prophylactic platelet transfusion should remain the standard for patients with acute myeloid leukaemia

3. Hypoproliferative low plt more likely to bleed than ITP.

No linear relation between 10K in ITP compared to other causes.

Myeloproliferative neoplasms

U shaped phenomenon

Rate of bleeding is lowest between 200-600K. Above 600K or lower than 200K  higher bleeding noted.

> 600K--> Why is bleeding seen? Reasons below:

• acquired VWD. 
• reduced fibrinogen binding leads to acquired plt dysfunction. 
• endothelium in MPN contribute to bleeding phenotype. JAK2 mutations+ can be seen in the endothelium

Aspirin major hemorrhage 0.4% P vera low dose ASA, any bleeding 9%

What if the patient is already on aspirin, gets diagnosed with P vera or ET, and now has a new clot?

REVEAL study

Answer: stop asa, switch to anticoagulation if new VTE while on aspirin due to 3 fold increased risk of bleeding in MPN

Tyrosine kinase inhibitors in Heme malignancies

a. Ibrutinib: affects collagen mediated plt aggregation through glycoprotein receptors. Any bleeding 38%, risk of major bleed ( 3/4) 3%. Mantle cell has a higher overall risk of bleeding, unclear if this is due to ibrutinib.

Low plt count prior to starting ibrutinib was the greatest predictor of hemorrhage.

What about the need for aspirin or anticoagulation in patients with ibrutinib?

Aspirin is ok, 

AC does cause increased bleeding, but combination of Aspirin and AC significantly increases bleeding

b. Dasatinib: overall hemorrhage 25 %, rarely severe.

Most bleeding is GI bleeding.( lower GI 59%,22% UGI). Bleeding can happen even if plt >100K.

Like ibrutinib, dasatinib also inhibits plt aggregation mediated through collagen. But unlike ibrutinib, antiplatelet effects are reversible in 48 hr.

Acute promyelocytic leukemia

low plt, low fibrinogen, increased PT/PTT

5% intracranial hemorrhage

Increased fibrinolysis also noted. (Increased Annexin 2 on APL cancer cells overwhelms natural alpha-2 antiplasmin leading to fibrinolysis)

ATRA corrects the above mechanism by reducing Annexin 2.

Coagulopathy of APL management:

a. start ATRA empirically in the ER

b. Fibrinogen > 150 rather than 100 ( cryo or fibrinogen concentrates)

c. Plt target count > 20-30K

d. avoid invasive procedures

Hematological neoplasms and thrombosis

 Risk assessment models

ET- IPSET-T

Lymphoma Rome model

Myeloma SAVED and IMPEDE models

Khorana risk score over estimates risk of thrombosis in indolent lymphoma so does not work.

DOAC can be used based on studies such as ADAM-VTE, Caravaggio, Hokusai etc, but the percentage of heme malignancies was low.

Interestingly, heme malignancies:

- have more arterial thrombosis

- thrombosis at unusual sites

- can be due to treatment leading to thrombosis

Hypereosinophilic syndrome

If eosinophil count > 6K and duration of disease > 12 months, higher risk of thrombosis

1/2 are arterial, 1/2 venous events

40% can have thrombosis

May benefit from prophylaxis in ambulatory setting.

No increased risk of bleeding.

Chronic MPN

JAK2 and MPL higher risk of thrombosis, compared to wildtype

Arterial thrombosis 60-70%

CNS, splanchnic 15%

Platelet counts do not correlate with thrombosis, but rather WBC count > 15K correlates with thrombosis

Ruxolitinib rx reduced risk of VET ( 1.2% versus 8% best available rx)

Hct < 45 and aspirin 100 mg ( RR0.42) improves thrombosis free survival(ECLAP study)

AIRPORT MPN- ongoing study comparing apixaban versus aspirin

JAK2 mutated CHIP

25% with thrombosis, consider aspirin prophylaxis

CML

Is not prothrombotic, but imatinib ( 1% at 1 yr), nilotinib( 6%) ponatinib ( 25%).

Aspirin or plavix for prophylaxis. Consider dose reduction of ponatinib.

MDS 5 q minus

Platelets are higher, rx with lenalidomide should be prophylaxed

ALL

Risk factor: CVC, age, L asparaginase

Over 30 yr 40% risk of thrombosis with L asparaginase

CNS thrombosis in regimens with L asparaginase

Lymphoma

Risk of thrombosis < 5% HL, indolent

15% NHL

Primary mediastinal B cell with bulky masses 70% have thrombosis at presentation

Primary CNS lymphoma also with high VTE

Compression is an important factor, 95% happen in the first month

Rome score is the best for lymphoma

Three risk levels: Highest risk ( CNS involvement), intermediate ( poor PS, bulky disease), everything else is standard risk.

No guidelines for prophylaxis

MGUS:

Not associated with increased risk of  Thrombosis, except light chain MGUS 

Myeloma

use risk stratification tools liked SAVED and IMPEDE score.

DOAC can be used for prophylaxis ( high risk) ,aspirin for low risk. DOAC not approved but US phase IV trial.

Pearls:

1. Elevated PT/PTT in non APL leukemia

- there is no correlation in a nonbleeding patient

- no need to provide FFP in nonbleeding patient without liver issues

2. Coronary angioplasty in Ibrutinib? If antiplatelet or AC needed, change Rx for CLL? Consider switching to acalabrutinib or zanubrutinib.

3. ALL : LMWH versus heparin ( UFH with antithrombin)

Coagulopathy of L aspariginase therapy: Guidance statement ISTH

4. Empiric antifibrinolytic therapy is not recommended in APLA thrombosis in CNS.

5. Afib in MPN: if non valvular Afib, ok to start 

6. Stopping TKI before surgery: Dasatinib is reversible, Ibrutinib is not reversible ( covalently binds) platelets and inhibits collagen induced aggregation

7. What anticoagulation if thrombocytopenic patients with heme malignancy?