Ute Hasiba

Asymptomatic Structural Liver Disease in Hemophilia

In a study of persistent abnormalities of liver-function tests in hemophilic patients deficient in factor VIII or IX and treated with factor VIII or IX concentrates, we examined 14 liver biopsies from 13 anti-HBs-positive patients. None had any symptoms of liver disease. All had chronically abnormal levels of alanine aminotransferase. Histologic studies showed chronic persistent hepatitis in eight patients, chronic active hepatitis in four and fatty infiltration with portal fibrosis in one. Indirect immunofluorescence of antiserums containing anti-HBs or anti-HBc (or both) revealed nuclear and cytoplasmic fluorescence in the hepatocytes of eight of 12 patients. Specificity testing of these antiserums confirmed that hepatitis B viral markers are present in the hepatocytes of these anti-HBs-positive patients. These histologic derangements are probably related to frequent treatment with blood products obtained from multiple donors and to the persistance of hepatitis B virus in hepatocytes despite the presence of circulating anti-HBs.

Corticosteroid Therapy for Acquired F VIII:C Inhibitors

The appearance of an acquired inhibitor to factor VIII clotting activity (F VIII:C) in a non‐haemophiliac is an uncommon phenomenon; but, when it occurs, represents a difficult therapeutic problem. Cyclophosphamide has been the most frequently used form of therapy while corticosteroids, when used alone, have been felt to be ineffective. During the past 25 years, 18 of these patients have been evaluated in Pittsburgh. Their mean age was 63·7 years. Nine were female and nine male. Sixteen of the 18 received corticosteroids as their primary form of therapy. Eleven of the 16 (69%) showed clinical and laboratory improvement. Seven of the 11 had a complete response and the remaining four a partial response. Five patients demonstrated no improvement with corticoid therapy. The time to response varied from 4 to 41 d (x̄ 15·8). It was concluded that corticosteroids when used alone provide therapeutic results comparable to immunosuppressive therapy in the treatment of acquired inhibitors to F VIII:C and therefore represent a therapeutic alternative to immunosuppressive agents.

Chronic Liver Dysfunction in Multitransfused Hemophiliacs

Liver dysfunction and exposure to the hepatitis B antigen were assessed by serum transaminase (SGPT and SCOT) levels and HBsAg and anti‐HBs during a three year period in a group of 118 patients with factor VIII or factor IX deficiency. The 107 HBsAg negative patients were divided into four groups according to their mode of therapy. Persistently abnormal transaminase values were present in 51 per cent of patients with a large exposure to factor VIII concentrates, in 43 per cent with a small factor VIII exposure and in 37 per cent exposed to prothrombin complexes. This was contrasted with abnormalities in 8 per cent of patients treated only with cryoprecipitate. The incidence and degree of serum transaminase abnormality appeared independent of a past history of jaundice. All patients without persistent antigenemia who had been treated with pooled plasma products showed antibodies to HBsAg. High titer anti‐HBs prior to initial fraction therapy appeared protective against jaundice. The eleven patients with persistent antigenemia had significantly higher transaminase levels than the HBsAg negative group.

DiC-like syndrome after envenomation by the snake, Crotalus horridus horridus.

After envenomation by the timber rattlesnake (Crotalus horridus horridus) a young man showed massive swelling and ecchymoses of the involved extremity, generalized petechiae and a large hematoma of the left upper eyelid. Two weeks later he was completely well. The first blood sample was incoagulable and showed high titers of fibrin split products by the MISFI and staphylococcal clumping tests. Immounoelectrophoresis showed both D and E fragments, but only D was present at 18 hours. The profound thrombocytopenia and hypofibrinogenemia gradually improved, and split products disappeared. In vitro the venom had thrombin-like activity, clotting fibrinogen or plasma and aggregating platelets. These activities could be inhibited by antivenom but not by heparin. There was no evidence that thrombin formation was actually involved: hence, the syndrome is called DIC-like.

The high risk of chronic liver disease in multitransfused juvenile hemophiliac patients.

Eighty-seven asymptomatic children with either hemophilia A or B were treated before they were 21 years of age. Seventy-two received factor concentrates and 15 cryoprecipitate or fresh-frozen plasma only. Thirty-two of the 72 in the former group have persistently elevated alanine aminotransferase values compared to one of 15 in the latter group. In a subset of children treated with factor concentrates before five years of age, four of seven are chronically HBsAg positive. Liver biopsies were performed in 13 of the 32 asymptomatic patients with abnormal ALT values in the fraction group. It is recommended that until further data become available, children with mild hemophilia and all less than 5 years of age should receive only cryo or FFP.

Comparative hematology and coagulation: Studies on rodentia (Rats)

Blood from adult male Wistar rats clotted rapidly in glass or siliconized tubes; the clots retracted and did not lyse. The serum prothrombin, plasma prothrombin and activated partial thromboplastin times were shorter than those of normal humans. In contrast, the thrombin and reptilase times were longer than those of normal human plasma, due apparently to the presence of a low-grade thrombin inhibitor in rat plasma. Coagulation factors, X, VIIIR:vW and IX assayed lower in rat than human plasma, while factors VIII:C and anti-thrombin III were higher. Values for other coagulation factors (II, V, VII, XI, XII and Fletcher) fell within the human range. Platelets were small and numerous. They aggregated well with ADP but poorly or not at all with collagen, ristocetin, thrombin, epinephrine, arachidonic acid and pig or bovine plasmas. Leukocytes numbered 4-8 X 10(3) cells/mm3, a near human range and were predominantly lymphocytic. Erythrocytes were small (MCV = 56-60 fl) and numerous (5.5-6.4 X 10(6) cells/mm3).

Liver dysfunction in Pennsylvania's multitransfused hemophiliacs

Transaminase values [alanine amino transferase (ALT) and aspartate amino transferase (AST)] and markers for hepatitis B were serially determined in 558 hemophiliacs exposed to blood products. Hepatitis B surface antigen (HBsAg) persistent for over 12 months was present in 6% of the patients. Antibody to hepatitis B surface antigen (anti-HBs) was noted in 90% of the 259 patients treated with factor VIII or IX concentrates but in only 49% of the 43 patients treated with fresh frozen plasma (FFP) or cryoprecipitate. Persistently abnormal transaminase values were noted in 31% of the patients treated with commercial concentrates but in only one (2%) of the patients exposed to cryoprecipitate or FFP. This difference continued even when the two groups of patients were matched for the amount of blood products, up to 50, 000 units, which they had received in the study period. In the concentrate-treated patients, no correlation could be found between transaminase values and the number of units of factor VIII or IX they had received during the six years of the study (1973–1978).

A hemophiliac dog colony: Genetic studies and coagulation findings in hemophiliac and normal dogs

A colony of hemophiliac dogs was developed as descendants of a single affected Pomeranian. Over a 13 year period, a total of 29 hemophiliac dogs survived to the age of 6 months or longer. Eleven were female and 18 were male. All five of the possible matings in a sex-linked recessive inheritance pattern were accomplished and the offspring fell into the expected sex and disease groups. Twenty-one dogs died from untreated hemorrhages which usually occurred in loose tissues or body cavities during the night. Clinically, there were no hemarthroses but 22 other hemorrhages responded promptly to treatment with dog cryoprecipitate. Coagulation studies showed that the hemophiliac dogs averaged about 0.23 U/ml equivalents of human F VIII:C while normal dogs averaged 8.0 U/ml equivalents of human. Fs V, VII, II, X, IX, XI and XII were higher than human in both normal and hemophiliac dogs. Dog fibrinogen fell within the human range and Fletcher F was very low.

Prekallikrein (Fletcher factor) deficiency in clinical disease states

Abstract Plasma prekallikrein activity was measured in a clotting test in 315 consecutive patients undergoing coagulation profiles during the seven month period between January 1, 1979, and August 3, 1979, using substrate from one of our patients with severe Fletcher factor deficiency. Among the 68 patients with significantly reduced Fletcher factor activity (

Comparative hematology: Studies on class aves, domestic turkey (meleagris gallopavo)

Abstract 1. 1. The mean clotting time (C.T.) for turkey blood was 71.0 min in glass and 83.0 min in siliconized tubes. Accelerated C.T.s with rabbit brain or partial reagent were over 60 sec but with turkey brain or RVV they were less than 20 sec. 2. 2. Fibrinogen averaged 450 mg/dl. Coagulation factors, assayed in human systems, were very low with the exception of XIII and VIII (0.57 U/ml). 3. 3. Thrombocytes aggregated during clotting and with collagen but not with ADP. Thrombocytes contained microtubules, an open canalicular system, a large nucleus but no α granules or dense bodies. 4. 4. Hemostasis appeared dependent on an extrinsic pathway.