1. Thrombocytopenia Jason Corbeill PA-C

2. Platelet facts Chunks of cytoplasmic fragments of a megakaryocyte (in bone marrow) Chunks of cytoplasmic fragments of a megakaryocyte (in bone marrow) Surface contains receptors Surface contains receptors Cytoplasm contains secretory granules Cytoplasm contains secretory granules Lives 8-10 days Lives 8-10 days 1/3 is sequestered in spleen (emergency pool) 1/3 is sequestered in spleen (emergency pool)

3. Platelet function 1. ACTIVATES and releases messenger molecules/effector enzymes 1. ACTIVATES and releases messenger molecules/effector enzymes 2. ADHERES to area of broken vessel utilizing Von Willebrand factor. 2. ADHERES to area of broken vessel utilizing Von Willebrand factor. 3. Recruits additional platelets (AGGREGATION) with fibrinogen binding to platelet surface receptors. 3. Recruits additional platelets (AGGREGATION) with fibrinogen binding to platelet surface receptors. 4. PROMOTES thrombin production 4. PROMOTES thrombin production

4. The numbers Normal is 150-400k Normal is 150-400k Below 125 or so is concerning Below 125 or so is concerning Below 50k is very concerning and surgeries should be postponed Below 50k is very concerning and surgeries should be postponed Below 10-20k requires PLT transfusion-risk for spontaneous bleed. Below 10-20k requires PLT transfusion-risk for spontaneous bleed. Refer to hematologist Refer to hematologist

5. Signs/Symptoms of low platelets Bleeding in areas of weak structural support (mucous membranes) Bleeding in areas of weak structural support (mucous membranes) Bleeding in areas of dependency (ankles) Bleeding in areas of dependency (ankles)

6. Signs/Symptoms cont. Petechiae—small 2-5mm deep red – purple flat, non palpable lesions usually in dependent areas Petechiae—small 2-5mm deep red – purple flat, non palpable lesions usually in dependent areas Purpura—areas of confluent petechiae— can be a few centimeters Purpura—areas of confluent petechiae— can be a few centimeters “blood blisters”—purpura in mouth “blood blisters”—purpura in mouth Gingival bleeding Gingival bleeding menorrhagia menorrhagia

7. Signs/Symptoms cont GI bleeding GI bleeding Easy bruising Easy bruising Hematuria Hematuria CNS bleed CNS bleed

8. 3 mechanisms causing a low platelet count : Accelerated destruction Accelerated destruction Impaired production Impaired production Abnormal distribution (hypersplenism) Abnormal distribution (hypersplenism)

9. Differential of thrombocytopenia due to accelerated destruction EDTA clumping—lab abnormality EDTA clumping—lab abnormality ITP-idiopathic (immune) thrombocytopenic purpura and it’s mimics. ITP-idiopathic (immune) thrombocytopenic purpura and it’s mimics. HUS-TTP HUS-TTP DIC/sepsis DIC/sepsis Alcohol induced Alcohol induced Hereditary Hereditary HIT (heparin induced thrombocytopenia) HIT (heparin induced thrombocytopenia)

10. A word about true ITP Caused by splenic destruction of PLT due to autoantibody (immune response) that views the platelet as foreign Caused by splenic destruction of PLT due to autoantibody (immune response) that views the platelet as foreign Red and white cells are normal Red and white cells are normal Bone marrow is normal Bone marrow is normal No splenomegaly No splenomegaly No lymphadenopathy No lymphadenopathy Peripheral smear is normal (exc low PLT) Peripheral smear is normal (exc low PLT)

11. Mimics of ITP via immunologic pathway Lupus Lupus Lymphoma Lymphoma CLL CLL Infections (including HIV) Infections (including HIV) Sarcoidosis Sarcoidosis Solid tumors Solid tumors Mononucleosis Mononucleosis Drugs—quinine, quinidine, gold, heparin, sulfonamides Drugs—quinine, quinidine, gold, heparin, sulfonamides

12. Treatment for true ITP Prednisone 1mg/kg Prednisone 1mg/kg IVIG IVIG WinRho if Rh D positive WinRho if Rh D positive Splenectomy Splenectomy Vincristine Vincristine Cyclophosphamide Cyclophosphamide Rituxan Rituxan Romiplostim (Nplate) Romiplostim (Nplate)

13. A word about HUS-TTP Hemolytic Uremic Syndrome-Thrombotic Thrombocytopenic Purpura Precipitated by an antibody causing excessive VWF multimers leading to excessive platelet aggregation Precipitated by an antibody causing excessive VWF multimers leading to excessive platelet aggregation Small vessel endothelial damage is likely precipitationg factor Small vessel endothelial damage is likely precipitationg factor Platelets are used up in forming microscopic thrombi Platelets are used up in forming microscopic thrombi Microangiopathic hemolytic anemia as result Microangiopathic hemolytic anemia as result

14. Signs/symptoms HUS-TTP Neurological deficits—confusion, etc Neurological deficits—confusion, etc Renal failure Renal failure Thrombocytopenia Thrombocytopenia Elevated LDH Elevated LDH Anemia Anemia Schistocytes on peripheral smear Schistocytes on peripheral smear Helmet cells/burr cells on peripheral smear Helmet cells/burr cells on peripheral smear Purpura/petechiae Purpura/petechiae

15. HUS-TTP treatment Plasmapheresis--Plasma exchange of 40mL/kg daily until PLT > 100k and fall in LDH. Plasmapheresis--Plasma exchange of 40mL/kg daily until PLT > 100k and fall in LDH. Supportive care Supportive care No platelet transfusion!!! No platelet transfusion!!!

16. Special Exam Slide HELLP syndrome HELLP syndrome –Hemolysis Elevated Liver enzymes Low Platelets –Preeclampsia/eclampsia –Recover after delivery –May need plasmapheresis

18. Many words about DIC (disseminated intravascular coagulation) Under normal circumstances… Under normal circumstances… –Tissue Factor released at site of injury –Leads to formation of thrombin at site of tissue injury –Leads to activation of platelets and coagulation cascade at site of tissue injury

19. DIC –Leads to local thrombin->fibrinogen->fibrin plug –Plasmin eventually dissolves plug –Whole process is tightly regulated by inhibitory proteins (antithrombin, Tissue factor pathway inhibitor)

20. DIC In DIC however.. In DIC however.. –Tissue factor released at injury site –Leads to formation of thrombin at site of tissue injury and throughout the entire vasculature –Leads to activation of platelets/coagulation cascade throughout the entire vasculature –Leads to platelet, fibrin deposition throughout entire vasculature.

21. DIC Plasmin, antithrombin, TFPI unable to keep up with out-of-control coagulation cascade. Plasmin, antithrombin, TFPI unable to keep up with out-of-control coagulation cascade. Results in tissue ischemia, consumption of platelets, fibrinogen, coagulation factors V and VII, prothrombin. Results in tissue ischemia, consumption of platelets, fibrinogen, coagulation factors V and VII, prothrombin. Leads to bleeding as all components of clotting cascade used up in useless clots. Leads to bleeding as all components of clotting cascade used up in useless clots.

22. DIC—but wait, there’s more! Not only does one have an out-of-control activation of the clotting cascade in DIC but there is also a second component. Not only does one have an out-of-control activation of the clotting cascade in DIC but there is also a second component.

23. DIC-Fibrinolysis Eventually, plasminogen makes plasmin and the widespread fibrin clots begin to break down Eventually, plasminogen makes plasmin and the widespread fibrin clots begin to break down –Releases fibrin split (degradation) products –FSP enhances bleeding by inhibiting platelet aggregation –Plasmin also breaks down remaining circulating clotting factors and fibrinogen worsening bleeding even more.

24. DIC labs So, lab values should show both a consumptive bleeding diathesis AND a fibrinolytic process. So, lab values should show both a consumptive bleeding diathesis AND a fibrinolytic process. –prolonged PT (intrinsic pathway/PTT (extrinsic pathway) –Low fibrinogen (it’s being used to make fibrin) –Low platelets –Elevated FSP/D-dimer –Low antithrombin

25. DIC—why? Release of tissue factor into circulation Release of tissue factor into circulation Extensive vascular endothelial injury exposing tissue factor Extensive vascular endothelial injury exposing tissue factor Enhanced release of tissue factor by monocytes in response to various cytokines/endotoxins. Enhanced release of tissue factor by monocytes in response to various cytokines/endotoxins.

26. DIC-Why? Infections—bacterial/viral Infections—bacterial/viral –Acute uncompensated DIC Malignancy—Trousseau’s syndrome (chronic compensated DIC) Malignancy—Trousseau’s syndrome (chronic compensated DIC) –More thrombotic than bleeding Aortic aneurysms/hemangiomas Aortic aneurysms/hemangiomas Abruptio placentae/retained dead fetus Abruptio placentae/retained dead fetus Trauma Trauma

27. DIC-Why? Snake bites Snake bites Heat stroke Heat stroke HELLP HELLP

28. DIC signs/symptoms So patients with DIC should show signs/symptoms leading to release of tissue factor and the resultant widespread thrombus formation and bleeding diathesis. So patients with DIC should show signs/symptoms leading to release of tissue factor and the resultant widespread thrombus formation and bleeding diathesis.

29. DIC signs/symptoms Bleeding—from everywhere Bleeding—from everywhere Septic shock Septic shock Renal failure Renal failure Respiratory failure—pulmonary hemorrhage/ ARDS Respiratory failure—pulmonary hemorrhage/ ARDS Hepatic dysfunction Hepatic dysfunction CNS changes CNS changes Evidence of cancer/acute promyelocytic leukemia Evidence of cancer/acute promyelocytic leukemia

30. DIC-Treatment Underlying cause Underlying cause Plasma transfusion ? Plasma transfusion ? Platelet transfusion—only if severe bleeding? Platelet transfusion—only if severe bleeding? ? Heparin to promote antithrombin- thrombin binding. ? Heparin to promote antithrombin- thrombin binding. ? Antithrombin infusion ? Antithrombin infusion

31. Thrombocytopenia due to impaired production Invasion of marrow by malignant cells Invasion of marrow by malignant cells Bone marrow hypoplasia Bone marrow hypoplasia –Due to chemo, drugs  Chloramphenicol, gold, phenytoin, sulfonamides

32. Thrombocytopenia due to impaired production Treatment Treatment –Platelet transfusions –Treat underlying cause –Hold offending drug –Amicar—plasmin inhibitor

33. Thrombocytopenia due to abnormal distribution Hypersplenism Hypersplenism –Normally 30% of platelets reside in the spleen –In cases of splenomegaly the spleen will sequester more platelets, resulting in a decrease in circulating platelets –Caused by portal hypertension/lymphoma

34. Thrombocytopenia due to abnormal distribution Treatment of hypersplenism: Treatment of hypersplenism: –Splenectomy –Remember to vaccinate for encapsulated organisms prior to splenectomy

35. Cases 1. So, 35 y/o female truck driver presents to outpatient clinic with bruises. 1. So, 35 y/o female truck driver presents to outpatient clinic with bruises.

36. Cases 2. 55 y/o male in ED s/p MVA with multiple open fractures. Postoperatively develops PLT 15k, bleeding from everywhere. 2. 55 y/o male in ED s/p MVA with multiple open fractures. Postoperatively develops PLT 15k, bleeding from everywhere.

37. Cases 45 y/o female teacher admitted with plt count 20. 45 y/o female teacher admitted with plt count 20.