class: center, middle, inverse, title-slide # Bleeding and Thrombosis: A double edged sword ## @ National Hematology Update XI, 2018 ###
Dr Suman Kumar
, Army Hospital (Research & Referral), New Delhi ### 15 April 2018 --- class: center, middle, inverse # Introduction --- # Background - Based on thrombotic potential - **Prothrombotic processes:** Prevent leakage of blood from vasculature to outside (bleeding) after its disruption - **Antithrombotic processes:** Prevent blood from getting clotted inside intact vasculature - **Intact vasculature:** _Antithrombosis >> Prothrombosis_ - **Disrupted vasculature:** _Prothrombosis >> Antithrombosis_ ??? Based on thrombotic potential, processes in the body can be divided into prothrombotic and antithrombotic. The purpose of prothrombotic processes are to prevent bleeding and purpose of antithrombotic processes are to prevent the blood from getting clotted inside intact blood vessel. When the vasculature is intact, there is a predominant antithrombosis and in the presence of disrupted blood vessel, prothrombosis is the predominant process. --- # Prothrombotic process (Components) - **Physiological:** - Tissue Factor, vWF (subendothelial layer) - Phospholipids (ubiquitous) - Activated Platelets - Coagulation Factors - Antifibrinolytic system - **Pathological:** - _ACTIVATED ENDOTHELIUM_ - _PRO-INFLAMMATORY STATE_ - Activating antibodies against platelets ??? The components of prothrombotic processes can either be physiological or pathological. Tissue factor, vWF from subendothelial layer, phospholipids which are present ubiquitously, activated platelets, coagulation factors and antifibrinolytic systems are physiological components and activated endothelium, pro-inflammatory states and activating antibodies against platelets are the pathological components of the prothrombotic processes. --- # Antithrombotic process (Components) - **Physiological:** - Intact endothelium - Circulatory antigoagulants (PC, PS, AT) - Fibrinolytic system - **Pathological:** - Inhibiting antibodies against coagulation factors, vWF, platelets - Thrombocytopenia - Abnormal platelet function (decreased activation/aggregation) ??? Similarly,intact endothelium, circulatory anticoagulants (PC, PS, AT)and fibrinolytic system are the physiological and inhibiting antibodies against coagulation factors, vWF, platelets, thrombocytopenia and decreased platelet functions are the pathological components of antithrombotic processes. --- class: center, middle, inverse # Indicators of (PRO/ANTI) THROMBOSIS ??? After learning about the processes, let us dwell into the indicators of the occurence of processes. --- # Components of the process of (pro/anti) thrombosis - Platelets & vascular integrity - Coagulation system - Anticoagulation system - (Anti) Fibronolytic system ??? As already told the slide shows the components of prothrombotic process. Lets discuss about indicators for each component separately. --- # Platelets and vascular integrity - **Platelet count** - **Bleeding time (standardised method)** - Platelet aggregation study ??? Platelet count, standardised bleeding time and platelet aggregation studies are routinely done indicators of platelet function and vascular integrity. -- - _Decreased platelet counts and increased bleeding time_ indicates **antithrombotic state** ??? Decreased platelet counts and increased bleeding time indicates antithrombotic state. -- - Thrombocytosis and decreased bleeding time: Relation with prothrombotic state **Not Clear** ??? On the contrary, there is no clear cut relation between thrombocytosis and decreased bleeding time. --- # Coagulation system - **Prothrombin Time (PT)** - **Activated Partial Thromboplastin Time (aPTT)** - **Thrombin Time (TT)** ??? PT, aPTT and TT are the routinely available indicators for coagulation system. -- - Fibrinogen level, Fibrinogen functional assay - Factor levels - Mixing with normal plasma to detect inhibitors ??? Fibrinogen level and functional assay, factor levels and inhibitor screening tests are more specialised indicators. -- - _Increased PT/aPTT/TT, decreased fibrinogen, decreased factor levels_ indicate **antithrombotic state** - Increased fibrinogen, increased factor levels: Relation with prothrombotic state **Not Clear** ??? Increased PT/aPTT/TT, decreased fibrinogen, decreased factor levels indicate antithrombotic state, but the opposite are not related in a clear cut manner with prothrombotic state. --- # Anticoagulation system - Protein C, Protein S, Antithrombin level/activity - Levels not clearly correlated with (pro/anti) thrombotic state in asymptomatic people ??? PC/PS and AT are the indicators which indicates the state of anticoagulation system. Unlike the previous two systems, the levels of the present indicators are not clearly related to pro or antithrombotic state in asymptomatic people. --- class: inverse, center, middle # Discrepancies between indicators ### Prothrombotic and antithrombotic manifestations in same patient ??? Diagnostic and therapeutic dillemma occurs when indicators indicating both pro and antithrombosis occur in the same patient at a given time. Our treatment decision depends on the predominant process occuring inside the patient at that time. The above is the main theme of presenting this talk. Now I will classify the situations and present them. --- class: center, middle, gray-background ## 1. Thrombocytopenia and thrombosis (Endothelial dysfunction) ??? The first sub group is thrombocytopenia with thrombosis which occurs due to endothelial dysfunction. The above the manifestation of a wide array of diseases. Now I would like to present on endothelial dysfunction. --- # Endothelial dysfunction - **Endothelial dysfunction** -> Activation and Aggregation of platelets - **Endothelial dysfunction** -> Pro-inflammatory and Prothrombotic state - .red[Leads to **Thrombotic Microangiopathy** = **Microangiopathic Hemolytic Anemia** (schistocytes, raised serum LDH) + **Thrombocytopenia** + **Thrombosis**] - Thrombocytopenia is not protective against clinically detectable thrombosis ??? Endothelial dysfunction is the culminating point of many a processes and it leads to activation and aggregation of platelets and creates a proinflammatory and prothrombotic state. Endothelial dysfunction usually lead to the syndrome of thrombotic microangiopathy which consist of microangiopathic hemolytic anemia, thrombocytopenia and thrombotic state. Microangiopathic hemolytic anemia is characterised by the presence of anemia, schistocytes, increased serum LDH and negative Direct antiglobulin test (Coombs test). In these processes, presence of thrombocytopenia is secondary to a prothrombotic process and so it is not protective against clinically detectable thrombosis. --- # Clinical situations of thrombocytopenia and thrombosis due to Endothelial Dysfunction - **Disseminated Intravascular Coagulation (DIC)** .red[(commonly has bleeding manifestations)] - **Thrombotic Thrombocytopenic Purpura (TTP)** .red[(can have bleeding manifestations)] - **Heparin induced Thrombocytopenia and Thrombosis (HITT)** - **Antiphospholipid Syndrome (APS)** ??? The above are the common clinical situations which follow the syndrome of endothelial dysfunction mediated thrombocytopenia and thrombosis. DIC and to some extent TTP, can have an anticoagulation state characterised by clinically detectable bleeding. --- # DIC - **Tissue factor** induced **coagulation cascade activation** -> Disseminated microcirculatory **fibrin** strands -> **TMA** - Compensated phase: **Prothrombotic** -> Decompensated phase: **Antithrombotic** - Increased D Dimer (indicator of fibrinolysis), thrombocytopenia, MAHA - Prolonged PT/aPTT/TT, decreased fibrinogen indicates **decompensated phase** - **Heparin indicated for compensated phase** -> Coagulation factors, platelet, fibrinogen replacement for decompensated phase ??? Increased tissue factor in circulation is the initiating factor in DIC. It leads to activation of coagulation cascade, leading to formation of fibrin strands in microcirculation, which leads to phenomenon of TMA. It has two sequential and overlapping phases: compensated, which is thrombotic and decompensated, which is antithrombotic. It is characterised by increased D dimer which indicates increased fibrinolysis, thrombocytopenia and MAHA. The late decompensated pahse is characterised by additional abnormalities like prolonged PT, aPTT, TT and decreased fibrinogen. Heparin as an anticoagulant is indicated in compensated phase. The disease progresses to decompensated phase when replacement of coagulation factors, fibrinogen and platelets is the mainstay of treatment. --- # Thrombotic Thrombocytopenic Purpura - **Decreased ADAMTS 13** (congenital deficiency, autoantibodies) -> **Ultrahigh molecular weight vWF** in circulation -> **Excess platelet activation** and endothelial activation -> **TMA** - MAHA, normal PT/aPTT - Disseminated microinfarctions: Renal Failure, CNS involvement - GI symptoms: abdominal pain, diarrhea; Cardiac involvement: arrhythmia, myocardial infarction - Petechiae, bleeding + - Severe thrombocytopenia common - **Patients with bleeding, before undergoing invasive procedure: Platelet transfusion indicated** ??? TTP is caused due to decreased circulatory ADAMTS 13 levels, which can be due to either decreased production in congenital cases and presence of inhibitory antibodies against ADAMTS 13 in most of the acquired causes. It leads to failure of degradation of ultralarge vWF, leading to excess platelet activation and aggregation and formation of microcirculatory platelet thrombus resulting in TMA. It has MAHA and normal coagulation parameters and characterised by widespread organ microinfarcts, predominantly involving kidneys, brain and to some extent GI tract, heart and rarely lungs. Severe thrombocytopenia is common and is characterised by mild to severe bleeding. The management involves replacement of ADAMTS 13 levels and extraction of antibodies by plasma replacement and exchange. Usually platelet replacement is contraindicated, but in patients with severe thrombocytopenia with bleeding and before underegoing invasive procedures, platelet transfusion can be done safely. --- # Heparin Induced Thrombocytopenia and Thrombosis - **Activating antibodies** against **Heparin (of larger molecular weight) + PF4 complex** -> **Endothelial and Platelet Activation** -> **Thrombocytopenia and Thrombosis** - Thrombocytopenia due to antibody mediated clearance by spleen and platelet consumption in thrombus - **No TMA** - Arterial thrombus - Thrombocytopenia is moderate - Non-heparin (UFH/LMWH) parenteral anticoagulation - **Patients with thrombocytopenia and bleeding, before undergoing invasive procedure: Platelet transfusion indicated** ??? It is an unusual immune mediated disease, in which the body develops IgG antibodies against complex of heparin (larger molecular weight) and PF4. The antibody is an activating type and leads to activation of platelets and endothelium. It does not lead to TMA and usually cause arterial thrombus. Thrombocytopenia is moderate and being a prothrombotic state, non heparin parenteral anticoagulation is continued. As with TTP, platelet transfusion is relatively contraindicated, till the time patient develops severe thrombocytopenia, and she bleeds or is about to undergo invasive procedure. --- # Antiphospholipid Syndrome - **Antibodies against antiphspholipids** (Cardiolipin, B2GP1) -> **Platelets and endothelium activation** -> **Thrombosis and thrombocytopenia** - **Mechanisms of thrombocytopenia:** Immune mediated destruction (ITP), TTP, HIT (in patients on heparin) - Primary or secondary - Thrombocytopenia is varied - Anticoagulation + - **Asymptomatic thrombocytopenia (~ 80000/cu mm):** only observation - **Severe thrombocytopenia (~ 10000/cu mm) and/or bleeding:** Platelet transfusion, irrespective of cause - **Underlying cause** of thrombocytopenia needs to be treated --- # Antiphospholipid Syndrome (contd) - **Safety of anticoagulation with thrombocytopenia in a patient with thrombosis** - Platelets > 50000/cu mm: safely anticoagulate - **Lower platelets and active bleeding: Increase platelets and then anticoagulate** --- class: center, middle, gray-background ## 2. Thrombocytopenia and thrombosis ??? Now I will discuss about the conditions where thrombocytopenia is not due to endothelial dysfunction, but due to the underlying disease process and thrombocytopenia marks state of antithrombosis. These patients may have separate prothrombosis processes running and can have thrombosis due to them. --- # Clinical conditions - Paroxysmal Nocturnal Hemoglobinuria - Connective tissue diseases (ITP with thrombosis) - Hematological malignancies ??? These are the clinical conditions. --- # Rules to follow - **Platelets >= 50000/cu mm:** Safely anticoagulate - **Platelets < 50000/cu mm:** Increase platelets to safe levels and then anticoagulate - **Actively bleeding due to thrombocytopenia:** Arrest bleeding by increasing platelets and then anticoagulate ??? In these patients, in addition to the treatment of underlying disorders, if platelets are above 50000 and they are not bleeding, it is safe to anticoagulate them. If platelets are less than 50000, we have to raise platelets above 50000 and then anticoagulate. Same approach is to be followed in an actively bleeding patient. -- - .red[**Antiplatelets are dangerous and to be avoided**] ??? Antiplatelets like aspirin are dangerous in these patients and should be avoided at all cost. --- class: center, middle, gray-background ## 3. Thrombocytosis and bleeding ??? Now I will discuss about the clinical condition where patient has thrombocytossis (marker of prothrombotic state), but has bleeding manifestations. --- # Essential thrombocytosis with Extreme thrombocytosis - Platelets >= 10,00,000/cu mm - Acquired vWD - **vWF activity assay to be done prior to starting Ecosprin** - **Active bleeding with thrombocytosis** - Replace vWF (cryoprecipitate, impure plasma derived Factor VIII concentrate) - Reduce platelets (Hydroxyurea) ??? One of the common occurence of the above phenomenon occurs in patients with ET who have platelets more than 1 million. These patients are more prone for bleeding manifestation as they develop acquired vWD due to increased consumption of vWF by the increased platelet mass. Before starting antiplatelets to patients belonging to the above subgroup, it is wise to get vWF activity assessed. In an actively bleeding patient, we have to replace vWF to him by transfusing cryoppt or impure plasma derived factor VIII concentrate and we have to reduce platelets by hydroxyurea. --- class: gray-background, middle # Conclusion - Managing antithrombotic and prothrombotic processes in same patient is a tricky one - Thorough understanding of underlying pahophysiology is a must for successful treatment --- class: inverse, center, middle # THANK YOU